In this JCO Article Insights episode, Subodh Selukar summarized findings from the original article published in the January 2024 JCO issue: “The Importance of Low and Moderate Grade Adverse Events on Patients’ Treatment Experience and Treatment Discontinuation” and accompanying editorial “Patient Experience, Adverse Event Reporting, and Clinical Trial Design”. The summary provides information regarding low and moderate grade adverse events and the patient experience in clinical trials. TRANSCRIPT Welcome to the JCO Article Insights episode for the January 2024 issue of Journal of Clinical Oncology. This is Subodh Selukar, your host, and today I will be providing a summary on 2 articles focused on low and moderate grade adverse events. The first article, titled “The Importance of Low and Moderate Grade Adverse Events on Patients’ Treatment Experience and Treatment Discontinuation” by Dr. O’Connell and colleagues, investigated low and moderate grade adverse events and the patient experience in clinical trials. Their article is accompanied by an editorial entitled “Patient Experience, Adverse Event Reporting, and Clinical Trial Design” by Dr. Neuman.  In clinical trials, a standardized system for reporting adverse events is the Common Terminology Criteria for Adverse Events (or “CTCAE”) established by the NCI, the United States National Cancer Institute. The CTCAE categorizes adverse events at 5 severity grades across 26 system organ classes. However, some clinical trials may only report adverse events at grade 3 or higher, with one possible rationale being that low and moderate grades are unlikely to affect patient safety or key trial endpoints. In Dr. O’Connell’s article, the team investigated how the numbers of grade 1 and 2 adverse events related to patient self-reported side-effect burden and treatment discontinuation. To do this, they analyzed data from the Phase 3 trial E1912 conducted by ECOG-ACRIN comparing two treatments for chronic lymphocytic leukemia. They chose this trial as an example because the study data included all adverse event grades throughout the duration of treatment for each patient. The authors studied side-effect burden based on GP5, which is the fifth item in the FACT-G subscale in the Functional Assessment of Cancer Therapy. GP5 rates the patient’s agreement with the statement “I am bothered by side effects of treatment” in the past 7 days, and it has previously been connected with adverse event grade and treatment discontinuation. For treatment discontinuation, the authors focused on those discontinuations that were recorded as being due to “adverse events, side effects or complications.” They found that, for each adverse event grade, there were, on average, more adverse events in cycles that ended with a patient discontinuing treatment compared to other cycles. Next, they used Bayesian models to assess how the numbers of grade 1 and grade 2 adverse events in a treatment cycle were associated with the odds of higher side-effect bother and odds of treatment discontinuation, after adjusting for cycle number, treatment and occurrence of grade 3 or higher adverse events within the cycle. Baseline GP5 was also included in the models, and these models also accounted for the inclusion of multiple cycles for each patient. When adjusting for baseline GP5, treatment, cycle and presence of grade 3 or 4 adverse events, both the number of grade 1 and the number of grade 2 adverse events were each strongly associated with increasing side-effect bother. The adjusted odds of treatment discontinuation were also higher with more grade 2 adverse events. However, with the same adjustment variables, the odds of treatment discontinuation were actually lower with larger numbers of grade 1 adverse events. In their primary analysis, they focused on adverse events that were attributed to treatment, so they excluded non-treatment-related adverse events from the counts. Sensitivity analyses including these adverse events have similar conclusions but with a weaker magnitude of effect. They attributed this to issues like existing adverse events not causing new bother. Next, the authors analyzed whether symptomatic versus asymptomatic adverse events affected these results by re-fitting the models and separating the predictors into numbers of asymptomatic and symptomatic grade 1 or 2 adverse events. In these results, they found no evidence for associations between numbers of asymptomatic adverse events at any grade and side-effect bother. On the other hand, they found strong evidence for associations with symptomatic adverse events of grade 2 and 3 or higher both for side-effect bother as an outcome and with treatment discontinuation. Asymptomatic grade 2 adverse events were associated with treatment discontinuation but not side-effect bother, and symptomatic grade 1 adverse events were associated with side-effect bother but not treatment discontinuation.  ·       The authors conclude that adverse events of all grades, especially symptomatic adverse events, should be recorded regularly in cancer clinical trials. Formal patient reported outcomes are not typically collected as frequently as adverse events are recorded, so identifying patients with a high number of lower grade adverse events could be used to facilitate early supportive care to improve patient quality of life and reduce the likelihood for treatment discontinuation. ·       They also highlight their result identifying lower odds of treatment discontinuation with larger numbers of grade 1 adverse events. They provide one explanation that patients may perceive grade 1 adverse events being associated with treatment efficacy, but this perception changes with higher grades.  In their call to collect more lower grade adverse events, the authors acknowledge that recording more adverse events may be time-consuming and burdensome for sites and recommend cost-benefit analyses to develop future guidelines. ·       This balance between the benefits and costs of increased adverse event data collection is the focus of Dr. Neuman’s editorial. Dr. Neuman acknowledges that Dr. O’Connell’s article provides a convincing argument for how low grade adverse event information is valuable, but notes the clinical trial context that current efforts at the NCI are to more efficiently conduct cancer research, which could be supported by streamlining data collection. ·       Requiring the collection of low grade adverse events could have important impacts to trial logistics. Due to the high volume of low grade adverse events, reporting all low grade events could delay reporting higher grade and more serious adverse events; and it would require an increase in the effort of clinical trial research staff, which would be difficult if not accompanied by an increase in reimbursement to sites. ·       Dr. Neuman suggests 3 approaches to balance the costs and benefits of collecting low and moderate grade adverse events. First, investigators could consider limiting low-grade adverse event reporting to the experimental arm. The standard of care regimens may not always have low-grade adverse event data available, but this may still be justified when there is extensive clinical experience with the standard of care. However, this approach is only practical when the experimental arm is not blinded. ·       A second approach for moderating the effort in collecting low-grade adverse events is to limit collection to symptomatic adverse events, connecting with Dr. O’Connell’s example E1912 dataset. This approach could be addressed by prespecifying types of symptomatic adverse events that would be most impactful during the trial design phase. ·       Dr. Neuman’s third suggestion is to plan for a follow-up study after the phase 3 trial to collect low-grade adverse event data and their impact on patients’ experiences and treatment discontinuation. This would be beneficial by only requiring low-grade adverse events in an experimental regimen that has successfully passed phase 3. However, a new study would require funding and site enthusiasm, which could prove challenging. ·       Overall, Dr. Neuman emphasizes that investigators should develop trial-specific considerations and engage with the relevant stakeholders during study design. Because of the complexity of adverse events in these patient populations, the best uses of grade 1-2 adverse events will likely continue to develop in the future. In their article, Dr. O’Connell’s team studied grade 1 and 2 adverse events as separate predictors, but I would be curious to know how the accumulation and trajectory of these adverse events affect the patient experience. For example, even if the severity does not rise to grade 3, an increasing trend in a patient’s adverse event severities could signal the treating physician to modify study dose or to discontinue the treatment. I’m not sure if that type of information was available in their trial E1912, but perhaps that could be a factor to consider for the future. And, of course, it will be important to assess how these grade 1-2 adverse events relate to the patient experience in different studies, especially across different cancer patient populations, acknowledging that this is inherently challenging to study because the data to inform this research is not universally available. As Dr. Neuman indicates, trial-specific goals and expertise will remain critical when considering the data collection for a given trial.  That concludes this episode of JCO Article Insights regarding a summary of the article “The Importance of Low and Moderate Grade Adverse Events on Patients’ Treatment Experience and Treatment Discontinuation” by Dr. O’Connell and colleagues and the editorial entitled “Patient Experience, Adverse Event Reporting, and Clinical Trial Design” by Dr. Neuman. This is Subodh Selukar. Thank you for your attention and stay tuned for the next episode of JCO Article Insights.

Dr. Shannon Westin and her guest, Dr. Ash Alpert and Spencer Adams, discuss the paper "Debunking Sex and Disentangling Gender From Oncology" recently published in the JCO. TRANSCRIPT The guests on this podcast episode have no disclosures to declare. Shannon Westin: Hello and welcome to JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I'm your host, Shannon Westin, Social Media Editor and GYN oncologist by trade. I'm so excited to be discussing a very important manuscript. This is "Debunking Sex and Disentangling Gender from Oncology," which was published in the JCO Online on May 26, 2023. So I'm joined by two of the authors here today on the podcast. First is Dr. Ash Alpert. They are an instructor of medicine and hematology at Yale Cancer Center. Welcome. Dr. Ash Alpert: Thank you. Shannon Westin: And we also have Spencer Adams. They have a bachelor's in public health, are a certified health education specialist, and are currently pursuing a master's in public health at Western Michigan University. Welcome, Spencer. Spencer Adams: Thank you for having me. Shannon Westin: So let's get into it. I'm so excited. First off, I just want to say thank you because I learned a ton from this paper, and I'm hoping to be able to implement some of these changes that we're going to discuss over the next few minutes at my own institution. So I wanted to just make sure we kind of level set and everyone's on the same page. So let's start off by discussing ontological oppression. Can you explain to the listeners what this means and how it relates to sex and gender and oncology? Dr. Ash Alpert: Sure. So, ontological oppression is actually a concept from one of my colleagues at Yale, Robin Demroff, who's a philosopher. Ontology is a way of thinking about what exists and how we categorize what exists. And so ontological oppression is discrimination or stigma that happens because of the ways people imagine us fitting or not fitting into social categories. For example, if we think that people are women or men based on their sex assigned at birth, then it makes sense that we would think of transgender people and nonbinary people as abnormal, weird, or pathologic. In oncology, if we think of ovarian cancer as something that happens to women and a man with ovarian cancer comes into our clinic, we may be confused or uncomfortable. We may respond to those feelings by denying his identity, for example, thinking he's actually a woman or using the wrong pronouns or name for him or even potentially denying him care. And we have some data to suggest that clinicians respond to lack of knowledge about transgender people by treating them as abnormal, weird, or bad in some way.  Spencer Adams: Yeah. And to add to that, when we consider how we classify people, first, there's a problem within that. There's an ethical problem within that, but it's an idea or a construct that society has created and wants people to fit into these nice little boxes just because it's easier to digest, or you make the person more palatable if they're able to do these things. And life is not like that. We have differences, and we have things that make people fit outside the box. And I believe that when we keep reminding people that a box exists or a social construct exists, you're stifling who they are, their personality, their guiding light. You're stifling a lot of things about that person and ignoring something that's incredibly important to them. Shannon Westin: I think that along those lines, kind of taking that to the next step, it would be really helpful to discuss a little bit more around this interaction between sex assigned at birth and gender and what assumptions are made. And I think you kind of started along this, like, how that impacts oncology care. But in your paper, you did, I think, a really great job of really laying out a lot of the problems that happen in this space, and I'd love to explore that more right now. Dr. Ash Alpert: So sex is a designation made when a baby is born by somebody viewing that baby's external genitalia. And so I think we all, as doctors, know that that designation doesn't necessarily tell us what that person's karyotype is, what their later hormonal milieu will be, what their internal anatomy is, and it certainly can't tell us anything about their gender, which is how someone sees themselves as a man, woman, nonbinary, or something else, and usually develops around the age of four. And even though I think that we all know that, we're so used to sex and gender being used interchangeably, not just in the ways that we talk to each other, but in everything about the way that we do our work. And so it becomes very difficult to disentangle these concepts for ourselves.  And we have used sex in particular as a proxy for so many other factors where it doesn't necessarily function. And parts of medicine are based on that. So it's very hard to start to unpack and disentangle those things. For example, the ways that we talk about certain types of cancer can be linked with gender, like we were talking about earlier, women with ovarian cancer, men with prostate cancer. And that's the way that we talk to each other. But it's also in our clinical trial eligibility criteria, sometimes, it's in our patient facing materials, it's in the ways that we name our clinics, the ways that we talk about our work. So then even just sometimes occupying space to get oncology care can be a form of being misgendered.  Spencer Adams: Yeah, I think it's dangerous to conflate the two, sex and gender. As Ash was saying, that one is a visual inspection, the other is who the person is. And if we claim to be an institution that does patient-centered care, how can we be patient-centered if we are not properly respecting the patient? And to do that, you have to respect their gender as well. I see also one of the things that I want to add to the list is clothing that the patient is offered, especially going to a "women's clinic." We can change that to "reproductive health clinic," but usually the clothing is pink and that may be dysphoria-causing for some of our transgender and gender nonconforming friends. So it truly is in everything that is client facing, that is how the structural building is made. It truly is not just how we talk to each other, but how society runs.  Shannon Westin: Yeah, let's talk a little bit more about training because I think that will be pretty important as we try to change these things. So the way we're trained in medicine and oncology, regarding sex, regarding gender, how does this negatively impact the health? We've talked a lot about the mental health, definitely impacts, but also, I think, overall physical health. Dr. Ash Alpert: Well, I think something that we started to talk about, but didn't talk about in detail is not just the conflation of sex and gender, but the ways that this concept of sex is used as a proxy for a number of other factors, including anatomy, hormonal milieu, karyotype, and body size. One of the ways that this becomes problematic is in our laboratory values for example. Laboratory values are developed, as far as I understand it, based on looking at large studies of people that are categorized as women or men and looking at averages. So, averages are helpful, but they can't necessarily tell us about disease or no disease. So, for example, if a large number of cisgender women have iron deficiency that is undiagnosed, and we use their averages, then we're going to continue to underdiagnose iron deficiency anemia going forward.  So, the ways that we've tried to use sex as a proxy for a number of things doesn't just hurt trans people, but potentially leads to very imprecise data in general. Specifically for trans people, we know that many trans people have negative experiences with care, that this leads to people avoiding care and likely leads to decreased screening for cancer and delayed cancer diagnoses. So we don't have a lot of data about this, but we do have some data to suggest that transgender people may present later with later stage cancers, be less likely to be treated, and have poorer outcomes than cisgender people. Spencer Adams: And I think it's important to add that there are physicians who will - we call it like, “the trans illness" - but they will blame everything that you're experiencing on the fact that you're transgender or the fact that you're on hormones or the fact that you had the surgery, and say that you need a specialist. So you can't just go to your primary care physician anymore for the flu because they'll just blame it on your medical transition. When we take that into consideration, I think there's a whole host of physical ailments that come from just being denied care. I don't know if that is from the physician's own personal stigma around trans people or just them not being trained in trans healthcare to where they feel confident in going into that room. So it's a twofold attack. First, we need to make doctors who are competent in trans healthcare, and then second, we need to have more inviting spaces for trans and gender nonconforming people. Shannon Westin: I think the next step is really better understanding this idea around degendering care, specifically in oncology, but I could really talk about medical care as a whole, but let's focus on what you all brought forward in the paper. I would love to hear how we think this idea of degendering care will promote better healthcare. And then, I think, some practical actions. What can we do on a day-to-day basis? And you've already started peppering this through this discussion but I’d love to like bullet point it out for the listener.  Dr. Ash Alpert: Yeah. So the way we described it on our paper was: “disentangling oncology is a conscious and explicit disentanglement of gender, anatomy, hormonal milieu, karyotype, and other biological factors. In oncology, diagnoses, epidemiology, and knowledge production. As well as,” - and I think this is an important part and that's maybe the harder part of the paper - “eliminating sex from our conceptual framework of bodies and disease”. So, in other words, we're really trying to say that not only do we need to disentangle gender and sex, but we need to debunk the idea that sex is an immutable fact of the body that says something important about a person and their biology. Instead of thinking about sex as this immutable fact of the body, can we really break down and think about what exactly are we measuring? Is it anatomy, hormones, karyotype, size, or stigma?  In terms of practical actions, some of the things we had in our paper include that oftentimes, the words "woman" or "man" can be replaced with the word "people." So like a very easy change. And actually, ASCO and the NCCN, both in the last few years, have worked to degender their guidelines by doing just this simple change. Then we also need to do this on our websites, in our patient education materials, and in our clinical trial eligibility criteria. Because if you have a trial for prostate cancer that says that one of the inclusion criteria is being male, then whether or not you actually mean that as an inclusion criteria, a transgender woman or her physician may see that as a barrier to enrollment.   Ensuring that, as Spencer was saying, that gowns, binders, and wigs are available that are gender-neutral are available for all genders. Ensuring that people have access to bathrooms, so making sure gender-neutral bathrooms are available. And often, this is as simple as taking a one-style bathroom and putting a sign on it that says "gender-neutral." Ensuring the names of clinics, mammography suites, and titles do not contain gender. Ensure that intake forms don’t conflate gender with biological factors. For example, in a clinic I used to work in, one of the questions on the intake form was, "If you are a woman, when was your last menstrual period?" Which if I’m a man and I have a period, it might be hard to figure out how to answer that question.   Spencer Adams: One of the biggest barriers for trans and gender nonconforming people is that intake form. It is the first person that you meet or see when you go to any healthcare establishment because that sets the tone for whether or not this establishment is trans-friendly. If you have, as Ash said, a "for women only" box or descriptor on your intake form, that is a sign that maybe they're not as trans-friendly as they could be. Or if you see "women's clinic" instead of "reproductive health clinic" or whatever, that could be a sign that they may not be as gender-friendly as they could be. These little changes actually make such a big impact on the trans community, and it's something that I believe would be very much appreciated and would close the gap between trans and gender nonconforming people and the medical community. Dr. Ash Alpert: I know that for me, going to a doctor's office, these small moments, although they may seem small to other people, really add up in terms of stress. People talk about microaggressions, and I think that's really a good way of conceptualizing what it's like to have these little irritations or hits that happen over and over again throughout a clinical encounter. And I think in particular, for folks who are dealing with a cancer diagnosis and treatment, which can be experienced as a traumatic event, having these recurrent denials of identity on top of that can lead to additive trauma in a way that can be very distressing and have negative sequelae for patients. Shannon Westin: Yeah, we're trying to look around this idea of allostatic load and how we can actually measure this because I think when we talk to policymakers about this, around not just the trans community, but also around underrepresented minorities, and the stresses that impact their risks of cancer, and how it's not just their race or ethnicity that's driving it, it's all of these microaggressions and everything. We get a lot of like, "Really? That's not science." So, I definitely think doing a better job around being able to objectively measure these other things and move forward in a very objective direction is going to help. Because if one of those things we know it's there, but for people who aren’t as ready to believe or understand that, it helps to have and embed that objective data. So that gets into the epidemiologic potential and cancer prevention. Dr. Ash Alpert: Yeah. In some ways, we can't do much about the data that have been collected in the past, but we can start to think about them more critically and describe what we think is really going on in what we were calling sex or gender categories. But going forward, we can really think about collecting data on our clinical trials and in our large population-based surveys that actually speak to biological factors. So, if what we're concerned about is whether or not someone has ovaries, we can ask for an anatomy inventory. And when we're interested in hormonal milieu, we can check hormone levels. When we want to know about chromosomes, we can check a karyotype. And if what we're interested in is stigma, then we can ask about stigma, or we can ask about things that we think may cause someone to infer stigma. Once we have data that’s much more nuanced and granular, we’ll be able to better extrapolate it to all people in a much more rigorous and precise way, including trans people. Spencer Adams: When it comes to cancer treatment and diagnosis within the trans community, it's such a unique thing because we have to consider also the social determinants of health. And this built environment that we've created, such as a hospital or cancer wing, or whatever you want to call it is directly impactful. As you were saying before, this microaggressions that add on and on to our trans friends. So, I think that when we look at the data and we look at stigma, we also have to look at where people are– We have to meet people where they are. It's going to be very difficult to bridge the gap between the medical community and the trans community when it comes to stigma. But if we have competent doctors trained in trans care and not always pushing off for a specialist, then I think we'll get better data.  One thing that happens to trans people is doctors feel as if they cannot diagnose because being trans is seen as a disorder that they see as out of their wheelhouse. First, they classify it as a disorder, and secondly, they think it's outside of their wheelhouse. So they would refer to an endocrinologist or someone else to provide the care that the person is seeking. We call it the "trans disease" or the "trans injury,” because if I come in with a broken leg and the first thing you say to me is to go to an endocrinologist because we don't understand how hormones work, that's not care, and that's not patient-centered care. And that's what we're all moving towards, I believe. All hospitals are moving towards this patient-centered care. And to do that, to be patient-centered, you have to understand the person as a whole, and you have to be able to treat the whole person and then make a treatment plan that is specialized and custom to that person. This may involve different routes people take in order to feel comfortable or achieve what outcome that they wish to achieve. But it's really a patient-centered approach that we have to drive home in order to make some change.  Shannon Westin: My last question is, what's next, and how do we get this information out? How do we actually enact? I mean, obviously this podcast reaches a lot of listeners, but beyond that, how can we educate people so that we can make these changes? This is something that hits close to home for me. I recently took over the gynecologic cancer center, which is where we house all below the belt malignancies. But there's work in progress, and we're discussing an overarching center to cover breast and gynecologic malignancies. And there's a discussion around how to title that. One of the suggestions was that it should be a "women's center," or something like that and that is not in line with what we've just been speaking about. So I think, certainly, that kind of individualized, like boots on the ground, people that are willing to speak up and say things and try to change these types of things, and I fully intend to do that - fingers crossed that it won't be me just waving my tiny fists in the air.   But more broadly, I’d love to see more education at ASCO, large oncology symposia and conferences. It needs to go to the people who are not aware. It can't just be an echo chamber of people who have already been talking about this and are already knee-deep. It needs to reach the broader oncology community so that people realize that this is an issue that involves all of us and that we all need to be addressing. And like you said, even simple things around replacing language and saying people and making sure that the trial eligibility are broad, those simple things that individuals can do can. But I also think like NCCN and ASCO, we have to do something around the organizational levels to really make an impact.  Dr. Ash Alpert: Yeah. And I think that the things that we talked about the we can do as individual clinicians, there’s the things that large institutions like NCCN and ASCO can do to sort of send out the inclusive messaging that is needed. And I think in the middle, we can create teams that are institutions of folks who we can be in allyship with to think about what are the most urgent changes that need to happen and the most feasible changes and start with those and then just keep going. Some of the changes that we make now will help us in the years to come, so I think being focused on the now and the future at the same time is helpful.  Spencer Adams: I think that the teams within our individual institutions is really a great approach to this. When it comes to figuring out the next steps to be more gender-inclusive, I really think that institutions should get data from their community. They should understand the makeup of their community and see if that is something that aligns with the makeup of their hospital. Because we can go and talk about doctors getting training in trans care or more doctors of color being in your hospital to make the BIPOC community feel more accepting. But if we don't have teams whether it’s diversity, equity, and inclusion teams, or whatever you want to call it, that are willing to push to make policy change within the hospital, then there will be no movement. So, we really need to get people within their hospitals to give them the power to really push what has been taught for so long and really challenge the status quo and allow us to move forward with gender equity. Shannon Westin: Well, I think that is the perfect mic drop moment, and I just want to thank both of my guests. Spencer, this was awesome and I always take copious notes when I talk with you all because I learn so much. It inspires me to try to do what I can at my institution and within the field of gynecologic oncology to make things better. So I hope that others who are listening are just as inspired as I am. And to our listeners, thanks again for tuning into another episode of JCO After Hours. Please check out our other podcast offerings wherever you get your podcasts. Have a wonderful day. The purpose of this podcast is to educate and inform. It is not a substitute for professional medical care and should not be used for the diagnosis or treatment of individual conditions.    Guests on this podcast express their own opinions, experiences, and conclusions. These opinions do not necessarily reflect those of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an endorsement by ASCO.      

Dr. Shannon Westin and her guests, Dr. Judy Garber and Dr. Geoffrey Oxnard, discuss the paper "Germline EGFR Mutations and Familial Lung Cancer" recently published in the JCO. TRANCRIPT The guest on this podcast episode has no disclosures to declare.   Shannon Westin: Hello, and welcome to JCO After Hours, the podcast where we get in-depth on articles that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, Social Media Editor for the JCO and Gynecologic Oncologist by trade. And it is my great pleasure to speak today with you about an amazing manuscript entitled, “Germline EGFR Mutations and Familial Lung Cancer.” It was published in the JCO on August 14, 2023.  The authors have no conflicts of interest, and they are Dr. Geoffrey Oxnard, he's a Thoracic Oncologist and Associate Professor, Hematology and Medical Oncology at Boston Medical Center.  Welcome, Geoff. Dr. Geoffrey Oxnard: Hi, Shannon. Thanks. Shannon Westin: And Dr. Judy Garber, the chief of the Division of Cancer Genetics and prevention at the Dana-Farber Cancer institute in Boston. Welcome, Judy. Dr. Judy Garber: Thank you. Hi, Shannon. Hi, Geoff.  Shannon Westin: So excited you both could be here. Let's get started. So first I just want to levelset for our audience. Can you speak just a little briefly about the incidence and mortality of lung cancer and how that's been changing over time? Dr. Geoffrey Oxnard: Sure. Lung cancer is common and it's deadly, more than 200,000 cases a year in the United States, more than 100,000 deaths a year in the United States. But I think importantly, it's evolving. Its biology is evolving as smoking incidence goes down. We've identified these genomic subtypes of lung cancer that are sort of increasingly apparent and important as we think about its treatment. Outcomes are changing with emerging therapies, presentation is changing with lung cancer screening and with a growing ability to now find cancers early and prevent them. And so it's in that setting of a very dynamic disease that we chose to study a really unique little slice of it, which is germline risk. Shannon Westin: So let's take that one step further because I think that's really interesting. You mentioned the genomic aberrations and kind of how you're using that to target. Can you expand upon that a little bit more for me? Dr. Geoffrey Oxnard: Lung cancer that I've long studied is different than breast cancer when Judy has long studied because we think about its somatic alterations, we've always thought about KRAS mutations, EGFR mutations, and smaller and smaller splice limit. ALK, RAS, RET HER2, etc. And so tumor testing in lung cancer has one of the first to be standard across on solid tumor oncology. And the germline genetics was kind of an afterthought and is the flip, I think, of how genetic testing evolved in the breast cancer space for example. Dr. Judy Garber: I might argue a little bit if breast cancer was earlier and it was subtyped some molecularly it doesn't have as many molecular subtypes yet perhaps as lung cancer. But we've all been studying the somatic space to look for targets for therapy. And the germline space, certainly in breast cancer, came much earlier. And everybody knows about BRCA1 and 2. Now, we hope everybody knows about Lynch Syndrome, but certainly not everybody's thinking about inherited lung cancer risk. Dr. Geoffrey Oxnard: Yeah, these have converged. I think 10 years ago when this kicked off, I felt like a super outlier for thinking about, wait a second, what about the genetics behind all this that is leading to this strange variable presentation of lung cancer? For example, we know that in Asian populations, one type of lung cancer, EGFR mutant lung cancer, is more common. There must be some geneticness that leads to that. What explains the sort of pattern of presentation of these genetic subtypes in the populations we see in the US, that’s pretty unclear?  Dr. Judy Garber: So, I think, Shannon one of the clues about all this came from the fact that the EGFR mutations were being identified in the tumors. And then I really should let Geoff tell this story, but as the amateur thoracic person in the room here, to me, it was so interesting that there were the EGFR mutations, then there was treatment exploiting EGFR mutations, and the most common resistance mutation was this T790M variant. But when labs started testing EGFR, there was a small group of people who had that resistance variant without ever having been treated at all. So that was the obvious question, what was it doing there? And that's where Geoffrey came in.  Dr. Geoffrey Oxnard: Yeah, this is a patient I met more than a decade ago at my fellowship in MSKCC. She'd been living with a T790M mutation in her tumor for years and years and years. I was like, “Well, I don't understand. Why is this sitting there?” And she had this sort of slightly mysterious history of lung cancer in her family. And we realized, wait a second, this T790M was behind her cancer from the beginning, and in fact, might have been the basis of why she developed lung cancer. And so that actually motivated a career development award I submitted to the Conquer Cancer Foundation of ASCO, a grant I received, and that then led to a program that I led at Dana-Farber under Judy's mentorship, where over the past decade, we sort of focused in and studied this strange, rare syndrome, really to dig into inheritedness as a kind of different flavor of lung cancer genetics.  Dr. Judy Garber: Well, and now it's really a good time to think about this because we're recognizing there are younger cancers, colon cancer, like an epidemic, and lung cancers, and we're not sure how many of them are genetic or come from other exposures. Geoff talked about the differences in Asia, some of which are certainly genetic, some which may be environmental, especially in the lung, where that's such an issue. But trying to sort these things out, you have to be willing to think a little bit differently. And that was fun when Geoff came from the lung program, interested in the germline, we said, “Oh, we have to do this.”   Shannon Westin: Well, let's talk about what you did. I would love to hear and I know the audience would as well about the design of this study, so called INHERIT study. Very good name. I love a good name. This is a good one.   Dr. Geoffrey Oxnard: Yeah. So that stands for Investigating Hereditary Risk of T790M, INHERIT. I forget where we coined that. Let me give you a case example. A patient presents in his 40s. I remember this man. He has an EGFR mutation in his tumor. He has a T790M in his tumor as well. He had routine tumor testing that lung cancer patients were getting. And he says, “Oh, also, my brother had lung cancer in his 40s just a couple of years ago. He was a smoker, though. He never had genetic testing.” And so this patient we test on the study, we hypothesized that when patients present with T790M at diagnosis, that it would be a representation of an underlying germline EGFR mutation. Our hypothesis was that about 50% of the time T790M at diagnosis would be explained by a germline behind the doll. And that that could then empower families like this one to understand the kinds of lung cancer they're getting in their family, the kinds of treatment they should be getting, and the kinds of testing they should be getting to look for lung cancer at risk early on.   It really saddens me that in a family that doesn't know about this condition, the brother would never get testing and would never think that I might be getting or might never get testing, might not be disposed to getting testing, and might not realize there's a therapy available to target that EGFR mutation if he died young without even much treatment. But this individual, we tested his lung cancer, we found him a therapy, we put him on a pill therapy that could last a very long time. And so we set up a program with a consortium alchemy, the Addario Lung Cancer Medical Institute, where we enrolled at three sites, both at Dana-Farber in Boston, Vanderbilt, and Ohio State, with some motivated investigators there that we appreciate their collaboration.  But also, again, this is now more than 10 years ago, set up shop where people could enroll remotely, that if you found a T790M in your tumor, for whatever reason, you could reach out to the team at Dana-Farber centrally and get consented online and even get counseling. And this is one of the early ways of getting this remote participation. And you can imagine, over the course of the study, we quickly ran out of individuals at any given site, but that remote enrollment accelerated and really allowed us to get to the large population of remote study. Dr. Judy Garber: We were lucky that things were happening. The things you don’t expect. So EGFR testing was not routine at that time. And the EGFR testing that had developed in Dana-Farber and NGH became standard of care at Dana-Farber so we were finding those patients, and then grew outside as well, at institutions and testing labs. And these people would somehow emerge so we were very lucky that we were able to set up remote testing. We could send and get a saliva sample and be able to test. Or these were people who got tested through their own doctors, found out they had this mutation and then went online and said, “Who knows anything about this?”  I would say that we and our amazing genetic counselors who spoke to all these patients, took their detailed family histories, got their other information, and were able then to really build out these cohorts so we can understand them. And to look at, for example, Geoff’s question, it was really his question, “Why did we have such clusters in certain parts of the country? Could it be that there were the so-called founder mutations that somebody had this mutation and they spread their genes around so that they’re around the country and that turned out to be true. Shannon Westin: It's so fascinating, and I love how you kind of almost crowdsourced getting these patients to you because I was mystified because it's such a rare aberration and you had so many patients. Let's talk a little bit maybe about your patient population and who volunteered, and is it reflective of kind of you do think, the general population? Dr. Geoffrey Oxnard: I want to give a shout out to the GO2 Lung Cancer Foundation. That really was a lot of the ‘rah rah’, getting people to know about this, having some word of mouth and spreading the word. And so certainly there are physicians around the country that have been like found patients that I've got to know because they sent us patients to study over the years. We ended up getting germline testing on 141 individuals who presented eligible for testing because of either a relative or a mutation that was suspicious for inherited. Most of those were enrolled remotely, in the end, as you might expect. We found what you might expect, that this was Mendelian in its inheritance, that if you had a first degree relatives, they had 50% chance of having this. And so we sort of slowly built these pedigrees of individuals who once they were positive, would refer in their relatives and say, “Please go get testing. Let's describe our family and help understand our risk.”   It ended up boiling down to six individuals with a germline EGFR mutation from 39 different families. I remember one family where two different cousins presented separately to the program, not knowing each other was participating. And so, of course, there's not that many of these families around the United states, but we're really very lucky to have touched so many different individuals. What did we find? That if you had a germline EGFR mutation, your tumor almost always had an EGFR mutation. That really is the dominant biology of lung cancer that presents in these affected individuals, that it presents young, that the likelihood of developing lung cancer is around 55% by age 40 to 50. So it really is– I'm trying to make sure I'm quoting that right, actually, Shannon, I'm looking at the numbers here, but it was a really broad range of diagnosis.  We had a 28-year-old who was affected and an 83-year-old who was affected. I saw a family where the grandson had lung cancer, but his father and grandfather who had germline EGFR mutations, did not. So variable penetrance. Judy, of course, told me, “Geoff, this is the way families present. Come on, Geoff.” But other families, incredible penetrance– not everyone having lung cancer, many of them smoking, some of them not smoking. But for these families, what a sense of empowerment to say, “Oh, this helps explain what's going on in our family, why this is happening at a younger age.” And helps explain the therapies that we had some concern about giving these potent EGFR inhibitors originally, understanding every cell in their body has this EGFR mutation. Are we going to somehow cause toxicity? No. These potent therapies can be effective, can be tolerated, and can work for many years. So we really feel hopeful that we've described a syndrome that's out there that people see and that has a distinct presentation, a distinct treatment pattern, and a clear association with lung cancer risk. Dr. Judy Garber: And I think that now the opportunity is to say, can you find these people before they get their lung cancers? Some of them have abnormalities on scans. Think of it's like the APC, the polyposis coli of lung cancer. You can see these adenomas forming, but we can't really predict exactly who's going to develop tumor when. And that, I think, is a challenge that families have to help us with because we need to continue to identify some of these people who have not had cancer. They have children. They want to know what to tell them besides not smoking adamantly and maybe with some hopes that we're going to do some screening.  I am afraid there probably is not good data that EGFR inhibitors could be used for prevention, but it's tempting to think that way. So there's plenty of work to do still to sort out the questions. This is the nature of genetics. We often find inherited susceptibility and people want to know, “Well, why would I want to know? What am I going to do about it?” And here I would say, “We're going to figure out what's your risk more specifically, and how can we help reduce that risk, in addition to telling you not to smoke.” Dr. Geoffrey Oxnard: I do want to allude to Judy's comment about founder effect. I didn't tell you exactly about the presentation, but these families, first off, we only found germline EGFR mutations in Caucasian individuals and in black individuals, and it was mostly in the United States and in fact, enriched in the southeast United States. And don't get me wrong, we had enthusiastic participation from Vanderbilt. But still it seemed like there was more southeast United States prevalence. And even families I met in the Boston area would say, ‘Oh yeah, I have relatives going back to Arkansas.”   And so we ended up with a bit of a suspicion for this geographic enrichment, studying the genomes of these affected individuals, and in fact did find a very large region of chromosome 7 that was shared in more than 90% of the folks we tested, suggesting a founder effect in the southeast United States, probably white and black. And that goes back hundreds of years, maybe 200, 300, 400 years, as far as we can estimate, making me think that this is a fairly unique syndrome that we're seeing in North America, but actually may not be prevalent in other parts of the globe. Though we did identify a single individual in Australia, it might be a unique phenomenon in North America. Dr. Judy Garber: At least more common. But these days, people travel, so hard to know. Shannon Westin: I don't know if you've gotten a chance to do this - any other cancer type seeming to be associated with this mutation? Dr. Judy Garber: No, fortunately not. Shannon Westin: Okay, very interesting. And what about outcome? What was the association, or was there any association of these mutations with cancer related outcomes? Dr. Geoffrey Oxnard: I would say the survival of these cancers isn't that different than EGFR mutant lung cancers. If they get to effective therapy, they can live for years on therapy. If they don't, they can do quite poorly. One interesting finding is that they can present in a multinodular fashion that might be multiple primaries. And so you can kind of use an approach of eliminating individual clones. Sometimes it's been described these different tumors have different mutations, and so you might treat them like a stage IV lung cancer, but actually they lived for a long time because actually they had multiple stage I lung cancers, so it can present a little bit differently. And then we tried to collect CT scans on affected carriers who did not yet have lung cancer to see if they might develop lung cancer. It was not required on study, and it's sort of an area of future investigation. But as you can imagine, lots of lung nodules and certainly anecdotes of individuals where we found early precancers through the screening effort, motivating the investigation that Judy was alluding to. Dr. Judy Garber: I think this is what you expect in inherited predisposition that you have an earlier chance. So some of them are younger, not the 84-year-old, but that they could be younger, that they could have multifocal disease, that their biology could be different, but could be the same, maybe accelerated, maybe not. Some of these are slower. And I think that's why we're excited to be able to continue this work with the group at Dana-Farber.  Now, Jaclyn LoPiccolo is going to lead the INHERIT study, but much of the team is the same. And now the focus will be even more on trying to really quantify the risk and help think about prevention strategies and screening for these patients. It's a little tricky to want to do too much chest CT screening. On the other hand, there are lower dose CTs now, and we hope the guidelines will clarify the role of inherited risk. At ASCO this year there were a lot of talks about inherited lung cancer risk, but nothing is quite as well characterized as, I think, the T790M population. Shannon Westin: Well, thank you all so much. This was fascinating. I learned a ton and I know our listeners did as well. And thank you to our listeners. This was “Germline EGFR Mutations and Familial Lung Cancer.” Again, published in the JCO August 14, 2023. So go check it out and check out our other podcasts on the website or wherever you get your podcasts. Have an awesome day.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

In this episode of JCO Article Insights, host Dr. Soldato discussed with Dr. Knikman and Dr. Cats the findings of a study that assesses the influence of fluoropyrimidine dosing based on DYPD genotype on both progression-free and overall survival. The article, featured in the December edition of JCO, presents groundbreaking and reassuring data. Furthermore, it highlights emerging research challenges aimed at refining the prescription practices of one of the most widely utilized chemotherapy agents, striking a delicate balance between safety and efficacy. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Davide Soldato: Welcome to this JCO Article Insights episode for the December issues of the Journal of Clinical Oncology. This is Davide Soldato, and today I will have the pleasure of interviewing Dr. Knikman and Dr. Cats, respectively first and corresponding authors of the manuscript titled "Survival of Patients with Cancer with the DPYD Variant Alleles and Dose Individualized Fluoropyrimidine Therapy: A Matched-Pair Analysis."  Dr. Knikman is a clinical pharmacologist and assistant professor at the UMC Utrecht, while Dr. Cats is a gastroenterologist specializing in gastrointestinal oncology at the NKI in the Netherlands.  Welcome, Dr. Knikman and Dr. Cats, and thank you for accepting our invitation today.  Dr. Annemieke Cats: Thank you so much for the invitation. Davide Soldato: So I just wanted to start by discussing the manuscript that you published. But before delving into the results of the manuscript that was published in the JCO, I just wanted to ask if you could give a brief overview of the DPD polymorphism and explain a little its relevance in the clinical practice.  Dr. Annemieke Cats: The DPD polymorphism is very important in the metabolism of fluoropyrimidines. Fluoropyrimidines have been in practice for over seven decades now in the world and more than 2 million people received fluoropyrimidines in the beginning of this millennium. The indications for fluoropyrimidines have only been extended since then, so a lot of people are receiving this fluoropyrimidines. But with the good side of that there’s also another side and that is that there are a lot of side effects encountered by this chemotherapeutic drug. In the 1990s, it became clear that DPD was a key enzyme in the metabolism of fluoropyrimidines. Dr. Jonathan Knikman: To better understand the toxicity associated which fluoropyrimidines are accompanied by, we have to take a closer look at the metabolism of fluoropyrimidines, and more specifically at the key metabolic enzyme which is dehydropyrimidin dehydrogenase, DPD in short. This enzyme breaks down the main active metabolite into inactive metabolites because 5-fluorouracil is the main active metabolite which is metabolized into inactive metabolites. However, if this enzyme does not function properly, this could lead to higher exposures of the active metabolites and subsequently more toxicity. This can be caused by mutations in the gene encoding for the DPD enzyme, which is the DPYD gene, and single nucleotide polymorphisms, so mutations in this gene can lead to less functional DPYD enzymes, subsequently can lead to more toxicity.  Davide Soldato: So basically, patients that are harboring these SNPs in the gene encoding for the enzyme have a higher risk of toxicities. I think what is really important about the manuscript you published is that, apart from looking at the toxicities, side effects and pseudo profile among these patients who harbor these SNPs you also wanted to check whether this was associated with some reduction or at least with inferior clinical outcomes. The endpoints you selected were progression-free survival and overall survival. But I was really interested, and I think our readers and listeners would be interested in understanding a little bit the methods of the study. What was the cohort of patients that was selected? Was this a cohort composed only of patients with gastrointestinal malignancy or also different types of malignancies? And in this second case, if you included the patients with different types of malignancies, did you have any methods to be sure that there was not any differences among these patients at the very beginning? So basically, how you handled all the confounding factors that could potentially impact the analysis of clinical outcomes. Dr. Annemieke Cats: To start your question, we have to go back to a previous study we performed, which was a prospective, multicenter study we performed in the Netherlands in 17 centers in which 1100 patients that had an indication for fluoropyrimidine therapy were included. In these 1100 patients, there were about 85 patients that were heterozygous carriers of a DPYD variant. What we did, we compared these two groups with each other, but before the DPYD carriers started, they had a reduced dose. The *2A variant carriers and the *13 carriers, they received a 50% dose, and the 1236 and 2846 they received a 75% dose. Those patients, a large amount of them consisted of patient with colorectal cancer, about 60%. And also breast cancer patients consist for a large amount of this group, it was about 20%. And then the rest were esophageal and gastric cancer mostly, and there was a group consisting of rare tumors as well like anal cancer.  The comparisons showed that toxicity in the variant carriers was higher in the wild-type patients that received 100% dose. So despite those reductions, toxicity was higher in the carriers. But when we compared the variant carriers with historical controls, we saw that, especially for *2A, there was a large reduction of toxicity to a lesser amount. This was also the case for the 2846 variant carrier. But to a much lesser extent, there was a reduction in the 1236 carriers which worried us and this was the basis for a Clinical Pharmacogenetics Implementation Consortium (CPIC) to give a recommendation for starting for all these variant carriers with a 50% dose when treatment with fluoropyrimidine was indicated. Davide Soldato: Thank you very much for the clarification. So basically, you started from one previous prospective study that was composed of a mix of different cancer types. And then in the study that you now published in the Journal of Clinical Oncology, you also added an additional part of patients who were carriers of this variants. I imagine that there was some variability between patients who were carrying the variants and those were not carrying a variant. So I wanted to understand a little bit, did you perform a matched analysis or did you try to be sure that there was not any confounding factors that could impact the results? Dr. Jonathan Knikman: Yes, we performed an exploratory retrospective matched-pair analysis and we used a matched-pair analysis to select patients which are comparable between the DPYD variant carriers and the DPYD wild-type patients to ensure that on the most important factors, they were comparable and outcome was also comparable. In this matched-pair analysis, we compared progression-free survival and overall survival between DPYD variant carriers treated with the reduced dose and DPYD wild-type patients treated with the full dose. We matched these patients on five matching variables which were primary tumor type, stage of cancer, age within a range of plus or minus 10 years, sex, and treatment regimen to ensure the these patients as comparable as possible.   Davide Soldato: And so now, moving on a little bit to the results, what were the results in brief regarding progression-free survival and overall survival for patients who were harboring a variant in the DPYD gene and those who were wild-type for this gene? Dr. Annemieke Cats:The results of our study showed that there was no significant difference in progression-free survival and overall survival between the DPYD variant carriers pooled as one group, treated with the reduced dose, compared to wild-type patients treated with the full dose. This suggests that DPYD-guided dosing can be performed safely without compromising treatment effectiveness. However, when we take a closer look at the individual variants, our study showed that progression-free survival and overall survival were not negatively impacted by DPYD-guided dosing in the 2846 and the DPYD *2A variant groups. However, in the group of 1236 variant carriers, we did find a significant difference in progression-free survival with a hazard ratio of 1.43, indicating that progression-free survival  was shorter compared to the matched wild-type patients treated with the full dose. However, no difference was found in overall survival.   So based on results on this study, we can conclude that DPYD-guided dosing can be used while treating patients with fluoropyrimidines without compromising effectiveness and improving safety. However, when patients do not experience toxicity or experience minimal toxicity, it is important to escalate the dose guided by toxicity to ensure maximum exposure to the treatment.  Davide Soldato: Thank you very much. That was a very comprehensive overview of the results. I was really wondering regarding the variants in the 1236. So the one that you said was associated with a shorter progression-free survival. At the very beginning, Dr. Cats very well explained that in the first prospective trial that was done, among these patients, toxicity was still higher or they experienced more severe toxicities, even with a 25% dose reduction compared to what was planned. So I was wondering if you could speculate a little bit. Do you think that this reduction in the progression-free survival might potentially be associated with these higher rates of severe adverse events, and that maybe this has created a little bit of a gap in the adherence to chemotherapy? Dr. Annemieke Cats: We looked into the mean dose that the 1236 variant carriers received, and this was about 75% of the dosage. So the dosage was what the protocol prescribed for the study. And also the number of cycles did not differ from the wild-type patients. So, I think the patients did not stop earlier with their treatment than was intended to. What we did see however is that in the whole group, only 10% of the variant carriers had some kind of dose modification, which could be both an increase of the dose or a reduction of the dose. So, there were only a few patients where the dose was modified. We know that the 1236 variant carriers are a very heterogeneous group. DPD enzyme activity also shows a wide range, ranging from normal to very low dose even we described a patient with a homozygous 1236 mutation. And we would expect that there would be no DPD enzyme activity, but there was still some activity in this patient.  Davide Soldato: That's a very good insight on this particular topic. So, just related to the conversation that we were just having, do you think that in general, for all DPD variants, and in particular, as we discussed, for the 1236, do you think that genotyping is sufficient for now to understand which is the right dose for these patients, to balance toxicities and to obtain the best clinical outcomes? Or do you think that we need more sophisticated or more integrated types of monitoring? Should we, for example, in the 1236, look more carefully at pharmacokinetics and so understand if these patients can receive higher doses because maybe, as you were saying, the activity of the enzyme is really higher than what we are expecting based on the genotype? Do you envision something like this happening in the future, or do you consider it as a potential line of research on this topic?  Dr. Jonathan Knikman: It's a very interesting question, and it's something we've thought about a lot. At the moment, I think genotyping is the way to go and is the most robust and most validated method currently available with fluoropyrimidines. And I think it's a bit of both. Currently, as mentioned, I would recommend DPYD genotyping, and also in the 1236 variant carriers, as we have seen in previous studies, that toxicity is still increased even while administering 75% dose instead of a full dose. So we see that there's still more toxicity. However, our study also shows that progression-free survival is shorter compared to wild-type patients. So, it's quite a complex situation as we still have more toxicity, but the progression-free survival is also shorter, and that's where we would advise the dose escalation part. So, I think it's a combination of genotyping and escalating the dose when possible, if there is no toxicity or limited toxicity, to ensure maximum exposure and to minimize the effect on progression-free survival while still trying to reduce toxicity. Dr. Annemieke Cats: This is a very important question because we do not completely understand why toxicity is higher in the 1236 with a 25% dose reduction that may compromise progression-free survival. So we have to look in closer detail, and currently we are looking in closer detail to what do we have for a pharmacokinetic analysis, that you mentioned. What about DPD activity, enzyme activity? Can you titrate on that? And I think for now, it still stands that we should start with a 50% dose, but with the possible effectiveness of the dose in mind, you should go with an early titration, and I would say something about 25%. Although having said that, I have no data to underline this. And if you have the possibility to go for DPD enzyme activity in addition to genotyping, that would also help you to titrate doses on that. And that's where we stand now. But we need to know why these 1236 variant carriers have such a large range in activity and toxicity. Davide Soldato: I also think, and I can ask you if you agree with me, that this analysis is really very important because I think it's one of the first reports regarding the analysis, specifically of progression-free survival and overall survival based on variants of DPD. But at the same time, I think that we also have to underline for our listeners that this was still a retrospective and exploratory analysis. So it's true that you observed this association with shorter progression-free survival. But still, I think that we will need also more core studies to validate these findings and to be really sure and also to perform additional analysis as to what the mechanism is as you were saying. I don't know if you agree on this limitation of the study, despite its importance in regarding clinical outcomes. Dr. Annemieke Cats: We certainly agree with you that we have to keep in mind that it is an exploratory, retrospective analysis. Having said that, a randomized controlled trial certainly has some difficulties in it as well. Nowadays, it is not feasible to give patients with a DPYD variant a full dose. In 2018, there was a lawsuit in Oregon, and now recently in Ontario, Canada. There's also a lot of rumor in the news because of patients getting a full dose while having a DPYD variant. So the lethality of the toxicity in some variant carriers makes it not ethical to perform a randomized controlled trial. So we have to look for different designs that reflect real-world data and learn more about the genotype and also in different ethnicities. It is also very important because what we have studied considers the white population mostly and that's also a direction that future research should go to.  Davide Soldato: Thank you very much. That was very insightful, especially the last part regarding ethnicity and the possibility that also these variants might be different according to that.  So I think that the main message that we should pass is that when prescribing fluoropyrimidines, genotyping of DPD is fundamental because toxicities among patients harboring these variants can be severe and can also be lethal. You performed this retrospective exploratory analysis that provided us with overall reassuring data. There is still more research to be done, especially for the 1236 variant. So I think that that probably is our bottom line and main message for our listeners.  And I just had one final question because in the manuscript that you published, you had localized, locally advanced, and also metastatic cancer that were all grouped together. Do you think that an additional line of research would be to specifically look at how these impactful outcomes only in the locally advanced and localized cancer compared, for example, with the metastatic? Dr. Annemieke Cats: You raised a very good point because there is a lot of variety within this study, and now you're mentioning locally advanced, local, or metastatic cancer. It's also within the cancer types. We studied different cancer types as well to reach a large amount of patients. It would be good to have a more homogeneous population that you can derive your conclusions from. So, I think that would certainly help us in the future, and we should look into whether we could do this together because before we had such a large population, we would need several countries to work together.  Davide Soldato: Yeah, you're totally right. Thank you very much for underlining that last point.  Thank you very much, Dr. Knikman and Dr. Cats, for being here with us today and for explaining to us and our listeners the results of your research. That concludes this episode of JCO Article Insights. We discussed the manuscript titled "Survival of Patients with Cancer with DPD Variant Alleles and Dose of Individualized Fluoropyrimidine Therapy: A Matched Pair Analysis." This is Davide Soldato, your host. Thank you for your attention, and stay tuned for the next episode.  The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Shannon Westin and her guest, Dr. Michael Anne Kyle and Dr. Nancy L. Keating, discuss the paper "Prior Authorization and Association With Delayed or Discontinued Prescription Fills" recently published in the JCO. TRANSCRIPT The guest on this podcast episode has no disclosures to declare.  Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast that goes in depth on articles and manuscripts published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncologist and Social Media Editor for the Journal of Clinical Oncology. And as always, I'm so excited that you've joined us, and none of the authors have any conflict of interest today. We are going to be discussing a very exciting piece of work, “Prior Authorization and Association with Delayed or Discontinued Prescription Fills,” recently published in the Journal of Clinical Oncology. And I'm thrilled to be joined by the two authors of this important work. The first is Michael Anne Kyle. She's a PhD research fellow in the Department of Healthcare Policy at Harvard Medical School.  Welcome, Michael Anne.  Dr. Michael Anne Kyle: Hi. Thanks for having me. Shannon Westin: We're so excited. And the second is Dr. Nancy Keating. She's Professor of Healthcare Policy at Harvard Medical School and Professor of Medicine at Brigham and Women's Hospital in Boston.   Welcome. Dr. Nancy Keating: Thank you. It's great to be here.  Shannon Westin: So, we'll get right to it. First, I always like to level set because we have such an interesting and diverse audience. Can one of you describe the process and goals of prior authorization? What does this mean for our groups that maybe haven't experienced this? Lucky them.  Dr. Michael Anne Kyle: Prior authorization is- the process can take many forms. Basically, what we're describing is before you can be prescribed a treatment, in this case, we're looking at medications, you have to submit a request to the payer, to the insurance company, asking for approval to receive that treatment, or in this case, that drug. The doctor's office does have to do a ton of work, but very often, the patient also receives a lot of the communication. So, there's a lot of work for everybody in prior auth often. And the uses of it- in principle, the purpose of prior authorization is to confirm that the reason this medication or this treatment is being prescribed is because the patient meets the criteria for need. So that can mean, you want to confirm that you have the right tumor markers for the drug that's being prescribed. You want to confirm that you are aligned with guidelines. And then I think the thing that's often on many people's minds is that in the US, we don't have a lot of controls on drug pricing, but drug prices are very high. And so, I think we often think about prior auth as being a mechanism to try and contain costs.  Shannon Westin: And this isn't new, right? So, this is a process that's been going on for a while. I'd love to hear you speak a little bit about, maybe, some of the changes, like how have the requirements for prior authorization been changing over time, especially for patients with cancer? Dr. Michael Anne Kyle: That's a great question. And that was the first step we took in this work because we've heard from oncologists, from patients, from researchers, that prior auth has been increasing. And we did find, looking at Medicare data, that that is true, that the use of prior authorizations for oral oncology drugs, so that will be Part D outpatient drugs you get at the pharmacy, has been rising over the past decade. And I think what's really interesting to point out here is we found the use of prior authorization increasing both for branded drugs and for generic drugs, and for specialty drugs, which are high cost, as well as non-specialty drugs, which are typically lower cost. So, across the board, prior auth is increasing. And why is this happening really is the million-dollar question. Some of it is surely like we have accelerated approvals happening predominantly in oncology. So, you could imagine that you do need to verify some evidence of these newer treatments, but some of it is a little bit harder to interpret. And that was one of the things in our paper that we were very interested in because we also see a lot of prior auth on drugs that have a very well-established record of efficacy. And we know our first-line therapies often now include some generics, and yet we still see that they have prior auth. And the reason for that is less clear. Shannon Westin: Yeah. Just as a gynecologic oncologist, coming from this standpoint of PARP inhibitors, which have long been established as a standard of care and for years now have been a frontline treatment, we're getting so much pushback around that, and it's a huge issue because that impact of delays and things, and I know that's your work. So, I think that's one of the reasons I was very enthusiastic about this because I think it has such broad-based impact across all of our patient populations.   So, I think that kind of definitely transitions into this. What are the potential negative impacts in this process of patients? And I would say not only patients with cancer, but what do we know also in patients with other disease types that are facing this prior authorization issue as well? Dr. Michael Anne Kyle: What we were curious about is there's a sense that prior auth is increasing, the trends show it's increasing. And we were wondering, does that matter for patient care? And we could think about the benefits of prior authorization being like double-checking that you're getting the right treatment. But the negatives are that you can be delayed in getting treatment, and that can either be because you're going through the initial process or there can be some error or denial or dispute in a prior auth process that delays your access. And the clinical implications of that would vary by drug, how that would affect your treatment. In this case, in this paper, we're talking about drugs, but for any treatment, the implications would depend on what the treatment is and what the patient's condition is. But I really want to draw attention to this other piece, which is that it's stressful not to have your cancer medicine. And so even if you ultimately end up getting it, the time that you're on the phone trying to figure it out is time taking you away from other things. It's stressful. And very often, patients with cancer are taking multiple drugs and have complex health issues. So, they may be dealing with this for multiple parts of their care. And that can add up. Shannon Westin: Perfect. Thank you. So, I guess next is to talk about how you address this. Let's talk a little bit about the overall objectives of the study that you just published and maybe briefly kind of go through the design for our listeners. Dr. Michael Anne Kyle: What we were interested in doing, like I said, was trying to figure out what happens with prior authorization at the point of care. And our study looks at 11 oral anticancer drugs in Medicare Part D. And the reason for that is because data available to look at prior auth is fairly limited. And Medicare Part D for the outpatient formularies does have indicators for whether a drug has a prior auth. So, we were able to use that. The next piece is we're not inside the office understanding why these treatment decisions were made. So, what we decided to do was say, “Okay, let's look at patients who've been consistently taking this drug.” And we said, “Okay, let's say you've had to have at least three fills in the past four months.” And we sort of take that as an indicator that you're able to access this drug and it seems to be working for you. And then what we do is we look at who are patients in plans, same drug, same plan, where the plan introduced a new prior auth on this drug they're taking, as compared with patients in plans who did not have a change in their prior auth policy. And we said, “Okay, there's this new prior authorization introduced, does that affect whether you get that next fill or how long it takes to get it?” Dr. Nancy Keating: I want to emphasize Michael Anne's point about these are patients who are already successfully filling and regularly taking their drugs. And unfortunately, due to data limitations and the inability to see prescriptions that aren't filled, we would love to look at the same question with people that are starting on a new drug but weren't able to do so but would imagine that you might even see bigger impacts in those patients. We both recognize from a health policy standpoint that there could be benefits of prior authorization policies. But it's also very unlikely to think that for a patient that's regularly filling an anticancer drug over a long period of time, that there's a reason that that patient should not be on that drug. And so, this is an area where we think that there may be really limited benefits of prior authorization, but potential harms.  Shannon Westin: Yeah, it makes sense. And of course, it would be. There's always the ideal way to set research up, and then a practical way. So, I was struck by what you chose. I thought it was really very practical and rational and made a lot of sense. And certainly, there are inferences that we can make based on what you found. So, let's talk about that. Let's talk about your primary findings. What did you see as the impact of a new prior authorization policy on patient care? Dr. Michael Anne Kyle: We found that for the patients who had a new prior auth policy introduced in their plan, compared to patients who didn't have a prior auth change, their odds of discontinuation within the next 120 days increased by about 7.1 times higher odds of discontinuation. And then for delays, we found that people were delayed an average of 9.7 days from when we last saw that they were expected to run out of their drugs based on their last fill, we said, “Okay, what's the last day we expect you to have meds on hand, and then when do we actually see you fill again if we see you fill? And the average delay there was 9.7, about 10 days. And that's a fairly conservative estimate that we decided to make. And I'm sure you and Dr. Nancy Keating can elaborate on how that's not just passive time. There's a lot of people scrambling around, probably in that interval, trying to close the gap. Shannon Westin: I mean, you said it, like, 10 days. It's a huge time. And it's not just time sitting there twiddling your thumbs. They're probably stressing, anxious. They might be having side effects related to stopping their medication. They might be taking other medications and reduce the efficacy of the combination. I mean, there's so many implications here of the impact. Dr. Nancy Keating: They're also calling the office, trying to get through to the office. Then the doctors are calling, trying to get through. People are like, what's going on here? Why isn't this medicine there? And so, there's a lot of individual patient and clinician effort that's happening at this time as well. Shannon Westin: And I think, of course, you were limited by the databases that you were using and what you're able to access, but I think it really does make me wonder, what's the impact on cancer related outcomes. We know about delays in certain therapies and things and how that can negatively impact survival and response and all of those types of things. And I wish we did have access to that kind of data because obviously the time and the things that you've been able to demonstrate are important, but the more objective data we can get around patient outcomes, I think will help us impact the actual policies that are being implemented here.  Dr. Nancy Keating: Right. And just to underscore too, Michael Anne highlighted the delays, but also there was a substantial increase in discontinuation within 120 days. So, there are some people that seem to not be able to get the med, maybe found another way to get it, or maybe were able to get samples from a drug company that we couldn't observe, but that's also concerning that there might be some people who fell through the cracks.   Shannon Westin: A very good point. I think that it's hard to know, but the potential there of losing the drug that's actually working for you is really distressing for providers and patients both.   One other thing I noticed that was interesting. Can you speak a little bit about some of the other factors that were associated with these findings with the treatment delays and what other things may be impacting these outcomes? Dr. Michael Anne Kyle: We looked at some patient characteristics and insurance characteristics that may be associated with delays. And I just have to note here that our sample is fairly small because prior authorization is so prevalent. There aren't a lot of switchers. So, this sort of limited the amount of depth we could go into. But here's what we can tell you, which is that people who are under 65, so in Medicare that will typically be people who have eligibility through disability, were filling about a day later than that 9.7 average people, female sex also filling 0.7 days, nearly a full day later. Similarly, and this is compared to males and then compared to white, non-Hispanic patients, patients who are black and patients who are Hispanic Latino are filling about 0.6, 0.7 days later, which is, of course, quite concerning, given our desire to have a more equitable health care system. And then finally, we linked our data to census data. And for patients living in a residential zip code with higher rates of poverty, we found that for each 10-percentage point increase in proportion of residents in that zip below the federal poverty level, the delay was about 2.5 days. So, what you can sort of take from that is the risk factors in particular are in Medicare being younger, which I would say is having a disability, female sex, non-white, and people living in high poverty zip codes. And given what we know about racial segregation, I think the odds are likely that the patients themselves would potentially also be low income. Shannon Westin: That's what's so important about this work, is it raises an awareness of, really, who's being impacted by this. Because I just want to draw back to kind of what you said at the beginning, that this is meant to do cost containment. It's meant to help the healthcare system. But what we're seeing in practice is it may be helping in some specific areas, but it's certainly creating quite a detriment. So perhaps there are other mechanisms that we could be exploring from a policy standpoint to try to work on cost containment, but not put the burden on the patients or on the people that are giving this health care. So, I think that's why I was so struck by this work.  I guess the next question is, what are your next steps for the research, and how can we use these data to help the patients?   Dr. Michael Anne Kyle: What a great question. I'll start, and then I'll let Nancy give her thoughts too. We're lucky that prior authorization is a very active policy area right now, both at the state and federal level. There's a great deal of interest in sort of certainly improving a lot of the information systems. Perhaps we can move away from the fax machine finally in 2023. I think there's a lot of policy relevant action happening around trying to make prior authorizations electronic, and you can automate them and make a lot of this move faster. There are also larger questions about what is the right price for a drug and how do we distribute it to people that I think are a lot more fundamental than any one study, but I think this is just another way. When we think about financial toxicity, there's just many challenges that come back to some way to this root cause of care is very expensive, and this is, I think, prior auth is one of the side effects of that.  And so, hopefully, to help patients, we can get this data in the hands of policymakers who are trying to bring us to a more modern prior auth system. And hopefully also to payers, I would be very excited to see a little bit more examination of, like when is prior auth appropriate versus when is it not. I think there are cases where prior authorization is very appropriate, and we shouldn't take it away. But one of the drugs in our study is generic imatinib, and perhaps that is a lower value prior auth. And so, I'd be very interested in seeing payers think more strategically about when is prior appropriate, both to improve access and improve equity, and then also to improve the provider burnout and the poor docs who are really struggling under the weight of this. Dr. Nancy Keating: Yeah, I couldn't agree more with everything that Michael Anne said, but really, we'll underscore that last point. The prior auth policy seems like it's this very broad policy and the way that it's implemented, it's sort of like, let's just hit everything and not take a nuanced, thoughtful approach. But just like Michael Anne said, generic imatinib, really? And then back to this point of patients that are doing well on a drug, people are not going to be taking anti-cancer therapies if they don't need to. And so there just doesn't seem to be any reason to implement a prior authorization policy on a drug that is being well tolerated. And so really, I think there could be a lot more thought and nuance put into applying these policies within health plans. Shannon Westin: Yeah, I think that's a perfect way to end this. I would just add, I think this is beyond anticancer therapy for our patients with cancer. I mean, we're seeing it now with supportive care medications. And to your point, I mean, generic antiemetics, and you're like, come on, this is ridiculous. So, I think that this type of work is- the best type of work always spurs more questions and gets us fired up about what to do next. So, I just want to again commend you on all of this important work, and we need to add more data here so that policy will change. And so, thank you both for your hard work in this area and for taking the time to educate our listeners. I'm sure we're going to hear a lot of intriguing questions for you about this work, and hopefully that'll move our policy forward.   And thank you, listeners, for checking in again with JCO After Hours. Again, we were discussing prior authorization in association with delayed or discontinued prescription fills. I'm so grateful to Dr. Kyle and Dr. Keating for joining me today, and I hope you all will listen to our other podcast offerings wherever you get your podcasts. Have an awesome day.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and it is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Shannon Westin and her guest, Dr. Nanda Horeweg and Dr. Carien Creutzberg, discuss the paper "Molecular Classification Predicts Response to Radiotherapy in the Randomized PORTEC-1 and PORTEC-2 Trials for Early-Stage Endometrioid Endometrial Cancer" recently published in the JCO. TRANSCRIPT  The guest on this podcast episode has no disclosures to declare. Shannon Westin: Hello everyone, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on manuscripts published in the Journal of Clinical Oncology. I'm your host Shannon Westin, Social Media Editor for the JCO and GYN Oncologist by trade. And I'm so excited about today's topic because it is a GYN Oncologist dream. Before I start, please note that none of the authors have any conflict of interest. We are going to be discussing molecular classification predicts response to radiotherapy in the randomized PORTEC-1 and PORTEC-2 trials for early-stage endometrioid endometrial cancer. And this was published in the JCO on September 20th, 2023. And we're going to be speaking to two of the lead authors. First is Nanda Horeweg. She's a senior researcher in the Department of Radiation Oncology at the Leiden University Medical Center in the Netherlands. Welcome. Nanda Horeweg: Thank you. Happy to be here. Shannon Westin: And Dr. Carien Creutzberg. She's professor at the Department of Radiation Oncology at the Leiden Medical Center as well. Carien Creutzberg: Thank you. Shannon Westin: So, let's get into it. And I want to really level set because we have a mixed audience here. So, why don't you start by speaking about the incidents and mortality of endometrial cancer? Nanda Horeweg: Yes, of course. Endometrial cancer is the sixth most common cancer in women with around 400,000 new diagnoses made globally each year. And a woman's lifetime risk to get endometrial cancer is around 3%, and the median age, the diagnosis is 61 years. Most of the women who are diagnosed with endometrial cancer are diagnosed at an early stage, around two thirds, and they have an excellent prognosis. Actually, the five-year survival rates are around 92%. For stage 2 disease, this is actually already going down a bit to 74%. Therefore, stage 3 disease is only 48%. Women that are diagnosed with advanced disease have only a five-year survival, 15%. Shannon Westin: So, given that we know the majority of endometrial cancers are diagnosed at this early stage, prior to your evaluation, what was known about the optimal way to treat this early-stage patient population? Carien Creutzberg: Well, of course, the PORTEC trials were done … were started PORTEC-1 in the 19th of the last century, and PORTEC-2 in 2002. So, at that time, there were still many, many women treated adjuvantly with external beam radiation therapy. And we just developed risk factors to decide on their risk and the incidents for radiotherapy. And in PORTEC-2, because in PORTEC-1 we had seen that most of the recurrences in these early stage cancers were in the vaginal fold, we compared local vaginal brachytherapy only three sessions within full course of pelvic radiotherapy and showed that it had similar pelvic control and survival. Of course, this study, which Nanda conducted, was a long-term analysis with many new factors known from the translational research in the tissue samples of these patients who participate in PORTEC-1 and 2. And in the meantime, we've developed much more knowledge on the molecular factors and other important factors such as LVSI, which tell us much more about the individual prognosis to patients. So, the treatment has been developing greatly in the past 20 years. Shannon Westin: Yeah, and I think this is a great case of less is more, right? We were doing so much for so many people that really didn't need it. And so, really tailoring who needs less treatment, who doesn't need any treatment, and then also, conversely, who may need more treatment that would be missed by the traditional risk factors that you're speaking of. So, I think that brings us right into my next question, which is just bringing the audience up to date on the cancer genome atlas and how that's changed the way we classify endometrial cancer. Nanda Horeweg: Yes, I think the molecular classification of the TCGA has shaped the way we think about endometrial cancer, and has huge impact on decisions on adjuvant treatments in the years to come. The TCGA performed an extensive characterization of the endometrial cancers and found that in fact, this disease exists of four different groups. And the first of the groups I'd like to discuss is the ultra-mutated group, which is characterized by POLE mutations. And this group is shown to have an excellent prognosis in many independent studies. A second group that also has a high mutational burden is characterized by microsatellite instability, and mismatch repair deficiency and has shown to have an intermediate prognosis. Then there's another group that has a low mutational burden with high copy number alterations and frequent TP53 mutations, and these have a poor prognosis. And then lastly, there's a group that does not have any of the classifying features and is often called non-specific molecular profile or TP53 wild type. And this group also has an intermediate prognosis. And then finally, there's a small group of cancers that has more than one of these classifying features, the so-called multiple classifiers. And the WHO 2020 has developed an algorithm which can be used to classify them into the four groups. And that's first on the POLE status. And for the POLE wild type tumors, they are assigned according to mismatch repair deficiency status. And for those that are mismatch repair proficient than POLE wild type, they are classified according to the TP53 status into NSMP or p53 abnormal. Carien Creutzberg: Yeah, that is because of in the ultra-mutated and hyper mutated groups, many of the other mutations are secondary mutations in the context of the ultra-mutated stage, and they behave like the first molecular group. Shannon Westin: Yeah. So, that POLE mutation is going to trump anything else, and it's so important. And I will just say as a sidebar, it's been challenging with the price of next gen sequencing sometimes to get that for everyone. So, sometimes for us when we see a p53 mutation, we actually go back and do the full next gen sequencing to make sure that we're not going to act on that core prognostic feature when it really is in the setting of that more simplistic or that more positive prognostic place. So, this is great, we already kind of highlighted a little bit PORTEC-1 and 2, but if you don't mind, I would love to get the audience a little bit more information just maybe about the populations that were included as we were figuring out how aggressive to be with radiation just to remind people of that, or to teach them that if they haven't gotten a chance to look at those studies. Carien Creutzberg: Yeah, that's important to know because PORTEC-1 was still in the era that we also treated intermediate risk stage 1 endometrial cancer patients. So, deep invasion with grade 1 and 2 or superficial invasion with grade 2 and 3. That's what we defined at that point. Then we compared external beam radiation or no further treatment, showing no survival difference, but a higher risk of recurrence with higher risk being older age over 60, grade 3 for deep myometrial invasion. And we kept those high intermediate risk factors as also similarly found by GOG-99 at the time to do PORTEC-2. So, at the time, about 50% of patients did not have an indication for adjuvant therapy anymore, and with a high intermediate risk population for PORTEC-2, we compare external beam or vaginal brachytherapy and found the benefit of vaginal brachytherapy. A simple outpatient treatment, very short with almost no side effects ensuring local control. And nowadays, using the molecular classification of PORTEC-4a, we've compared achieving treatment with or without use of the molecular factors to designated treatment. So, the standard arm is vaginal brachytherapy and investigational arm is first, a molecular risk profile. And then we give no radiotherapy for those with a favorable profile, then a brachytherapy for the intermediate ones, and for the small group is either extensive LVSI or TP53 mutation or L1 chem overexpression external beam. And we hope to show that less overtreatment and less undertreatment will benefit these patients. Shannon Westin: Yeah, I'm very much looking forward to the results of PORTEC-4a. But let's circle back and talk a little bit about your amazing work here. So, how did you leverage those patient populations from PORTEC-1 and 2 for the current study? Nanda Horeweg: Yes. Well, the PORTEC-1 and 2 study provided a unique opportunity to look into differential treatment effects for radiotherapy. And that is because these are randomized trials, so the groups are comparable, and we have long-term follow-up data that's of very high-quality. In addition, as Carien said earlier, she had the vision already back in the nineties to directly ask the patients permission for the collection of the tissue. So, we have a broader complete biobank for both of these trials, which is quite unique. And our colleagues, Professor Smit and also Charlene Goseff from the pathology department, they have done extensive work on molecular classification, and have molecularly characterized all these cases. So, this allowed us to include 880 patients in this study, which is the largest so far. And besides like the very good starting point that we have of PORTEC-1 and 2 is that we also chose a design that was optimized to conduct like real causes, the causal effects of the molecular class on radiotherapy response. So, we tried to preserve this randomization effect, the exchangeability of the groups as much by working with the intention to treat population and not excluding any patients, except for when they did not have the molecular classification assessed. And also, we looked at areas in the body that were irradiated in one group and not in the other one to really observe the effect of radiotherapy as much as possible. So, looking to the entire pelvis, so local and regional recurrences in PORTEC-1 and looking at pelvic recurrences in PORTEC-2. Shannon Westin So, how were the intervention outcomes in this study different based on the TCGA classifiers? Nanda Horeweg: Before I tell you the results of biomolecular group, I think it's good to have the starting point of the analysis here. So, the no hypothesis of my study was to see whether there was any difference, and no hypothesis is that there's no difference. So, if we find a significant effect, then we can actually say that we found something. And if we start with the POLE group, we did not find any significant difference between the groups allocated to radiotherapy or not. But we did see not a single recurrence in any of the patients that we included from both of these trials. So, technically speaking, we did not find a predictive effect of the molecular classifier, but a prognostic effect. There's no one's having recurrence, so we can deduct from that, that radiotherapy is probably over treatment. Then for the MMRd group, we did observe some recurrences, but these were not significantly different between these three groups. So, based on this study, we cannot draw conclusions on which type of radiotherapy we should give to the patients or whether we should give radiotherapy at all. This was very different for the p53 group. There, the patients had lots of recurrences, unfortunately, as we expected, but we saw a big difference in outcome compared between no radiotherapy at all if it's vaginal brachytherapy where we still had lots of recurrences, and EBRT where we hardly saw any recurrences in the pelvis. And that difference was significantly different. So, that's an indication that these patients need more than just vaginal brachytherapy, even though it's only stage 1 endometrioid endometrial cancer. And then in the last group, the NSMPs, we saw even a different pattern where patients who had had external beam radiotherapy or vaginal brachytherapy, both had an excellent local regional control, and the ones that did not receive any treatments had more recurrences. And this was also very significant. So, there, you would conclude that both therapies are appropriate, but of course, the toxicity profile for vaginal brachytherapy is much more favorable than that of EBRT. Shannon Westin: We really are getting kind of consistent data around p53 needing more treatment. And I think the natural question that comes here, for me at least, and I know we can't answer it with the work, is would chemo be — would that be that extra treatment, when we saw with PORTEC-3 that the group needed the chemotherapy the most. So, I think we'll have to continue to work through that and determine is any more treatment what we need or specific treatments really the best. So, this is so intriguing and it's nice that it's consistent, that we're seeing that across these different studies that really kind of lends strength and validity, I think to what we're finding. So, one of the actions that we're kind of moving towards and that you advocate certainly in your paper is omitting therapy for patients with POLE mutations. Are there any ongoing studies around that that will help us confirm that this is safe for our patients? Nanda Horeweg: Yeah, that's a very good point. I think the evidence is strong enough now to conduct prospective trials. And of course, these are ongoing, the PORTEC-4a trial was already briefly mentioned there. The patients with poor mutations will be randomized between observation and vaginal brachytherapy. So, that will give us a good indication whether in this high intermediate risk early-stage group omission is safe. And in addition to that, we are also conducting with the RAINBO Consortium, the RAINBO-BLUE trial, wherein patients also with high-risk features, so non-endometrioid isotypes, LVSI and higher stages are included. And also in those patients, we investigate whether the de-escalation of treatment is safe. So, we're definitely looking forward to those results to be able to transfer this knowledge to clinical practice later on. Carien Creutzberg: And maybe it's nice to add that RAINBO BLUE is connected to the Canadian Taper trial. Taper being a general de-escalation trial where the POLE patients in that trial are also feeding into the RAINBO-BLUE. And I know that in North America, many centers will participate in the Taper trial. Shannon Westin: Yes, I think everyone is very excited and I think it'll be nice to have these two very strong studies that will help us really confirm that that is 100% a test that needs to be done, cost are not — and that will help avoid overtreatment of patients. So, in line of that, have you all experienced any challenges with implementing molecular testing across patients with endometrial cancer? Any thoughts on how we could potentially simplify? You talked about the rational promise algorithm, which I think is excellent, but I'm just curious to hear your thoughts on this. Nanda Horeweg: The implementation of the molecular classification can be challenging. We have to be honest about that. And usually, it's the assessment of the POLE status that's causing the problems because that's usually done with NGS, which is quite expensive. It requires a lot of knowledge in the laboratory and it's also a bit time-consuming. So, that is the bottleneck for most laboratories and for most settings. But this is already changing in a couple of places, like in the UK and the Netherlands, it's being reimbursed by healthcare insurances, and also, in many tertiary care centers in other countries, they're already systematically performing this test. But of course, there will always be places where this is not feasible. And luckily, there are also cheaper alternatives coming up and are already available at the moment. So, one of them is, for example, standard sequencing, which is not so expensive, but a bit labor intensive. Some colleagues we work with from India have implemented that in their clinical practice and are perfectly able to molecularly classify the endometrial cancers in daily practice. Another alternative is a test that we've developed in Leiden that's called the QPOLE test, which is based on qPCR, so that's a technology which we use for our COVID test around the world, so that can be done almost anywhere. And with that, you have a very high accuracy to detect unknown pathogenic variants. And this is also published in JCO Global Oncology, and can be implemented in any center after a local validation step. And even like more companies nowadays are realizing that this is important. So, I think commercial tests are already becoming available and very more on the market soon. So, I am really hoping that it'll be more available to endometrial cancer patients. Carien Creutzberg: And they'll offer them at a very low cost and also a rapid turnaround because NGS can take like 10 days. But realizing on a more national level, if you have found one patient with a POLE mutation, the omission of cycles of chemotherapy with all of the patient care around in the hospital is worth much more than just a few POLE tests. So, we have to look at this and that's I think why our healthcare reimbursement came through that if you look at a population level, it is cheaper, and we'll do an extensive cost analysis in PORTEC-4 just to show this. Shannon Westin: That is such a good point. I love that and all of the downstream issues that happen potentially with radiotherapy or with chemotherapy, that's really brilliant. And I'm going to take that back, I love these podcasts. I always learn stuff that I immediately start to use. So, I guess then the last question is, what's next for this particular research and how might we validate what you found? Nanda Horeweg: Yes. Well, as mentioned earlier, for POLE, we have already put the next step in place. So, PORTEC-4a has completed accrual almost two years ago, and we're very much looking forward to do the final analysis within one to one and a half years. So, that will be one of the important next step. And of course, the POLE-BLUE trial is open at the moment, and within a couple of years, we also hope to learn more about this group. So, that's very exciting. Then for the mismatch repair deficient group, while we did not find any particular sensitivity for radiotherapy, and I also don't think that we will conduct another large randomized radiotherapy trial in this group — I think the results that we've observed in the metastasized setting, were really impressive results with immunotherapy are the way forward for this molecular class. And I think the next thing we should do now is prove whether this works or not in the adjuvant setting. And if that's starting with the high-risk patients, which is something we are currently doing in the MMRd-GREEN trial, which is ongoing in the Netherlands, and soon, will open internationally. And from there on, we can work forward if we see that also in this setting the immunotherapy works well. Shannon Westin: And I think GY020 also — NCI trial is also looking at the addition of immunotherapy to radiotherapy in that irony at risk. Carien Creutzberg: Absolutely. Nanda Horeweg: Yeah. And the KEYNOTE-B21 as well — oh, well, already complete accrue. Shannon Westin: The B21, yeah. So, I think those are good. Yeah, that's a really good point for that MMRd group that the immunotherapy really is the way to go, and then more work to be done with the no specific molecular profile. Nanda Horeweg: The NSMP, I think like for the early-stage group, it's quite clear that vaginal brachytherapy is a therapy of choice. But you can of course, try to identify those at such a low risk that you could deescalate treatment. And that's of course what's being done in the Taper trial and also in part, investigated in the PORTEC-4a trial. Carien Creutzberg: And those with higher risk NSMP that we are revisiting hormonal treatments because 90% are estrogen receptor positive, and they have a clearly better prognosis than those with estrogen receptor negative tumors. So, those with estrogen receptor positive tumors can in RAINBO-ORANGE, which will be run led by the UK group, see if we can improve quality of life with less intensive adjuvant treatment. And then you came to the p53 group, that's a good one to stop with. Nanda Horeweg: Yeah, we have very good indications that radiotherapy and chemotherapy is working well for this group. And this is also in line with the guidelines that have been issued in the last few years by many societies. So, I don't think we should change this base of the treatment consisting of radiotherapy and chemotherapy. But since the prognosis is still rather poor, we need to add systemic agents to reduce the risk of metastasis. And preferably, this should be like well-designed based on a proper biological underpinning, plus something that's not too toxic since we're combining the three therapies together. So, this is what we try to do in the RAINBO-RED trial where we will investigate the addition of a PARP inhibitor to chemoradiation in the p53 group. Shannon Westin: Oh, I love that. That's been my whole career, is adding PARP inhibitors wherever I can. Carien Creutzberg): We might also want to mention the HER2 inhibitors, which are also in about 20% of the p53 group has HER2 overexpression. And there is a trial being set up in NCI with trastuzumab and pertuzumab. Shannon Westin: My only concern with that one is I think that the antibody drug conjugates are so much more powerful, the TDX data that we just saw from DESTINY is so impressive. And so, I do wonder, like if we need to move on from kind of some of the older HER2, and get with the program and use some of these more powerful drugs. But with that, I just want to thank Dr. Creutzberg and Horeweg. This was such a great discussion, and obviously, near and dear to my heart talking about endometrial cancer, but I hope our audience enjoyed as well. Just as a reminder, this was a discussion on molecular classification predicts response to radiotherapy in the randomized PORTEC-1 and PORTEC-2 trials for early stage endometroid endometrial cancer, published in the JCO on 9.20.23. I am your host, Shannon Westin, and I hope you'll check out more JCO After Hours wherever you get your podcasts. Have an awesome day. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

In this JCO Article Insights episode, Davide Soldato provides summary on two articles published in the November issues of the Journal of Clinical Oncology. The first article provides data on the prognostic effect of physical exercise on overall mortality and cancer-related mortality in a pan-cancer analysis of the PLCO study. The second article provides data regarding the impact of BMI on treatment-related adverse events and adherence to Palbociclib in the PALLAS trial. Overall, results of these study support the need to conduct studies investigating lifestyle behavioral factors and their impact on outcomes in survivors of and patients diagnosed with cancer. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Davide Soldato: Welcome to the JCO Article Insights episode for the November issue of the Journal of Clinical Oncology. This is Davide Soldato, your host, and today, I will be providing a summary on two articles focused on the impact of exercise on cancer prognosis and of BMI on treatment side effects. In the first article titled Pan-Cancer Analysis of Postdiagnosis, Exercise, and Mortality, Lavery and colleagues investigated whether higher exercise was associated with a reduced risk of mortality among individuals diagnosed with cancer. The authors conducted a pan-cancer analysis using data from the Prostate, Lung, Colorectal, and Ovarian cancer screening study or PLCO, using data from a questionnaire that was administered to participants in the study at a median of nine years after initial randomization. The questionnaire including 12 questions related to physical activity, both occupational and non-occupational. Of these 12 questions, four were used to assess the prognostic impact of moderate and strenuous exercise evaluated both in terms of frequency, so a number of sessions per week, and duration of exercise sessions. The exposure to exercise was defined according to international guidelines, and patients were so divided among those who had a moderate intensity exercise defined as at least four days per week with each session on average for 30 minutes in duration, and strenuous intensity exercise equal or more to two days per week with each session on average of at least 20 minutes in duration. So, based on this definition, the patients were categorized as either exerciser, if they were meeting the recommendation or non-exercisers. Additionally, to assess the existence over those response relationship between exercise and mortality, the authors further categorize patients on a four level scale as reporting no exercise, exercise, not meeting recommendation, meeting recommendation, or exceeding recommendation. The primary endpoint of the study was all-cause mortality, and secondary endpoints included cancer mortality and mortality from other causes. This study included more than 11,000 patients diagnosed with cancer. 38% of them reported meeting guidelines recommendation with a median of 44 and 19 minutes spent in moderate and strenuous exercise respectively. Individuals belonging to the group of exerciser were more frequently male, non-smokers, and with a lower prevalence of cardiovascular diseases. The most common cancer diagnosis were prostate cancer, breast cancer, and colon cancer observed respectively in 37%, 20%, and 7% of the participants. Patients who died within six months from the completion of the questionnaire were excluded from this study. A median follow-up time between this landmark point and the last follow-up was 11 years. More than 4,500 deaths were observed in this period, and less than half were related to cancer meeting. Meeting exercise recommendation was associated with a 25% risk reduction in all-cause mortality, a 21% risk reduction in cancer mortality, and a 28% risk reduction in mortality from other causes. In particular, five-year cancer mortality rate was 12% among exerciser and 16% among non-exerciser. Interestingly, the positive prognostic effect of exercise was observed starting within the first five years of observation, but persisted up to 20 years afterwards. An inverse to those response relationship between exercise and mortality was observed, so increasing exercise was overall associated with incremental reduction in the risk of death. The authors compared patients reporting no exercise with those reporting exercise under at the recommendation or over the recommendation. For all-cause mortality, the risk reduction was equal to 25% among those reporting exercise below the recommendation, and increased to 35 and 36% among those meeting and exceeding recommendation respectively. Similar results were observed for cancer mortality, risk reduction ranged from 19% in those reporting exercise below recommendation, up to 33% for those exceeding recommendation. Finally, the authors investigated the effect of exercise on mortality by cancer type, and observed a significant reduction in cancer mortality only for head and neck cancer and renal cancer. While reduction all-cause mortality and mortality from other causes were observed across a wide range of cancer, including breast, endometrial, and hematopoietic and prostate. The study confirms previous findings by showing an inverse relationship between higher level of exercise and lower risk of all-cause mortality, and provides novel insights on the topic by reporting that those response association, data on other causes of death, and edited analysis by cancer site diagnosis. All limitation of the study is related to the generalizability of the findings. The study included only patients that were alive at a median of 4.5 years after cancer diagnosis, which might have applied to selection of patients with good prognosis, and thus, reducing the number of cancer mortality events. Additionally, these patients were willing to complete an additional questionnaire in the context of the trial, which might be related to a higher motivation in engaging in healthy lifestyle behaviors. The study did not replicate previous findings observing a reduction in cancer mortality for breast, colon, and prostate cancer, among those reporting higher exercise. Although this might be related to the inclusion of long-term survivors in the study. In the second article titled Impact of BMI in Patients With Early Hormone Receptor-Positive Breast Cancer Receiving Endocrine Therapy With or Without Palbociclib in the PALLAS trial, Dr. Pfeiler and colleagues investigated the impact of BMI on side effects, adherence to treatment, and efficacy of palbociclib in the PALLAS trial. Just as a reminder, PALLAS is a randomized clinical trial that investigated whether the addition of two years of palbociclib to standard endocrine therapy in patients treated for stage two, three hormone receptor-positive HER2-negative breast cancer could improve invasive disease-free survival. Previous report of the trial showed that palbociclib did not improve invasive disease-free survival compared to endocrine therapy alone. More than 5,500 patients were included in this analysis, and among them, more than two third at a BMI equal or over 25 diagnoses with 32% being overweight and 30% obese. Overweight and obese patients were more frequently older and coming from North America rather than from Europe. In line with the age difference, normal weight patients were treated more frequently with Tamoxifen alone or in combination with ovarian function suppression or with aromatase inhibitors in combination with ovarian function suppression. No differences in tumor characteristics was observed according to BMI. However, there were some minor differences regarding the type of surgery and administration of chemotherapy. The authors observed that side effects of palbociclib were significantly different according to BMI and in particular, they observed a lower incidence of a hematological toxicity among overweight and obese patients. Conversely, higher rates of arthralgia, nausea and diarrhea were observed among overweight and obese patients, both in the palbociclib and in endocrine therapy alone. In particular, regarding hematological toxicity, the authors observed that overweight and obese patients experienced a significantly lower incidence of overall neutropenia, grade 3 and grade 4 episodes of neutropenia. For example, looking at grade 3 neutropenia, the incidence was equal 44% in the obese population versus 64% in the normal weight cohort. Differences in incidence of neutropenia remains significant even when adjusting for confounding factors, including previous administration of chemotherapy, age, ECOG performance status, and race ethnicity. Furthermore, a lower incidence of overall thrombocytopenia was observed in the overweight and obese cohort. The lower incidence of hematological toxicity led to significant differences in those reduction, early discontinuation, and relative dose intensity for palbociclib. At six months, only 29% of obese patients reduced to those of palbociclib compared to 50% in the normal weight cohort. Similarly, only 20% of obese patients permanently stopped palbociclib compared to 35% in a normal weight group. Finally, the risk of palbociclib early discontinuation was 25% lower for each additional 10 units of BMI, even when accounting for additional potential co-founders. As a consequence of a lower dose reduction and lower rates of early discontinuation, the relative dose intensity for palbociclib was significantly higher among overweight and obese patients compared to normal weight ones. Efficacy of palbociclib was not different according to BMI, neither in the palbociclib bar, nor when assessing patients in both arms. However, these analyses are performed with a relatively short, medium follow-up time, and a low number of events. So, in conclusion, this report from the PALLAS trial shows that higher BMI was associated with a more favorable safety profile, especially regarding hematological toxicity, and a lower risk of treatment discontinuation. These findings are in line with previous data obtaining the metastatic setting with other CDK4/6 inhibitors, and support the existence of a different pharmacodynamic profile influenced by BMI that translates in a more favorable toxicity profile. At present, differences in BMI do not seem to affect palbociclib efficacy, but further analysis with additional follow-up time and events, as well as by type of endocrine therapy administered are planned in the PALLAS study. That concludes this episode of JCO Article Insights. In these episodes, we summarized findings from two studies, the first titled, Pan-Cancer Analysis of Postdiagnosis, Exercise and Mortality by Lavery and colleagues. This trial shows that higher level of exercise are associated with lower risk of all-cause cancer specific and other cause mortality, although with some differences according to cancer site. The second article titled Impact of BMI in Patients with Early Hormone Receptor-Positive Breast Cancer Receiving Endocrine Therapy With or Without Palbociclib in the PALLAS trial by Dr. Pfeiler and colleagues observed a significant different side effect profile for palbociclib according to BMI, but no differences in efficacy. This is Davide Soldato, thank you for your attention and stay tuned for the next episode of JCO Article Insights.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions.Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

In this "Podcast Takeover," Dr. Lidia Schapira guest hosts to discuss with Dr. Shannon Westin her own JCO paper, which reports on the DUO-E Trial. Dr. Ramez Eskander also joins in this lively discussion. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I am your host, Shannon Westin, Social Media Editor of the JCO and Gynecologic Oncologist by trade. And actually, I'm super excited today because we are going to have a podcast takeover because we are discussing my own work, which was simultaneously presented at the European Society of Medical Oncology 2023 Congress and published in the Journal of Clinical Oncology on October 21st, 2023. And this was the DUO-E trial, “Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer.” Because we’re discussing this work and we wanted you to have an unbiased podcast discussion, Dr. Lidia Schapira, who is a Professor of Medical Oncology at Stanford University and an Associate Editor of JCO and the Art of Oncology podcast host, is going to take over this podcast and really just pepper me with questions about this exciting work.  Welcome, Dr. Schapira.  Dr. Lidia Schapira: Thank you so much. It's such a pleasure to be with you. Dr. Shannon Westin: And before I turn over the reins, I also want to introduce one of my colleagues, who’s going to be providing quite a bit of insight on this topic, Dr. Ramez Eskander, who is Professor of Obstetrics, Gynecology, and Reproductive Sciences at the University of California, San Diego. And you will know he’s the principal investigator of the GY-018 study, which established pembrolizumab and chemotherapy as the new standard of care in endometrial cancer. Welcome, Ramez.  Dr. Ramez Eskander: Thank you. Thank you, Dr. Westin. It's a pleasure to be here. And congratulations again to you and your study team for this exceptional work.  Dr. Shannon Westin: Thank you. And congratulations to you.  Dr. Schapira, thank you for being here and please do take it away. Dr. Lidia Schapira: So let's start by having you tell us a little bit about the standard of care for women with endometrial cancer and advanced endometrial cancer prior to this study. Ramez, I'm going to direct this question to you first. Dr. Ramez Eskander: For many years, actually since about 2012, carboplatin and paclitaxel, which ironically is a chemotherapy backbone really across all of our gynecologic tumors, emerged as the preferred doublet chemotherapy regimen for the management of advanced-stage metastatic or recurrent endometrial cancer. It evolved through a series of different clinical trials, in fact taking us from whole abdominal radiation, systemic chemotherapy, comparing single agents to doublets and then triplet regimen of TAP to carboplatin and paclitaxel, which ultimately, then, following the presentation of GOG Protocol 209 and its publication, as the chemotherapy backbone, being carboplatin and paclitaxel. And it’s been that way for many, many years. Dr. Lidia Schapira: And how effective is the regimen? Dr. Ramez Eskander: The response rates to carboplatin and paclitaxel are actually quite reasonable in the patients who have advanced-stage disease, particularly if they haven't had prior systemic chemotherapy. Response rates in the 50% to 60% range. The issue is that the responses tend to be limited and disease recurrence is an expectation in these patients who have advanced-stage disease. And so that really highlighted the importance of trying to continue to advance therapeutic opportunities in these patients to improve long-term outcomes.  Dr. Lidia Schapira: As we think about improved long-term outcomes, we're thinking about a better treatment and also a kinder treatment, perhaps one that is also less toxic. Can you talk a little bit about the population of women with endometrial cancer? Are these older women? Do they have comorbidities?  Dr. Ramez Eskander: What we’re seeing is, interestingly, there has been an evolution a bit in this space. Historically, we used to think about endometrial cancer as—the phrases we used to use are type I and type II. These type I tumors, we would say, are estrogen-driven malignancies; they tend to be seen in overweight or obese patients. And we would identify them in a theoretically younger patient population. And then we had these type II, or what we termed estrogen-independent malignancies, that we would see in an older patient population. Of course, with obesity came metabolic syndrome and other cardiovascular comorbidities, etc. But really, that narrative has evolved dramatically, and that’s really something that will be highlighted in, I think, our discussion of these studies today, where the nomenclature that we used to historically use has evolved because of our understanding of the molecular characterization of this disease. So we’ve really gone away from that, and now we understand that we’re seeing all of these different heterogeneous endometrial cancer types amongst patients of different ages, different comorbidities, different races and ethnicities. And so it’s created a more complex picture for us. But certainly, there are comorbidities that these patients face, and that’s important as we look to identify treatments strategies that are both effective and tolerable. Dr. Lidia Schapira: My final question before we jump into this very exciting study is about the Cancer Genome Atlas work. Can you tell us how that’s changed the thinking and the design of the studies? Dr. Ramez Eskander: It was a seminal publication, really, back in 2012/2013 looking at an assessment of endometrial cancers to try and determine whether or not all of these "endometrial cancers" that we used to enroll on a single study are similar or divergent. And it’s important because the study I referenced that really established the standard of care, GOG Protocol 209, as carboplatin and paclitaxel, there was no real consideration of molecular characterization at all. We enrolled all patients onto this study without thinking about these variables, of course, because it was designed, conducted, and completed before the TCGA data emerged. But what we learned from the TCGA is there appeared to be four distinct molecular subgroups. There were the POLE-mutated patient population. There was the mismatch repair deficient or MSI-high endometrial cancer population. There was the copy number-high or what we say are the p53-mutated. And then the last cohort was called the NSMP (no specific molecular profile). But now, that’s even evolved; some people term it TP53 wild type. That’s a bit of even a heterogeneous cohort amongst itself. So we’re going to take these subsets, independent of POLE and an MSI-high, and we’re going to look at TP53 or copy number-high, and that will probably be divvied out further, and the NSMP, and that will probably be subdivided. But really, it gave us these four components, which has then evolved. Many of you may have heard of the ProMisE algorithm or ProMisE Plus, which looked to take the data from TCGA so that we can start to really look at it in clinical practice. So it’s really revolutionized how we think about these patients, how we think about the disease, and how we design trials.    Dr. Shannon Westin: And I just want to add to that because I think that it's so important, what Ramez said about the way we were developing trials, the way we were designing trials. We knew that these classifiers—we were learning these classifiers are prognostic. Now what we’re really trying to hone in on is how predictive they are. And certainly, one of the major classifiers that we’re going to talking about today is mismatch repair status, and that is most definitely predictive of response to therapies. But we’re still learning about the other classifiers and how we might adjust the way we treat people, even deescalating care for certain patients. That is still being proven in clinical trials, although we suspect that it’s going to be borne out as other clinical trials report. Dr. Lidia Schapira: It's a perfect segue to this current trial. Tell us a little bit about the objectives and the design of DUO-E. Dr. Shannon Westin: As Ramez said, the standard of care was chemotherapy. And so we wanted to see if there was a way to improve outcomes for these women with advanced and recurrent endometrial cancer in a really clinically relevant, meaningful fashion for patients. And so we knew that this TCGA classifier, the mismatch repair, was so important, and we thought that the addition of immunotherapy to chemotherapy would most certainly work in that population but could even work in the entire population because, generally, endometrial cancer seems to be a little bit more responsive to immunotherapy and to activation of the immune system than, say, some of our other gynecologic malignancies. And so we set out to see what the addition of durvalumab, which is a PDL-1 inhibitor, would add to chemotherapy. And this was two chemo as well as followed by durvalumab maintenance.  But even further, we had some really kind of exciting science data from our lab that said that if we combined a PARP inhibitor with immunotherapy that we could accentuate on the response to therapy and we could get more benefit. And there's kind of a lot behind that, but essentially, what we thought was that the damage that's caused by the PARP inhibitors would create an activation of different immuno-pathways, like STING pathway and activating cytokine release, and that we would get this synergistic activity. So one of the other objectives was to see if the addition of the olaparib, the PARP inhibitor, to durvalumab in that maintenance setting could even further improve benefit. So we had a dual primary endpoint looking at progression-free survival, so the amount of time people live without their cancer coming back. And that endpoint was first, the durvalumab-alone arm to control, and then the second portion of that was the durvalumab/olaparib arm back to control. Dr. Lidia Schapira: So before you tell us about the results, tell us a little bit about the study itself. I mean, I was very impressed that you did it in so many different locations. Tell us about that effort.  Dr. Shannon Westin: This was a huge collaborative effort both with the GOG Foundation, the Gynecologic Oncology Group Foundation, as well as ENGOT, which is our European colleagues that do amazing clinical trials. But in addition to that, we really worked very closely with our industry partner to really make sure we spanned the globe. And so we had groups from all over the world that participated and really were exceptional. The care that was taken and the hard work that went into this type of study across the world really can't be overstated. We were very lucky to have a wonderful infrastructure group. We met weekly for a long time, just keeping an eye on the data and making sure that everything was as positive as possible and, of course, that we were watching the outcomes of the patients very closely and making sure that there was no evidence of harm or issue. And so it really did take a village, truly, to run this study and to ensure that at the end of it, we got really great data that we can trust. Dr. Lidia Schapira: So tell us the results. Dr. Shannon Westin: So DUO-E was positive for both of its primary endpoints, which was very thrilling. So for the first analysis, which is the durva-alone arm to control, we saw a reduction in the risk of progression of 29%, so a hazard ratio of 0.71. And then the addition of olaparib seemed to further enhance this benefit, so a 45% reduction in the risk of progression for a hazard ratio of 0.55. But what's really exciting is our follow-up time was pretty long; it was about 17 months, so we were able to look at a couple of different analyses, including an 18-month landmark analysis where we saw approximately 50% of the patients were still alive progression free at 18 months, as compared to only 21% of patients being alive progression free in the control arm. So there was a doubling in that progression-free survival time point at 18 months, which is thrilling. Dr. Lidia Schapira: So Ramez, as an expert in the field, what was your reaction when you read or heard these results?  Dr. Ramez Eskander: It's exciting, honestly. So we have gone a long time without seeing really significant successes in the endometrial cancer space, a testament to the fact that we hadn't yet developed our understanding of how we could move this needle forward. But Dr. Westin and the DUO-E team conducted an exceptional clinical trial, as you mentioned, international study, rational and important hypothesis to adjudicate. And what we saw here was both now we had other studies—the RUBY trial, the GY018 trial, the  AtTEnd—and now here DUO-E, which added this hypothesis of PARP maintenance in addition to checkpoint to try to augment response and consistent, really provocative data, exciting, in line with what we've seen and hopefully will continue to drive the science in this space, most importantly. Dr. Lidia Schapira: So let me ask you a follow-up question to that. What kind of scientific questions are in the air now as a result of this trial and what the trial found? Dr. Ramez Eskander: Oh, goodness. Shannon and I could both take this, I'm sure. But I think in the dMMR population, we recognize that there's a ton of data that is supportive of the fact that these tumors are immune responsive, particularly in dMMR endometrial cancer, whether it's an epigenetic promoter hypermethylation, or a mismatch repair gene mutation. I think the data has emerged that immunotherapy is here to stay for these patients in the newly diagnosed advanced stage, even chemo naïve, who need adjuvant therapy.   The pMMR population, this is where we're seeing more and more questions emerge because we realize that that may be a cohort of different cancers. And I'll let Shannon speak to this briefly, but even the incorporation of the PARP inhibitor, in addition to the checkpoint, there's a biologic rationale for combining those two together to augment response. And to see the benefit in that trial—arm three and arm two, we can look at descriptively and look at the differences, but who are those patients? Where is the PARP and the checkpoint most effective? How do we expand that to a larger population of patients potentially? These are questions that emerged because, as Dr. Weston will allude to, I know we also talk about HRR mutations, which are captured, but we even have a lot to understand about that in endometrial cancer, where we've had more research in the ovarian cancer space. Dr. Shannon Westin: Being mindful of time, because I have, like, 1,000 hypotheses that have been generated by this study, which, I think, shows it's a great study, right? Because you get some answers, and as our colleague Brad Monk says, “The only definitive study is the negative studies.” This most certainly was not that. But just kind of expanding on what Ramez said, the interesting thing about DUO-E is that really the biggest benefit for the combination of the durvalumab and olaparib was in that mismatch repair proficient group. And I personally thought that we were going to see accentuation of the impact in the mismatch repair deficient group based on the science, but that just wasn't borne out by the data. It doesn't seem that the combination has that much to add in that mismatch repair deficient group. And when we tease out the mismatch repair proficient group, I think that's where a lot of interesting information is going to come because, to Ramez's point, we're going to tease out: Is it driven by the P53-mutant population? Is it driven by the population that has homologous recombination deficiency? How do we even measure homologous recombination deficiency in endometrial cancer? So I'm super excited about what we found and how that may help us to make those decisions for the patient in front of us.  The other thing I think needs to be made mention of—and this was something we saw in DUO-E as well as AtTEnd—we had a large population of patients that were recruited in Asia, 30%. Interestingly, when we look at the forest plot, that group doesn't seem to benefit as much from the addition of the olaparib. So we really need to tease out what's different about that population because what Nicoletta Colombo presented around AtTEnd, it looked like they didn't benefit from the atezolizumab either in that study. So there's clearly something different about that population, and we have a really big opportunity to look at that since we had such a large proportion of patients that were enrolled there. So that's another, I think, really intriguing question. Dr. Lidia Schapira: So how does this fit in the context of endometrial cancer treatment, and what are we going to do with patients in the clinic? I'd love to hear both of your perspectives, starting with you, Ramez. Dr. Ramez Eskander: It's an evolving answer, to say the least. What we can say definitively is that we have a United States FDA approval for the regimen of dostarlimab plus carboplatin and paclitaxel in the mismatch repair deficient, advanced-stage/recurrent or metastatic patient cohort. And again, that's because the magnitude of benefit that we saw in the RUBY trial, which looked at that, was actually analogous to what we saw in 018, AtTEnd, and DUO-E, again, consistently highlighting the benefit of the IO and the dMMR. We have yet to see how this is going to evolve the landscape in the larger patient population, which is the pMMR patient population. And it may be that based on the data that we have, we will see immunotherapy plus carboplatin and paclitaxel as the new standard of care in the pMMR cohort, or it may not. That's yet to be defined. And I think Dr. Westin will add to this, but I think that's also going to depend on the perception of how we view the cohort. Is it one group of patients? Are we going to have to think about subsets within the pMMR population? That is an active conversation. Dr. Shannon Westin: I would just add, having treated patients on this combo regimen with the durvalumab and olaparib, I have multiple patients that still remain on study, and this—we're looking at three and four years out. I just never saw anything like that before with standard chemotherapy, so there's definitely something here. So I want to know who those patients are, who benefits really the best from the combination, and who could we just give the immunotherapy to and get that same benefit. So we obviously always want people to live as long as possible. That's the bottom line. But we don't want to overtreat. And so I think balancing that is really important. Dr. Ramez Eskander: The point that was made earlier: We have yet, aside from MMR response to checkpoint, within the pMMR population, we understand that there may be subsets, but we have yet to prospectively validate that these molecular cohorts within the pMMR population are truly defining response to a particular therapeutic strategy. So we have to be cautious not to limit the treatment opportunities for these patients without having the data that we need to do so because, as Dr. Westin mentioned, for us—whether it was the Gy018 trial, the RUBY, the DUO-E trial—what we saw is there are pMMR patients who have a dramatic response even though they are “biomarker negative.” They're pMMR, they're TMB low, they're not POLE mutated, but yet they still derive a dramatic benefit. And so that goes back to the hypothesis about why we're even combining checkpoint with chemotherapy in which, for example, in lung cancer, there's been established success and approval. So I think we're all eager to see these strategies emerge as treatment opportunities for the pMMR patients as we work to still develop additional effective opportunities. Dr. Lidia Schapira: So, based on all of this and sort of the new twists on the scientific hypotheses that are now generated, what are the next steps? Dr. Shannon Westin: Well, I think we have to see if these drugs are available for patients. So looking at things like compendium listing and regulatory approvals obviously is going to be very important. But from the things that I can control, we are looking at the different molecular subtypes and understanding the different mutation status and trying to tease out who may be driving the biggest benefits so that we can help advise and make sure that we're doing the right thing for the patients. Dr. Lidia Schapira: And wearing my supportive care hat, I have to ask you, Shannon, about the tolerability. We often find that the quality of life and studies come out after, sometimes months or years after, the original trials are published. So let me take this opportunity to ask you now: How did women tolerate these drugs? Dr. Shannon Westin: The bottom line, Lidia, is, as expected, when you add additional drugs, you see additional side-effects. I think the good thing is that we're very comfortable with immunotherapy and we're very comfortable with PARP inhibition in gynecology because we have had access to these agents and so we know how to manage the toxicities. And so, from a standpoint of incidence, there was a higher incidence of grade three and higher adverse events in the group that had durvalumab/olaparib. But this was primarily driven by anemia, which is as expected and is usually pretty time-limited at the start of olaparib. From a long-term standpoint, there was a slightly higher proportion of patients that discontinued therapy, but it actually wasn't as much as I was worried about. So we saw a 19% discontinuation rate in the group that was just the control arm, and that went up to 24% in the dual arm, so definitely higher, but not that much higher. And when we moved to maintenance, which is really where—that's where the arm becomes unique, it was much lower at about 12%. And so that's exciting to me, that patients were able to stay on a drug and were able to tolerate it.  And then, to your other point, we do have a very nice patient-reported outcomes plan, and that is actually being analyzed as we speak with the hope of presenting it at the next major meeting, our Society of GYN Oncology meeting in March. So not right away, but I think in a pretty timely fashion, we'll have those data. Dr. Lidia Schapira: Congratulations, Shannon, on leading and presenting this wonderful study. So it's been a real pleasure to chat with the two of you. Dr. Ramez Eskander: Thank you. Dr. Shannon Westin: Thanks so much, Lidia. I really appreciate it. Thanks, Ramez, for being here.  And I will just say thank you to all of our listeners. We really hope you enjoyed this episode of JCO After Hours, where we discussed the DUO-E trial, which is a phase III trial evaluating durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer. And again, please do enjoy this publication that was online at the Journal of Clinical Oncology on October 21st, 2023. And do check out our other podcast offerings wherever you get your podcasts. Have a wonderful day. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

In this JCO Article Insights episode, Davide Soldato interviews Dr. Jacob Sands, medical oncologist at Dana Farber Cancer Institute (Boston, MA) and Assistant Professor at Harvard Medical School, on their paper “First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01”. The interview offers a deep dive into the safety and efficacy data of this novel drug and puts these data in the context of the current treatment landscape of NSCLC and of the revolution that ADC are bringing into the oncology world. TRANSCRIPT Davide Soldato: Welcome to this JCO Article Insights episode for the October issue of Journal of Clinical Oncology. This is Davide Soldato, and today I will have the pleasure of interviewing Dr. Jacob Sands, co-author of the manuscript titled, “First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01.” Dr. Sands is a Medical Oncologist working at Dana-Farber Cancer Institute in Boston and Assistant Professor at Harvard Medical School. His main field of research and clinical interests revolve around improving screening and diagnosis of lung cancer and also on developing novel therapeutic agents for this disease.  So, welcome Dr. Sans, and thank you very much for accepting our invitation today.  Dr. Jacob Sands: Happy to join. Thanks for having me. Davide Soldato: I just wanted to start with a very general question because I think that we are going to discuss a very important study and the manuscript that you co-authored is going to look at the safety and the efficacy of this novel ADC datopotamab-deruxtecan that is targeting TROP2. But I just wanted to have a little bit of context before starting to discuss the safety and efficacy data. So the population that was included in the study included more or less 60% of patients that received three or more lines of therapy and also 20% of patients who received five or more lines of therapy. So I think that this is a very particular population, especially considering that we are speaking about non-small cell lung cancer. And so I wanted to get from you like a general context, like what are the therapeutic options for these patients normally in clinical practice and what do we expect in terms of outcomes and in terms of toxicity? Dr. Jacob Sands: Yeah, so as you point out, this is a highly pretreated population in general, which is to say that they've really gotten the most effective lines of treatment up to this point. Now, we certainly do see some efficacy from some of the later lines of therapies in some patients, but inherently there is a decreasing response rate and decreasing durability of these responses as patients get further along in their treatment courses as far as lines of therapy. So it's generally considered to be a challenging clinical scenario, which is part of what makes the data that we're going to discuss, I think, so meaningful.  Davide Soldato: Yeah, I think that especially if we look at the population that was included first, I think that the very particular thing is that included both oncogene-addicted and non-oncogenic addicted patients, and also the great majority of these patients received the most effective treatments that are available because they all received more or less immunotherapy and platinum-based chemotherapy, if I'm not mistaken. Dr. Jacob Sands: That's right. And that's an important distinction that you're drawing in the patients with oncogenic drivers and, of course, there's plenty of data with this compound with Dato-DXD in that population as well. But broadly speaking, in the non-oncogenic actionable alterations where they've gotten chemo-immunotherapy, those really are the most meaningful. Of course, docetaxel has been a long-standing second line that I'd say there is less and less enthusiasm about that as a line of treatment as we've seen some of these other more novel therapies that have just a better toxicity profile in particular, but also some with really durability that we don't quite see with docetaxel as well. And so once you're getting past that, you're really now reaching a bit deeper to then have something that is well tolerated and has efficacy. That's a setting where we really need it even more.  Davide Soldato: So, going back to the results of the study, as we kind of pointed out, this was a very standard classic with a Bayesian design, phase I dose escalation and dose expansion study of this novel ADC datopotamab-deruxtecan. So I just wanted to go over with you and to provide our listeners a little bit with some data regarding the doses that were explored and then what were the doses that were selected for the expansion. And also to discuss a little bit the safety data. We were discussing the tradeoff between risk and benefit, especially in patients that are very pretreated, searching for these kind of sweet spots between the toxicity and the efficacy. So I just wanted to put in context a little bit the data that you reported in the manuscript. Dr. Jacob Sands: Yeah, that's right. So, like phase I’s go, we started with a low dose at 0.27 milligrams per kilogram, and dose escalations occurred up to 10 milligrams per kilogram. The 10 milligram per kilogram dose did have toxicities that really made it not considered to be tolerable, and that mostly being mucositis and skin. And so it was then back down to 8 milligrams per kilogram. And then there was a dose expansion at 4, 6, and 8 milligrams per kilogram. The 4 and 6 milligram per kilogram doses had 50 patients enrolled within those cohorts and 80 patients within the 8 milligram per kilogram cohort to then get much more data, of course, for efficacy and tolerability within those levels. Ultimately, each of them really demonstrated some efficacy as well as general tolerability. The 6 milligram per kilogram dose was really the one selected overall for further testing and future trials based upon the data out of this one that we're going to discuss further. Davide Soldato: What were the main side effects that you observed in the trial? And particularly, do you think that there is some kind of special toxicity that should be looked at when using this novel type of ADC? Dr. Jacob Sands: Certainly there are some novel toxicities to really pay attention to. And maybe I'll just point out before diving into the toxicities, that this is in many ways chemotherapy. The antibody drug conjugates, as listeners probably know, are an antibody that has a linker bound to chemotherapy, what's called the payload. And in this case, it's a topoisomerase I inhibitor with the antibody, the TROP2. So the cells on the surface, when there's TROP2 expression, the drug binds to that, gets pulled into the cell and releases that chemotherapy intracellular, but it is still chemotherapy. And so some of the toxicities are things that we commonly see with chemotherapy drugs. Although, broadly speaking, I would say we're able to deliver higher doses of that chemo to the cells in this kind of targeted dosing of chemotherapy to give the chemo intracellular.   Now, that being said, some of the toxicities that we see from this drug in particular that are a bit different is the stomatitis, mucositis. That is something that has occurred. Now, I've found that if it's really severe, then with a dose reduction that has really substantially improved any toxicities with future dosing. And at a 6 milligram per kilogram dose, a dose reduction to 4 milligram per kilogram is still within a dose range where we saw plenty of efficacy within the trial that we're discussing. That being said, if one can help patients tolerate it better, if it's more mild symptoms, if it's not severe, then that's better in maintaining that dose. And interesting things like ice chips at the time of infusion, so cold within the mouth, kind of like the cold caps to try to reduce alopecia at the time of infusion of the chemo may help some steroid rinses also can be helpful. But really these are things to help prevent stomatitis from being severe. It's harder when that occurs, then the treatment for improving it is a bit different.   We do know, though, that that does improve with time. So even when it was severe with that infusion, it does improve as patients get further out from those doses. Of course, another one is dry eyes or irritation within the eyes. And if that is severe, then or even mild actually, I'd say when there's any known toxicity like this is to involve ophthalmology. Now, within this trial, ophthalmology was involved and patients had to get a baseline eye exam and they would get checked at different time points throughout the course of the trial. And so they were being monitored. I did not have anyone who needed to stop the drug because of this. The patient I had with the longest standing response to therapy did have some dry eye. It was not bothering him so much. And he had this real aversion to using eyedrops. It was very hard for him to make himself use these. But when I told him, “Look, if this gets worse, you might have to come off the trial, that it might not be our decision just by the way the trial describes it, if this gets worse.” And so for him, the fear of having to come off the drug was really the thing that helped him to then start using his eyedrops, which really helped to control that a bit more. And so that is something to monitor for.  But the biggest thing really is interstitial lung disease. This is something that is a complex topic, I think because it's something that we need to be very aware of and monitor for. At the same time, a diagnosis of interstitial lung disease can be challenging. There really were not cases where we had pathologic confirmation of this diagnosis. These are clinical diagnoses in the cases on this. Now there was an adjudication committee that would review all of the data and come to a determination of whether this looked like drug related ILD or not. But for clinicians, when you see a patient whose scan shows some inflammatory markings or inflammatory appearing markings on a scan, we see that all the time with other drugs too. And so determining what is potentially incidental versus drug related, I think in most cases on a trial when we're unsure, we lean toward drug related. And in some cases there are reported out severe cases of drug related ILD.  I think the really difficult thing that I'd want people to take away from all of this, though, the bottom line is, yes, we need to be very aware of the potential for drug related ILD while at the same time, we need to not reflex, just call things drug related ILD and really make sure that we're doing a workup when feasible rather than just that bottom line conclusion. We see it at a rate related to the drug, and I do think it's real. But we also need to, when treating individuals, try to identify any other potential etiology. I did have one patient that really looked absolutely classic for this diffuse drug related ILD that ended up ultimately really being what looked more like tumor progression in just a radiographic pattern that looked more like an inflammatory process than it did the way we would typically see cancer progression. And so this has really, for me, I think, highlighted this as a topic where I'm diving a bit more into that description.  Davide Soldato: And I also think that in the population of lung cancer patients, as you were saying, this is even more complicated because frequently these are patients who had a history of smoking, who can have concomitant infections where progression is easier in the lung. If I think, for example, other ADC that have already been tested, for example, in breast cancer, it might be far easier to detect and to adjudicate an ILD to the drug that we are using compared to what could be, for example, for lung cancer patients.  So if I understood correctly, the toxicity that in your opinion as a clinician, they are more complicated to treat, let's say on a more daily basis, are more stomatitis and inflammation, but maybe the one that you experience as potentially more severe are always related to lung toxicity.  Dr. Jacob Sands: Well, I think the scary thing about the ILD is that we have higher grades of ILD, and this is a toxicity that then can become life threatening. When we see a grade I or a grade II ILD reported in numbers, where we see, okay, this looks like it's really happening, and then see some really higher grade toxicities, I think the concern amongst clinicians then is if they're seeing lower grade, which of those can potentially progress to those higher grade, which then becomes life threatening toxicities. Whereas dry eyes certainly can become a nuisance, we didn't see any blindness or something like this, and the stomatitis resolves as you hold the drug, and in some cases, really before the next cycle even comes, it's just more a matter of controlling the discomfort, which can be severe. I'm not minimizing that. I think that's why ILD stands out so much, is that that becomes a potentially life threatening thing.  And to your point exactly, these patients with a smoking history on other drugs, we see these inflammatory findings. Now, in some cases, we know it can be from the drug. In other cases, we see it and know that it's essentially incidental. And I'll say to patients, “Hey, we see this. It's something we'll monitor on future scans, and these can wax and wane.” When you have a patient on a drug with a high attention towards something like ILD, there can be- what I'm cautioning against is a reflex attribution to that drug. In all cases. I'd urge clinicians to individually assess each of these patients to get a sense of whether they think that that's going on for that person, knowing that it's often not possible to say with 100% certainty in any of these cases. But we often see waxing and waning inflammatory findings. And in many of these patients with heavier smoking histories, in particular, there can be waxing and waning respiratory symptoms. So the question is, are there instances where there is what really is an incidental inflammatory findings and incidental respiratory waxing and waning that then suddenly we call a grade II?  At the same time on the other part of that, if there is something that seems like it really may be drug related ILD, is doing that work up and really evaluating and diagnosing that before it progresses to a point that really there are severe symptoms. And it's kind of trying to do both of those things on the opposite ends of the spectrum that I'm speaking toward at the same time. Davide Soldato: Just on a personal note, do you think that, as we continue the development of these drugs that are associated potentially with lung toxicity, do you think that we also need to pay attention to the drugs that were immediately previously received by the patients? What I mean is, do you have the feeling that the previous treatment could potentially impact on the risk of developing this type of toxicity in the lung? Dr. Jacob Sands: I don't know that we yet have data to draw any real conclusions around that. But you raise an important question within this, and what potential toxicities could be related to prior treatments or synergy across those. Of course, we see inflammatory findings within the lungs and pneumonitis with prior immune-related therapies, and that it would be a good prompt to the question you're asking. And that in particular, we also see this in some of the targeted treatments, although not nearly to the same percentages. I don't know that we can draw conclusions from this. I would speculate that the mechanisms of action of each of these drugs are so different that I would not hypothesize real synergy in those toxicities. But it is certainly something to be aware of and an important question that you're raising. Davide Soldato: I think that, apart from the safety data that I think we dissected, the other end of the spectrum would be finding a drug that this very pre-treated population could still give us some efficacy data. So you already mentioned that, in the dose expansion cohorts, so 4, 6, and 8 milligrams, we had more or less signals of activity and of efficacy of these novel drugs. So the therapeutic options, as you were mentioning, are potentially docetaxel or other types of mono chemotherapy. But we know that the objective response rate is not that high, and that progression-free survival is not that long with these types of drugs. And potentially the safety profile could also be complicated in patients that are also pre-treated. So I just wanted to discuss a little bit the efficacy data and to see if there is really promise in this type of delivery of chemotherapy as you were saying with the ADC. Dr. Jacob Sands: We saw response rates of about 25% across all three of those cohorts. The manuscript outlines the 4, 6, and 8 milligram cohorts within a chart showing the efficacy outcomes. And really it's around 25% across the three of those, which in this patient population, as we've discussed, heavily pre-treated, to have a response rate of 25% is really quite promising that there really is a substantial treatment effect. On top of that, we also see a duration of response of really around 10 months. So, in the patients that are having a response, there really is some durability. Now, it's tragic that 10 months is considered durable within this population and it really highlights the ongoing need for further drug development because I don't think anyone would say that 10 months is enough, we need dramatically better. But within the context of what we currently have, a 10-month duration of response is really quite meaningful and a response rate of 25%.  Now, it also describes a disease control rate. And I always have to put a little asterisk to this. I think we see this increasingly - the disease control rate being reported - and it always looks quite a bit better than the response rate. And that's essentially incorporating stable disease. And although I would never claim that everybody with stable disease is truly benefiting from a drug, across all of the studies where this is reported out, there is a spider plot which really highlights a number of patients that are not considered responders, but with responses, a handful of them beyond six months of disease control, even though they're not considered responders, and one of them beyond a year with still ongoing disease control. So, even within that stable disease group, I'd say there are some who are really clinically benefiting from the drug, which is to say that really, even beyond the 25% response rate, we are seeing some others that are truly benefiting from this.  Davide Soldato: Yes, and I also think that for these patients, especially when they can develop very rapidly symptoms that can potentially also impact quality of life, having a drug that achieves this level of stability - with maybe no deterioration in clinical symptoms - I think that it's still probably a very meaningful objective to obtain for this type of population. Of course, I think that with future studies we will also have probably health-related quality of life data that will tell us more about the impact of this type of drug in this setting. But I still think that this could be potentially a relevant endpoint, even if we don't achieve what we officially consider as a response as per resistor criteria.  So I think that we have talked a little bit about the efficacy data. So, we are kind of entering a novel area where more and more ADCs are being tested, are being included in clinical practice. For example, if I think about breast cancer, we already have two that are approved that can be used, the same in bladder cancer. So, as you participated in this phase one trial, I just wanted to have your opinion: if you think that, in the future, we are going to evolve completely towards this type of delivery of chemotherapy, using what we call now "smart drugs" in terms of delivery of these cytotoxic agents. Dr. Jacob Sands: It'll be interesting to see. We certainly will see other generations of ADCs. I mean, I think we're really just at the beginning with this technology. We certainly have now a very solid foundation to build upon, where we have effective targets and effective payloads. We've highlighted some of the toxicities we're seeing from that. Also, I'd highlight within this drug with TROP2, the amount of expression has not seemed to really be a driver in this. And some of that may be the bystander effect, which I'd call a real benefit of the drug, where the payload as a drug goes through apoptosis and lysis, that payload that releases then into the surrounding- toward the surrounding cells is membrane permeable and crosses into other cells, leading to potentially more efficacy. That technology in itself, I'd say, is something that we may see incorporated further into next generations of ADCs. Whether there can be improvements in preventing toxic drug in other sites like the stomatitis, for example, with newer generations that evolve from this, we'll see.  I don't know that I would anticipate all chemotherapy ultimately going through ADC technology, but I certainly believe that this is the beginning of what I would call a whole new class. But would future cytotoxic treatment happen more so through ADC than just broad circulating payloads? If we can call it that. And I certainly think we'll see a lot more development like that. But you know, we may see other ways of developing the cytotoxic drugs in other forms of delivery as well. It'll be exciting to see as we go forward. Davide Soldato: I also think that one of the major challenges that we probably will have to deal with, in probably not so long, is also the sequencing of these types of agents. We are starting to have, as I was saying, accumulating data regarding the efficacy of these drugs. And some of them share either the same payload or they target the same antigen on the cell. And so, do you think that we will need as a new line of research to really go into the field of cross resistance when we are using and trying to sequence these types of novel agents?  Dr. Jacob Sands: We're seeing that across various tumor types. I mean, to stick with lung in particular and small cell lung cancer, we've seen DLL 3 really be a demonstrated target for small cell lung cancer. And now we have a handful of drugs being developed that target DLL 3. How would we potentially utilize those drugs? In what orders and which ones over others is going to be an area for discussion, much like the area you're raising here, where we see TROP2 directed treatments. And so which one would you choose? On top of the fact that there are other targets, in this case, we're talking about TROP2, but of course, there's HER3 that we've seen, and especially when we're talking about an EGFR population, EGFR mutation population, we've seen good efficacy with this TROP2 antibody drug conjugate, as well as the HER3. And so how would we order those? And they both are using the same payload.   If we're talking about both of the deruxtecan compounds, this is going to take some sorting out. I think with time, it'll be tough. I don't know if we'll end up seeing head to head studies in this or if this is going to end up being shaped more by expert committees and their descriptions. But I imagine we'll see some heterogeneity in the treatment pathways at different centers just based upon preferences and familiarity with these different drugs. Of course, assuming that they all end up ultimately being approved and then that efficacy and tolerability that we're seeing continues to pan out in future trials. Davide Soldato: So we were mentioning before that there is a very big line of development for this novel ADC. And I think that there are also some trials that are exploring the role of data DXD so the datopotamab-deruxtecan in lines where patients have received less therapy or in combination with other agents. So I wanted to ask you if you could give us some insights regarding the ongoing trials, if you know about them. And also what do you think could be the area of a met need where this drug could potentially give the most effect? Dr. Jacob Sands: It'll be interesting to see. In the first line setting we have TROPION-Lung07 and TROPION-Lung08. These are studies with PDL-1 expression of less than 50% or greater than or equal to 50%, the greater than equal to 50% being plus pembrolizumab versus pembrolizumab alone. The less than 50% essentially being an incorporation with or instead of chemotherapy along with the platinum-based therapy plus pembro. And so that one is a more complicated three-arm study. Now, essentially what this is looking at is incorporating this antibody drug conjugate in place of chemotherapy for potential tolerability when given concurrently with the platinum and pembro. Whether or not we'll see some synergy with the chemo and the pembro, I guess I would hypothesize that we would likely see at least similar to when giving the chemotherapy, or at least that's the hypothesis driving the trial design.   If anything, whether we note improved tolerability relative to those getting, I'd say the carboplatin component, because certainly within non-squamous, non-small cell, pemetrexed is generally very well tolerated. And so that's a bit tougher to beat out from a toxicity standpoint. The trials are really designed based upon the efficacy that we've seen from this trial you're pointing out. I think by the time that this podcast is heard, we'll have the data from TROPION-Lung01 that'll be reported out as well in the second line setting versus docetaxel as that data is near release. These are areas for ongoing attention, certainly. Davide Soldato: Thank you, Dr. Sands, for being with us today. This concludes our episode of JCO Article Insights. We discussed with Dr. Sands the results of the manuscript titled, “First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01.”  This is Davide Soldato. Thank you for your attention and stay tuned for the next episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Shannon Westin, Dr. Stephanie Wheeler, and Dr. Caitlin Biddell discuss the paper "Economic Evaluation of a Non-Medical Financial Assistance Program on Missed Treatment Appointments Among Adults With Cancer," a simultaneous publication, podcast, and presentation at the ASCO Quality Care Symposium.

Shannon Westin speaks with Holly Prigerson and Alfred Neugut about their thought-provoking editorial, "You Get (Offered) What You (Can) Pay For: Explaining Disparities in End-of-Life Cancer Care."  

A variety of perspectives are explored as Dr. Westin speaks with Dr. Jennifer Mack, Dr. Chun Chao, and Mallory Casperson about end-of-life care planning in adolescent and young adult cancer. TRANSCRIPT The guest on this podcast episode has no disclosures to declare.  Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get down and dirty with manuscripts that are being published in the Journal Clinical Oncology. And I am your host, Shannon Westin, GYN Oncologist and Social Media Editor of the Journal of Clinical Oncology. I am so very excited to have a number of guests with us today to discuss a very important paper entitled “Discussions About Goals of Care and Advanced Care Planning Among Adolescents and Young Adults with Cancer Approaching the End of Life.”  And I'm joined by several of the authors of this important paper. The first is Dr. Jennifer Mack. She is the Associate Chief in the Division of Population Sciences, an Associate Professor at Harvard Medical School and Senior Physician in Pediatric Hematology Oncology at the Dana-Farber Cancer Institute. Welcome, Dr. Mack. Dr. Jennifer Mack: Thank you. Dr. Shannon Westin: We also have Mallory Casperson. She is the cofounder and CEO of the Cactus Cancer Society. They provide online support programs and resources to young adult cancer survivors and caregivers in the comfort of their own homes. Welcome.   Mallory Casperson: Thanks for having me. Dr. Shannon Westin: And then, finally, last but not least, Dr. Chun Chao. She is a Senior Research Scientist in the Division of Epidemiologic Research in the Department of Research and Evaluation at Kaiser Permanente Southern California. Welcome.  Dr. Chun Chao: Thank you. It's a pleasure being here. Dr. Shannon Westin: So I want to get right into this. I think that there certainly has been a lot of discussion, at least at our institution as well as at the ASCO level, around advanced care planning across all patients with cancer and anyone with a diagnosis of cancer. And I would love to just start and level set and make sure all of our listeners are all on the same baseline around the incidence and prevalence of cancer in adolescents and young adults. Like, first, define what are the age groups that we're looking at here? How common is cancer in this population? Dr. Jennifer Mack: Right. For this study, we defined adolescents and young adults as individuals aged 12 to 39. And right now, about 90,000 adolescents and young adults are diagnosed with cancer in the United States each year. Those numbers are also rising, so more and more are diagnosed each year, and because of that, we think it's increasingly important to pay attention to the needs of this population. This population really experiences a whole range of different cancer types, some of which are more common in children, some of which are more common in adults, but the most common ones include breast and gastrointestinal cancers, sarcomas, germ cell tumors, leukemias, lymphomas, and brain tumors. Dr. Shannon Westin: And your manuscript notes that adolescents and young adults seem to receive medically intensive measures at the end of life. Now, how common is this across this group? And do you all have a sense of some of the reasons that we see this increased use of these measures? Dr. Jennifer Mack: That's a great question. We and others—actually, the early work that led to this study was done with Chun. We had previously found that most adolescents and young adults receive at least some kind of medically intensive care at the end of life. And that includes things like being hospitalized, being in the intensive care unit, receiving chemotherapy, and spending time in the emergency room near the end of life. And so, if you take all of those together, about two-thirds of adolescents and young adults receive at least one of these near the end of life.  And we don't know the reasons for this. There are probably complex reasons. Some adolescents and young adults may actually want to receive these kinds of measures, maybe because they're young and they want to do everything they can to live as long as they can. And some patients in this age group are parents to young children, and they may be making choices to prolong life and be there for their kids. But we also know that if we look at older adults, most people who know they're dying don't want to receive this type of care, which is also associated with more suffering and with poorer quality of life. So it's also possible they're making these choices because they don't fully recognize they're approaching the end of life or because they haven't had opportunity to plan for this time through conversations with their medical teams. Mallory Casperson: I think the conjecture, too, that a young adult is likely to focus on extending life, even in a situation where palliation is the stated goal, is a really great conjecture. This population is really burdened by these unique psychosocial issues that are driven by the extreme disruptions that cancer has on major life milestones. Like Jenny said, they may have young children at home, they may have a new spouse at home, still be trying to advance at work, you name it. So this period of young adulthood is really characterized by constant change. And it's possible that these young adults are being driven to stay present in their lives for really as long as possible to reach some of these goals or even just to support their young families as they reach their own goals. Dr. Shannon Westin: I really appreciate that context, and I'm going to always bring it back to what I know as a provider of gynecologic cancer care, where we see quite a bit of young people at the beginning of their life, at the beginning of their fertility. And I think it is so important to keep that context in mind as we're designing interventions and studies and things like that. So I really appreciate that, having the ability to kind of see from that standpoint. So I think you guys have convinced me this is important. We know the reasons. So why don't we just lay out the objectives of this particular study and give our listeners a brief review of how it was designed? Dr. Jennifer Mack: Great. We wanted to know how often adolescent and young adult patients with incurable cancer have discussions about prognosis and end-of-life care planning before they die. And a secondary goal was to understand whether having earlier discussions would change the type of care that's delivered. So, for example, having those discussions about goals of care earlier in their illness, could that make them less likely to receive intensive measures?  So, to do the study, we conducted a retrospective review of health records for nearly 2,000 adolescents and young adults who died between 2005 and 2019 after receiving care in one of three centers—the Dana-Farber Cancer Institute, Kaiser Permanente Southern California, Kaiser Permanente Northern California—and looked for documentation of discussions about care planning. For this study, we focused on patients who either had stage IV disease at diagnosis or who had experienced a recurrence because we wanted to ensure that we had a population of young people who were living with advanced disease and not people who might have died suddenly and unexpectedly during treatment, because they might not have had the same opportunity for end-of-life care planning. So we really wanted to focus on those who had the poorest prognoses. Dr. Shannon Westin: It's a really large group of people and, I think, hopefully fairly representative. I guess my question is, when you're looking at the group that you were able to kind of pull from in this retrospective database, which I think can sometimes be limited, do you feel like it was fairly representative of the population that's out kind of across the States, let's say? Dr. Chun Chao: So I think it's a real strength that we included two different care settings in this study, so a tertiary cancer center and community-based cancer care. Therefore, patients who seek care in each of these settings are representative in our study. I think this design really increased the generalizability of our findings. And on a further note, in this study, we actually observed very similar care patterns across all three study settings. So that was quite reassuring. Dr. Shannon Westin: So reassuring. And I think it brings up a point that I wanted to make, and I also agree was a strength of your study, is having that across the academic center and then a large integrated health plan. And I guess I'm just curious how your collaboration came to be to kind of come across different groups and, of course, the inclusion of Mallory from the patient advocate side. I think this is a testament to your powers of collaboration. I'd just be interested in how that kind of came to be. Dr. Chun Chao: So this goes back to almost 10 years ago. I think, at that time, people started to really recognize that adolescent and young adults with cancer were a very understudied group, but they are also very challenging to study. So, for example, AYA cancers, adolescent and young adult cancers, are fortunately not very common. Although the number is increasing, you do need a large population base to study them. So, at that time, researchers at Integrated Health Systems started to really see that we had an opportunity here to really contribute to this knowledge gap, leveraging the resources that we had at these health systems, especially the ones that have a very large membership and a long-term retention of these members and also a comprehensive electronic medical record system.  At that time, my colleague and I published a study that demonstrated the feasibility of using these resources to do follow-up studies of long-term health outcomes of AYAs with cancer. And I think that we might have attracted people's attention to utilizing the resources at these health systems to do such studies. So Jenny was the one who really saw the need or the lack of data or the need of high-quality data to really improve care for our AYAs who are at that end-of-life stage. So she reached out to a research network called the Cancer Research Network, who I think that the people there connected Jenny with me because I was also starting to work on long-term health outcomes of AYA cancer survivors, adolescent and young adults. After we talked, we were like, “We have to get this funded. We have to get these questions answered. These questions are so important.” So, as Jenny mentioned, we did a pilot study that really showed there is a lot of burden of medical intensive care at the end of life for our young patients. And, as often is true with research, this opens up a lot more additional questions that we needed answers for. So we have been working together since then.  Mallory Casperson: I came into this group sort of by accident. My background is in engineering. I was about halfway through a PhD when I needed to leave a couple years outside of my first cancer diagnosis. And I was at ASCO staffing a booth for my organization and just happened to meet a researcher from Kaiser Permanente Northern California, and the rest is history. That introduction sort of got me into this world, and, once you know one person, you get to meet others. And it's just been a really, really wonderful opportunity to help, I think, insert the patient voice. But also, for me, I just love research and data. And so getting to help advance the conversations happening around adolescent and young adult care in this research setting and in these settings where we are getting to look at very large datasets has just been really, really wonderful. Dr. Shannon Westin: These are my favorite parts of these podcasts, these stories of how things kind of came to be. And, at the risk of taking too much time there, I love the story, and I'm so in awe of you guys.  I guess, let's get to the bottom line. What did you guys find? Did you find what you expected in regards to advanced care planning and goals of care in this population? Dr. Jennifer Mack: So we felt that most patients had documented discussions about prognosis, about goals of care, about palliative care, hospice, and their preferred location of death before they died. Dr. Shannon Westin: So I was actually kind of impressed at that. It seemed like a lot. I was expecting—I don’t know what I was expecting, but I think I was expecting less documented discussions because, in my own practice, I don't necessarily think I do a great job of this. So was that in line? Were you expecting to see such kind of high levels of documentation? Dr. Jennifer Mack: I really agree with you. I was impressed with the fact that most patients had these discussions. Many of them had more than one discussion about their goals of care. So their providers were going back and having follow-up discussions, making sure that their goals of care were the same and weren't changing over time. So I agree. I was pleasantly surprised with how often these were happening.   I would say I'd love to see these discussions either happening with everyone or at least offered to all patients so that they can say whether they want to have them or not. So, in this study, 17% of patients never had a discussion about goals of care. And non-white and Hispanic patients had lower rates of discussions than white patients. So there are some potentially important gaps here that need attention. But I also think you're right; there's a lot of good news here. Clinicians are making consistent efforts to talk with patients about their wishes for care, and then they're documenting them, which is an important thing because it allows those wishes to be known by everybody on the care team and helps to ensure that they're going to be carried out. Dr. Shannon Westin: I was also intrigued by the finding of the younger patients having earlier discussions around advanced care planning and hospice and goals of care. Any thoughts as to why that might be? Again, I felt like it was a little bit opposite of what I was expecting, not having a ton of background in the area.  Dr. Jennifer Mack: I was surprised, too. We had to check the numbers a couple of times just to be sure because it wasn't what I was expecting. And we don't know for sure what the reason for this is, but I think one possibility is that some of these discussions with the youngest patients, or for the youngest patients, are happening with family members, maybe their parents. And it's possible that clinicians are a little more comfortable or more likely to talk with parents than with the young patients themselves. And so that could actually increase rates of discussions for that group.  One thing we didn't assess was who was there for the discussions. It's not always documented. There's more to learn there about who was there and more about what was discussed. But that was our guess is that these may be family discussions more so than patient discussions. Dr. Shannon Westin: That really makes a lot of sense. And then I guess the next natural question is when we have these earlier goals-of-care discussions or when we have these discussions at all, what did you guys see on the impact of those kind of medical interventions that happened after? Dr. Jennifer Mack: Yeah. We found that when goals-of-care discussions happened earlier, more than a month before death, that adolescents and young adults were less likely to receive some of these intensive measures that we've talked about, so less likely to receive late-life chemotherapy, care in the intensive care unit and emergency room, and less likely to be hospitalized in the last month of life. So, even though these findings were observational, it creates the potential that having discussions earlier can help reduce some of these intensive measures and refocus care on palliation, if that's what patients are looking for. Dr. Shannon Westin: I think that's a really important point because we often bring our own thoughts and beliefs into the care of our patients and think, “Well, I wouldn't want those things.” And I think making sure we know where the patient is—and Mallory, I'd just be interested to get your thoughts here. How do we best approach those things and try to avoid—you know, we want to give advice where advice is needed, and we want to make it clear what the goals or what the potential successes might be. But I'd be really interested to hear your thoughts around framing those discussions and making sure that people understand what can be gained from those types of intensive treatments. Mallory Casperson: Yeah. I think it's important with patients in this situation—and it was discussed in the paper, but the idea of timing, how frequently are we having these care preference types of conversations, and how often are we reframing things with the patient based on how goals might be changing? I think that's a huge piece of the equation because, especially when we're talking about 30 days before death, 60 days before death, things might change quite rapidly from week to week and so having some of those things in mind.  And then it wasn't discussed as much on this paper, but it definitely has been in other work by both of these authors, as well as other just end-of-life research, but this idea of who is in the room for these conversations, I think, is another really important piece of this. Because a caregiver might have different preferences and goals than a patient. If a patient is 15 versus a patient is 25 versus a patient is 39 is also going to change things, and it's going to change the perspective that their caregivers bring to the equation. And so I think who is in the room and how are we doing that very difficult thing of weighing people's opinions in the situation, I think, is very complicated and also very important to figure out. Dr. Shannon Westin: And I think that that leads to my next question: How do we get more of that information? What do you think are the next steps for this particular work? And also, I would just say, how do we guide that? I mean, I struggle with these conversations. It doesn't matter if my patient is 22 or 82. I think trying to meet people where they are is one of the critical pieces. So what's next for this work? How do we help inform these discussions for the caregivers and for their providers? Dr. Jennifer Mack: I think you're right that we do think an important next step is promoting earlier discussions about goals of care and advanced care planning, partly because it gives patients time to reflect on what's important to them, to digest the news, and then make thoughtful decisions that are best for them. But from a research perspective, I think, as we do that, we need to understand more deeply what adolescents and young adults want from these conversations. What topics should be addressed, with whom, and how should they be discussed? And we've also learned from other work, including work that the three of us have done together, that goals of care for adolescents and young adults aren't always as simple as wanting care focused on palliation or prolonging life, this kind of binary thing. Often, there are these other equally important goals, like making sure their loved ones are okay, what's going to help them the most, having opportunities to nurture and deepen their relationships, and finding ways to attain their life goals and meaning while they're living with advanced disease.  So all of these different aspects, which aren't always a typical part of goals-of-care conversations, could be integrated to help support the kind of wider goals that are held by adolescents and young adults with cancer.   Mallory Casperson: I think, too, adding to that, we've talked about how AYA patients' goals of care have changed over time. So I think timing is a thing that could be added into future work, which is a difficult thing, I think, to gather from some of these records sometimes. But also, I think thinking through what these different words mean to different populations and how we're defining them is really important, too. So just an example outside of end-of-life care: When you tell a 30-year-old who's going through cancer that exercise is important during treatment and you talk to a 70-year-old going through cancer that exercise is different, that means different things, and they themselves have different context around what that word means in their normal life. And so I think when we throw out words like “palliation,” “palliative care,” and just general end-of-life conversations, that the same context applies. When an AYA agrees that maybe palliative care is the goal, what does that mean to them, and what are they bringing to the conversation in terms of their younger perspective than an older population that we're potentially more used to working with? So I think framing these ideas and how they might differ between populations is another thing that would serve as future work in this AYA end-of-life care space. Dr. Shannon Westin: Great. Well, thank you all so much. The time just flew by. This was such a great discussion of an incredible topic, and I just want to thank you all again for your hard work in this space.   And thank you to all of our listeners. Again, we were discussing the manuscript “Discussions About Goals of Care and Advanced Care Planning Among Adolescents and Young Adults With Cancer Approaching the End of Life.” And this is published in the JCO, so go check it out. And please do go check out our other podcast offerings and tell us what you think on Twitter. We'll see you next time. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

In this JCO Article Insights episode, Davide Soldato summarized finding from the original article published in the September JCO issue: “Mortality Benefit of a Blood-Based Biomarker Panel for Lung Cancer on the Basis of the Prostate, Lung, Colorectal, and Ovarian Cohort”. The summary provides information regarding the ability of a blood-based panel of 4 biomarkers in improving the identification of individuals at risk of developing lethal lung cancer and potential of combined screening strategies to improve trade-off between potential harms and benefit of the screening process.

Dr. Mahdi Sheikh and Dr. David Zaridze join Dr. Shannon Westin to discuss how quitting smoking after diagnosis may impact survival in kidney cancer. TRANSCRIPT  The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello everyone, and welcome to another episode of JCO After Hours. This is the podcast where we get in-depth on manuscripts that have been published in the Journal of Clinical Oncology. As always, I'm your host, Shannon Westin, Gynecologic Oncologist and Social Media Editor for the JCO. And I am so excited to be here today. We are going to be discussing the paper, “Smoking Cessation After Diagnosis of Kidney Cancer Is Associated With Reduced Risk of Mortality and Cancer Progression: A Prospective Cohort Study,” which was published in the JCO on March 29, 2023. And this very intriguing paper, I have two of the major authors from this paper. First is Mahdi Sheikh, who is a scientist and epidemiologist at the International Agency for Research on Cancer, the World Health Organization in Lyon, France. Welcome, Dr. Sheikh. Dr. Mahdi Sheikh: Thank you very much, Dr. Westin, and thanks for having us. Dr. Shannon Westin: And then with Dr. Sheikh is Dr. David Zaridze. He is the Director of the Department of Clinical Epidemiology at the N.N. Blokhin Russian Cancer Research Center in Moscow and also the President of the Russian Cancer Society. We are with greatness today. Dr. David Zaridze: Thank you. Thank you very much. Nice to be with you. Dr. Shannon Westin: Very nice to be with the two of you. So, let's get started. I first wanted to just level set. Could one of you review just the overall incidence of kidney cancer and what proportion of patients with kidney cancer are known to be smokers at diagnosis? Dr. David Zaridze: The figures I'm going to present are rates. They are adjusted to standard world population. Why am I saying that? Because in America you sometimes use adjustment to the US population. These figures will be different from what you are accustomed to see. Okay, incidence of kidney cancer in Russia, in men, 14.1 per 100,000. I compare this with the United States of America, men, 16.5. Very small difference. Women in Russia, 8 per 100,000. In the United States of America, 8.8 per 100,000 of population. Exactly the same. Very close. These rates are sort of high-ish, but there are very high rates, for example, in the Czech Republic, where rates are more than 20 and other Central European countries. In Russia, kidney cancer mortality in men is 6 per 100,000. In USA, 3 per 100,000. In women in Russia, 1.9. In the United States, 1.3. I would say that there is a difference in mortality in men, not much in women. The incidence of kidney cancer is increasing in Russia sharply, sharply. Since 1990 it has increased - it’s tripled. It increased from 5 per 100,000 in 1990 to 14 per 100,000 in 2019. Mortality is stable or declining. This is suggesting that kidney cancer is overdiagnosed in Russia and probably elsewhere. But this is not a problem of our discussion now. The frequency of the prevalence of smoking in kidney cancer patients. It is estimated that 15% to 20% of patients with kidney cancer smoke. In Russia, we have results only from our study. 18% of patients smoked at admission to our cancer center. Dr. Shannon Westin: Got it. Okay, good. Well, that's really helpful, especially to those of us that don't take care of patients with kidney cancer every day. It helps us just understand. And I guess the next question is what do we know about the impact of tobacco cessation on the risk of kidney cancer? So you were talking about that increasing incidence. How does tobacco cessation impact that? Dr. Mahdi Sheikh: Tobacco smoking is a known risk factor for kidney cancer and an estimated 17% of the kidney cancer burden worldwide can be attributed to tobacco smoking. There is a recent meta-analysis of 56 studies that was published a few years ago that clearly showed a dose-response relationship between smoking and kidney cancer, meaning that the more cigarettes a day you smoke, the risk of kidney cancer will go up. For example, the risk that was shown for five cigarettes per day was 20%. It goes up until 70% for 30 cigarettes per day. And also with a duration, the more years you smoke, the risk for kidney cancer will go higher. However, the good news is that when you quit smoking, there is strong evidence that the risk for developing kidney cancer will be lower compared to if you continue smoking. And there is some evidence that shows again dose-response relationship, meaning that the more years you spend in quitting smoking, the lower your risk would be for developing kidney cancer compared to if you continue smoking. So this is not only about renal cancer or kidney cancer but also true about many other cancer sites as well. Dr. Shannon Westin: Okay, that's super helpful. And then I guess prior to your study that we're about to talk about, did we have any information on what happens when patients quit smoking after their diagnosis? Any limitations to those data that were available? Dr. David Zaridze: You mean the data which was prior our study? You know, the negative effect of smoking after diagnosis has been shown nearly three decades ago. The information exists already for thirty years, but it was largely ignored not only in clinical practice but also in clinical trials. And I have to stress that in clinical trials this information is still ignored. I came across these studies and decided to review them some time ago. All they were case-control studies and to my knowledge, none of them assessed the effect of quitting smoking. I decided to review these studies and included this review in my book, Smoking: A Major Cause of Cancer, which was published in 2012 and was dedicated to Professor Richard Doll's anniversary. In fact, this was a stimulus for the study we are discussing. And in fact, the component of this study we are discussing today was built in and baked into the existing cohort study to which we added the active follow-up component for assessing the changes in smoking habit and disease status. Dr. Mahdi Sheikh: If you review the evidence, before publishing this study just like a few years ago, we find that there are many studies published talking about the effects of smoking cessation on cancer survival. However, as David mentioned when you go deep into these studies, you’ll find a lot of limitations. First of all, most of these studies are retrospective studies, which means that either case-control or retrospective course that patients developed the outcome, and then some investigators came to see their records to assess or ask family members before they developed the outcomes. There are a lot of biases with these types of studies. And with the epidemiologic study, perspective study that we did, has less limitations compared to retrospective ones. Another one is that when we go into the study you see, they only assess a small number of patients, small sample size. Some studies just assess 10 smokers, some assess like 30. By this study we try to assess a large number of smokers who quit smoking after diagnosis. Another limitation is that– First, let's see what exposure and what setting we are talking about. We're talking about smoking which is a very dynamic behavior. People quit smoking and they relapse smoking and they quit smoking and so on. So if you access this exposure for only a limited time, for example, for one year, then you may miss what happens after that which results in misclassification of some of the participants. So repeated assessment was not done in other studies that we did here in this study. Another one, you are talking about special setting patients who are diagnosed with cancer. These patients have special circumstances, they have treatments, they have family support, they might go under the stress of cancer, and all these different stages at diagnosis. And most studies that are available, they didn’t account for this. They didn't adjust or they didn't try to understand the role of these compounding factors, as we call it in epidemiology, on that, the thing that we're trying to address. And a prospective study, as I said, long follow-up time. Even the very few prospective studies that were available for other cancer sites that have only one year or maximum two years of follow-up with this type of exposure, so it is important to follow them for a long time. Another thing I would say was exposure assessment. Not only did we repeatedly try to assess exposure among participants, but try to call the people– David and his team who did the study in the field, called the participants and tried to ask the family members and sometimes their physicians about their smoking behaviors. When you go to current evidence you see, mostly smoking behavior was assessed using the record that is available like treatment records or patient records, which again has some limitations if you do not assess exposure among qualified participants. Finally, we're talking about a dynamic behavior in the follow-ups. Some people might change smoking. But there is a very important thing, in this study, we also collect at the time of quitting smoking. There's a very important thing in statistics we call Survivorship Bias, meaning that, if you were assessing an exposure doing the follow-up and if you do not pay attention to this, you will assess an exposure that is a proxy of people who lived longer. Meaning that people have enough time, they have a long time, and those who have longer time, will have more time to quit smoking. And then you will be assessing this, actually, not the exposure, but you're only assessing people who quit smoking, and then whatever you assess, you would end up with a beneficial effect. But if you have the time of quitting smoking and follow up and all these statistical things and lower sample size, you are able to account for this very very important bias in epidemiology. Dr. Shannon Westin: Before we go further, I'd love for just a bit of a description of exactly how you laid out your study to really add to where this data are so limited around survival and tobacco cessation. So maybe review the primary/secondary objectives, basic design, just to make sure our listeners are all on the same page. Dr. David Zaridze: The study has classical prospective cohort design that the study, which was basically a basic study, in which the new component was built in. This study used a user’s questionnaire-based exposure assessment and molecular epidemiologic approach. I mean that, in addition to the questionnaire approach, we collected blood and tumor tissues for molecular studies. All patients with kidney cancer admitted to the cancer center were interviewed at admission before receiving any treatment. A structured lifestyle questionnaire was used. Participants were asked about their lifetime smoking history which included questions about the duration and frequency of smoking cigarettes, the average number of cigarettes smoked every day. They were also asked about their lifetime history of alcohol drinking. The questions included questions about exposures to carcinogens other than smoking, and health conditions, including chronic kidney diseases, hypertension, diabetes and so on. Height and weight were measured. Today, this study generated and continues to generate plenty of results and papers published in most prestigious journals such as Nature Genetics, for example. So, as you know, we started from 2012, we started the follow up of the cohort members, we were focusing on Moscow residents and the follow-up includes regular annual contacts with the patients personally or via telephone or with patients’ household members, etc. Again, we collected information about changes in smoking behavior and disease status. We also used information from the regional cancer registry to confirm the information obtained from patients. The average period of follow up was eight years. And this is quite a long follow-up. Repeated assessment of smoking status reduces the likelihood that exposure to smoking was misclassified. However, regrettably, the self-reported information on smoking was not supported by biochemical tests, for example, by blood cotinine testing. To my knowledge, this is the only prospective cohort study in patients with cancer, not only with kidney cancer that have collected data on participants' smoking status prospectively for quite a long time. The average follow-up time was eight years. Dr. Shannon Westin: That was incredible. That definitely caught my eye. And I was looking, I was like, “Oh, how many did they lose?” And you guys kept 80-100% of the patients. I just was so impressed by that. And now hearing the mechanisms in which you did that, it makes sense. You were very diligent, multiple ways to contact patients and confirm the data. So you really are to be congratulated for the work that you're able to achieve. Dr. Sheikh, I'd love to hear, you talked a little bit about how some of the studies didn't really think about confounding variables. Can you kind of highlight some of the confounding variables that you all controlled for in order to really assess the impact of the cessation on survival? Dr. Mahdi Sheikh: Thanks to the high-quality data and also the large sample size and the way the study was designed, we were able to adjust for a lot of confounding. So we tried to adjust for all these things. So we used three approaches. The first approach was adjustment. When you ran this in the analysis, we tried a statistical model, we tried to adjust for these confounders like age, sex, treatment, socioeconomic status, smoking intensity, alcohol, and other factors. This is one effect, one approach. The second approach was stratification, meaning that we come and see the effect within people who have been diagnosed with only earlier stage tumors to see if the effect among people with earlier stage tumors differs with the effect that we see among people with higher stage tumors. But again, if you read the paper, you see that we saw the protective effects of smoking cessation on both groups of people, those who were diagnosed at earlier stages and those who were diagnosed at later stages. And also heavy smokers or mild to moderate smokers, again, we tried stratified analysis excluding those heavy smokers and saw the effect, again, among those who were light smokers or moderate smokers and also with the heavy smokers. I want to say that we tried all these types of analytical approaches and we really saw the protective effects across all patient subgroups. Finally, I talked again about the survivorship bias. So we used really strict statistical approaches to address this confounding, and because we had the time of quitting, we had the follow up time and all these things. And, again, whatever we did in the study we still could see the effects of smoking and all this is due to the good design, the large sample size, and the good questionnaire data that we have. Dr. Shannon Westin: That's awesome. I think, of course, now let's get to the bottom line. 40% reported that they quit smoking after diagnosis with none relapsing during the time period. And what did you see was the impact on overall survival as well as cancer-specific survival? Dr. Mahdi Sheikh: So we tried several outcomes - overall survival, cancer-specific survival, but also progression-free survival. And then because we had the large sample size we could assess all this. Interestingly, we saw the effect on all the three outcomes that we assessed. So the overall survival was better among those during the quitting time and also the cancer-specific survival was also better and also progression-free survival was better among all these participants. Dr. Shannon Westin: I think most people that have read this paper - and if you haven't read this paper you should run to read it right now - I really was impressed with that kind of clear benefit across cancer-specific mentality across all subgroups regardless of how much they smoked. So I don't know why you get a sense of like, “Oh, if you smoke a little bit you wouldn't see as big of an impact,” but a very clear impact. And I would love to hear why you think smoking negatively impacts these outcomes. How does the cessation help? This is a perfect time for that. Dr. Mahdi Sheikh: When we review the evidence about how smoking cessation may be beneficial for patients, for the survivorship of patients with cancer, we come to five mechanisms that are suggested in the literature. So the first one can be, is suggested, that is altered cancer biology. Smoke and tobacco smoke contain numerous carcinogens and mutagens. So it has been shown that cancer cells that are exposed to tobacco smoke, they may become more aggressive and the risk of metastasis might go higher and also, angiogenesis and all other effects on the biology of cancer cells. So it may affect the cancer cell biology. Another suggested mechanism might be altered immune response. So tobacco smoking affects the immune system and then the immune response among those who are exposed to tobacco might be affected by tobacco smoking. So their response to the cancer cells but also other bacteria, viruses, and other things might be affected as well. The third possible mechanism suggested altered drug metabolism. It has been shown that tobacco smoke and smoking can affect some of the enzymes that have metabolic responsibilities and metabolism of the drugs. So that can affect the washout period for the drug. It might not stay enough in the blood or vice versa as well. It might affect the toxicity. There is some evidence about this. The fourth mechanism suggested is about increasing treating-related complications or treatment-related complications. People who smoke have delayed wound healing, they have more complications, the surgery, the time they spend at the hospital might be longer. And this is also part of which smoking may affect the outcomes that we saw here. And finally, that is we are talking about tobacco smoking and patients with cancer are human beings with all these systems. So we know that smoking causes damage to the cardiovascular system, to the pulmonary system and also to the lungs and other things. So this is why we see different outcomes are affected by cancer. Dr. David Zaridze: I was impressed by the data that exposure to tobacco smoke condensate induces changes in tumor microenvironment. For example, it inhibits formation of interferons, interferon alpha and gamma, inhibits the migration to tumor microenvironment of the immune cells. The number of CD8+ T lymphocytes, T killers, are significantly lower in the tumor microenvironment of current smokers compared to former smokers and never smokers. And even more interestingly, the number of PD-L1+ cells are also lower in the tumor microenvironment of current smokers than former or never smokers. This is probably very important in terms of effectiveness of impairment by smoking of the immunotherapeutic approaches in cancer treatment. Dr. Shannon Westin: That's very important and we know the microenvironment has a huge impact on just the way the cells respond to treatment and develop resistance and so that makes a lot of sense. Okay, well, this has been amazing and I think one thing that you just said just struck me, Dr. Sheikh, that you've obviously shown this in lung cancer and you're looking at this in other cancers. I guess the question is: What should we be doing? How should we be implementing tobacco cessation efforts across all cancer diagnoses to help all patients that have really any diagnosis of cancer? Dr. David Zaridze: Let me first underline the clinical importance of these results. The benefits from quitting smoking are comparable or even superior to those recorded in the clinical trials of modern kidney cancer treatments such as immune checkpoint inhibitors. I refer to the results of pivotal trials in advanced renal cell cancer in the frontline setting and these results were reported at ASCO Meeting 2023 recently in May. If you compare the results of our study with results of these pivotal trials, it is very impressive. It is clear that our findings strengthen the case for making tobacco cessation treatment a standard part of the routine health care for all people with cancer, however, smoking is still quite high in cancer patients. And I would like to quote Peter Shields who is saying that, in the United States,10% to 50% of cancer patients smoke. As far as Russia is concerned, in our study, 80% of kidney cancer patients smoke, and in our lung cancer study, 58% of cancer patients smoke.  The barrier is that the oncologists do not believe or are accepting with a great deal of skepticism the results of our study. They don't believe the idea that anything else besides surgical, radiological, or medical treatment could improve the outlook of cancer patients. It's difficult for them to apprehend. Many of them think that smoking cessation after diagnosis is simply a waste of time. Many patients simply don't know that smoking cessation after diagnosis may be beneficial for them. In addition, they are pessimistic and they feel discouraged to quit smoking, as they might think it is too late. I would like to quote my favorite quote: “Smoking cessation treatment has to become the fourth pillar of cancer treatment, one that could affect cancer treatment outcomes as powerfully as surgery, chemotherapy, or radiation therapy.” This is Dr. Fiore, 2019. Dr. Shannon Westin: Thank you so much. And Dr. Sheikh, anything to add there around cessation efforts? Dr. Mahdi Sheikh: As we saw the results of these studies that smoking cessation is feasible and it is accessible at a minimum cost for many patients, it should really be integrated in the  management of patients with cancer. It is feasible, it is cheap, it is accessible. But unfortunately, when we review the evidence we see that only less than half of the physicians, like around 40% of physicians, send the patients to tobacco smoking cessation services. And even some do not discuss this issue. And as David mentioned, they do not know the effect of smoking cessation. So when you go through these studies to find the major barriers, in addition to what David had mentioned, we find two important points. First one is lack of education or experience in providing tobacco cessation interventions among those who deal with patients with cancer. So they do not have the education. And second is lack of available resources for referrals. Now we’re not only talking about the United States but also many other countries even high-income countries, we do not see the resources for referrals on smoking cessation services in cancer care settings. The take home message probably from this study and also from these barriers, would be for three groups. First, for the policymakers, we would recommend sustainable funding should be dedicated to tobacco cessation services. As we saw, the effect is huge and seems to be a very big effect and it is cheap so why not implement this smoking cessation service within cancer care settings.  And the second one, tobacco treatment training programs for healthcare providers. This is also very, very important that we try to implement this training program in the curriculum of healthcare providers, especially those who deal with cancers and tobacco-related outcomes. And also for physicians, we recommend that physicians should assess and address tobacco use in all patients with cancer. They should talk about this topic and also show the benefits of quitting smoking. And patients with cancer who smoke should be supported to stop smoking at any time and each visit after diagnosis is not like some time pass, as we saw, all patient subgroups could benefit from smoking cessation. This is important.  But something also very, very important that we shouldn't forget that cancer itself causes a lot of fear and anxiety and stress. And smoking cessation sometimes may be associated with stress and more anxiety. So it is very, very important to think about this point and provide the psychosocial support to patients who quit smoking. Sometimes they may relapse just because of the fear and anxiety they have. So it's not only showing the evidence, but also supporting these patients, telling them how to do that and also supporting them emotionally and also psychosocially. And finally for the patients, I would like to give this message that we see and we know that it is never too late to quit smoking. As David said, patients may feel like, “It is too late now I've developed cancers,” but no, it's really not too late. And if you quit smoking at any time after diagnosis, you would benefit a lot from smoking cessation. Dr. David Zaridze: In the United States there are guidelines, several guidelines for smoking cessation, specifically for cancer patients because smoking cessation in cancer patients is very different from smoking cessation in general population. In the general population, we more or less succeeded, I would say, and we have to look now at this direction to the smoking cessation in cancer patients. And this is a message to WHO, that countries, members of WHO, based on the recommendation guidelines of WHO, develop their own specific guidelines for smoking cessation in cancer patients. And that should be used in all cancer clinics and that should be a must, absolutely important part of anti-cancer treatment. And as I already told, it should be the fourth pillar in cancer treatment, as treatment, as surgery, chemotherapy and radiation. Dr. Shannon Westin: Thank you both. That was such a great discussion, and I hope that we've convinced everyone that this is a critical effort that they need to be addressing every day.  I just want to thank everyone who listened. This has been "Smoking Cessation after Diagnosis of Kidney Cancers Associated with Reduced Risk of Mortality and Cancer Progression: A Prospective Cohort Study", again published in the JCO on March 29, 2023. Thank you guys again for listening to JCO After Hours. Please check out our other podcast offerings. You can check them out on the website or wherever you get your podcasts and let us know what you think about the podcast on Twitter. Dr. David Zaridze: Thank you. Dr. Mahdi Sheikh: Thank you very much.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Shannon Westin and her guest, Dr. Helena Yu discuss the paper "HERTHENA-Lung01, a Phase 2 Trial of Patritumab Deruxtecan (HER3-DXd) in EGFR-Mutated NSCLC Following EGFR TKI Therapy and Platinum-Based Chemotherapy" published in the JCO during the World Conference on Lung Cancer in Singapore.     

In this JCO Article Insights episode, Emily Zabor interviews Dr. Gregory H. Reaman, the Scientific Director of the Childhood Cancer Data Initiative at the National Cancer Institute, on their paper titled  “The Childhood Cancer Data Initiative: Using the Power of Data to Learn From and Improve Outcomes for Every Child and Young Adult with Pediatric Cancer”. Dr. Reaman introduces us to the initiative, its goals and structure, and what has already been achieved since its launch. TRANSCRIPT The guest on this podcast episode has no disclosures to declare.  Emily Zabor: Welcome to this JCO Article Insights episode for the August issue of JCO. This is Emily Zabor, JCO's Biostatistics Editorial Fellow. And today I am interviewing Dr. Gregory Reaman, the Scientific Director of the Childhood Cancer Data Initiative at the National Cancer Institute, on their paper titled “The Childhood Cancer Data Initiative: Using the Power of Data to Learn from and Improve Outcomes for Every Child and Young Adult with Pediatric Cancer.” Dr. Reaman, welcome to our podcast. Dr. Gregory Reaman: Thanks very much, Emily. Appreciate the invitation. Emily Zabor: Dr. Reaman, could you start by introducing yourself and describing your involvement in the Childhood Cancer Data Initiative? Dr. Gregory Reaman: I'm Gregory Reaman. I'm a Pediatric Oncologist. And I guess my involvement with the CCDI began shortly after the initiative was announced at the State of the Union media address in 2019, which was followed shortly thereafter by the formation of a working group by the NCI's National Cancer Advisory Board Board of Scientific Advisors. Given my role at the FDA at that time as Associate Director for Pediatric Oncology in the Oncology Center of Excellence, and the fact that I was the founding Chair of the Children's Oncology Group, I was an ex-officio member of this working group. So from very early on, I had involvement. I formally joined the NCI in November, left the FDA to assume the position as Scientific Director of CCDI. Emily Zabor: That's great. So you've really been involved from the start. I had not really been familiar with the initiative until I read this paper. And as a cancer biostatistician, I was really excited to learn about this initiative, which sounds like it will ultimately create a very valuable data resource to be used for research purposes, among other things. So I think it's a really interesting project. So for our listeners who may not be familiar, could you describe the motivation for and goals of the Childhood Cancer Data Initiative? Dr. Gregory Reaman: As I mentioned, this really is a very unique initiative, venture, if you will, on the part of the Cancer Institute and in large part driven by this fortunate infusion of funds to support childhood cancer research. And given the fact that pediatric oncology is very much a collaborative enterprise, it really does sort of follow that data sharing and using the power of data, its ability to be used by multiple investigators, irrespective of the source, aspirationally can improve outcomes for children cancer. The three primary objectives– actually, this working group that I mentioned earlier put together a white paper that had 24 specific recommendations to the NCI. But there were three foundational objectives or goals. One was to learn from every child diagnosed with cancer, irrespective of the institution where they were diagnosed to receive therapy, to develop an ecosystem that would enable the submission, aggregation of data, and harmonization in a federated system that could then be accessed and used by investigators and analyzed to ultimately improve outcomes. And then one objective, which was a little bit more specific, and that was to really focus on the opportunity to genomically classify tumors from newly diagnosed pediatric cancer patients, because this was something that obviously is much more widespread in the adult population, given the advent of targeted therapy and precision oncology and its more widespread use in medical oncology than pediatrics. And although many large academic institutions do have resources, the majority of smaller institutions do not. And when it's necessary and preferable to accurately and timely identify or diagnose a child's cancer that may actually provide information on treatment recommendations, the ability to do that and have it covered by insurance is sometimes problematic. So developing a program that would not cost patients or institutions anything and then make that data available to patients, families, and providers, as well as making it available for secondary research use, was a major goal and objective. Emily Zabor: Yeah, that sounds like such an important initiative. The Molecular Characterization Initiative, which I understand has already enrolled and characterized the genomics of 751 participants just in the first year, I think is what the paper reported? Dr. Gregory Reaman: That's correct. That was in the first year. We're now beyond the first year and we're approaching 2000 patients that have had their tumors genotyped and about 1500 results that have been returned to patients and providers. Emily Zabor: That's fantastic. So with this linkage to the clinical data, that's going to be an extremely important data source. And I understand that the participation is currently limited to members of the Children's Oncology Group, which consists of over 200 children's hospitals, universities, and cancer centers. Can you describe in more detail what information it currently provides and how this initiative is going to be advertised and implemented to ensure complete participation across all of these member sites? Because that sounds like a really big challenge. Dr. Gregory Reaman: Limiting the participation to the Children's Oncology Group initially was in no way meant to be exclusionary, but really provided an opportunity for linkage to clinical data. Since the Children's Oncology Group really represents nearly all of the pediatric cancer programs in the United States and some programs even outside the US, in Canada, and a couple of European sites, Australia and New Zealand, it was felt that given the resources that currently exist within the COG for specimen procurement, specimen submission, and then DNA and RNA extraction through the COG's Biopathology Center at the Nationwide Children's Hospital would really facilitate having the sequencing done at a single site, single institution, using a single platform. And also it provided an opportunity for some clinical data, including demographics, diagnosis, radiographic data, and treatment data that could be collected somewhat longitudinally from patients enrolled on the MCI. Looking to make this as broad as possible since the objective of the CCDI is to learn from every patient, and every patient that we're concerned about not being able to capture adequately within the Children's Oncology Group are older adolescents and young adults with cancers that are more frequently seen in the pediatric population. So we are looking at ways to work with the COG's Biopathology Center to see if we can create systems that we can actually have specimens submitted from patients seen at institutions outside of the COG and molecularly characterized the same way. And that will be important as we launch another new planned initiative called the Coordinated National Initiative for the Treatment of Rare Pediatric and Young Adult Cancers. Emily Zabor: Okay, that makes sense. So those adolescents and young adults are harder to capture since they're not being seen at those COG member institutions. Okay, well, that sounds like a big challenge to find those patients at their institutions and get them involved, but I think it's an important piece of this for sure. Dr. Gregory Reaman: I should also point out that there were opportunities for some of the larger well, for all of the NCI-designated cancer centers, the pediatric programs associated with those cancer centers, to submit genomic data on newly diagnosed patients. That was something that actually transpired early on in the history of CCDI. So those data are in the CCDI's ecosystem. Emily Zabor: Oh, that's great. So you collected the existing data. Dr. Gregory Reaman: Right.  Emily Zabor: That kind of leads into my next question about aggregating data sources. With these disparate sources of pediatric cancer data, it seems like the aggregation is a lofty and important goal, but once that's complete, you're going to have this data ecosystem, which you said was one of the main goals of this initiative. I was wondering if you could tell us who will have access to this data ecosystem and what will be required for individuals to gain access. Dr. Gregory Reaman: All of CCDI was predicated on this really being a community initiative if you will, so multidisciplinary and community-based. So patients, families, advocates, clinical researchers, physician providers, basic and translational researchers, researchers in public health and epidemiology. So there will be different levels of data that will be available to specific individuals. Patient-level data will be deidentified through a system of APIs that will be used that will enable the association of clinical data to existing molecular data and outcome data that might be available in the ecosystem. Those data will be- there are many data in the ecosystem that will be open source and available to anyone who is interested. This includes data from the NCCR in the Childhood Cancer Data Catalog, which is basically a listing of some close to 300 pediatric cancer databases that are available. The patient-level data will be sort of a controlled access. So there will be a requirement for individuals, investigators who wish to access that data, to sort of be certified, if you will, utilizing NCI and NIH data sharing requirements. Emily Zabor: That makes sense. Yeah, you mentioned deidentification, but especially when we're dealing with these kinds of rare diseases, patient privacy does seem like it could be a concern. So what exactly are you doing to ensure that that is not something that gets violated through this process? Dr. Gregory Reaman: I think there's every attempt to eliminate any PPI, HPI, obviously. So, again, most of the clinical data that are being provided currently are data that's coming from the Children's Oncology Group, where for every patient enrolled or registered through the COG and enrolled on a clinical trial, there is a COG ID number that is associated and that will be available only to the NCI and the CCDI to link it to unique specimen identification numbers, which are the only numbers that will be available to any investigator. So no one will be able to make the connection from the specimen identifier to the unique patient identifier in the COG. Emily Zabor: That's great. And that way, you can really get access to all of the detailed data without concerns about privacy. Dr. Gregory Reaman: Correct. And then being able to link all of these disparate data sets will really require the identification or the development, I should say, of a participant index. So that is one of our highest priorities right now in developing a CCDI participant index so that we would be able to link the identifier or clinical data with any research data or biologic data that may be available on patients to facilitate research plans and programs. Emily Zabor: And through that process, is there also some method involved for identifying duplicated data? Because I assume some of these patients may get seen at different institutions over time, and that could be a concern that they end up in the database multiple times. Dr. Gregory Reaman: That's exactly why I think developing the participant index is so critical to, number one, link, and number two, to avoid, prevent duplication, because you're absolutely right. There may well be the same patient data in multiple data sets, which are, of course, disparate. And the only way that they're going to be really utilizable and made interoperable is by linking them to the specific patient or individual patient. Emily Zabor: Great. And do you have an idea of the timeline when that part would be complete and this data ecosystem would be available to researchers?  Dr. Gregory Reaman: The ecosystem is already available to researchers. We launched several months ago the CCDI hub, which is sort of the entryway or entry point, if you will, for access to the ecosystem. We hope to actually have the participant index up and running, and it's something that we've been working on for over a year, but actually available and utilizable within the next several months.  Emily Zabor: That's fantastic. We'll have to go check out the CCDI hub that's already out there then. Before we end, is there anything you'd like to share with our listeners that we haven't already discussed? Dr. Gregory Reaman: Well, I think the one program that I mentioned just briefly, the Coordinated National Initiative for Rare Pediatric and Young Adult Cancers, we see there's a real opportunity to address a major unmet need. Fortunately, all pediatric cancer is rare, but there are some cancers that are extremely rare and for which there are, in many cases, no defining standard of care, and in many cases, there are no treatment protocols because of the difficulty mounting studies with such small patient numbers. So we see this as an opportunity to actually develop a registry that will provide, hopefully, natural history data that will inform clinical trials. All of these patients will be enrolled on the Molecular Characterization Initiative. So there will be the opportunity to hopefully learn if there are specific molecular drivers of some of these cancers that could inform the use of targeted drugs in a therapeutic approach to some of these. And we're looking to do this international collaboration with colleagues in the EU as well. So that is something that we just launched a task force  to develop a listing of core critical data elements to collect on patients and then developing the registries for a number of these rare cancers. Emily Zabor: That sounds like it's going to be a really valuable resource for planning and designing future clinical trials, so I'm glad to hear about that. Dr. Gregory Reaman: And we would invite anyone who's interested to find out about the CCDI, to find out more about the CCDI, which they can do through cancer.gov/ccdi. There is an opportunity for people to register for newsletters. We have a series of webinars, many of which are designed now to actually provide training on some of the resources and platforms that are available currently through the ecosystem and things that we have all planned for future developments and use. So as I said, this is a community venture and we look to expand the community in every way possible. Emily Zabor: That sounds great. So hopefully our listeners will take note of some of those resources in addition to this paper being out there, which will guide some people in the right direction to learn about this really great initiative for childhood cancer.  So, Dr. Reaman, it has been a pleasure speaking with you. And thank you so much for joining me today on this episode of JCO Article Insights. Dr. Gregory Reaman: Thank you very much. It's been great to be here. Appreciate the opportunity.  Emily Zabor: This concludes this episode on the article, “The Childhood Cancer Data Initiative Using the Power of Data to Learn from and Improve Outcomes for Every Child and Young Adult with Pediatric Cancer.” Thank you all for listening and please tune in for the next issue of JCO Article Insights.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Shannon Westin, Dr. Abbas M. Hassan, and Dr. Leticia Nogueira discuss the impact of heatwaves on cancer care delivery and what can be done about it. TRANSCRIPT The guests on this podcast episode have no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on manuscripts that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncologist and Social Media Editor for the Journal of Clinical Oncology. I'm so excited to be here today to discuss a very thought-provoking manuscript. This was published on June 10, 2023, in the Comments and Controversies section of JCO, and it’s entitled “Impact of Heatwaves on Cancer Care Delivery: Potential Mechanisms, Health Equity Concerns, and Adaptation Strategies.”  And I am thrilled to tell you I am joined today by two of the authors of this very important manuscript. Dr. Abbas Hassan is an intern in the Division of Plastic Surgery, Indiana University School of Medicine. Already reaching for the stars, publishing in the JCO as an intern, that has to be a record. Congratulations and welcome, Dr. Hassan. Dr. Abbas Hassan: Thank you for having us. Appreciate it. Dr. Shannon Westin: And with Dr. Hassan is Dr. Leticia Nogueira. She is now the Scientific Director of Health Services Research at the American Cancer Society. Welcome, Dr. Nogueira. I'm so excited to have you. Dr. Leticia Nogueira: Excited to be here. Dr. Shannon Westin: Let's get right to it. This topic is very timely. We are currently enjoying several weeks of greater-than-100° weather here in Texas, where I am, and across the United States. Why don't we start by just defining heatwaves in general and what their global impact is on morbidity and mortality? Dr. Abbas Hassan: Yeah. So, I mean, it's the Texas heat, right? It's hard to ignore it when you're sweating buckets, right? So this kind of extreme heat isn't just a Texas problem. It's happening everywhere, so from Australia to Europe and across the US. And what we're experiencing, my friends, are heatwaves. They're like the unwanted guests at a barbecue, showing up uninvited, hanging around for at least two straight days. Now, defining a heatwave isn't straightforward as it might sound, with various different definitions across studies and policies. But one thing that is clear: heatwaves aren't just about discomfort. They're deadly. They're claiming more than 5 million lives globally every year.  Now, let's just imagine for a moment the year 2020. Not exactly a walk in the park. And on top of that, everything else, heatwaves cost over $4.5 billion in damages in the US. And that's probably just the tip of the melting iceberg, considering the tricky task of identifying exact heatwave periods. Dr. Shannon Westin: And you said it's really hard to define, so I imagine that that makes it really difficult to study. Hopefully, I think we've already gotten our first call to action is coming up with some type of consistent definition so we can truly look at this in a scientific fashion. I guess I'm asking you to predict, but I'll do it anyway. What do we expect to happen over the next 30 years in regards to the climate change we're seeing and maybe overall temperatures across the globe? Dr. Abbas Hassan: The way things are going, we're probably going to need a lot more sunscreen and a lot more ice cream. In all seriousness, the outlook is pretty stark. By 2023, we're looking at 8.1 million of our fellow Americans facing temperatures hotter than 125°F. And fast-forward to 2053, the number skyrockets to like 100 million. So that's a 13-fold increase. Remember when we thought 2014 was hot? And then 2015 came in, then 2016, and now all the way to 2020. Each year seemed to outdo the last, making the past seven-year span the warmest we've ever experienced. So we're not just dealing with a few off years. We're in the midst of a trend that's heating up our planet and impacting our health at an alarming rate. Dr. Leticia Nogueira: Yes, I would like to add to that, exactly what Dr. Hassan said. We don't really need to worry about or focus on what temperatures are going to be in 30 years. It is here now. The threats of climate change are here now, threats of extreme heat, no matter how we define it, right? Because it could be number of days above a certain temperature threshold, and that threshold is usually established by the previous 30 years. And we've already seen these jumps in temperatures in the previous 30 years, especially in most recent years. So these hazards, these threats, are already here. No future projections necessary to understand the hazards and the detrimental consequences of exposure to extreme heat due to climate change. Dr. Shannon Westin: Well, let's talk a little bit about that. And specifically, I would love to hear kind of what we've been seeing as far as the impact of heatwaves on health outcomes. I think our group would be interested in knowing, what are some of the things that you're seeing and you’re experiencing? And then further, what are the things that make people more vulnerable, let's say, to the climate hazards? Dr. Abbas Hassan: Yeah, let's dive in a bit more into what makes us vulnerable to these heatwaves. When you think about vulnerability, the key elements are, one, increased exposure; two, increased sensitivity; and three, decreased ability to adapt. So think about it this way: Let's say you’re—not sure if you guys play this—let’s say you're playing a game of tag, and the sun is it. Now the sun is pretty good at tag, so anyone spending a lot of time outside—that's increased exposure—is more likely to get tagged. Then you have some players who are, for various reasons, they’re slower or less agile. So this can be due to age, health conditions, or other factors that make them more sensitive to heat. They're not able to dodge the sun as quickly. So that's increased sensitivity. And finally, imagine some players are dressed up  in heavy clothing, unable to change into something cooler. They don't have the resources to adapt. So that represents that decreased adaptive capacity. While everyone playing this game can feel the burn, there are some who are more at risk.  So, for example, individuals with cancer are particularly at risk because they have various physical, psychological, socioeconomical consequences of their diagnosis, treatment, and even their path to survivorship. And this can include everything from weight loss to tumor, compromised immunity, side-effects from medications, and even financial stressors, making their game of sun tag especially challenging. So when we talk about the impact of heatwaves on health, it's not a one-size-fits-all issue. Our vulnerability is a complex combination of various factors that can leave some of us more at risk than others. And it's this understanding that can help shape our approach to tackling the challenges that climate change brings. Dr. Shannon Westin: That was very well stated, and I think I want to dig in a little bit deeper on some of the broad factors you covered, especially as it relates to patients with cancer, who obviously fit in the category of vulnerable to really all those pieces. So I'd love to dig in a little deeper. So let's talk a little bit more about age. I know that certainly patients with cancer can be any age, but it does seem to affect patients that are older or more elderly. How might that impact sensitivity to these heatwaves? Dr. Abbas Hassan: Okay, so dig a little deeper here. The reality is that getting older comes with its fair share of challenges, and one of them is increased sensitivity to heat. So as we age, we become more susceptible to heat. And this is particularly true for individuals over the age of 65, many of whom are also dealing with a cancer diagnosis. In fact, the number of seniors with cancer is expected to nearly double by 2060. So heat sensitivity in this group is due to several factors. First, our body's ability to regulate heat, or thermoregulation, declines with age, much more like an old car cooling system not working as it once did. So this means we're less able to handle extreme heat, making us more vulnerable during heatwaves. And this vulnerability is especially concerning for older cancer patients because some cancer treatments can cause additional complications, such as kidney injury, which can impair our cooling systems even further.  Additionally, these treatments can lead to dangerously high levels of hypernatremia and hyperkalemia, and this can lead to serious complications like cardiac arrhythmias. So in other words, the aging process coupled with cancer and its treatment can make older folks more susceptible to the harsh impacts of heatwaves. Dr. Shannon Westin: That makes sense. So you started to touch a little bit on comorbidities with discussing heart disease and arrhythmias and how that might impact. Are there other comorbidities that are certainly quite common in patients with cancer that can impact health conditions related to climate change? Dr. Leticia Nogueira: Yes. So, in addition to, as Dr. Hassan mentioned, some chemotherapy drugs inhibiting thermoregulation makes it harder for people to control their body temperature, several cancer treatments also impact kidney function, and kidneys are important organs for body temperature regulation. Even some cancer treatment drugs also lead to cognitive impairment, which makes it harder to recognize heat stress and heatstroke symptoms. It could also impair mobility and the ability to go look for a cooling, safe space. There are several other cardiorespiratory comorbidities that can also impact sensitivity to extreme heat. And we cannot forget that cancer diagnosis treatment comes with socioeconomic consequences as well, because it impacts the ability of individuals to remain employed or maintain the same level of income. And these socioeconomic consequences also impact the adaptive capacity that Dr. Hassan was mentioning, such as installing air conditioning or improving insulation during a heatwave or throughout the year, which makes individuals diagnosed with cancer more vulnerable to these threats. Dr. Shannon Westin: You had mentioned some of the economic challenges here. I'd love to speak a little bit more about that, and I think we certainly see this in vulnerable populations just in general, being able to receive their cancer treatment or make it on time for their treatments. In addition to that, are there limitations around accessing resources or things that would help protect people during these heatwaves? Dr. Leticia Nogueira: Yes, we see a lot of barriers in access to resources in communities that have been targeted for marginalization or they are experiencing barriers in access to resources. Right? We can start with some of the ways that our urban centers are built. Concrete and asphalt trap heat in urban centers, leading to this effect called the urban heat island. So you see almost a 20° difference between urban centers and more suburban or rural areas when it comes to these hot days. And that, of course, increases exposure to extreme heat, which is one of the components of vulnerability.  Then you have sensitivity. If there are barriers in access to healthy resources, healthy foods, places to exercise, and there are, for example, an increase in targeted advertising for tobacco or alcohol outlets in the neighborhood, that has been shown to be associated with an increased prevalence of several chronic health conditions. And as we were discussing, these chronic health conditions also increase sensitivity to climate hazards.  And then, of course, there is adaptive capacity. We were mentioning the challenges faced by people who have been diagnosed with cancer in being able to afford some of the infrastructural updates that are necessary to cope with extreme heat. And the same challenges apply for people who are experiencing other types of socioeconomic distress, making it harder for these communities to prepare and respond to the challenge posed by heatwaves.  Oh, there's one more thing. I just wanted to mention that this is a concern, the adaptive capacity, not only for these communities that are facing barriers in access to resources. With climate change, there's been an increase in power outages. So, even if you can afford to use AC, it does not mean you're going to be able to use it during a heatwave because these power outages are becoming more frequent, especially as people turn up their AC and overwhelm the electric grid. So this is a concern for all US residents, not just people from lower socioeconomic levels or cancer patients. Dr. Shannon Westin: You are speaking my language, coming from Texas, where our grid is a constant source of-- Dr. Leticia Nogueira: I lived in Texas for a while. Yes. Dr. Shannon Westin: I know you did. I saw that in your bio. Okay, well, I think we got the scope. I'm appreciative of the level of detail that you all were able to cover in such a short period of time. So I think now let's move towards the kind of action items, like what can we do? How can we mitigate some of these issues, or all of these issues? Start wherever you think your lowest hanging fruit is, I would say. Dr. Abbas Hassan: Okay, absolutely. So addressing the challenges that climate change presents, especially for vulnerable groups like cancer patients, is, I would say, a lot more like putting together a jigsaw puzzle. It requires us to work on multiple fronts at once and fit all the pieces together to form a complete picture. So let's walk through this puzzle together. So picture this: Our first puzzle piece involves upgrading our healthcare infrastructure. We need to gear up our systems with surveillance, monitoring, and even staffing to swiftly detect and respond to heatwaves. The second part of the puzzle is that our healthcare workers, or providers, need to become more aware of climate change. They need to provide guidance to their patients that suits their cultural context and language, discussing things like what they need to wear during a heatwave, the best way to travel, even what changes to make in their diet. But how would our healthcare providers turn into these warriors? Well, that brings us to our next piece, like continuing medical education. So, by providing education opportunities into medical and public health curriculums, we can create a force of well-prepared healthcare providers and professionals ready to fight the challenges of climate change.  And also considering how heatwaves can affect our medications. As temperatures rise, we need to think about developing thermostatic medications that can withstand the hotter conditions. It's like equipping our medications with their own little heat shields. Lastly, I think, which is perhaps most importantly, we need to be stewards of our own environment with our own healthcare systems. This includes reducing our carbon footprint and advocating for heat equity. So a concept that ensures that everyone, irrespective of their socioeconomic status, has access to and protection from heatwaves’ related risks. So, just like that jigsaw puzzle, every piece plays a crucial role. By working on those front lines simultaneously, we can build a more resilient, equitable healthcare system ready to face the rising temperatures. Dr. Shannon Westin: Okay, you absolutely win on JCO After Hours for the best examples. The puzzle pieces. I’m just—I am, like, obsessed. This was—you're amazing. Dr. Leticia Nogueira: Playing tag, right? He's a natural. Dr. Shannon Westin: Playing tag, the sun exposure. I was like, this is like… I have to say you are very well suited for this type of work. Dr. Abbas Hassan: You're too kind. Thank you. Dr. Shannon Westin: And honestly, I think when you put it like that—sometimes these kind of problems seem so big and overwhelming, but when you kind of break it down into those chunks, it does seem doable. And I think almost every time on this podcast I bring this up, but I'm going to do it again. What can we do to change policy, right? We need a policy change. Like, some of what you mentioned is medical education, things like that. But really, what about lawmakers? What do we need to be talking to our lawmakers about so that we can get broad-based policy changes that will help us enact some of these strategies that you just so well described? Dr. Leticia Nogueira: I also wanted to add something I think is relevant to both here, and that is that the United States healthcare system is the second largest industry when it comes to emissions in the US. Emissions from the US healthcare system alone surpass emissions from the entire United Kingdom. So there is a big component of this strategy here to recognize that it is anthropogenic, manmade emissions that are causing climate change and leading to these detrimental health consequences. In our role, there are only so many Band-Aids we can put on this side before we start evaluating how we’re actually contributing to the problem.  And here is where this jigsaw puzzle and the policy and “I'm getting overwhelmed” kind of all comes together because there are several different efforts that are both climate mitigating and also improve climate adaptation. For example, switching towards clean energy sources that are generated on-site at healthcare systems can decrease the emissions of these institutions and also make them more resilient to power outages that, as we talked about, are only becoming more frequent. And there are several other examples. And you were asking about policy. I think that one of the recent advances when it comes to policy-level interventions comes from the Inflation Reduction Act, where we have a lot of incentives for shifting towards more clean energy sources and decreasing our environmental impact with our professional activities that we need to keep in mind as we're trying to protect the health and safety of cancer patients. Dr. Shannon Westin: Great. Thank you so much. And I guess that we're getting towards the end of this. It's gone by very fast, and I personally am writing down my to-do list of things I need to do tomorrow. What is next for you all for your work in this space? Dr. Leticia Nogueira: I think that, as a researcher, there’s a few different things that we can do. Similarly, as you are a clinician or a psychooncology or any of these other professions. One of them goes back to Dr. Hassan was saying surveillance and measuring the effects because that increases awareness and provides the background evidence that's necessary for developing and implementing solutions, right? And then, of course, being champions within our own institutions so that we are both trying to solve the problem when it comes to protecting the health and safety of patients. Is it possible to use electronic health records to identify those who are most vulnerable? Can we expand on data sharing and information sharing so we can build on lessons learned from previous heatwaves and do better next time? And then how, of course, can we contribute to reducing the emissions from our own institutions so we stop contributing to the problem we're trying to solve? Dr. Shannon Westin: Well, this was so educational, and I am so pleased that we had an opportunity to talk to you about this really important paper. I just want to thank, again, Dr. Hassan and Dr. Nogueira for taking the time to review this and really for thinking through this very important problem. And I hope it inspires all of you to look at what your institutions are doing and determine what strategies you might be able to utilize to start to mitigate some of these problems.  Again, we were discussing the Comments and Controversies manuscript “Impact of Heatwaves on Cancer Care Delivery: Potential Mechanisms, Health Equity Concerns, and Adaptation Strategies,” which was published in the Journal of Clinical Oncology June 10, 2023. If you haven't read it, run, don't walk, to do so. And please do check out our other JCO After Hours podcasts on our website. And if you have any problems, reach out to me on Twitter. I'd love to chat. Have a great day. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

In this JCO Article Insights episode, Davide Soldato interviews Dr. Naqash  from University of Oklahoma. Dr. Naqash provides insight into the original article published in the July JCO issue: “Safety and Activity of Immune Checkpoint Inhibitors in People Living With HIV and Cancer: A Real-World Report From the Cancer Therapy Using Checkpoint Inhibitors in People Living With HIV-International (CATCH-IT) Consortium”. The interview offers a deep dive into the manuscript results on efficacy and safety of Immune Checkpoint Inhibitors in this specific population and offers insights on future research direction in this space. TRANSCRIPT The guest on this podcast episode has no disclosures to declare.  Davide Soldato: Welcome to this JCO Article Insights episode for the July issues of JCO. This is Davide Soldato and today I will have the pleasure of interviewing Dr. Abdul Rafeh Naqash, the author of the manuscript titled "Safety and Activity of Immune Checkpoint Inhibitors in People Living with HIV and Cancer: A Real World Report from the Cancer Therapy Using Checkpoint Inhibitors in People Living with HIV-International Consortium."  Dr. Naqash is an Assistant Professor of Hematology-Oncology at the University of Oklahoma and a Medical Oncologist working at the Stephenson Cancer Center. His research interests revolve around early-phase clinical trials in solid tumors, lung cancer, and the study of immunotherapy, biomarkers, and resistance.  Welcome, Dr. Naqash, and thank you for accepting our invitation today. Dr. Abdul Rafeh Naqash: Dr. Soldato, thanks so much for having me. I'm really excited to discuss this article with you today. Davide Soldato: So I just wanted to go a little bit over the manuscript with you. So basically, this is a retrospective multicenter study that was conducted across the US, Europe, and Australia by the CATCH-IT Consortium. And so the aim of the study was really to investigate the safety and the activity of immune checkpoint inhibitors among patients diagnosed with cancer and also living with HIV. The article examined two different cohorts, and I just wanted to start with a brief explanation of how the two cohorts were built so that our readers can get a little bit of understanding of what you did then. Dr. Abdul Rafeh Naqash: Sure. Before I take a deep dive into the cohorts, Dr. Soldato, I would definitely like to mention the premise and the background for this paper as to why we did what we did. And one of the primary reasons was that people living with HIV, historically, there have been very limited number of trials that have included these individuals. So it becomes a very important question from a disparity standpoint. And most often we end up, in the real world setting, we end up extrapolating data from clinical trials, but not necessarily know what is the outcome of these individuals in the real world setting.  So there have been some very important studies in the last three years or so in people with HIV as far as clinical trials with checkpoint inhibitors go, but most of those trials have been limited by the number of patients, number of people that have been part of those trials. So we wanted to understand it from a broad perspective, whether it is from a broad geographic perspective or from a heterogeneous patient population perspective, which is why we built this consortium called the CATCH-IT Consortium, which basically stands for Cancer Therapy Using Checkpoint Inhibitors in People Living With HIV-International Consortium. And this required a lot of effort from a lot of different centers, including those in the US, Europe, and Australia, as you mentioned. And then we ended up having data worth around 400 plus patients, close to 400 patients or so. And then we wanted to look at obviously outcomes, whether it's related to a certain tumor such as lung cancer, which we did in this case, or a pan tumor assessment of toxicities and safeties.  So, to your question, the cohorts that we basically had, we had close to approximately 390 patients that we included in the safety analysis. So first we looked at the safety analysis, which was the entire cohort, and then out of those we excluded around 12 patients or so. Those were patients that were treated in the adjuvant setting. So in the metastatic advanced setting, we had close to 378 individuals that we assessed clinical outcomes for. So, response rates, progression-free survival, and overall survival. And then as far as a separate cohort, we looked at non-small cell lung cancer, which was the most commonly represented tumor type, with approximately 111 patients that had non-small cell lung cancer. We did exclude a certain proportion of those that were earlier stage, stage III.  So in the stage IV, basically we ended up matching in this separate cohort, around 60 odd patients or so of non-small cell lung cancer to 110 stage four, non-small cell lung cancers. So basically it was a one-to-two matching and we chose the same site. So if a site had, let's say, two people with HIV and lung cancer treatment checkpoint, we tried to match it to approximately four to five patients from the same site and we used some variables for matching so that we had some level of homogeneity between the HIV patient population and the non-HIV positive lung cancer individuals. So that's basically cohort A was around 370-something patients, tumor agnostic advanced metastatic setting. Cohort B was lung cancer individuals matched to non-HIV positive lung cancer treatment checkpoint inhibitors. Davide Soldato: Thank you very much. That was very clear. Just to go back to what you were saying before because I think that this is very interesting. You mentioned that patients living with HIV were mostly excluded from clinical trials and in the few that included them, there were some restrictive criteria in terms for example of CD4-positive cells in the blood. And so I was wondering if when you included the patients inside of this cohort, you also had this type of exclusion criteria or you chose a broader population to make the results more generalizable and applicable in clinical practice.  Dr. Abdul Rafeh Naqash: Right, a very important question. Thank you, Dr. Soldato. So yes, previous clinical trials have had some level of restrictions as far as the inclusion of these individuals, but in our study, this was a real-world study, basically, patients whoever presents to the clinic with a history of HIV, they were all included. So we did not restrict it to certain CD4 counts or viral loads because the important thing was we wanted to understand the ground situation of how these individuals do, irrespective of some of these limitations. As far as what we identified as baseline CD counts or HIV viral load positivity, we took three months before immune checkpoint initiation as a cut off so obviously there's a limitation there. We didn't have results of these CD4, CD at a viral load assessments done like the day of or the week before in some patients. So we took three months and we included individuals that had received at least one or more dose of immune checkpoint therapy between January of 2015 to October of 2021, which was our database lock.  And then obviously the regimens included immune checkpoint anti-PD1, PD-L1 monotherapy, or in combination with other anticancer agents including anti-CTLA-4 or chemotherapies targets, which is important to point out here. So the trials that have been mostly done in this space are single-agent checkpoint inhibitors or anti-PD1 with anti-CTLA-4. There's not much data for immune checkpoint inhibition combined with other agents such as targeted therapies, chemotherapies. So we had some of that data in this cohort, which kind of made it interesting. Davide Soldato: Yeah, I think that it's very interesting and it's very wise to choose very broad eligibility criteria for these type of studies because it really answered to the question that we identified and that we spoke about in the beginning.  So going back to the results, you said that the cohort A, so the one that included all the patients, irrespectively of the type of tumor that was diagnosed, it was mainly for evaluating what was the safety of immune checkpoint inhibitors in patients living with HIV and with a concurrent cancer diagnosis. So I was wondering if in this cohort you identified some differences compared to historic data in terms of, for example, incidence of grade three or higher toxicities or incidence of immune-related adverse events in general, and if maybe there was some adverse events that was very characteristic or particular in this cohort. Dr. Abdul Rafeh Naqash: So immune-adverse events is a very interesting question not only from this cohort but in general because it overlaps with this question of autoimmunity and cross T cell cross reactivity. And this is a unique patient population where we have the ability, although not fully but to some extent, to look at the role for CD counts and also look for patterns of adverse events.  To answer your first part of the question, we didn’t see any significant differences for the types of adverse events. We did see the incident was a little lower than what you would expect in the real-world setting for non-HIV individuals. Whether that has something to do with how the immune system is constructed in these individuals, nobody knows. We did look at CD4 and CD8 counts. As far as absolute CD4 counts, about 200 or below 200, we didn’t see a difference as far as the cumulative incidence for immune checkpoint inhibitor-related adverse events. When we did a ratio of CD4 to CD8 of greater than 0.4 and compared it to less than 0.4, we did see that at around 24 weeks, there was a difference in terms of the cumulative incidence for adverse events. It was around 10% versus 26% when we use that cut-off of 0.4, suggesting that there might be some role of how the peripheral immune system results in the related adverse events in these individuals, but it’s a very important question.  I think there are ongoing evaluations that are being done from other prospective studies that had collected blood samples in these individuals. But generally, we saw the same range of adverse events, diarrhea, colitis, pneumonitis, hepatitis. We did have a few patients who had  a history of opportunistic infections, but we didn’t see any significant reactivation there which was part of the safety assessment in our analysis.    Davide Soldato: So basically, because I think that in HIV patients, even if those included in the study were almost all were on antiretroviral therapy, but you didn't observe any opportunistic infection that developed during the course of immunotherapy. Dr. Abdul Rafeh Naqash: You're absolutely right, we did not. In fact, we are trying to look at that in a different setting, in a different cohort because there have been some data on mycobacterial reactivation in individuals in general, not just HIV, but in our cohort of 400 odd patients, we did not see any new opportunistic infections. Davide Soldato: I think that one aspect that pops into my mind right now is also that we have kind of some data regarding also possible HPV reactivation in these types of patients treated with immune checkpoint inhibitors. So maybe that could be also something that you would be interested to look at in the future, I imagine.  Dr. Abdul Rafeh Naqash: Yes, we are planning to look at HPV-driven cancers actually for starters, anal and head and neck. We are also looking at hepatitis B-related HCC in a separate ongoing cohort. So there are definitely subsequent steps that we are currently involved in as far as viral-driven cancers and concurrent HIV is concerned. Davide Soldato: Thank you. I think that's very interesting. And I was wondering, you mentioned in the beginning that this patient clearly they have some degree of immune dysregulation or at least some type of dysfunction in terms of immune presentation and immune activation. So I think that one of the concerns or one of the worries of using immune checkpoint inhibitors in this population could also be that the efficacy that we see in patients that do not have HIV could be lower. Could you comment on this if you found any differences both in the cohort including all cancer, but also in the cohort B, that I think you had the strategic idea of pairing these patients living with HIV with patients that were not living with HIV. So I think that this brings very important data to the space. Dr. Abdul Rafeh Naqash: Yes, we tried to look at this one from a tumor-agnostic perspective and a tumor-specific perspective. So the tumor agnostic perspective was looking at a different set of cancers which included skin cancer, melanoma, lung cancer, non-Hodgkin's lymphoma, small cell head and neck, and a couple of other cancers. And one of the things we noticed was that there was a trend, so there was differential efficacy as far as the cancer type is concerned. So for example, skin, Hodgkin's lymphoma, Kaposi sarcoma, melanoma had the highest response rates, somewhere in the range of 60s to 40s. On the other hand, viral-driven cancers such as anal cancer, HCC, head and neck actually had very low response rates, less than 15% or so. So that begs the question of what is going on and we don't necessarily know, which is why we are trying to concentrate on the viral-driven cancers first. Because as you know, melanoma, Kaposi’s do have historically shown better responses to checkpoint inhibitors.   Now do we know if when we compare these responses or survival to non-HIV individuals in clinical trials, are the outcomes similar? I would say in some of the tumor types the outcomes were somewhat inferior and in some of the tumor types the outcomes were somewhat similar. So for example, lung, we did compare non-small cell lung cancer. As I mentioned, we had two cohorts, we matched it to a non-HIV cohort and there we looked at progression-free survival and overall survival. And again the caveat is that this is a retrospectively matched cohort, this is not a prospectively matched cohort. So these are individuals that are not matched for each and every variable. They're matched for certain top three or four variables as much as we could accommodate. And based on that we didn't see a difference in the progression-free survival and the overall survival when we did an assessment.  In fact, we looked at it at a 42 month period where we looked at the restricted median survival time and it was not different, was around 17.8% for people with HIV and 18.4% for people without HIV as far as progression-free survival, and around 42% and 41% overall survival at the two-year mark. So basically there is not much significant difference which reiterates the fact that in the right setting, these individuals could be safely treated with immune checkpoint inhibition and could perhaps have similar outcomes. Maybe not in all tumor types, but in some tumor types. But at the end of the day, and we mentioned this in our manuscript also in subsequent work that we are trying to do, we have emphasized on the fact that it has to be a multidisciplinary discussion between the patient, the physician, the medical oncologist, the treating oncologist, and the infectious disease person. Because these individuals have a lot of complicated aspects because of the underlying HIV and taking that into perspective and then assessing risk-benefit is an important discussion.  So the goal of this work was not to establish that immune checkpoint inhibitors are absolutely beneficial or absolutely safe. The goal was more to create awareness that people in the real-world setting actually can benefit, which the next step would be to have more trials and perhaps modify inclusion criteria in clinical trials so that you can have a more inclusive approach, including these individuals.  Davide Soldato: Coming back to the multidisciplinary approach because I think that this is very interesting and should be really implemented when we have this type of patient. From the data that you collected, did you add any indication that maybe this patient treated in the real-world setting were not managed in such a multidisciplinary way? Dr. Abdul Rafeh Naqash: The easiest way to point that out is that most of these people or many of these individuals did not have HIV viral loads or CD4 counts done before treatment initiation. And that's an indirect surrogate for telling you that these are things that should have been thought of, but were not thought of if the individual taking care of these people either did not have expertise as far as HIV is concerned or did not have a colleague on the infectious disease side who was actively managing these people.  So that's an important indirect way where we kind of got a sense that there has to be more awareness about multidisciplinary care. And especially the immune adverse event situation in these individuals can get complicated because of the way their immune system is constructed and having that multidisciplinary care is very important. We didn't specifically collect data on what teams or what subspecialists were involved in each individual's care, but I think that would be an important assessment for maybe a future quality improvement project to look at why or how some of those things were not done so that it can lead to future improvements. Davide Soldato: So, just expanding on that, you said that you didn't have much data in terms of CD4 cells or in terms of viral load. But for what you had inside of your cohort, did you see any modification of these parameters that we know that are very important in patients living with HIV under immune checkpoint inhibitors therapy? Dr. Abdul Rafeh Naqash: Again, a very important immunological question, I think as far as what we saw- so we had close to around 74, 75 individuals that had CD4 T cell counts available. And we didn’t see differences between baseline and post-immune checkpoint therapy changes in CD4 counts. Similarly, we didn’t see a difference as far as HIV viral load and we had HIV viral loads present in around 107 individuals and we didn’t see a difference. Now, again, 30% of our cohort was CD4 count less than 200, and 70% was CD4 count more than 200, , which is again, important to highlight because many trials don’t take individuals with the CD4 count less than 200. But in general, we did not see a difference in this pre and post-assessment both for viral load and both for CD4 count. Now trials in this space have ongoing assessments that they are doing. The AIDS Malignancy Consortium does have a trial looking at changes in CD4/CD8 counts or viral loads. In fact, the CITN trial which is a pembrolizumab trial published a couple of years back did have an assessment done as far as CD4 counts and viral loads are concerned. And I think they did see a slight increase in the CD4 counts and there are some aspects about how the immune system may change with an immune checkpoint inhibitor. But I think the strength of the data is not that much, and I think we probably need more patient samples to assess why or how some of that could change or what implications it would have for patients.  Now, there is another concept of HIV viral latency removal that some of the listeners might have heard of, especially in the HIV setting, where you were given an immune checkpoint inhibitor and it can lead to reversal or reduction of the HIV reservoir, which can somehow impact the CD4 counts, and also lead to elimination of the viruses through CD8. But again, that’s a more complicated assessment and we didn't have data for it.   Davide Soldato: Thank you very much. That was very interesting also for future perspectives in this topic.  I just wanted to ask you if the idea for the research came more from ensuring equity in terms of care delivery for patients living with HIV or if it was more also to investigate the immunological components that we discussed just as far or a good mix of the two. Dr. Abdul Rafeh Naqash: I think the idea actually stemmed from this individual who's the first author, Dr. Talal El Zarif and co-first author Dr. Amin Nasser from Dana-Farber, reached out a year and a half back and they wanted to look at outcomes from an HIV standpoint and see what the real world setting is. And the goal was they would have their data and we would have our data and we would eventually collect the data together or combine the data together. But then after some conversations, we started looking at the available data, the available literature, saw that there was a decent gap in what we know. And I know there are some brilliant groups in the HIV space, especially at the NCI. In fact, Dr. Kate Lurain and Dr. Ramaswami are good collaborators of ours and they worked in this space and are currently developing trials in this space. But it just did seem like this would be a more interesting approach of answering a real-world question and then also looking at the disparities of it because as an early-phase drug development trialist, I still see a lot of trials, in fact, majority of the trials, say people with HIV or history of HIV are excluded.  Now, the NCI has made important efforts in that space of including those individuals, but I think we still have some ways to go. So basically the idea came from two trainees who were extremely enthusiastic and wanted to pursue this. And I, obviously, seeing their level of enthusiasm and excitement, I was excited too. And then importantly, if you look at the paper, we have a bunch of authors, we have close to 79, 80 authors on that paper. And the primary reason was that each center contributed in certain ways, including patients' data and then expertise. And this ended up being a huge community effort from the oncology community, where everybody's individual effort led to something like this coming to fruition.  So it was a multitude of different aspects, but yes, it all started with a question of how these individuals do and the current data where they're missing gaps, and we wanted to sort of supplement those gaps and provide insights using this important real-world data set. Davide Soldato: Thank you very much for the insight on how the idea came to be.  Is there anything else you would like to add or to summarize for our listeners? Dr. Abdul Rafeh Naqash: Well, first of all, I appreciate the opportunity to discuss our paper here. I would like to thank you and of course the JCO staff for organizing this, and also the JCO Journal for giving us the opportunity to publish this important work. Some of the things that we would like to highlight as outcomes from this paper, as we sort of discussed, but to summarize those: we saw that we didn't have any significant safety concerns, obviously. We saw that some patients in certain tumor types do benefit, similar to what you might expect in a non-HIV setting in the real world as well.  And of course, this was the largest real-world data set of people with HIV and cancer. And we have ongoing efforts in different directions, as I mentioned to you. And we are more than happy to collaborate with anybody who has good ideas because this is a community-level data set. It was created for the community, by the community, and the goal is to utilize this data set. So if there is a listener out there who's interested in collaborating, who has an idea, we're more than happy to share the data set in the right setting. And then hopefully, everybody has the opportunity to lead different efforts in the space. Davide Soldato: Thank you again for being with us today, Dr. Naqash. To hear more from Dr. Naqash, please check out ASCO's JCO Precision Oncology Conversation Podcast.  So this is Davide Soldato. In this episode of JCO Article Insights, we discussed the results of the manuscript titled, “Safety and Activity of Immune Checkpoint Inhibitors in People Living with HIV and Cancer: A Real World Report from the Cancer Therapy Using Checkpoint Inhibitors in People Living with HIV-International Consortium.” Thank you for your attention and stay tuned for the next episode.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

Dr. Shannon Westin and her guest, Dr. Andreana Holowatyj, discuss the paper "Clinical Multigene Panel Testing Identifies Racial and Ethnic Differences in Germline Pathogenic Variants Among Patients With Early-Onset Colorectal Cancer," recently published in JCO. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of the JCO After Hours podcast, the podcast where we get in-depth on manuscripts and interesting papers that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, and it's my pleasure to serve not only as a GYN Oncologist but as an Associate Editor for Social Media for the JCO. And as always, I'm super excited about the paper that we're going to discuss today. This is “Clinical Multigene Panel Testing Identifies Racial and Ethnic Differences in Germline Pathogenic Variants Among Patients With Early-Onset Colorectal Cancer.” This has been published in the JCO. And I am so excited to be accompanied by the last author, Dr. Andreana Holowatyj, who is an Assistant Professor of Medicine and Cancer Biology at Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center.  Welcome. Dr. Andreana Holowatyj: Thank you, Dr. Westin, for having me. I'm really excited to get to talk about this paper. Dr. Shannon Westin: So are we. And please note that we do not have any conflicts of interest with this work.  So let's get started. First, early-onset colorectal cancer is any colorectal cancer diagnosed before age 50. So I just wanted to level set. Can you give us a bit of background on the incidence of early-onset colorectal cancer? Dr. Andreana Holowatyj: Sure. All of the attention recently has been drawn to the fact that in contrast to incidence of colorectal cancer decreasing among adults over age 50, we've seen over the last several decades, this uptick—alarming uptick, in fact, in colorectal cancers among individuals diagnosed younger than age 50 years, or, as you point out, we call early-onset colorectal cancer, largely with reasons that are unexplained overall, which has drawn a lot of concern and attention as to what are the factors driving this marked increase in early-onset colorectal cancer both in the United States and globally. Dr. Shannon Westin: And what do we know about the burden of early-onset colorectal cancer across different racial and ethnic groups? Are there disparities in survival like we've seen in some of the other cancer types? Dr. Andreana Holowatyj: Yeah. So recently, a paper published demonstrating this greater shift towards early-onset colorectal cancer, where now we're seeing approximately 1 in every 8 adults with colorectal cancer being diagnosed under age 50. Add to that prior studies have shown that the proportion of early-onset colorectal cancer cases or incidence is actually higher among individuals who identify as non-White compared to those who identify as non-Hispanic White. We previously published in JCO a paper that assessed disparities in survival among early-onset colorectal cancer patients and strikingly found that individuals who identify as non-Hispanic Black had poorer survival compared with non-Hispanic Whites, both in colon and rectal tumors, specifically for young individuals. However, and of striking interest, we did not see these survival disparities between Whites and individuals who identify as Hispanic, which further led us to question what may be some of the biological, environmental, and other factors that may actually be driving some of these disparities by race and ethnicity, both in incidence but also in outcomes. Dr. Shannon Westin: So that kind of brings us to this study. Will you walk us through what the objective of this study was? Dr. Andreana Holowatyj: Yeah. So the underlying question really is what could be the role of germline genetic features or germline predisposition in early-onset colorectal cancer disparities? We know from prior studies published in JCO and other journals that about 14%-25% of early-onset colorectal cancer cases have a germline predisposition. However, these populations have been of limited size and, more importantly, of limited diversity. So we really wanted to tackle that question to understand what is the prevalence and spectrum of germline genetic features in early-onset colorectal cancer by race and ethnicity. Are there differences? Where do these differences lie? And what can this information really tell us in better understanding the early-onset colorectal cancer burden? Dr. Shannon Westin: Well, now, well, just talk us through the design that you employed to achieve these objectives. Dr. Andreana Holowatyj: We were fortunate to partner with a nationwide clinical testing laboratory to identify individuals who were between the ages of 15 and 49 years when diagnosed with the first primary colorectal cancer over about a five-year study period. We were able to identify around 4,000, or specifically 3,980 individuals, who identified as non-Hispanic White, non-Hispanic Black, Hispanic/Spanish or Latino, Asian, or Ashkenazi Jewish who had clinical multigene panel testing uniformly for 14 genes that have a known susceptibility to colorectal cancer overall, to really examine the prevalence and spectrum of genetic features across these self-identified racial/ethnic groups.  Dr. Shannon Westin: And what was the overall prevalence of germline mutations in this population? And did it differ kind of overall in the different racial and ethnic groups? Dr. Andreana Holowatyj: Overall, the prevalence of germline genetic features when assessing 14 colorectal cancer susceptibility genes in this population was pretty consistent with prior studies at 12.2%, seeing about 1 in every 8 patients present with germline genetic predisposition. However, when we teased these numbers apart across racial/ethnic groups, what we saw is the prevalence of these germline genetic features ranged from 9.5% in individuals who identified as Asian to 10.3% of individuals who identified as Black, 12.4% as White, 12.7% for individuals who identify as Ashkenazim, all the way up to 14% of individuals who identify as Hispanic within this population. So we saw a wide—a decently wide breadth of prevalence across these racial/ethnic groups overall. Dr. Shannon Westin: And of course, as a gynecologic oncologist, I'm always centering myself and thinking about Lynch Syndrome. So how did the prevalence of mutations in the mismatch repair gene differ between racial and ethnic backgrounds? Dr. Andreana Holowatyj: So really interesting question. Overall, about 7% of individuals in our cohort presented with a pathogenic or likely pathogenic variant in the mismatch repair gene. But what we saw is that the prevalence of Lynch Syndrome varied from 3% or so of Ashkenazim individuals all the way up to 9.9% of Hispanic individuals. We saw that variance in MLH1 strongly differed across racial/ethnic groups, particularly in the Hispanic population, that accounted for some of these differences. Dr. Shannon Westin: And then were there any differences in some of the other germline mutations that you explored? Dr. Andreana Holowatyj: Yeah, we also observed differences in the prevalence of APC mutations, although largely attributable to the p.I1307K variant in Ashkenazim individuals, as well as CHEK2, monoallelic MUTYH, and PTEN. Dr. Shannon Westin: Okay. Interesting. I was intrigued about those findings for the monoallelic MUTYH variants. Do you think we should be potentially doing increased screening in specific populations based on your results? Dr. Andreana Holowatyj: Yeah, so I think to kind of put this into context, most people probably know that biallelic MUTYH variants yield MUTYH-associated adenomatous polyposis and, of course, confer a strong increased risk of colorectal cancer development. In monoallelic carriers of MUTYH variants, there really is limited evidence to guide clinical management, and this is an evolving area. Per NCCN guidelines, unaffected individuals with a monoallelic MUTYH pathogenic variant and a family history of colorectal cancer in a first-degree relative are recommended to get colonoscopy screening every five years beginning at age 40 or 10 years prior to the age of that first-degree relative of colorectal cancer diagnosis.  However, for individuals with a monoallelic MUTYH variant and no known family history of colorectal cancer, it's inconclusive as to whether specialized screening and surveillance are warranted. Current studies conducted in European or predominantly White populations have reported conflicting evidence as to whether there is an increased colorectal cancer risk for carriers of a monolithic MUTYH pathogenic variant. I don't think we're quite there yet to make a conclusive decision on whether increased screening is warranted in the population or not. I think the evidence is leaning towards potentially seeing not a strong increased colorectal cancer risk, but we'll have to wait and see on some additional studies to be conclusive in that area. Dr. Shannon Westin: I was also intrigued—the lack of difference in germline features between Blacks and Whites was stark. I mean, why do you—what do you think might have led to us not seeing a difference there? Dr. Andreana Holowatyj: I think there's potentially two avenues for this. I want to caveat the fact that this could be attributable to a limited sample size. Although we had about over 1,000—just over 1,000 individuals who identified as non-White, there's still potential selection bias in this cohort. However, we have included about a comparable number of individuals who identified Blacks and Hispanics herein, which does raise this question of we see differences in germline genetic features between Whites and Hispanics, but the lack of difference between individuals who identify as White and Black kind of yields possibly two avenues. If germline genetic features do contribute to racial/ethnic differences in early-onset colorectal carcinogenesis and outcomes, then there's a chance that we have not yet identified ancestry-specific variants associated with early-onset colorectal cancer. This has marked implications in the development and equitable design of multigene panel tests.  However, we also know that beyond genetics, the interplay with biology, social determinants of health, and behaviors could also underlie these distinct patterns. We recently demonstrated in a separate paper that we see actually differences in the tumor mutation burden between individuals who identify as Black or White, which is supporting the idea that a distinct tumor biology may be driving early-onset colorectal cancer disparities. And if there are no germline genetic features, then the question is really how does that interplay of the environment—some of these other complex interrelated factors, how could that be driving disparities in early-onset colorectal cancer incidence and outcomes, particularly for individuals who identify as Black? Dr. Shannon Westin: And I guess that kind of leads to my next question. The testing platform that you studied, is it all-inclusive? Are there other mutations that might be relevant, or just we don't know yet? Dr. Andreana Holowatyj: Yeah. So I think one of the advantages of this study is that all individuals had clinical multigene panel testing for the 14 genes that we evaluated overall. However, while that's a strength of the study, it's also a limitation, given that we only queried 14 genes with unknown colorectal cancer susceptibility, which really is a first step, yet a key step, in further studies and supporting further discovery of potential ancestry-specific variants or genes associated specifically with early-onset colorectal cancer predisposition. Dr. Shannon Westin: That makes a lot of sense. And I guess that's the next kind of natural question is so what do we do next, right? Where do we go? How do we move this forward? Dr. Andreana Holowatyj: Yeah. So I think one of the advantages of this approach and being fortunate to partner with the clinical testing laboratory is that the study was nationwide among individuals who, of course, had multigene panel sequencing. But at the same time, we were able to accumulate a sufficient number of cases to be able to study these patterns across population groups. I think the natural next step from multigene panel testing is based upon these findings to move into clinical exome sequencing to be able to not only move towards identifying genetic ancestry, since that's, of course, the biological construct—and I would be remiss if I didn't acknowledge that race and ethnicity is a social construct but was all that was available in the context of this present study—but also will allow us to query the entire exome and understand and dive deeper into some of these questions: variants of uncertain significance and also potential ancestry-specific variants. Dr. Shannon Westin: Well, great. Well, this is super intriguing, and I know this is going to get a lot of excitement and attention from our readership. So I just want to thank you again for taking the time to review this really important paper, “Clinical Multigene Panel Testing Identifies Racial and Ethnic Differences in Germline Pathogenic Variants Among Patients With Early-Onset Colorectal Cancer.” Again, I'm Shannon Westin, and I'm just so grateful that everyone came to listen to JCO After Hours. Please do check out our website for other podcasts you might have missed. Have a great one.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

In this JCO Article Insights episode, Emily Zabor summarizes two original articles from the June 1st, 2023 Journal of Clinical Oncology issue: “A Clinical Genetic Risk Score for Predicting Cancer-Associated Venous Thromboembolism: A Development and Validation Study Involving Two Independent Prospective Cohorts”  by Muñoz et al,  and “Derivation and Validation of Clinical Risk Assessment Model for Cancer Associated Thrombosis in Two Unique Healthcare Systems” by Li et al, as well as the accompanying editorial “Fine Tuning Venous Thromboembolism Risk Prediction in Patients with Cancer” by Jean Marie Connors. The original reports describe the development and validation of two new risk prediction models for venous thromboembolism in cancer patients and the editorial puts them into context of existing tools. TRANCRIPT  The guest on this podcast episode has no disclosures to declare. Emily Zabor: Welcome to JCO Article Insights for the June 1st, 2023 issue of JCO. I'm your host, Emily Zabor, JCO Biostatistics Editorial Fellow. Today, I will be providing summaries of three articles.  The first article, titled “A Clinical Genetic Risk Score for Predicting Cancer-Associated Venous Thromboembolism: A Development and Validation Study Involving Two Independent Prospective Cohorts” by Andres Muñoz and colleagues, describes the development and validation of a risk score for venous thromboembolism in oncology patients based on both clinical and genetic features, called the ONCOTHROMB score. In developing this model, the authors sought to address the fact that venous thromboembolism is among the leading causes of death among patients with cancer. Whereas hospitalized cancer patients are typically treated with thromboprophylaxis, outpatient treatment with thromboprophylaxis is only suggested for patients at high risk for venous thromboembolism identified according to the Khorana score.  The authors sought to determine whether incorporation of known genetic risk factors along with clinical factors would result in improved predictive accuracy. The risk score was developed in a cohort of 364 patients and was validated in an external cohort of 263 patients. The primary outcome of interest was venous thromboembolism within six months of a cancer diagnosis. The authors used logistic regression with backward selection with a p-value threshold of 0.25 to first select the genetic variants to include in the genetic risk score and then to separately select the clinical features to incorporate. Then the genetic risk score and clinical features were combined into a single multivariable logistic regression model, and backward selection was performed again.  The final model included nine genetic variants, tumor site, TNM stage, and a BMI of greater than 25. In the validation data, the ONCOTHROMB score using a threshold selected with the Youden index resulted in an AUC of 0.686 as compared to an AUC of 0.577 for the Khorana score with a threshold of 3. The ONCOTHROMB score had statistically significantly higher sensitivity, whereas the Khorana score had statistically significantly higher specificity. The authors conclude that the ONCOTHROMB score demonstrated improved predictive ability and should be investigated further in clinical trials.  The second article, titled “Derivation and Validation of Clinical Risk Assessment Model for Cancer Associated Thrombosis in Two Unique Healthcare Systems” by Ang Li and colleagues, describes the development and validation of a risk assessment model for venous thromboembolism, pulmonary embolism, and lower-extremity deep vein thrombosis in oncology patients undergoing systemic therapy. The authors developed this model to address the increased morbidity and mortality associated with venous thromboembolism among cancer patients and the fact that risk reduction for use of thromboprophylaxis as well as the efficacy-safety trade-off, and cost-effectiveness have been shown to be higher among patients selected as high risk for venous thromboembolism.  The primary outcome was venous thromboembolism within six months of treatment initiation. In the development data set, the authors used lasso-penalized logistic regression analysis to shrink some of the covariates to zero as a form of variable selection, then a multivariable logistic regression model was fit to the remaining covariates and those with an estimated odds ratio greater than 1.2 or less than 0.8 were retained in the final model. A linear risk score was created from the resulting beta coefficients. The risk assessment model was developed in a cohort of 9769 patients and validated in an external cohort of 79,517 patients. The final model included eleven factors: cancer subtype, pre-therapy BMI greater than or equal to 35, pre-therapy white blood cell count greater than 11, pre-therapy hemoglobin less than 10, pre-therapy platelet greater than or equal to 350, cancer staging 3 to 4, targeted or endocrine monotherapy, lifetime history of venous thromboembolism, history of paralysis and immobility in the last 12 months, recent hospitalization lasting greater than three days in the last three months, and Asian Pacific Islander race.   The final linear risk score was stratified into six categories and then dichotomized based on overall venous thromboembolism incidence of 7%, resulting in about half of the patient population being classified as high risk for venous thromboembolism. In the validation data, the model was associated with a c-statistic of 0.68 as compared to 0.6 for the Khorana score with a threshold of 2. Sensitivity analyses demonstrated that the model had similar discrimination in subgroups according to age, sex, and race-ethnicity. The authors conclude that their new risk assessment model has the potential to improve patient selection for thromboprophylaxis. The third and final article titled “Fine Tuning Venous Thromboembolism Risk Prediction in Patients with Cancer” by Jean Marie Connors, is an editorial accompanying the two previously summarized articles. Dr. Connors emphasizes that venous thromboembolism is the second leading cause of death in cancer patients, second only to cancer itself, and that while treatment with thromboprophylaxis has been shown to significantly reduce the occurrence of venous thromboembolism in randomized controlled trials, since the overall risk of venous thromboembolism is so low, treating all patients would result in significant overtreatment. Therefore, prediction tools are needed and many have been developed, with the Khorana score being the most widely used because it is the best validated and easy to calculate.   Dr. Connors observes that in the risk assessment model by Li and colleagues, more granularity is added to the  Khorana score by stratifying gastrointestinal cancer subtypes and by adding aggressive NHL, myeloma, brain tumors, and sarcoma, and also incorporates additional cancer-specific and patient-specific risk factors. But while this risk assessment model reclassified approximately 25% of patients in both the development and validation sets, as compared to the Khorana score, there was only modest improvement in discrimination. With the c-index improving from 0.65 to 0.71 in the development set and from 0.6 to 0.68 in the validation set from the Khorana score to the new risk assessment model.   On the other hand, the ONCOTHROMB score developed by Muñoz and colleagues contains fewer clinical features as compared to the Khorana score but adds a genetic risk score based on eleven genetic variants. The Khorana score performed quite poorly in both the development and validation data in this study, with AUCs of just 0.58 and 0.56, so improvements to 0.781 and 0.720 were relatively large. Connors notes that prospective validation of both scores is still needed, especially of the ONCOTHROMB score in more diverse populations, as allele frequencies can vary widely and the studied populations were predominantly Western European. Connors cautions that there is still a need to demonstrate mortality benefit from venous thromboembolism prophylaxis and that the risk of bleeding and other complications must be properly weighed against the benefits.  That concludes this episode on the articles “A Clinical Genetic Risk Score for Predicting Cancer-Associated Venous Thromboembolism: A Development and Validation Study Involving Two Independent Prospective Cohorts” and “Derivation and Validation of Clinical Risk Assessment Model for Cancer Associated Thrombosis in Two Unique US Healthcare Systems,” and the associated editorial, “Fine Tuning Venous Thromboembolism Risk Prediction in Patients with Cancer.” Thank you for listening and please tune in for the next issue of JCO Article Insights.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Like, share, and subscribe so you never miss an episode and leave a rating or review.  Editorial:   Fine Tuning Venous Thromboembolism Risk Prediction in Patients With Cancer Derivation and Validation of a Clinical Risk Assessment Model for Cancer-Associated Thrombosis in Two Unique US Health Care Systems A Clinical-Genetic Risk Score for Predicting Cancer-Associated Venous Thromboembolism: A Development and Validation Study Involving Two Independent Prospective Cohorts Original Report:   Find more articles from the June 1 issue  

Dr. Shannon Westin, Dr. Lakshmi Sandhya, and Dr. Prasanth Ganesan discuss the use of olanzapine to treat chemotherapy-related anorexia, as recently published in JCO. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on manuscripts published in the Journal of Clinical Oncology. As always, I'm your host, Dr. Shannon Westin, GYN Oncologist and Social Media Editor for JCO. I'm very excited to be here today.  And please note that our participants do not have any conflict of interest.   So we are going to discuss a really exciting paper today entitled the "Randomized, Double-Blind, Placebo-Controlled Study of Olanzapine for Chemotherapy-Related Anorexia in Patients with Locally Advanced or Metastatic Gastric, Hepatopancreaticobiliary, and Lung Cancer." And this was published in the JCO on March 28, 2023, and has gotten a lot of excitement.  And so I'm very thrilled to have two of the authors with me today. First is Dr. Lakshmi Sandhya. She's a Junior Consultant at the SVICCAR Hospital in Tirupati, India. Welcome, Dr. Sandhya. Dr. Lakshmi Sandhya: Thank you so much for the opportunity to be here. Dr. Shannon Westin: And I also have the senior author here today, Dr. Prasanth Ganesan. He is a Professor in the Department of Medical Oncology at JIPMER, which is the Jawaharlal Institute of Postgraduate Medical Education and Research in Puducherry, India. Welcome, sir.  Dr. Prasanth Ganesan: Thank you. Thank you very much, Dr. Westin. It's good to be here. Thank you very much.  Dr. Shannon Westin: Great to have you both. So we're going to get right to it. I think this is an excellent paper and certainly something we see across many of our patients who are diagnosed with cancer and who are receiving treatment for cancer. But first, I want to level set. What is the true definition of chemotherapy-related anorexia, and really approximately how many patients do you think it impacts?  Dr. Prasanth Ganesan: As you know, anorexia itself is very common in advanced cancers. Almost like maybe 80%, 90% of patients have some form of anorexia. But at diagnosis, it depends on the type of cancers. Very high in upper GI cancers, esophagus, stomach, pancreas, or lung cancer. But when we talk about chemotherapy-related anorexia, we specifically mean anorexia that is brought on or probably worsened by chemotherapy. So this depends a lot on the regimen that is used. So studies in lung cancer, upper GI cancer that have used something like platinum agents, maybe as high as 50% to 80%. Now, the challenge is how much of it is contributed by the underlying cancer itself and how much of it is worsened by the chemotherapy. It's tough to say, but I think we all have seen that chemotherapy does kind of really increase the anorexia in many of these patients. So I would say the problem is common. Depends on the type of cancer, the type of agent being used, and also sometimes on how intently we are looking for it. Dr. Shannon Westin: You bring up a great point in really kind of making sure that we're screening our patients for it and understanding who's actually experiencing those things. And I do think putting it on our list of things that we, on a day-to-day basis, discuss with our patients is really relevant, although I will say sometimes we haven't done that because we don't have a good treatment. So that's what makes your paper so exciting. But before we get into the results of the paper, why don't we talk a little bit more about some of the factors that contribute to anorexia? Dr. Sandhya, I don't know if you want to elaborate a little bit on some of those. Dr. Lakshmi Sandhya: Yeah. So most important would be the cancer type and the type of chemotherapy agent being used. So, as we mentioned, some cancer types have high anorexia incidence even at baseline. So the most important and prominent would be the upper gastric cancers and the pancreatic and lung cancer. Among the chemotherapy types, I think the platinum agents are known to cause anorexia more often and also associated with nausea or vomiting. So anorexia and weight loss is not very common in other cancers like breast, if you see, or ovarian cancer during the therapy. In fact, there has been weight gain in most of the patients with breast cancer, and most of the data which comes from breast cancer show that weight loss is experienced only by around 5% of the patients. So we would say the factors contributing most commonly would be the type of cancer and the chemotherapy that is being used.  Dr. Shannon Westin: Yeah, I think it's a great point. As a gynecologic oncologist, we do a lot of platinum, but we balance it, especially in upfront with paclitaxel or taxanes and we're giving steroids as premeds for them. And so we definitely see patients expecting to lose weight and instead actually getting hungry with the steroid use and eating to some degree.  Dr. Prasanth Ganesan: So I just want to add that even targeted agents, when you use something like sunitinib or everolimus, some of these agents, even they have got anorexia, probably 20% to 30%. So we did not include them in our study, but I'm just saying that even with targeted agents, we do get anorexia, at least some of them. So it's a problem across them. Dr. Shannon Westin: Yeah, we've been using PARP inhibitors and definitely can see that nausea, vomiting, and anorexia in that population. So I appreciate you making a point that that wasn't included but could be potentially extrapolated here. And then I guess the other question that I have is how does anorexia impact cancer-related outcomes? Does it have an impact in that way? Dr. Prasanth Ganesan: I believe it does, but it's probably not in a direct sort of way. So anorexia is strongly associated with weight loss and some amount of cachexia, and weight loss per se has been associated with poor outcomes across the board. There's a lot of data, especially in lung, upper GI cancers, and even head and neck cancer where weight loss before or during therapy has been associated with poor survival impact. So, again—in pancreatic cancer, it’s associated with poor survival. So it’s difficult to pin the weight loss only on anorexia here because weight loss is often multifactorial, but yeah, anorexia is probably a significant factor which is also adding to that. So I would say indirectly, yes, anorexia has an impact on cancer-related outcomes. Yes.  Dr. Shannon Westin: And I guess just getting into kind of what we can do before we get into the novel findings in your study, I know we've tried to talk about some dietary-related interventions that we can utilize to combat anorexia. Anything that you all have found to be most helpful from a diet standpoint?  Dr. Lakshmi Sandhya: So, from the diet standpoint, I would say dietary counseling is generally recommended for all the patients. To be very frank, we don't usually have a dietitian to spare at our outpatient clinic to counsel all the patients. So this is not something we are able to practice in the clinic. But in this trial, of course, we had a dietitian who counseled all the patients, and she gave them a diet chart to follow and gentle advice on what item to use and which is good, specifically emphasizing on high-calorie and high-protein diet. So we did not find that any particular dietary intervention is impactful. If you’ve seen various studies on dietary intervention, they have shown mixed results on improvement of anorexia or weight gain. So we're not sure whether dietary counseling particularly has impacted the results. Dr. Prasanth Ganesan: Yes. Dr. Shannon Westin: Okay. And then I imagine that would be one of the reasons that led to your exploration of this agent of olanzapine to treat chemotherapy-related anorexia. And can you just walk us through any data that existed kind of prior to your study to support this work? Dr. Prasanth Ganesan: Yeah, definitely. I think olanzapine has been in the news for the last decade or so because we've been using it consistently for vomiting and nausea in patients getting emetogenic therapies. So there are at least three studies which we found for olanzapine in cancer anorexia. I think one was from Dr. Navari, and he had done a randomized trial comparing megestrol with megestrol plus olanzapine. And this was done in patients with advanced cancers, and they found about 35% of the patients in the olanzapine group had additional weight gain. So it was useful. And this was not a very recent study. It's almost done about 10 years back. Dr. Shannon Westin: Oh, wow. Dr. Prasanth Ganesan: Then, after that, there was an interesting phase I study by Dr. Naing, and that was from MD Anderson, and that looked at various doses of olanzapine also. And that was interesting for us because that's where we got our starting dose of 2.5 mg because even at this dose, there was an effect on anorexia. So that was a very useful study because we were also trying to figure out what is the best dose to use in our trial. So that's why we went with the 2.5 mg.  Dr. Shannon Westin: That's great. I know everyone's excited to hear about the results. So, Dr. Sandhya, do you want to walk us through the design of the study and maybe how you chose your patient population? I think you've already kind of hinted at it, taking people that at baseline have high levels of anorexia.  Dr. Lakshmi Sandhya: Yes, sure. So this was designed as a phase III randomized blinded trial. So we used olanzapine in one arm and the matched placebo in another. So we gave olanzapine at a dose of 2.5 mg once a day for 12 weeks. And similarly, a placebo which looked similar was given to the other group. So we assessed for weight gain as an objective measure and improvement in appetite as one of the endpoints, which is more of a subjective measure. And we wanted to focus on population where the problem of anorexia was maximum. So we focused on upper GI, lung and pancreas, and biliary tract cancers to make it more uniform when it comes to anorexia. Dr. Prasanth Ganesan: Just to add a point that, even though we had included three or four types of cancer, almost 60% of our patients were actually gastric cancer patients because that probably reflects the profile of patients that we see at our center. It's a very common cancer in our place, and the next common was the lung cancer. We had only about 15% of patients who had pancreaticobiliary cancer. Dr. Shannon Westin: That makes sense. Obviously, wherever we're enrolling is what we're going to see, but I think hopefully these data can be extrapolated across all cancer types. So you mentioned that your primary endpoint was weight loss as well as the improved appetite. Can you walk us through, Dr. Sandhya, what you found? What were your results? Dr. Lakshmi Sandhya: So we had two primary endpoints. One was weight gain, and the other was improvement in appetite. So we wanted to use weight gain, as I said, since we felt that it is more of an objective measure than measuring anorexia. And olanzapine in our trial improved weight more than 5% from baseline in 60% of the patients in the olanzapine group and 9% in the placebo. Correspondingly, we have also measured improvement in appetite by using various questionnaires, which are validated. So one was visual analog scale, and the other was FAACT AC subscale, which we used during this trial. So yes, olanzapine worked well. We had hoped to show improvement in weight in about 30%, but surprisingly, we found that the weight gain was about 60% in the olanzapine group.  Dr. Shannon Westin: That's so great. It's always nice when you outperform your wildest dreams. So congratulations. Were there other secondary endpoints you observed that were impacted by the olanzapine?  Dr. Prasanth Ganesan: Yeah. So we did have a bunch of secondary endpoints because, again, we were worried when we started off because this is a subjective endpoint and we're not really sure how it's going to pan out. So we looked at some endpoints like quality of life, obviously, and we also had some nutritional assessment with the SDA and consistently, all of these showed improvement with the olanzapine. And what is most interesting for us was the grade III/IV side effects of the chemotherapy regimens, and these were reduced in the olanzapine. So this was something which we were looking for because consistently—we had also done some earlier studies in elderly populations where we found that the nutrition was an important factor in determining the toxicities of therapy. So that's why we wanted that as an endpoint.  And in fact, we found that patients who started at lower doses in cycle one due to poor performance status and nutrition, many of them could actually increase their dose in their subsequent cycles and this was more commonly seen in the olanzapine arm. So this was something which was very pleasant and which was something which we found was very interesting. So we could deliver more better chemotherapy intensity in these patients, thanks to their better nutrition.  Dr. Shannon Westin: That's so exciting. Such a nice concrete thing for patients as well. I mean, obviously being able to gain weight is something that they could see and having that appetite, but knowing that they had less side effects from their chemo as well is such an important impact. I guess, on the converse side, were there any negative impacts to the olanzapine?  Dr. Lakshmi Sandhya: Not really. We specifically asked patients about olanzapine-induced side-effects like drowsiness. At this dose of 2.5 mg per day, we found very little side-effects which would be attributed to olanzapine. As we mentioned, overall side-effects were also lowered in olanzapine arm. So with short duration of three months and at this dose, we believe that olanzapine is fairly safe. Dr. Shannon Westin: And that’s great. And I’d be remiss—especially here in the States, this is high discussion around financial toxicity. As I recall, it’s a pretty inexpensive agent. Is there any kind of negative financial impact for the use of this drug?  Dr. Prasanth Ganesan: Yeah, this is the best part. In India, for three months, olanzapine costs about 300 rupees. That would be like $4 or something for three months of therapy. I think that's pretty easily affordable across the board. Most patients here can easily buy this. And I'm not sure about the cost in the US, but I'm guessing it would not be too high. It's been around for some time. It should be out of patent and things like that. So I think it's a very inexpensive drug.  Dr. Shannon Westin: Yeah, we like that, like reuse of an old drug to do something good. The other question I had for you all is just any thoughts about how these results might compare to other things that we use, like glucocorticoids or progestational agents? I know we didn't have that as a comparator, but just your thoughts on that. Dr. Prasanth Ganesan: So, in terms of efficacy in reducing anorexia, it's difficult to compare because, if you see the studies of steroids and megestrol, most of them have been done by patients with more advanced cancers, not necessarily patients who are getting chemotherapy in the front line. But we think the side-effect profile is what gives an advantage to olanzapine because three months of steroids, even if you say lower doses of dex at 4mg or something, which I would want to use in a newly diagnosed cancer patient. Megestrol also seems to have problems like DVT and is actually much more expensive, at least in our context. I mean, if you compare with these aspects, I would definitely put olanzapine ahead, but as you said, this is not a direct comparison between those so-called existing agents. Dr. Shannon Westin: Yeah, I think that's a very thoughtful answer, but I think something we just needed to cover, even though we know that it wasn't a randomized trial between those two. Any limitations, Dr. Sandhya, on these results? Anything that you wish you had done a little differently? Dr. Lakshmi Sandhya: Yeah. As such, it is applicable only in the context of upper GI and lung cancers, as we have mostly included upper GI and lung cancers, and most of the patients, almost two-thirds of the patients included in our study, were gastric cancers. So also the duration that we used was only for 12 weeks. So we don't know whether longer duration will benefit more or harm. And the sustainability of weight beyond 12 weeks, we have not actually looked into. So, yeah, maybe these are few limitations that we can think about. Dr. Shannon Westin: That's very true. And I think that—I mean, obviously, when we design trials, we have to have a limit. Do you have plans—are you able to follow these patients out a little further? Do you know if clinically they're continuing it off-trial?  Dr. Prasanth Ganesan: So we have done that. So we have been following them for their survival data, and we just completed the analysis. So I think we have to really publish that next. So it is looking interesting. So some interesting data there. So that's something which we found it very exciting. Dr. Shannon Westin: Okay, good. Dr. Prasanth Ganesan: So that is something which is out there. And we also looked at some data on improvement of their muscle mass and on their CAT scans, we looked at that. So that's also something which we are trying to analyze and see whether we can have more concrete or objective endpoints in terms of improvement of the muscle mass and adipose tissue and things like that. Dr. Shannon Westin: Okay, good. Well, we'll look forward to that in a future version of the JCO, I hope. I guess the last thing is where do we go from here? You kind of hinted at this a little bit. I'm kind of bummed because I was ready to start implementing this in my clinic tomorrow. Dr. Prasanth Ganesan: So it's just safe, it's effective, and it's cheap. So I don't see any reason we should not start implementing something like this straightaway. I use it quite commonly, definitely for patients who are part of the trial population. And even for any patients with advanced cancer on or off chemotherapy with anorexia or weight loss, I'm comfortable to use olanzapine at least for a short term. And many patients at least they come back and say that it does help them. And I've not seen any side-effects at this dose of olanzapine. So it seems very safe to use. I'm comfortable to put it in the clinic right away.  Dr. Shannon Westin: Dr. Sandhya, what do you think?  Dr. Lakshmi Sandhya: I feel, in this trial, we came across the safety part of it and also the affordability part of it, and definitely it has been very encouraging results, so yeah. So, day-to-day practice, it can be used. Dr. Shannon Westin:  Well, great. I think this is super-educational, and I hope everyone else is just as convinced as I am how important this work was and how potentially impactful it will be for our patients. I just want to again thank these wonderful physicians and researchers. Dr. Sandhya, Dr. Ganesan, thank you so much for your time and a little bit of a late time for this taping across the globe. So thanks again for being here. Dr. Prasanth Ganesan: Thanks, Dr. Westin, for giving us this chance.  Dr. Lakshmi Sandhya: Thank you so much. Dr. Shannon Westin: So, again, y’all, this has been JCO After Hours discussing the important paper, "Randomized Double-Blind Placebo-Controlled Study of Olanzapine for Chemotherapy-Related Anorexia in Patients With Locally Advanced or Metastatic Gastric, Hepatopancreaticobiliary, and Lung Cancer,” published March 28th, ‘23. We are just so grateful that you joined us and hope you'll check out the other podcast offerings on the website. Take care. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Host Dr. Shannon Westin interviews guests Dr. Ethan Basch and Dr Deborah Schrag on their JCO simultaneous publication paper at ASCO's 2023 annual meeting: "Patient-reported outcomes during and after treatment for locally advanced rectal cancer (Alliance N1048). TRANSCRIPT The Disclosure for guests on this podcast can be found in the show notes  Dr. Shannon Westin: Hello, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on articles that are published in the Journal of Clinical Oncology. It is your host, Shannon Weston, GYN Oncologist and Social Media Editor for the JCO. And I'm so thrilled to bring you our first podcast that will be a simultaneous podcast JCO publication and ASCO presentation at ASCO 2023, dropping on June 4, 2023. And it is an exciting one. We'll be discussing “Patient-reported Outcomes During and After Treatment for Locally Advanced Rectal Cancer: The PROSPECT Trial Alliance N1048” (10.1200/JCO.23.00903)  And let me introduce both of these amazing people that are going to be with us today. First is Dr. Deborah Schrag. She's the chair in the Department of Medicine at Memorial Sloan Kettering Cancer Center in New York City, New York. Welcome. Dr. Deborah Schrag: Thank you.  Dr. Shannon Westin: And then I'm also accompanied by Dr. Ethan Basch, the Chief of the Division of Oncology and Physician in Chief at NC Cancer Hospital at the University of North Carolina, Chapel Hill, North Carolina, my alma mater. So welcome.  Dr. Ethan Basch: Thanks, Shannon. Nice to be here. Dr. Shannon Westin: And this is a good one. I was really intrigued by this work and I can't wait to talk about this with the audience, and I think that you're going to get a lot of excitement around this. So let's dive right in. I think we should start, first, let's speak a little bit about the role of patient-reported outcomes, assessing patient experience, especially as it relates to the evaluation of new therapies. Dr. Ethan Basch: Yeah, I'm happy to take that question, and thanks for asking it. All of us who practice oncology or accrue to trials recognize that patients receiving cancer treatment are highly symptomatic, either from their disease or from the sequelae of treatment. And as such, assessing and managing symptoms is really a cornerstone of what we do as oncology providers or investigators. But unfortunately, there's now abundant evidence that we as clinicians or investigators miss many of the symptoms and side effects that our patients experience, in fact, up to half of them. And so over the years, there have been a number of strategies developed to try to bridge this gap to fill in the pieces. And patient-reported outcomes is the one that has emerged to fill this gap, by informing us about the experiences of our patients. And without patient-reported outcomes and trials, we really have an incomplete understanding of the properties of products, the experiences of patients. And so when we are trying to do a risk-benefit assessment, for example, from data in a clinical trial, if we don't have patient-reported outcomes, we actually have an inadequate assessment of what was happening on the ground in that trial, particularly when it comes to adverse event assessment.   Dr. Shannon Westin: I think it's been great how we've been able to start incorporating these more. But before we go too far down that line, this study was particularly done in rectal cancer and we have a very diverse audience. And so just to level set, can one of you speak a little bit about the current standard of care for locally advanced rectal cancer?  Dr. Deborah Schrag: So, rectal cancer has a nasty tendency to come back in the pelvis. And Shannon, you're an OBGYN, so you know how miserable that can be. These are called locally recurrent cancers and they are just miserable. They cause a great deal of symptoms and a great deal of suffering. And back in the 1970s and ’80s, a strategy to treat pelvic or local recurrence of rectal cancer was developed and that strategy was radiation. And it used to be that 10%, 20%, even 30% of patients who had rectal cancer surgery would have a cancer come back. And these were people who couldn't sit down, constant pain, leaking, trouble urinating, trouble moving their bowels.  Radiation was a tremendous innovation. Radiation has been part of the management of locally advanced rectal cancer since 1990. Since 2004, we've given that radiation before surgery in the neoadjuvant setting. So this has been the predominant way that we treat these cancers really for the last two decades. We give about five and a half weeks of chemotherapy and radiation. Patients then have surgery, recover from the surgery, and many, not all, go on to receive some postoperative chemotherapy. It depends a little bit on what's found at surgery. But those three phases, the chemoradiation phase first, followed by surgery, followed by chemotherapy has been the prevailing care standard.  When we launched this trial, we wondered whether we could improve upon that and whether we could capitalize on some of the innovations and discoveries, and advances that have taken place in the past couple of decades. Development of better surgical technique, better chemotherapy, better imaging. And that was really what this trial was about. But the key thing is really what Dr. Basch said at the outset. We cure these patients. More and more often, we cure these patients. And so we want people to live not just long, but well. And so we really have to pay close attention to the symptoms. And the only way we could do that was by actually asking patients to tell us what their symptoms were, both during the acute phase of treatment as well as longer-term as they were followed up and recovered.  Dr. Shannon Westin: Thank you so much. So I think this is a great time for us to just talk very briefly about the overarching PROSPECT trial. What were the two arms and how did it impact standard of care? Dr. Deborah Schrag: Essentially, the two groups in PROSPECT were a chemo first and radiation only if you need it group, that was the experimental group. And the standard control group was the chemotherapy and radiation for everybody. So the chemo and radiation therapy group involved our typical 5040 centigrade worth of pelvic radiation given over five and a half weeks. So Monday to Friday for five and a half weeks with some sensitizing fluoropyrimidine chemotherapy, and physicians and patients could choose whether that was given as oral capecitabine or as intravenous 5-FU, they work just the same, followed by surgery. So that's the standard group. The experimental group received six cycles of a very common chemotherapy regimen used in gastrointestinal cancer, FOLFOX, and gave that regimen six times two weeks apart, followed by restaging with a pelvic MRI and examination by the surgeon. If patients were responding and the tumor had decreased in size by at least 20%, patients could go straight to the operating room. But if patients were poor responders to chemotherapy, they had a second chance, if you will, to get the chemoradiation. We call that group the chemo first with selective chemoradiation group. That was the intervention. And we followed patients and our outcome was disease-free survival. And we have about five years of follow-up in our patients. So this is a very mature study.  Dr. Shannon Westin: And what happened? What were the results? Tell us, how did this impact standard of care?  Dr. Deborah Schrag: So the upshot is it was designed as a non-inferiority trial and it met the prespecified non-inferiority hypothesis. The exact point estimates were that at five years, essentially 80.4% and 78.6% of participants were alive and disease-free in each group. So that's really almost exactly the same at five years. And the results for overall survival and for local recurrence were also nearly identical. Dr. Shannon Westin: So congratulations. Why don't you now, if you could, walk us through how you assess the patient experience on this particular trial? So specifically looking at the endpoints that you assessed and also the time points that you chose.  Dr. Ethan Basch: Thanks for the question. I'll take that. So in this trial, particularly because it was a non-inferiority trial being conducted in a curative context, we really wanted to get a sense of the adverse effects, the side effects of the treatment that are most salient in this population. And so to do that, we used two different approaches. The first was that we selected 14 symptomatic adverse events from the patient version of the CTCAE, also known as the PRO-CTCAE. The patient version of the CTCAE was developed about ten years ago. The purpose of it is to enable the patient voice to be brought into clinical trials around those side effects for which patients are in the best position to answer. But this was really the first large randomized trial into which the PRO-CTCAE was integrated. So this is really a landmark for that tool which is maintained by the NCI. Dr. Deborah Schrag: The PRO-CTCAE was developed by Dr. Basch, and I was his partner. So I'm going to say that Dr. Basch shepherded this tool. This was his brainchild, this was his project, this was his labor of love. He had this vision that we could do better in oncology by engaging patients in reporting their own symptoms and way back in the mid-aughts when both he and I had less gray hair. He worked really hard to develop this system. Its precursor was developed at Memorial Sloan Kettering when Dr. Basch and I worked there in the aughts, and it was tested and found to make a difference, it was very well received by patients. The NCI was persuaded that Ethan was on to something and issued a contract, a large contract, which engaged, I believe it was eight cancer centers around the country. And it took a huge amount of work.  This system was developed with a way to get the right words so that patients would understand, so that we have things like construct validity, content validity, so that it would work in Alaska and Maine and Hawaii and New Mexico. The system has now been translated into over 30 languages, but this has really been a career-defining endeavor and labor led by Dr. Basch. He's had wonderful assistance from Amylou Dueck, amazing statistician who's helped, and I've been a good partner to him as well, and many others along the way. But this is really the culmination of a vision that it took more than a decade, almost two decades to realize.   And I would just say to any junior investigators out there with a good idea, sometimes you have to be patient and just keep at it, as Dr. Basch has. And now we're starting to see that PRO-CTCAE is becoming standard. It's integrated in many trials. He didn't start a company. It's freely available. The NCI has it. It's NCI intellectual property. Again, available around the world. I'm just very proud of my colleague and academic partner. Dr. Shannon Westin: It's a great, inspiring story, and I love how you spelled out the timeline because it's so true. Sometimes the best ideas do take a long time to get to fruition, so I love that story. Dr. Ethan Basch: The truth of the matter is that this idea of patients reporting their own adverse events was really hatched in conversations that Deb and I had together more than 20 years ago at a coffee shop on the Upper East Side. And I think the observation at that time was that we use the CTCAE for clinical investigators to evaluate patients' adverse events on trials. But that doesn't really make sense for highly subjective phenomena like nausea or fatigue. I mean, the only way an investigator can know about a patient's fatigue is if the patient themselves reports it. And it was our empiric observation in the many clinical trials that we had been involved with that it just seemed like that stuff was being underreported, and so then we subsequently unmasked that, in fact, is the case. In looking at multiple instances perspective, we found that, indeed, there's a massive underreporting of patients' symptomatic side effects in clinical trials.   This has been a partnership that Deb and I have had with other colleagues, again, for more than two decades. And so it is really gratifying in the PROSPECT trial to see this coming to fruition. I think the other piece of this, though, as long as we're handing out compliments or accolades, is that Deb has been working for more than a decade on the PROSPECT trial because of a belief that over-treatment or that treatment could be peeled away to improve the experience of patients. And I think the reason why Deb has had an interest in employing the PRO-CTCAE in this trial is because I think it's been her belief that what it's really about is the patient experience, especially in the non-inferiority setting. What's more important than what patients report themselves? And so Deb has championed this and made this happen. And it's no coincidence that Deb's PROSPECT trial is the first major trial the PRO-CTCAE was in, it's because she's a champion for the patient experience and the patient voice. So right back at you, Deb.   I would say the Pro CTCAE now is embedded in hundreds of clinical trials throughout the industry. I mean, it's really been widely proliferated. It's gratifying, and it shows the power of an idea. I'd say the PROSPECT trial is really the alpha for this approach. Dr. Deborah Schrag: I just would like to inspire physicians. I know there are doctors out there and investigators out there who have different ideas that are not mainstream or they want to take risks, and not everything is going to work out. And some kooky ideas are just that. They're kooky or different, and they're not going to work, but sometimes you’ve just got to hang in there. Dr. Ethan Basch: I think it does show the power of an idea, or certainly the power of an idea that Deb Schrag is involved with, which is always one to bet on, for sure.  Dr. Shannon Westin: I would like to get some advice here because we build in these types of PROs, we always are worried about how much burden is too much. How many things can the patients be asked to do and we don't want to put too much burden? You all had a really nice participation rate. I think it was like 83%. Any tips that you have for keeping patients engaged and encouraging participation and kind of walking that balance between how much is too much? Like, we want to get all the data we want to get, but how do we meet that balance?  Dr. Ethan Basch: So as Deb alluded to, we've come really far in 20 years, and the idea of engaging patients directly through connected health technologies, it's in the zeitgeist now. I mean, it's just a given. I mean, we're all connected in so many ways. And even patients who formerly have been so hard to reach generally can be reached with one interface or another. So in this trial, we used a strategy that I would really advocate for. So first we had an electronic PRO platform that could be accessed through the web or through a handheld device. But there was also what we call an automated telephone system or an IVR system, an interactive voice response system like what the airlines use when you get the electronic voice and you can use the push buttons or speak into it. And so we gave patients a choice of using either of those, the idea being to meet people where they are.   And then for those patients who did not report at the expected times, a CRA actually called them to recapture the information that was missed. And so by using this kind of strategy, we had a very high adherence rate and very little missing data. Just as a couple of quick asides, in this and other studies, we found that the patients who choose the telephone-type interfaces tend to be more rural. They have lower health literacy, lower SES, lower educational attainment. And so you really need to think about that with any technology like this one because there is a risk that this digital divide will increase disparities or representation in how we capture data or administer care. So the way that we did in this trial, I think kind of got it right in many ways and I think as an exemplar for other studies.  Dr. Shannon Westin: Thank you for that. That's I think hopefully helpful for all the young investigators in the audience that are designing these types of trials. On that same note, around the population, what about the population that participated in this trial? Again, as a GYN Oncologist, I'm always intrigued by our different areas of solid tumors. Do you think this trial is pretty representative of the population and specifically the group that participated in the PRO outcomes? Dr. Deborah Schrag: So the first part of your question I will answer second. The patients who reported are highly representative of the total population. So I don't think there's any issue there. If you look at what's called Table 1 for the trial overall and Table 1 for the patients who participated in PRO reporting, the characteristics, and attributes are the same. So the results generalized. So that's very good. The bigger issue was upstream with the participants who went in the trial. And I think the biggest place where we need to make improvements is to recruit populations of patients to clinical trials who are more representative of the United States of America. And we did not achieve that. We tried in this trial, but we did not succeed. So we have unacceptably low participation from African Americans. And the racial and ethnic diversity in the clinical trial does not reflect the racial and ethnic diversity in the United States or more importantly, of patients who get rectal cancer. This is for all kinds of reasons, people are marginalized, we've got structural racism that persists. We've got issues related to mistrust. And I would just say we need to do a hell of a lot better. We didn't fail here because we're bad or because we didn't try. It's a challenging, pernicious, and persistent problem, but it is an important one and it's an important deficit.  Dr. Shannon Westin: 100%. Yeah, I think across the United States this is an issue, globally as well, but especially I think we have an opportunity within our recruitment within the United States to really provide that diversity. So I think we're all familiar with the NCI and the push to have those plans, but yeah, I don't think no one would think you didn't try hard enough. I think it's definitely something that we are systemically dealing with. Dr. Deborah Schrag: Yeah, getting cancer treatment is hard. Getting cancer treatment when you're living with a lot of challenges, for example, poverty or single parenting or living in a marginalized community or with poor transportation access, or food insecurity is even harder, if not impossible. And because of the way these cooperative group trials are funded, we didn't provide any support for transportation or food or any of the other things. This was a publicly sponsored trial and I think it is worth us having a very serious conversation about what we need to do to subsidize and support trial participants to ensure that we do have more representative participation. We fell short here. Dr. Shannon Westin: Can you walk us through a little bit of the PRO findings during that, the new adjuvant chemo versus the chemoradiation group? What did you conclude? Dr. Deborah Schrag: We've got an OBGYN interviewing us here. The genesis of this trial for me personally, colorectal cancer is occurring more and more in young patients, and you can't carry a pregnancy to term once you've had pelvic radiation and it usually tips you into early menopause. And this is a real concern when we have 35-year-old women with rectal cancer.  Dr. Ethan Basch: So Deb already noted the non-inferiority results in the study, and I think in the setting of a non-inferiority result, the PRO findings become of interest. And in fact, the PRO results in the two arms are quite different from each other. The two key periods when we evaluated PROs were first during neoadjuvant therapy and then in the period following surgery, one-year post-surgery, and then 18 months post-surgery. So during neoadjuvant therapy, we evaluated PROs in the two groups, which again were chemotherapy alone with selected use of radiation, which in the end, very few patients required, versus the prior standard of chemoradiotherapy. What we found was during active neoadjuvant treatment, almost all symptoms were worse with the investigation arm with chemotherapy alone, in fact, eleven of the symptoms were worse. Now, this is not a big surprise because it's FOLFOX therapy and these are the symptomatic adverse events that we would expect to see being worse during FOLFOX chemotherapy. However, diarrhea was better with FOLFOX than it was with the standard of chemoradiation. And I think that, again, intuitively, is what we might expect.  What becomes interesting is the period 12 and 18 months after the surgery. And what we found in that in those time points was that the symptoms were either the same between groups but for three key symptomatic adverse events, they were significantly worse with chemoradiation therapy. And those specifically were neuropathy, fatigue, and sexual function. And Deb made a point earlier about one of the reasons that she conceived of the trial being concerned about sexual function or the ability to carry a pregnancy in young patients who undergo chemoradiation. And in fact, we see, perhaps not that surprising that sexual function is significantly better with the chemotherapy alone arm and that's durable.   I think there's a question mark about sensory neuropathy. We saw that neuropathy was better in the FOLFOX  arm and the chemotherapy arm at both 12 and 18 months. And one could see that as a little bit of a head-scratcher because we might expect to see that neuropathy would be worse in a FOLFOX arm because of the exposure to oxaliplatin as opposed to radiation. I think that that will warrant some further evaluation. But the empiric finding is that the late effects are in fact significantly worse in the chemoradiation arm for those three areas. Dr. Shannon Westin: Yeah, I was intrigued by the neuropathy because that's why in my experience, we don't use a ton of FOLFOX, but occasionally we'll treat our patients with mucinous ovarian cancer, and I feel like the neuropathy is a really difficult strategy. But I'm especially interested in those long-term adverse events after radiation. We do a ton of radiation for patients with cervical cancer and other of our cancers and I was really intrigued by this opportunity to potentially lose some of those long-term side effects. Any thoughts as to why there really wasn't a difference in that overall health-related quality of life at all these time points?  Dr. Ethan Basch: Yeah, it's a great question. So in this study, we did use an overall quality of life or health-related quality of metric and it was no different at any time point between the two arms. I think it's a limitation of the tool that was used. The tool that was used when this study was designed, it's called the EQ-5D. It's used in a lot of health economic evaluations for cost-effectiveness analyses in Europe, in clinical trials. So it gets dropped into a lot of studies but it really is not sensitive to the nuances of symptoms like we see in this trial. It asks about overall global physical function, anxiety, depression, but it really doesn't get into the weeds of neuropathy or sexual function, some of the domains that really were most important here. So I think some of this is that the tool just wasn't sensitive enough to pick up that nuance.  On the other hand, I think it's reassuring that a very high-level global health-related quality-of-life tool was no different. It suggests that big, big picture, there's not a huge difference in the overall functioning of people between these two potential treatment approaches. But when you get into the more detail, we do see the differences in those individual symptoms.  Dr. Shannon Westin: And then I guess the bottom line, how are we going to use these results to inform what we do for this patient population? Dr. Ethan Basch: Yeah, I think it's nuanced. I think that goal of collecting this kind of information, like any information on trials, is that when one of us walks into the room with a patient, we sit down to make a choice when there are different options is to say what are the pluses and minuses of each. So for a patient who's really concerned about those short-term acute toxicities like nausea and fatigue during neoadjuvant treatment, then they might want to go with the standard of chemoradiation. But if they're really concerned about bowel function, or if they're really concerned about long-term sexual function or to some extent neuropathy, then probably the better choice for them would be FOLFOX alone, chemotherapy alone, the investigational approach. But really it's more information for that shared decision-making. It's a little more nuanced, it's a little bit more for us to think about in those conversations with our patients, but it really helps patients ultimately to make an informed decision so they can know what to expect.  Dr. Shannon Westin: Well, I just want to say congratulations. I know you've convinced me, and I bet you've convinced everyone listening that we need to be incorporating the PRO-CTCAE in all of our upcoming large practice-changing trials. So congratulations on your work, not only in this trial but with that measure as a whole. It's really exciting.  Dr. Ethan Basch: Thanks so much. The evidence really does suggest that without employing a tool like the PRO-CTCAE or another PRO tool in a trial to understand the symptomatic adverse events from the patients directly, we will have an incomplete understanding of what's going on in that trial. And it's really to the detriment of us as investigators or to drug developers not to include these kinds of tools because we really won't understand the impact on the ultimate end users of the treatments which are the patients. Dr. Shannon Westin: Well, thank you so much, and thank you to our listeners. We have been hearing about the simultaneous publication of JCO and presentation at ASCO 2023 of the Alliance N1048 Trial: Patient-reported outcomes during and after treatment for locally advanced rectal cancer from the PROSPECT trial.   I'm so grateful for all of you who've listened. Please check out our other podcasts on the website and wherever you get your podcasts and otherwise. Hopefully, we'll see you around ASCO 2023. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Show Notes: Like, share and subscribe so you never miss an episode and leave a rating or review. Guest Bios: Ethan Basch is the Chief of the Division of Oncology and Physician in Chief at NC Cancer Hospital at the University of North Carolina. Deborah Schrag is the chair in the Department of Medicine at Memorial Sloan Kettering Cancer Center in New York City, New York.  Article: Patient-reported outcomes during and after treatment for locally advanced rectal cancer (Alliance N1048)  

In this JCO Article Insights episode, Davide Soldato summarizes three articles from the May 20th, 2023 Journal of Clinical Oncology issue: “Smoking Cessation After Diagnosis of Kidney Cancer Is Associated With Reduced Risk of Mortality and Cancer Progression: A Prospective Cohort Study, “Efficacy of a Smoking Cessation Intervention for Survival of Cervical Intraepithelial Neoplasia or Cervical Cancer: A Randomized Control Trial” and “Integrating Tobacco Treatment into Oncology Care: Reach and Effectiveness of Evidence-Based Tobacco Treatment across National Cancer Institute Designated Cancer Centers.” The articles discuss clinical outcomes in survivors of cancers who quit smoking, efficacy of a novel smoking intervention and implementation of tobacco treatment programs. TRANSCRIPT Davide Soldato: Welcome to this JCO After Hours issue summary for the May issues of the Journal of Clinical Oncology. This is Davide Soldato and today I will be reporting results from three articles published in the May issue of JCO. Today's episode is focused on smoking cessation, impact on clinical outcomes, efficacy of novel smoking interventions, and implementations of tobacco treatment programs.  The first article by Dr. Sheikh and colleagues is titled "Smoking Cessation after Diagnosis of Kidney Cancer is Associated with Reduced Risk of Mortality and Cancer Progression: A Prospective Cohort Study". We know that smoking is a relevant risk factor for development of renal cell carcinoma, and previous retrospective studies showed better survival among patients who quit smoking after diagnosis. However, prospective data on the topic were lacking up until this point. The study by Dr. Sheikh and colleagues included patients diagnosed with renal cell carcinoma who were current smokers at the moment of diagnosis and that were followed prospectively for an average of eight years. At study inclusion, patients responded to a structured questionnaire investigating smoking habits and other behavioral factors. Furthermore, clinical pathological data were extracted from medical records.  Subsequently, after inclusion, patients provided yearly information regarding smoking status and if applicable, date of smoking cessation. Follow-up information on vital status, eventual disease recurrence, and treatments were collected both from patients and from medical records. The study reports results among 212 patients who were current smokers at diagnosis; the majority were diagnosed with stage I tumors and had a high-level education. Over the eight-year average follow-up, 40% of patients reported quitting smoking, more than half of them shortly after diagnosis. Demographic, social, and tumor characteristics were comparable between patients who quit and those who continued smoking.  Smoking cessation was overall associated with improved outcomes. Five-year survival rates were significantly higher in patients who quit smoking compared to those who continued (85% versus 61%). This higher probability of survival was observed across all evaluated subgroups, including light versus moderate and heavy smokers, and patients with early and late-stage tumors. Similarly, five-year progression-free survival rates were significantly higher among patients who quit smoking (80% versus 57%). In multivariable, time-dependent regression models adjusted for age of diagnosis, presence of other chronic health conditions, number of pack years, alcohol drinking status, tumor stage, and treatment received during follow-up, smoking cessation was significantly associated with a lower risk of all-cause mortality, disease progression, and kidney cancer-specific death. The results were comparable when excluding from the analysis patients who quit smoking three and twelve months after diagnosis, and this is important because inclusion of these patients might have biased results considering that these patients might have survived longer and thus had more chance to quit smoking.  So, in conclusion, smoking cessation among patients diagnosed with renal cell carcinoma was associated with a 50% lower risk of death, a 46% lower risk of cancer-specific death, and a 55% lower risk of disease progression. These results are extremely important and informative as they reinforce the need to promote smoking cessation among patients diagnosed with renal cell carcinoma since the observed clinical benefit was at least similar to that of currently employed or emerging targeted and immunotherapy treatments. The second article by Dr. Vidrine and colleagues is titled "Efficacy of a Smoking Cessation Intervention for Survival of Cervical Intraepithelial Neoplasia or Cervical Cancer: A Randomized Control Trial". As for many other cancers, we know that smoking is a significant risk factor for the development of cervical cancer. Furthermore, smoking after a diagnosis of cervical intraepithelial neoplasia or cervical cancer was associated with poor treatment response, increased risk of recurrence and development or worsening of other chronic diseases over the survivorship period. Cervical cancer frequently affects younger women, those with low socioeconomic status, and also minority groups. Previous data obtained specifically in these groups showed reduced access to smoking cessation intervention and consequently worse consequences from continued smoking. Consequently, the development of effective interventions to improve smoking cessation in these populations is of critical importance. The study by Dr. Vidrine and colleagues included smoking patients diagnosed and treated for cervical intraepithelial neoplasia or cervical cancer, and not already using nicotine replacement therapy. As per clinical guidelines, patients received 12 weeks of combination nicotine replacement therapy with a patch plus lozenge, and with randomized one-to-one to a standard treatment group that received educational material and a letter referring to states’ tobacco cessation quick line at baseline three and six months or to the experimental intervention group. The experimental group received the standard treatment plus a novel 12 months intervention based on the Motivation and Problem-Solving approach or MAPS, aiming at facilitating and maintaining behavioral change. The intervention was co-developed with survivors of cervical cancer who smoked to target specific needs regarding smoking cessation, healthy behaviors, and other survivorship issues. The intervention was articulated on six telephone counseling sessions that were delivered over 12 months based on the needs of each patient. After randomization, patients were followed up prospectively at 3, 6, 12, and 18 months. The primary outcome of the study was self-reported seven-day point prevalence abstinence from smoking at 18 months, so, six months after the end of the intervention. The secondary outcome was biochemically confirmed seven-day point prevalence abstinence evaluated on saliva.   The study published in JCO reports results among 194 patients. The majority were non-Hispanic White, had low socioeconomic status, and were diagnosed either with cervical intraepithelial neoplasia or stage I cervical cancer. Unfortunately, the trial failed to demonstrate its primary outcome. At 18 months, the percentage of patients who quit smoking was similar, 14% in the MAPS group versus 12% in the standard treatment group. However, when examining longitudinally the percentage of patients who quit smoking at each of the four-time points, a significant interaction was observed between the smoking condition and the timing assessment. Consequently, the authors decided to investigate the percentage of patients who quit smoking at every single time point. In this analysis, a significantly higher percentage of patients who quit smoking was observed at 12 months in the experimental group, equal to 26% for the MAPS group intervention versus 12% in the standard treatment group. Furthermore, patients who completed at least four MAPS sessions had a significantly higher abstinence rate at twelve months, 38% compared to 8% for those who completed zero to three sessions.  So, in conclusion, this trial and the MAPS intervention resulted in a higher rate of abstinence at 12 months, although a considerable number of survivors relapsed six months after the end of the intervention, thus dissipating the overall effect. However, the results of this trial are extremely important because they highlight the need for further research in the field, first to improve patient engagement to smoking cessation intervention, and second, to promote sustained behavioral change that can be maintained even after the end of the active intervention phase.   Finally, the third article by Dr. Hohl and colleagues is titled "Integrating Tobacco Treatment into Oncology Care: Reach and Effectiveness of Evidence-Based Tobacco Treatment across National Cancer Institute Designated Cancer Centers." As highlighted by the previous two articles, smoking cessation is paramount for patients diagnosed with cancer and survivors of cancer. Despite the existence of specific NCCN guidelines on the topic, there is considerable evidence that smoking cessation is not commonly addressed in cancer care. So, as part of the Cancer Moonshot program, the Cancer Center Cessation Initiative was launched in 2017 with the objective of integrating evidence-based tobacco treatment into cancer care. The study by Dr. Hohl and colleagues aimed to assess the reach and effectiveness of tobacco treatment programs across NCI-designated centers included in the Cancer Center Cessation Initiative using six months of data collected from January to June 2021.  This cross-sectional study focused on two main outcomes. The first one, treatment reach, was defined as the proportion of smoking patients who received at least one tobacco treatment component over the total number of patients who reported current smoking examined in the included NCI centers. The second outcome was smoking cessation effectiveness, defined as the proportion of patients who reported seven-day point prevalence estimates of smoking cessation over the total number of patients who received at least one tobacco treatment component in the centers.  This study examined data from 28 NCI-designated centers where more than 600,000 patients were evaluated and treated. Median smoking prevalence was 7%, median reach was around 15%, and median effectiveness was around 18%. Some differences in reach and effectiveness were noted according to center characteristics, tobacco treatment program characteristics, implementation strategies, and components of the tobacco treatment programs. Smaller centers had higher reach but lower effectiveness, whereas the opposite was observed for larger centers. Additionally, centers with higher smoking prevalence had both higher reach and higher effectiveness. The centers that were implementing tobacco treatment programs center-wide had higher reach and similar effectiveness compared to centers where these programs were implemented only in part. A slightly higher effectiveness was observed in centers that targeted only outpatients, possibly due to different patterns of care and clinical outcomes among inpatients. eReferral systems to smoking cessation quick lines that were used by 90% of the centers were associated with increased effectiveness when a closed-loop system was implemented.  Regarding the type and the component of the tobacco treatment programs, almost all centers offered at least four quick line referrals at the second higher median reach of 17% and also effectiveness 19%. Face-to-face counseling with tobacco treating specialists had the highest median effectiveness, almost 20%. All the other components, including pharmacotherapy, telephone-based counseling, and point-of-care counseling, had similar median reach and effectiveness.   Overall, these results are important as they are able to inform future resource allocation, tobacco treatment program design, and implementation according to center characteristics in order to improve reach and effectiveness of these tobacco treatment programs.   This is Davide Soldato, and in this episode of JCO Article Insights, we discussed three articles on the topic of smoking cessation. The first article, by Dr. Sheikh and colleagues, described clinical outcomes among patients who quit smoking after a diagnosis of renal cell carcinoma and demonstrated that those patients who quit had increased survival benefits. The second article, by Dr. Vidrine and colleagues, reported the efficacy results of a novel intervention to promote smoking cessation among patients diagnosed and treated with cervical intraepithelial neoplasia or cervical cancer. The second article showed that, although the primary outcome was not reached, a higher percentage of patients quit smoking with this novel intervention at twelve months. Finally, the third article, by Dr. Hohl and colleagues, examined characteristics and implementation strategies of tobacco treatment programs among NCI-designated centers, and the results of this study will be important to improve the reach and effectiveness of this program over the years.   Thank you for your attention and stay tuned for the next episode of JCO Article Insights.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  Show Notes: Like, share and subscribe so you never miss an episode and leave a rating or review. Articles Smoking Cessation After Diagnosis of Kidney Cancer Is Associated With Reduced Risk of Mortality and Cancer Progression: A Prospective Cohort Study Efficacy of a Smoking Cessation Intervention for Survival of Cervical Intraepithelial Neoplasia or Cervical Cancer: A Randomized Control Trial Integrating Tobacco Treatment into Oncology Care: Reach and Effectiveness of Evidence-Based Tobacco Treatment across National Cancer Institute Designated Cancer Centers. Find more articles from the May 20 issue.  

In this JCO Article Insights episode, Emily Zabor interviews Dr. Gulam Manji from Columbia University Irving Medical Center. Dr. Manji provides insight into his editorial published in the April 10, 2023 JCO issue: "Adjuvant Gemcitabine and Nab-Paclitaxel Misses the Target in Pancreas Adenocarcinoma: Or Did an Effective Therapy Fall to the Definition of Recurrence?” (10.1200/JCO.23.00039). His editorial focuses on the JCO Original Report, “Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial” by Tempero, et al on the APACT Trial. TRANSCRIPT The guest on this podcast episode has no disclosures to declare.  Emily Zabor: Welcome to this JCO Article Insights episode for the April issue of JCO. This is Emily Zabor, one of JCO's editorial fellows. And today I am interviewing Dr. Manji from Columbia University on their editorial titled “Adjuvant Gemcitabine and Nab-Paclitaxel Misses the Target in Pancreas Adenocarcinoma: Or Did an Effective Therapy Fall to the Definition of Recurrence?” Dr. Manji, welcome to our podcast. You wrote this editorial to accompany the article, “Adjuvant Nab-Paclitaxel plus Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results from a Randomized Open-label Phase III Trial by Dr. Margaret Tempero and Colleagues.” That trial, called the APACT Trial, investigated the efficacy and safety of adjuvant nab-paclitaxel plus gemcitabine compared to gemcitabine alone in patients who had undergone resection for pancreatic ductal adenocarcinoma. So I wanted to ask if you could start by giving listeners a quick overview of the study design and the main findings from that trial. Dr. Gulam Manji: Yeah, sure, Emily. So, as you pointed out, it was a randomized phase III study in patients who had resected pancreatic carcinoma. The primary endpoint was independently assessed disease-free survival. Additional endpoints included investigator-assessed disease-free survival, overall survival, and safety. And we'll get back later on as far as the importance of investigator-assessed versus independently-assessed disease with survival because I think that that's the main point of discussion for today. The enrollment criteria were fairly stringent and included patients with macroscopic complete resection, ECOG performance status of either 0 or 1, and the peripheral tumor markers of CA 19-9 being less than 100. And patients were required to initiate adjuvant chemotherapy within 12 weeks. Patients received standard gemcitabine at 1000 milligrams per meter square, either with or without nab-paclitaxel of 125 milligrams per meter square once weekly for three weeks during every four-week cycle. Emily Zabor: Great. So I think that the main thing that we wanted to talk about today, and one of the main points you discuss in your editorial is the difference between the primary endpoint of independently assessed disease-free survival and the secondary endpoint of investigator-assessed disease-free survival. So can you describe the difference between those endpoints, how they were defined, and how they differed? Dr. Gulam Manji: Sure. So, independently-assessed DFS was determined by a radiologist who was blinded to treatment assignment, and new lesions followed RECIST 1.1 criteria. In contrast, the investigator-assessed recurrence was determined by the treating physicians using all available clinical information. So that could be abdominal pain, anorexia, probably elevation of peripheral tumor markers. And the other important aspect to the study is that the independent review was not performed in real-time to confirm investigator assessments. So patients who started subsequent therapy after recurrence by treating investigators were censured for the independently-assessed DFS analysis. So in this trial, 866 patients were randomized. And patients who are randomized to the experimental arm had a median independently assessed DFS of 19.4 months, while patients randomized to the control arm, which was gemcitabine alone, had a median DFS of 18.8 months. Now, when we compare that to the investigator-assessed DFS, the data looks quite different. Where the DFS was 16.6 months in the experimental arm compared to 13.7 months in the control arm. That is consistent with the five-year follow-up looking at the median overall survival, which was 41.8 months for the combination arm compared to 37.7 months for the gemcitabine alone arm. Emily Zabor: Okay, so there's some really interesting differences there. And I noticed that there were only 439 events according to the independently-assessed DFS versus 571 according to the investigator-assessed DFS. So that's a big difference in the number of events that I guess is coming from that additional censoring that was occurring due to the delay in the independently assessed endpoint. Is that right? Dr. Gulam Manji: Exactly. So you could envision a scenario where patients received chemotherapy and then on the investigator-assessed DFS, the investigators decided that the patient had recurred. However, that patient probably did not meet the RECIST or radiological criteria to determine that that patient had recurred. And hence, since it was not done in real-time, there was censoring that occurred for the independently-assessed DFS. So that's the reason why there was a difference in that number as you pointed out.  The decision to use independent DFS, disease-free survival, really was to remove investigator-associated bias and increase rigor to the study, which is commendable. However, unfortunately, that's not how we normally treat patients with aggressive cancer who have undergone surgical reception. And knowing that imaging modality is limited in identifying those patients, particularly in those that have peritoneal disease, or even more importantly, the patients who have recurrence within the surgical bed, I think is the issue.  Emily Zabor: Right. So the motivation behind selecting that endpoint was really good and well-motivated. Everybody wants to reduce bias and make sure we're taking out those kind of more subjective parts of identifying that. But it, unfortunately, missed some events as a result. Dr. Gulam Manji: Correct. I think that it delayed those events and that's what compromised the analysis because it was the limitations of the available modalities to determine when recurrence occurs. Emily Zabor: So how do these different definitions compare to other trials or previous trials? Dr. Gulam Manji: So previous trials that I'm aware of, it was the investigator-assessed DFS that had been used. And when you look at the data that was used in this trial, that concurs with what has historically been seen. And what I mean by that is that the original assumptions regarding DFS when this trial was being designed, used historical outcomes. Investigators see that DFS with adjuvant gemcitabine ranged anywhere from between 13.4 to 14.3 months. And the study had aimed to achieve a DFS improvement from 13.5 to 18.5 months. When you look at the investigator-assessed DFS, the ballpark of gemcitabine is very much in line with the previous historical data. So I think that the key discrepancy between the two DFS endpoints was likely a delay in accurately assessing disease recurrence when using the blinded radiological modality alone. And the second thing is, as you pointed out, a greater proportion of patients who were censored for independent assessments compared with those for investigator assessments was different. So that was between 40% versus 34%. So those two points, I think, were the key points that show the difference between independent versus investigator-assessed DFS and also that the independent-assessed DFS was not done in real-time. Emily Zabor: Yeah, that's really interesting and such a good point. And I think it really emphasizes how important it is to think carefully about these endpoint definitions in the design stage of these clinical trials and especially to think about when and why patients are getting censored and how that might impact the results.  So how do these results of this trial then, given the negative result of the primary endpoint, but that positive result on the secondary investigator-assessed endpoint, how do these fit in with other trials? And what do you think that means for patient treatment recommendations? Dr. Gulam Manji: Excellent point. So just to be clear, the APACT study did fail to meet its primary endpoint and hence gemcitabine and nab-paclitaxel were not indicated for patients in the adjuvant setting. The current standard of care are either modified FOLFIRINOX or gemcitabine combination with capecitabine. And those two regimens really remain a standard of care for patients. So what I do is for fit patients, I prefer modified FOLFIRINOX. However, in patients who are not as fit, gemcitabine in combination with capecitabine is the alternative.  Now, one could envision a scenario where gemcitabine and nab-paclitaxel may become relevant. It is, but only when I'm really pushed to do so, where I feel like there is no other regimen available optimally for a patient. And one could envision a scenario where you could have a patient who does not have the performance status to tolerate modified FOLFIRINOX and then you start that patient on gemcitabine in combination with capecitabine. However, I have experienced that that combination results in significant myelosuppression in patients in the United States. And then we have to do significant dose reductions or interruptions.  Now, in that case, where I feel like I'm reducing the dose of capecitabine to a point where the patient may not be potentially benefiting from that regimen, it's impossible to determine what dose would be efficacious when you're doing those dose reductions. That is the only scenario where I may be able to be pushed to consider gemcitabine and nab-paclitaxel, but only after also discussing with the patient the results of the current data and there being limited efficacy. Emily Zabor: That makes sense. So the treatment you would select would really depend on some patient characteristics and then how they do on the different treatments. Dr. Gulam Manji: Correct. Emily Zabor: So what do you think are the next steps for research in this area and in this disease?   Dr. Gulam Manji: I think that this clinical trial really demonstrated our inability to accurately pinpoint the time of disease recurrence using imaging modalities alone. And for patients who treat pancreas cancer, they would know that the recurrence patterns usually are either to the liver or to the peritoneum, or to the lung. However, in about 25% of the cases, the recurrence may be at the surgical site, and that's when things become tricky. After patients have undergone surgery, their scar tissue and the pancreas tumor is very dense, so it's difficult to determine that there's actually tumor growth. So that's where you really need help from other modalities. So should we get a PET scan? Is the patient symptomatic? Is a tumor marker going up in the absence of biliary obstruction? So all of those things need to be taken into account to truly pinpoint whether the patient has recurred or not. In peritoneal disease, you may need to ask the surgeons to help and have the patient undergo a laparoscopy to truly determine whether there is a peritoneal disease. And lastly, I think that incorporating ctDNA to better define whether there is a minimal residual disease will likely be a standard in the future. Emily Zabor: I see. Yeah, that makes sense. Incorporating some ctDNA biomarker information along with these really detailed clinical and possibly imaging assessments to determine recurrence seems like it would be really important in future trials to make sure you're capturing all of those recurrences accurately. Dr. Gulam Manji: Yeah, I think that that's critical before you can say that an adjuvant treatment is truly helping the patient. Emily Zabor: That's great. Well, I really learned a lot reading this article and speaking to you today. But before we end, is there anything else you'd like to share with our listeners?  Dr. Gulam Manji: Yeah, so I think we know that for a majority of patients who undergo curative resection, unfortunately, the disease recurs. And I think that that implies that, really, pancreas cancer is a systemic disease at the time of diagnosis. And despite aggressive adjuvant therapy, the median DFS, OS, and five-year survival rate show that we are impacting only a subset of patients with six additional months of chemotherapy. So I think that identifying predictive markers of response to systemic therapy, better selection of patients for surgery, perhaps using total upfront neoadjuvant therapy, an institution of maintenance therapy, and patients who are at high risk for recurrence, perhaps using ctDNA as a marker to determine who those high-risk patients are, all leads to help better design and identify patients who should really be treated systemically and patients who should undergo surgery. And lastly, with some glimmers of success from personalized vaccines may be on the horizon. And I'm hoping in the near future to treat minimal residual disease so that we can get the best outcome with minimal toxicity for our patients. Emily Zabor: That's great. That sounds like an exciting development for a disease that seems really tricky. Dr. Gulam Manji: Agreed. Emily Zabor: Well, thank you so much. It has been a pleasure speaking with you, Dr. Manji, and thank you so much for joining me today on this episode of JCO Article Insights.  This concludes the episode on the article “Adjuvant Gemcitabine and Nab-Paclitaxel Misses the Target in Pancreas Adenocarcinoma: Or Did an Effective Therapy Fall to the Definition of Recurrence?” Thank you for listening and please tune in for the next issue of JCO Article Insights.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement. Show Notes: Like, share and subscribe so you never miss an episode and leave a rating or review.  Guest Bio: Dr. Gulam Manji, MD, PhD is a medical oncologist at the Columbia University Irving Medical Center in New York.  Articles: Editorial: Adjuvant Gemcitabine and Nab-Paclitaxel Misses the Target in Pancreas Adenocarcinoma: Or Did an Effective Therapy Fall to the Definition of Recurrence? Original Report: Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial Find more articles from the April 10 issue.  

Dr. Shannon Westin, Dr. Rajendra Badwe, and Dr. Alastair Thompson discuss the JCO paper "Effect of Peritumoral Infiltration of Local Anesthetic Before Surgery on Survival in Early Breast Cancer." TRANSCRIPT The guests on this podcast episode have no disclosures to declare.  Dr. Shannon Westin: Hello, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on manuscripts that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, gynecological oncologist by trade, but serve as our JCO Social Media Editor. And I'm super excited to talk to you about a paper that was just published online, April 6, 2023, entitled “The Effect of Peritumoral Infiltration of Local Anesthetic Before Surgery on Survival in Early Breast Cancer.”   Before we start, I just note that our guests have no conflicts of interest.   And so I'm accompanied by two greats in the field. First is the principal investigator on this trial, Dr. Rajendra Badwe, who is the Director and Head of Surgical Oncology Division at the Tata Memorial Center in Mumbai.  Welcome. Dr. Rajendra Badwe: Thank you. Dr. Shannon Westin: And then, of course, I'm joined by Dr. Alastair Thompson, Co-Director of the Lester and Sue Smith Breast Center and the Section Chief for Breast Surgery at Baylor College of Medicine here in Houston, Texas. We should have met in person. Dr. Alastair Thompson: Great to be with you today, both of you. Thank you. Dr. Shannon Westin: So this is an exciting topic, and of course, as a surgeon, I'm super intrigued. So let's get started. First, I would love for you all to tell me about the rationale for modulating events at the time of surgery to improve survival in any cancer, but specifically in breast cancer as it was in this study. Dr. Rajendra Badwe: So we have been working on events at the time of surgery for quite some time. And for the first time, when I walked through the gynae OPD in Guy's Hospital, there was this cartoon of the cell being extruded for ovulation, and I felt a cell moving from one organ to the other is actually metastasis. And that's how we started working on it. And in the past few years, we have been—a decade or so, we have been publishing changes induced by event of surgery.   So what we did earlier before beginning this trial is picking up a core biopsy before I start surgery. So it's normoxic, well-ventilated as well as well-nutrition-provided tumor, and I do a core biopsy and send it for expression profile on next-generation sequencing. Then, when 50% of the tumor surface is denuded from the opposite side, which is not denuded, I do other core biopsy. And the third core biopsy is when the tumor is in my hand in breast conservation surgery.  So first was normoxic, second was hypoxic, and the last was completely anoxic tumor. And we found that the middle sample, which has never been studied, all our understanding of biology of breast cancer is based on the first core biopsy or the whole tumor sample post-surgery. The middle sample had approximately 800 genes going up and down on the next-generation sequencing mRNA, and majority of these were epithelial-mesenchymal transition, proliferation, invasion, motility. You name the hallmark of metastases, and they were up in the middle of surgery at least in 30% of the tumor. Now, if the cell surface on one side in a three-centimeter tumor ring to the cell at the other end of the tumor as to some invasion has happened, how quickly can it happen? The difference between the two biopsies was just about five minutes.  Obviously, it was some kind of an electrical stimulus that went across the tumor. That's what our assumption was. And if it was to happen through the voltage-gated channels, the downstream effect of voltage-gated channel being depolarized was the same channels that I mentioned, the hallmarks of metastases that I mentioned. And if we were to block it, it was easiest possible by local anesthetic. So that's how this trial was originated. And we did in 1600 patients local anesthetic, half of them randomly allocated to receive lidocaine 0.5% versus not. Dr. Shannon Westin: That is so intriguing. I have to look up this work. I definitely agree with you. We do a lot of pre-biopsies and post-biopsies, but the intra-tumor biopsy is so novel with being able to study the anoxic tissue. I'm so interested. And you kind of started to get into this. Can you dig in a little bit more around that role or how the mechanism of action of this peritumoral anesthetic infiltration might work in preventing metastasis and preventing some of the changes that you were able to see? Dr. Rajendra Badwe: So if adequate amount of local anesthetic injected would paralyze or block the voltage-gated channels, sodium channels, and if the sodium is not allowed to get inside the cell as a gush, the first depolarization does not happen. And the downstream effect of such voltage-gated channels being stimulated is induction of proliferation, induction of invasion, and increased motility of the cell, everything that is necessary for metastases to set in. In fact, somewhere close to about 200 genes that belong to the pathway that allows a cell to express epithelial-mesenchymal transition were upregulated during this hypoxic episode. And hypoxia also is known to produce these changes. So we now, out of these 1583 patients, in about 100 patients, we also have the middle sample. And that's being looked at on the third-generation—next-generation expression profile to see whether the effects that I mentioned just now, are they abrogated by local anesthetic as the underlying mechanism of reducing the metastatic potential or upregulating pro-metastatic pathways in cancer cells. Dr. Shannon Westin: It's so intriguing. I guess I wonder if you or Dr. Thompson can speak a little bit about the results of any studies looking at peritumoral anesthetic infiltration prior to the work that we're going to discuss today. Were there smaller studies that looked at this? Dr. Alastair Thompson: There have been a number of studies over the years, particularly some small studies from the Republic of Ireland, which have suggested that the use of local anesthetic in breast surgery might be beneficial. And then there have been some other larger studies really more thinking about the block of the surgical stimulus to the surgical site, for example, using paravertebral blocks. And we are aware that what is given as an anesthetic, whether it's an agent, intravenous agent, like propofol, or a gaseous agent, may also have some effect on the metabolic response to the trauma of surgery. So there's quite a building logical background to this particular trial. But to my knowledge, this is a unique trial which a group of surgeons have been able to implement a fairly simple technique, taking a very short period of time, but with almost as much impact as some of the major drug trials in terms of disease freedom and overall survival.  Dr. Shannon Westin: Great. So, yeah, let's get into—do you want to take us through the design of the study, Dr. Badwe? Dr. Rajendra Badwe: Yes, thank you. We had 1583 patients who were randomly allocated. These are women with early breast cancer, so essentially, T1, T2 breast cancer with or without lymphadenopathy in the armpit, and metastatic, disease-wise, M0. And these individuals, these patients, were randomly allocated on table to receive local anesthetic versus not. 796 women received local anesthetic, and 804 women did not receive local anesthetic. The adequacy of this local anesthetic was 0.5% of lidocaine being injected on all surfaces of the tumor as if from one pole of the tumor, I would open an umbrella, a needle going in all directions all around the tumor from one side and then from the other side. And if the tumor was larger than being covered by these injections, additional points of injections were done on all surfaces of the primary tumor. The adequacy was tested by inability of the surgeon to use electrical diathermy for dissection. So the surgeon had to use knife to get the tumor out. Because of so much of water content in the tissues, the diathermy would not work. And if it worked, that would mean the amount of local anesthetic injected was inadequate. So that was the quality control parameter.  Postoperatively, patients received standard treatment. We had assessment of the hormone receptors, HER2 receptors. And postoperatively, they received standard chemotherapy, which is—in great majority, was epirubicin or Adriamycin with cyclophosphamide, four cycles, followed by 12 weekly paclitaxel injections. And those who were hormone receptor-positive, premenopausal received tamoxifen, and postmenopausals received either letrozole or Arimidex. All patients who were more than four centimeter positive in tumor size or had lymph nodes positive received postoperative radiotherapy, irrespective of whether they had conservation or mastectomy. And all individuals who had conservation received postoperative radiation, which was the standard protocol.  Talking about those with HER2 positive or triple-negative or ER/PR positive, their distribution on either side was identical, very, very close, no different at all. 35% of those who were HER2 3+ or FISH positive received trastuzumab for a year on either side, but two-thirds of them did not receive trastuzumab because of the cost constraints in India. But the distribution of those who received versus not was identical on both sides. So that's the kind of general demographics of the women who were on the study. Dr. Shannon Westin: Great. I think now—I think everyone's ready for the good news. So how did the infiltration impact outcomes in these patients? Dr. Rajendra Badwe: The primary endpoint was disease-free survival. There were a total of 255 events, 109 events in local anesthetic arm and 146 events in the no local anesthesia arms. That gave us a 26% reduction, a relative reduction of 26%, which reached statistical significance at P 0.01. And at the same time, for overall survival, which was the secondary endpoint, there was a 29% relative reduction in deaths related to breast cancer, and majority of the patients who died died of breast cancer. The other cause of mortality was very little—to be precise, less than 1.5%, and that was also equally distributed on—identically distributed on both sides. So approximately 4% reduction in disease-free survival absolute and a similar 4% reduction in overall survival and the number of deaths. So this was the first trial that looked at preventing metastases than treating micrometastases. Dr. Shannon Westin: Yeah, and I think I would just call on Dr. Thompson here because I think you already started saying this. I mean, when you look at the simplicity of the intervention and the low-cost nature of the intervention and the impact as opposed to some of our “incremental benefits” that we see with different very expensive targeted therapies and immunotherapies, I'd love just to get your thoughts on that. Dr. Alastair Thompson: So, of course. I think this is an extraordinarily well-designed, very balanced trial. Yes, you can say that not all patients are treated the same way around the world. But there's been a rigor about this which is very attractive, and I think it's one of the reasons the Journal of Clinical Oncology has published it.  What is perhaps astonishing is that if we try to first do no harm, we're actually doing a very simple intervention, low cost, relatively easy. The patient is asleep, so it's not painful in any way. It's not toxic at the sort of levels of local anesthetic being administered. And yet we're managing that for every 25 patients who have this addition to their procedure, one of them is going to be disease free and one of them is going to be alive as a consequence in the relatively short term. So, in terms of balancing the issues of trying to implement something versus the benefits to a patient population, the balance is very much in favor of this really quite minor change in practice to give us quite a major, by modern standards, difference in outcomes.  Dr. Shannon Westin: Yeah, I think it's incredibly exciting, and I think, to your point around is it applicable, is it generalizable, I'd love to hear what you all think. I mean, is this something that we should be implementing across the globe? Dr. Alastair Thompson: Well, I think sometimes, we don't always do in our own practices what has been led and demonstrated to be effective elsewhere. And we need to really pause and, I would suggest, think hard whether such a simple intervention could be implemented on our next working day.  Now, many of us do use local anesthesia in the setting of breast surgery, whether it's mastectomy, axillary lymph node surgery, or lumpectomy. But the difference might be that instead of putting this local anesthesia towards the end of the operation, thinking about doing things up front and maybe, therefore, having an even bigger impact than simply good quality pain control and good quality patient care.  Dr. Shannon Westin: I would love also, just as we're kind of coming to a close here, to get both of your thoughts about how we might implement this. And again, this is coming from a somewhat selfish standpoint. How could we implement this in other solid tumors? So is there a way to replicate? Obviously, breast has a very local disease spread pattern. Is there a way to potentially replicate this in other cancer types?  Dr. Rajendra Badwe: So we have begun a similar study in my hospital for squamous cell carcinoma, as well as lung cancer. And I'm sure there will be efforts to replicate in many other cancers where it is possible to inject local anesthetic all around before we start the resectional procedure. But at the same time, we need studies to confirm that this is actually happening. If I were to take a step further and wait for the expression profile of those who have received local anesthetic versus not in this trial, and if it shows that the abrogation of effects related to the downstream stimulation of VGSC, the voltage-gated sodium channels, then it might just be a good idea to use something else. Because if local anesthetic is effective to the extent, say, about x amount, cannabis has about 200x effect on stabilization of voltage-gated channels. So that could be another intervention that can be explored in trials in any site. Dr. Alastair Thompson: So that's a good point. Where do we go from here? And I would suggest that perhaps thinking about which local anesthetic to inject—would a longer-acting local anesthetic be just as effective from a prevention of shedding of metastatic cells, would that give longer additional pain relief? Would it be possible to think about other tumor sites where we're doing a local reception, for example, in the gastrointestinal tract, elsewhere in the body, including lung, for resections? There's just a huge amount of potential which this landmark, practice-changing trial has really pointed us to. And I would envisage that in future podcasts, Shannon, you're probably going to have a lot of people talking with you about other trials that have followed on from this. Dr. Shannon Westin: I hope so because that will mean we're impacting our patients in a positive way. I'm just so thrilled to have the two of you here. This was such a fascinating discussion. It went by so fast, and I hate to bring it to a close. But I encourage our listeners to definitely read this incredibly important manuscript and communicate with us online on how we can move this forward.   Again, this has been JCO After Hours, and we've been discussing “The Effect of Peritumoral Infiltration of Local Anesthetic Before Surgery on Survival in Early Breast Cancer,” published online April 6, 2023. I'm so thrilled that you joined us today on the podcast, and I hope you'll check out our other podcast offerings. Have a wonderful day. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

Dr. Shannon Westin and her guest, Dr. Harvey Max Chochinov, discuss his article "Intensive Caring: Reminding Patients They Matter." TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and thank you so much for joining us for another JCO After Hours podcast. This is the podcast that gets in depth in manuscripts published in the Journal of Clinical Oncology. I'm your host, Shannon Westin, GI oncologist by trade and honored to serve as the Social Media Editor for the JCO.  And today we're going to be discussing a really exciting paper in the Comments and Controversies section called “Intensive Caring: Reminding Patients They Matter.” This has been recently published, and I'm so excited to have the author of this paper join us today, Dr. Harvey Max Chochinov, who is a distinguished professor in the Department of Psychiatry in the University of Manitoba, senior scientist with Cancer Care Manitoba Research Institute, and the cofounder of Canadian Virtual Hospice.   Welcome. So great to have you today.  Dr. Harvey Max Chochinov: Thanks, Shannon. Dr. Shannon Westin: And please note neither of us have any conflicts of interest, so we'll just get right started. So first, I just wanted to explore the title of your paper, “Intensive Caring.” Can you describe a bit about what that means? Dr. Harvey Max Chochinov: Well, we know that in medicine there are occasions when patients find themselves in such medical dire straits that they require intensive care. They've reached the stage where they certainly can no longer help themselves, and they require this kind of intensive approach that medicine is capable of offering. But intensive caring is meant to acknowledge that there are times when patients can be in such dire emotional straits that we need a way of being able to address that degree of abject suffering. So the idea of intensive caring was to try and provide language to describe that approach and, within the paper, as we're going to discuss, also to describe the ways in which we can actually deliver that kind of caring. Dr. Shannon Westin: Can you tell me a little bit about kind of when and where your inspiration for this work arose? Dr. Harvey Max Chochinov: The inspiration actually came from Dame Cicely Saunders. Dame Saunders was the founder of the modern hospice movement. There's a famous quote or adage that she said: “You matter because you are you, and you matter to the last moment of your life.” And this has really become kind of a central philosophical tenet of palliative care. But yet it struck me that although it describes this philosophical approach, implicit is also perhaps a clinical approach which says how do we, in fact, show patients—how do we demonstrate to patients or practice medicine in a way that actually affirms that patients matter? So that's where the title came from: “Intensive Caring: Reminding Patients They Matter.” Dr. Shannon Westin: There are so many pieces to this. I was so struck by what you said about these emotional dire straits. That's the best way I've ever heard it described. I feel like one of the major areas is that loss of hope and that feeling that you don't matter anymore. So what can we do? How do we, as practitioners, act and intervene to change that feeling? Dr. Harvey Max Chochinov: That's a wonderful question. The paradigm of contemporary medicine is we examine, we diagnose, and we fix. And yet, when it comes to addressing many elements of human suffering, it doesn't lend itself well to that paradigm because, of course, we know that there are things that are beyond the realm of fixing. So what we need, then, is to understand a way of approaching patient care where fix really is beyond our reach. How do we do that? It's by understanding that by being with the patient, by things like non-abandonment, all of these things are ways of maintaining patient engagement.  There was a wonderful study a number of years ago by Kelly Trevino in which she looked at the associations between suicidality and the intensity and the quality of the connectedness with the medical oncologist. And it turns out that that was the single most predictive factor regarding suicidality over psychological interventions or over psychotropic medication. So the way in which we start to address this kind of abject suffering, maintaining hope, is to understand that and acknowledge that there are things that we may not be capable of fixing. But the provision of intensive caring—and, again, the elements of intensive caring that I described in the article—give us ways of being able to be with patients that don't require fixing but require presence, require involvement, require ongoing commitment to the well-being of that individual.  Dr. Shannon Westin: This is a perfect segue because I was struck by that tenet of non-abandonment, you know, really committing to ongoing care. I wonder about this because we do have patients that transition to hospice, and often, in our group, they'll have an entirely new care team. And that's just part of that intensive caring that the hospice group provides. But I guess, in seeing it in these terms, I'm feeling a little bit like that may not be the ideal way for that transition to happen. So any thoughts on how we kind of combat that? Or how can we work together with hospice so that the patient feels still supported but still gets that hospice care that they so desperately need? Dr. Harvey Max Chochinov: Oh, for sure. Well, I mean, listen, we know that transferring of care is a technical task that can be accomplished by a single stroke of our keyboard on our computer. We transfer care. But there's nothing technical about the issue of caring, connectedness. And so it's unrealistic, and I don't think patients expect that all expertise resides in the hands of one individual or one team. But the reality is that when we've been looking after somebody for days, weeks, months, even years and they now have to transition to other care providers, although care can be transferred, I think there is still this human expectation of ongoing caring.   And caring doesn't necessarily require a great deal of time. It can be accomplished in really nuanced and subtle ways that really, I think, are within our grasp. Picking up a telephone, dropping by for a visit, putting a note in the mail simply to acknowledge that “I understand you're in hospice. Just want you to know that you've been on my mind. Hope things are going as well as they can for you and your family.” That demonstrates continued caring. It doesn't raise expectation that I, your medical oncologist who know you very well, am going to now intervene and take over your care. Dr. Shannon Westin: That's perfect. And I'm actually taking notes myself to—have a couple patients that I need to call today. So moving on to some of the other tenets, the Patient Dignity Question was really, I felt like, a revelation for me. It's so simple and so straightforward, and I feel like many of us, myself definitely included, don't feel like there's enough time, right, to dig into the details of every patient, kind of where they are in their process. Do you think this is something that everybody should implement today? Dr. Harvey Max Chochinov: So maybe backing up just for listeners to understand that the Patient Dignity Question asks patients, “What do I need to know about you as a person in order to provide you the best care possible?” We have done studies of the Patient Dignity Question, or PDQ, and there have been multiple studies and multiple translations around the world, probably the largest study being one that came out—Hadler, first author—several thousand patients at Memorial Sloan Kettering who were asked the Patient Dignity Question as part of the regular kind of palliative care consultation. I think the message that I take out of the PDQ research is that personhood should always be on our radar. And the reality is that if we don't understand at least the essence of who that person is, we can give lip service to providing person-centered care and lip service to maintaining dignity and all of those wonderful things that we say in position statements, but none of it will ring true if we don't have personhood on our radar. And it simply means that we need to be mindful of personhood.  I've asked patients, “So what do I need to know about you as a person to take the best care of you possible?” I've had people tell me, “I'm afraid to die alone.” I've had people tell me, “I am the victim of childhood sexual abuse.” I've had people tell me, “I'm a survivor of the residential school system.” One man said “I'm a former department head of medicine.” In fact, he was just a lovely man. He said when he was being treated for his cancer, he wanted to hang a sign on his bedpost that said, “PIP, Previously Important Person.” But what it says to me is that if we fail to acknowledge personhood, then essentially we're operating in the dark. When you have that kind of information about personhood, it just changes the way you see and experience that person, which makes for better patient care. Families are more satisfied. There's less discordance when it comes to goals of care, less likelihood of litigation because the reason that most people litigate is not because of medical misadventure. It's because they don't feel like they were treated like a person. They somehow feel like that was not acknowledged.   The other interesting piece of data out of the PDQ research is that when clinicians acknowledge personhood, they also report greater job satisfaction. So the reality is—and we know that one of the signs of burnout is emotional disengagement. So what our research has found is that if you give clinicians a way of at least maintaining some emotional engagement by finding out who this person is, not only are patients and families happier, but healthcare providers report greater satisfaction in the work they do. So the short answer is “Yes, I think we should be putting personhood on our clinical radar and finding ways that are feasible of making that happen.”  Dr. Shannon Westin: There's so many interesting tenets in this article and so many parts to the intensive caring. Some do seem to be elements of palliative care practice as well. So how would you say this is different or complementary?  Dr. Harvey Max Chochinov: I'd say indeed you're correct. I mean, some of the elements are probably ones that people in palliative care would recognize. And I don't necessarily think that that's a criticism or necessarily a bad thing. If some elements of intensive caring are accused of being old wine in a new bottle, a new bottle is something that can be very attractive. And if this can bring people back to understanding the human side of health care, well and good. I suppose what is unique about intensive caring are the constellation of elements that are described in the article—and all of the elements, by the way, are empirically based. So the article does lay out various elements of intensive caring and points out the empirical basis of each of those elements.   I think maybe the other thing that's unique about intensive caring is it begins to provide us a language for ways of being able to approach patients who are in these circumstances. Usually, in the face of this kind of abject suffering, our temptation is to feel the need to withdraw, maybe feelings of impotence, maybe feelings of failure. So intensive caring addresses all of those head-on by saying here is a way that you can effectively be with your patients, that you can mitigate their suffering, without feeling that your mandate is to examine, diagnose, and fix. It is a different paradigm, which says you can be present with and provide comfort to. Dr. Shannon Westin: Great. Now, what about therapeutic humility? Can you speak of it like that? I think many of us come into medicine because we like fixing problems. So how does this concept turn the paradigm on its head? You kind of already talked about it a little bit, but I think it's important to mention specifically.  Dr. Harvey Max Chochinov: I think anybody who's been practicing medicine for any period of time has had the experience of confronting things that don't lend themselves well to fixing. Let's take the instance of somebody who is near end of life, or even the instance where a patient has died, you're standing outside of their room, and the family is still there. You have some choices. You can either withdraw, just say, “There's nothing I can do; I've got other things that are more pressing,” or you can go into that room. Now, when you go into that room, you need to be able to put on the shelf any idea that you have the right words that are going to fix what ails this now bereft family.  But I think wise and seasoned clinicians—and I would put to you, see, clinicians who have therapeutic humility would say you go into the room. Why? Because being there, just being present with, acknowledging the loss—and it's not about what you say. Again, if you feel like you have to wait till you have the right words, you never will go in there. But if you just go in empty-handed and allow yourself to be in the presence of that kind of suffering, what any clinician who does that will say is it's of critical importance. It matters. It makes a difference. And so that is one example of therapeutic humility. And again, there are others because there is so much that we deal with. For those of us who deal with patients with chronic illness or incurable illness, the fact is that if you're not humble, you're going to find yourself perpetually feeling like you are failing, like you are not meeting patients’ expectations. What patients expect is not that you can fix what's not fixable. They expect you to be involved. They expect you to care. You will be there for them in times that are tough. Those are elements of intensive caring that are worth taking forward into practice. Dr. Shannon Westin: Well, this has been so educational. I feel like I could talk with you for another hour. But why don't we end by just speaking about the next steps for this work, and how can we make everyone aware aside from publishing in the JCO and putting out this podcast? What else can we do? Dr. Harvey Max Chochinov: Well, hopefully, the approach gives people both the language and the ways in which we can start to implement this in practice. I would hope that it kind of catches or takes hold in medical curricula, but not only in medicine but really in any setting where individuals are being trained who have access to patients. This is not just about doctors. This is about anyone and everyone who has patient contact because the reality is that irrespective of whether you're the medical receptionist or the person making the first incision, you have the ability to either affirm or disaffirm the personhood of the individual that you're in the presence of. That's both a responsibility and, as well, an opportunity. So hopefully, dissemination of this work spreads word that this is an opportunity that we can take hold of, hopefully for the betterment of patients and families and healthcare providers themselves.  Dr. Shannon Westin: Great. Well, thank you so much. You've been such an inspiration. I can't wait to start utilizing these in my clinic just tomorrow. So I really appreciate you, and I know all our listeners do as well.   Listeners, we appreciate you. Thank you so much for tuning into JCO After Hours. Again, we were discussing the Comments and Controversies article “Intensive Caring: Reminding Patients That They Matter.” I hope you enjoyed it. Please do check out the website and check out any other podcasts that are ongoing and let me know what you think. Have a great day.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

What factors could be excluding transgender people from oncology clinical trials, and what can we do to make them more inclusive? Dr. Westin discusses this important issue with her guests, Dr. Ash Alpert and Dr. Lola Fashoyin-Aje. TRANSCRIPT Dr. Shannon Westin: Hello, everyone, and welcome to another episode of the JCO After Hours podcast. This is when we get down and dirty into manuscripts that are published in the Journal of Clinical Oncology. And I am so excited about our topic today. We are going to be discussing a Comments and Controversies article that was published online in JCO October 27, 2022, and it's entitled “Addressing Barriers to Clinical Trial Participation for Transgender People With Cancer to Improve Access and Generate Data.” And please note all authors do not have any conflicts of interest.  It is my great honor to be accompanied today by two of the co-authors on this important manuscript. First is Dr. Ash Alpert, and they are an Agency for Healthcare Research and Quality T32 Postdoctoral Fellow in Health Services Research at Brown University. And I'm so excited to note that they will be joining Yale as an Instructor of Medicine quite soon.  Welcome, Dr. Alpert. Dr. Ash Alpert: Thank you. Dr. Shannon Westin: And I’m also accompanied by Dr. Lola Fashoyin-Aje, and she’s the Associate Director for the Oncology Center for Excellence at the Food and Drug Administration. Welcome. Dr. Lola Fashoyin-Aje: Thank you so much. It’s my pleasure to be here. Dr. Shannon Westin: So we'll get right to it. I'm so excited. I think this is a topic that many of us, almost all of us, are needing a lot of support, needing a lot of education, and I think let's start by level setting. So what we're going to be speaking today is about transgender people. These are persons whose gender identity does not correspond with what is commonly expected for them based on the sex registered for them at birth. Do we have information about how many transgender people will be diagnosed with cancer and what are the most common cancers they face? Dr. Ash Alpert: So, given many barriers to data collection about transgender people, we actually have very little quality data about transgender people's health outcomes in general and specifically around cancer incidence and outcomes. But what we do know is that at least 0.7% of the US population is trans. And the limited data that we have suggests that transgender people don't have higher rates of cancer than anyone else. So if you look at the numbers for the US, that translates into there being about 2 million transgender people in the US and about 900,000 transgender people who are diagnosed with cancer in their lifetimes.   The other data that we have is that it looks like transgender people who are on hormone therapy and have surgeries, therefore less of a chance of being diagnosed with prostate cancer. If people have had bilateral mastectomy, they have less of a chance of being diagnosed with breast cancer. And it does seem like from retrospective data that it's possible that people on estrogen therapy are more likely to be diagnosed with a breast cancer. So basically, all things that we would expect. And given that about one in 10 transgender people in the US are living with HIV, it's likely that trans people also have higher rates of HIV-associated malignancies.  Dr. Shannon Westin: And I wonder, what about screening? I would think that this could be a real difficulty. If people are misgendered, they may not be offered the appropriate cancer screening. I know I'm getting a little bit away from the crux of your talk, but I think this is so important. Dr. Ash Alpert: Yeah. So there's a number of barriers to screening, and two of the ones that come to mind immediately are that trans people, in general, have negative experiences with physicians. So one study suggested that one in three transgender people had had a negative experience with a physician in the last year and that given this, about one in four trans people avoid necessary health care. So that automatically means that trans people aren't getting screened. And then I think the other important thing that you're bringing up is that because of the ways that certain types of health care are associated with gender—so, in other words, getting a cervical PAP smear is associated with being a woman in the ways that we talk about those tests—there are many other barriers to trans people getting cancer screenings. And we do have some data from the literature that suggest that trans people have lower rates of cancer screenings than the general population, likely because of these two, if not more, reasons. Dr. Shannon Westin: I would anticipate that this could potentially impact, obviously, diagnosis, but then also cancer-related outcomes. Do we have data on that? I know that a lot of this is a data-free zone, so I appreciate you kind of just reviewing what we do know.  Dr. Ash Alpert: So Sarah Jackson published a paper that suggested that in some types of cancer, trans people are diagnosed later with more advanced-stage disease and have poorer outcomes. But, again, it's very limited data. Dr. Shannon Westin: Anything else that you want to talk about on that second question before I move on to the next one? Dr. Ash Alpert: Yeah. I mean, I think that the question you raised about cancer screening is also true about cancer treatment. And I think we may get into this in the paper as well, that certain types of cancer—like ovarian cancer, prostate cancer, testicular cancer, and endometrial cancer—are often, in the ways that we talk about them and the ways that we write about them in guidelines, associated with specific genders. So it's not just individual oncologists, but all oncologists are steeped in this language that associates specific types of cancer with gender. And so then it becomes not just something that's happening in the language between two people, an oncologist and a patient, but also in the optics of the clinics, the names of our clinics, our titles as physicians, that all may inadvertently and implicitly exclude transgender people from care.  Dr. Shannon Westin: It's interesting. As a gynecologic oncologist, I feel like I was just talking about this with someone, about this idea of women's cancer care areas and these very specific gendered kind of comprehensive cancer centers that are incredibly exclusive to this group of people. So I'm really glad that you highlighted that. It's very timely, too, because I think our group is talking about how do we want to name our center. So I appreciate this.   So this is an area of interest greatly to me is clinical trials just in general and participation in clinical trials and encouraging inclusivity and improving representation in clinical trials. So we've seen this. We've seen this in gynecologic cancers and other cancers that, obviously, clinical trials change the standard of care, but they also provide better outcomes for patients and people with cancer. So do we know—are there any data about the current state of participation of transgender people in clinical trials? Dr. Lola Fashoyin-Aje: Yeah, I mean, thank you for that question. The fact of the matter is that we don't really know what the current state of participation in clinical trials in oncology is. This is really part of the reason why the Oncology Center of Excellence at the FDA convened the mini-symposium that we're describing in the paper and the reason why we wrote the paper. I think the assumption that we make is often that the numbers are probably not great. But since we do not routinely collect the data that would help us to identify transgender individuals as part of clinical research, even if transgender individuals did participate in a trial, we would have no way, really, of knowing.  We also do not really have great data regarding what the benchmarks for participation would be because, as Dr. Alpert mentioned before, we don't routinely collect this data as part of the epidemiologic surveys that inform our understanding regarding the populations that are affected by cancer or even at the point of care. It's really very heterogeneous, the types of data that we collect and whether the way that it's collected is optimal. So we really have an information and data deficit that is quite significant for this population that really is needed to be addressed in both sort of systemic ways, but also in our individual settings in the way that we collect data and the way we engage with this population. Dr. Shannon Westin: Are there any interventions or outreach efforts right now ongoing to start collecting these data or even to start raising awareness that these data should be included? Because I'm just thinking of all the NCI trials we do and industry trials and the data that are collected, and you just don't see this, right? This isn't part of the data dictionary typically, right?  Dr. Lola Fashoyin-Aje: Dr. Alpert can speak to some of this as well. We reviewed this as part of the paper-writing process. But there are ongoing efforts to identify the best ways to collect data and identify the opportunities where we could improve upon where some data is already being collected but also making sure that there's sort of structural measures are being taken to ensure that as we collect those data, that we are handling those data appropriately. Because this is a population that really suffers disproportionately bias, discrimination, violence. And so we want to make sure that as we are encouraging folks to provide this kind of information, because we really think that it will help improve their clinical care outcomes as well as clinical trial participation access, but that we are also, at institutional levels, addressing some of the areas that are either explicitly or inadvertently creating barriers and creating environments that are not supportive or that are not safe for this population.  And so there are ongoing efforts. I can say that at a federal level, there's increasing recognition that we really are not doing a great job. And I think there are some recommendations for how to collect these data in surveys, but it may not necessarily be applicable to what we need to know in the clinical trial setting. And so there's so much work to be done still. Dr. Shannon Westin: Great. Dr. Alpert, do you have anything to add there? Dr. Ash Alpert: This could be a very long conversation, but I'll briefly say that there are a couple of things that are happening right now that suggest that things are moving along. One is that NCI put out an administrative supplement for NCI-designated cancer centers to apply for, through which they can begin to collect sexual orientation and gender identity data at the cancer centers. So that means that now that that's happened, cancer centers across the country are testing measures with which to collect sexual orientation and gender identity data.  And at Yale, I'm a part of a research team that is beginning to collect data, both based on some national recommendations and also based on some of our individual research and ideas about how to collect this data in a way that really provides transgender people the autonomy to identify and describe themselves in ways that really feel right to them and to us. I think there are exciting things in the works. But I also really appreciate the conversation we just had about safety because in my qualitative research, what I've found over and over again is that often transgender people are put into a very difficult situation where if they come out to their clinicians, they experience stigma and sometimes violence, and when they do not tell clinicians certain things about their medical histories, including that they are on hormone therapy or that they've had particular surgeries or specific information about their anatomy, then they're put in the position where they may not be receiving the best care because their clinicians don't have all the appropriate information. It's a very difficult situation for individual patients and also for those of us who are thinking systemically and structurally about how to improve what we know about cancer epidemiology and how to provide the best care for transgender people with cancer. Dr. Shannon Westin: I mean, I think that kind of dovetails nicely with my next question, is really trying to understand how some of these structural barriers might impact participation in clinical trials. So what are the barriers that are keeping these people off of these trials? And maybe how can we start to strip those barriers away? All in that, I think, highlighting that highlight of safety and inclusion. Dr. Fashoyin-Aje: I can start by touching upon some of this. I think one important area has to do with language, the language that we use, the signage that we use. And sometimes it's not even just what is explicitly stated but also what is omitted, what is silent, which may have adverse consequences as well. And that could be even worse because then you're sort of rendering a population invisible or basically really kind of reinforcing this idea that they're just not seen.  So I think one area that is really quite relevant in the regulatory setting has to do with eligibility criteria. And I think often, those are silent with respect to transgender individuals because, number one, people just may not know, so they just could fall off, and they just are not thinking that this is a population that I need to explicitly ensure that they are invited to participate in this trial. And then I think other times, there are a lot of assumptions made about whether or not it is safe, and some of those assumptions may be supported, and some of them are not supported. So I don't want to trivialize whether or not an individual is receiving hormonal therapy, whether or not that may have adverse impact on their outcomes in the clinical trial; that could very well be the case, but we just don't know most of the time, and so we don't explicitly state one way or the other. I think the other way is just sort of the kind of language that we use. Calling individuals women may exclude certain people; they may not be sure. I think a lot of people when they hear women, they're not thinking about transgender women. So, in the paper, we really highlight opportunities where we could be more specific about the language that we use so that it is clear what we're referring to. So if you are designing a study that is meant to test a drug in patients who have ovarian cancer, say that. You don't need to say “females with ovarian cancer” if you're not really explicitly—there would really typically not be any reason to exclude people just based on that without more information. And often that more information isn't actually collected.  So I think that's sort of part of what we are trying to highlight here, that there are things that can be done at a micro level, but there are things that can be done at a macro level, and really culture change is a really important part of this, this sort of thinking like which of my neighbors might want to be included in this trial? Which one of my children's friends might want to be enrolled in this pediatric trial? And just kind of thinking a little bit out of the box and thinking of ways to be more inclusive and then have reason to exclude rather than to start from a baseline of exclusion and then inviting people. Dr. Ash Alpert: Yeah, I think we highlighted three main areas of eligibility criteria that may inadvertently exclude transgender people. One was mentioning sex or gender in the inclusion or exclusion criteria when it's unnecessary. The second is mentioning hormone therapy but not specifically and explicitly stating whether hormone therapy used for gender-related purposes would be included in that. So, for example, we, I think, in the paper, describe a prostate cancer trial that excluded people with prior hormone therapy for prostate cancer, but I think it would be very confusing for me if I were a transgender woman on estrogen therapy, whether or not that excluded me from the trial because it's not specifically called out. And then we still see blanket exclusions for people living with HIV despite all the discussion and commentary about this. And that necessarily excludes many trans people because one in 10 transgender people in the US is living with HIV.  And then I think we also, in the paper, highlight that there's actually been qualitative research done with transgender people looking into the facilitators and barriers to participating in clinical trials, and we summarize them just saying that trans people suggest that they're more likely to participate in trials that are led by or staffed by transgender researchers, that explicitly benefit transgender communities, that provide resources, that address financial barriers, barriers to transportation, and that are integrated into health care that transgender people are already receiving.  So I think there are clear ways for cancer centers, principal investigators, to think about revising their trials to ensure that they are accessible to transgender people. And I think one thing that's hinted at in those suggestions is community-based participatory research in order to really ensure that the trials that we're writing are meeting the needs of community members. Dr. Shannon Westin: I think there’s always a huge opportunity to have advocates at every level reviewing our trials and our grants. And I don't know that we always do the best job of being incredibly inclusive of who we invite to the table to review those. So that part of the paper really spoke to me as someone who sits on different—task force for ovarian cancer and through the NIH and others, making sure that we really have a representative group that is reviewing these trials and ensuring that they are appropriately inclusive. So I really always like true action items because I think we all get really frustrated when we talk about a problem and say there's a problem and we wave our hands at the problem, but what we need are really goal-based solutions. And I think that was one of the parts of your paper that really I felt like elevated this paper, and now I think we just need to get it out so that it moves on beyond this workforce, this task force, and actually gets implemented on a day-to-day basis as we're developing these trials.  So I think I have one more question that I think we've kind of highlighted, but I want to make sure to put a pretty fine point on it. And you've talked a little bit about this, but we know that many transgender people are taking hormones so they can align their anatomy and their physiology with their gender. And we talked a little bit about exclusion around this, but I'd love to hear your thoughts about how can we better address this particular issue. And I’m just thinking of gynecologic cancers. We're using hormones constantly as a treatment. Breast cancer, same. So is there a way to align the drug development in this space but allow people that are taking these hormones for a different reason, a non-cancer-related reason? Dr. Lola Fashoyin-Aje: Yeah, I think, as we discussed, these exclusions can be both explicitly stated in the protocol, like Dr. Ash mentioned before, or it can be silent, where there just isn't information that would direct a provider or investigator one way or the other as to whether or not it is safe to enroll participants on the trial who are transgender and who are receiving hormonal therapy in that context. So addressing this really takes a lot of education for each one of us. And, as I mentioned before, it's a data-free zone. And I think, ultimately, what's going to make some of these recommendations that we made in the paper sustainable is really having data.   When we were preparing the symposium and when we held the symposium, it was quite clear that some of the available data regarding the safety of hormonal therapy—like does it increase the risk of cancer, what are the impacts on an investigational therapy—there's just a lot of inconsistent information, incomplete information. And so we really need a lot of research to be done to fill those data gaps. And that's why in the FDA Oncology Center of Excellence, we actually have an active funding opportunity right now where we're requesting proposals for applied regulatory science research to really understand the factors that affect safety and efficacy of underrepresented populations in oncology therapeutic development. And we specifically call out sexual and gender minorities as part of that because we recognize that that's sort of an area where safety is always sort of invoked. But we just don't know many times if that's actually supported. And so we really do need data.   I don't have a best-practices approach. I think it's important that an investigator or provider ask their patient if they are receiving this and do preliminary basic research about whether or not there's even opportunity for drug interactions, which is something you would be concerned about, or for increasing the risk of developing tumor or tumor progression, depending on the disease. But again, we just don't know. So I think it's really challenging to offer—as a representative of a regulatory agency, it's really challenging for me to offer a best-practices approach here, other than we should just collect the information and do some research to really better understand. Dr. Ash Alpert: Another thing that complicates this whole conversation is that historically, hormone therapy and surgeries have been used as a surrogate target for transphobia. Oftentimes, trans people have the experience of presenting to care for some symptom that we're having and having that symptom blamed on hormone therapy or surgeries when it's not related. So I think that complicates the ways that we're describing our research. That complicates national conversations about the safety of continuing hormone therapy in the context of a cancer diagnosis and treatment. And it definitely complicates conversations that individual transgender people and their oncologists have about whether or not to continue hormone therapy or how to manage the timing of surgeries in the context of cancer treatment. So that's not to stop or halt these really important conversations in this data gathering, but I think those are important considerations to keep in mind as we describe these questions, collect our data, and describe our findings.   Dr. Shannon Westin: Well, great. Well, this has been amazing, and I think that we wanted to put this podcast together so that we could get your very important findings out. How else can we get this out there? What else do we need to do? What are you all doing at the FDA? Dr. Lola Fashoyin-Aje: The symposium that we organized was a huge first step, and we are having those conversations internally about what the best approach is that is data-driven approach. But to be quite honest, I think that there are so many barriers to changing the status quo. And I think what's really important is the continued highlighting of these issues at every opportunity to not leave out this population when we're talking about equity and underrepresented populations and to keep making those changes in our own particular settings about how we use language, the recommendations that we give to sponsors. I'm speaking from the FDA now about inclusion.  And our research and policy priorities really have to reflect this as well. And so, at an organizational level, what are you doing to ensure that this population is safe, has access, and that you're really engaging them in determining what—there are so many issues to prioritize. Where do you start? What are the things that are more short term, and what are the things that are longer term? And these are conversations that we have with patients at the FDA, inviting them to talk to us about them in different product development contexts, but also more generally. Dr. Shannon Westin: Any last thoughts, Dr. Alpert? Dr. Ash Alpert: I really urge readers to take these issues into consideration in their clinical trials office, to their cooperative groups, and to continue to think about them as they're writing trials. I really appreciate—I think we really appreciate the opportunity to speak on this podcast and to potentially have more people hear about these concerns and think about them. Dr. Shannon Westin: Well, I really appreciate all the time that you spent, knowing that you are both very, very busy researchers.  Thank you all for tuning in today to JCO After Hours. We've been discussing the Comments and Controversies manuscript “Addressing Barriers to Clinical Trial Participation for Transgender People With Cancer to Improve Access and Generate Data.” I am very grateful to all of you for listening. Hope you'll check out other episodes of the podcast, and we'll see you very soon. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

In this JCO Article Insights episode, Davide Soldato interviews Dr Frederic Amant from UZ Gasthuisberg - Katholieke University Leuven. Dr. Amant discusses his clinical trial update published in the March 10, 2023 JCO issue, "Cognitive and Behavioral Development of 9-Year-Old Children After Maternal Cancer During Pregnancy: A Prospective Multicenter Cohort Study", by Van Assche, et al. From the International Network on Cancer, Infertility and Pregnancy, the article reports the cognitive development of 9-year-old children after maternal cancer during pregnancy. TRANSCRIPT The disclosures for the guest on this podcast can be found in the show notes.  Davide Soldato: Welcome to this JCO Article Insights episode for the March issue of JCO. This is Davide Soldato, and today I will have the pleasure of interviewing Dr. Frédéric Amant, corresponding author of the manuscript titled ‘Cognitive and Behavioral Development of 9-Year-Old Children After Maternal Cancer During Pregnancy: A Prospective Multicenter Cohort Study’ (10.1200/JCO.22.02005). Dr. Amant is a professor at the Ku Leuven in Belgium and at the University of Amsterdam, and he is the head of the Department of Gynecological Oncology of the Netherlands Cancer Institute and the Amsterdam University Medical Centers. Welcome, Dr. Amant.  Dr. Frédéric Amant: Hello, good evening. Thank you for the introduction.  Davide Soldato: So, Dr. Amant, you published this manuscript that reports the updated results of an ongoing prospective multicenter study. And this study is actually investigating cognitive and health outcomes in nine-year-old children that were born from women who were diagnosed and treated for cancer during pregnancy. So I wanted to ask if you could give us just a quick overview of the study design. What are the main outcomes that are investigated in the study, and also if you could give us some information about the results that you recently published in the JCO?  Dr. Frédéric Amant: Well, the study is a follow-up study of children that are now nine-year-olds. A large part of these children, we have been following up since birth. So the first paper on this cohort basically was in 2015. And at that stage, children were 18 to 30 months old. Well, what we have to say is that all these children, or the majority of these children, in fact, the mothers, were exposed to chemotherapy during pregnancy. So the results actually in children at 18 or 30 months were, in fact, reassuring. And at that time, that was actually a big novelty because it was the first study where children were prospectively followed up and when they were compared to a control group. This study was actually changed a bit; the idea that chemotherapy during pregnancy was not possible. From there, we started to further follow up to some extent the children, but also it increased the awareness that we can treat cancer during pregnancy, including chemotherapy during pregnancy.  This was followed up by a study two years ago in six-year-old children that was, in fact, also reassuring. Today, we discuss then the cognitive and the behavioral development of nine-year-old children when the mother was exposed to chemotherapy but also, in fact, cancer; all the diagnostic investigations, many women also received surgery, and actually, the children were controlled by researchers, by psychologists, by medical doctors to look into their general health. There were questionnaires to the parents, and then we assessed the IQ, we assessed memory tasks, and attention tasks.  Overall, the results are, in fact, reassuring for the several subtypes of treatments, including several subtypes of cytotoxic drugs, and there were no differences when we looked into the intelligence quotient, so the IQ between exposed and non-exposed children. We did see some interesting analysis, however. To some extent, we did see that, for example, the IQ score increased by 1.6 points for each week’s increase in gestational age. There was no difference in the full-scale IQ between the treatment types. Actually, in children prenatally exposed to chemotherapy, there was no association between full-scale IQ and the chemotherapy drugs, exposure levels, or the timing of the chemotherapy during pregnancy. So overall, the results are reassuring and indicate that during a critical maturation period of the child, when complex functions start to develop already and rely on the integrity of early brain development, this is actually reassuring. Especially, this critical maturation period means that when children are nine-years-old, we can test or do more complex tests when compared to children that are 18 months or 30 months, or even six years. So that is all reassuring news.   Another finding, however, was if you look at the IQ, there are several components of the IQ, and there we see that the verbal IQ was, in fact, lower, and that was especially in children who lost their mother or for whom the mother was in a critical period. So the mother's health was not so good. So this could be correlated to the fact that the mother and the environment of a child at that stage actually had less attention to the child, resulting in effect that the verbal development of the child was suboptimal. That is one possibility. We need to say, however, that these children overall were also more preterm born. So that is also a confounding factor. So the lower verbal IQ is in children that were more likely to have a mother in a bad condition, but they were also more likely to be born preterm. So we don't exactly know if it's the preterm birth or the poor condition of the mother that actually contributes to this. Anyway, I think what it is in effect is a message that we need to or that we bring to the family that we need to pay attention to this verbal development of the child.  So if we look into the overall data, I think there are some subtle differences. But overall, these children do, in fact, very well. They, apart from that, have normal behavior, they grow up very fine, there are no other problems. So this is important for physicians, for parents to be, where a decision nine years before needs to be taken, whether or not to treat cancer during pregnancy. I think that these data are then very reassuring that mothers can be treated and can receive chemotherapy during pregnancy since, also, after nine years, the children do, in fact, very well. And one can say children nine-years-old, but what about when they become older? So we don't have that answer yet, we hope to have that in the future. But what we can say is that if a child has a normal IQ and actually a normal development, that this is a very strong predictive factor that later on this will be normal as well. Of course, we don't know yet about fertility; we have no data on secondary cancers. Therefore, we need to follow up these children much longer, of course. But I think with this data, we can really reassure clinicians and parents to be that we don't have to interrupt the pregnancy or that we have to delay the maternal treatment, or that we have to deliver the baby very preterm, allowing doctors to treat after delivery. So it shows that we can treat the mother without delay and that the baby best stays with the mother as long as possible, and that maybe we can use these treatments to keep the baby as long as possible with the mother.   So I think these are the main results and the main message that we actually bring to our patients.  Davide Soldato: Yeah, exactly. I wanted to ask exactly that because from what you just told, so just to summarize for our listeners, we just heard that actually, exposure to cancer and treatment related to cancer during pregnancy actually is not associated with worse cognitive outcomes. And, probably, reading the paper, the strongest predictor of having a reduced IQ for these babies is more the fact of being born preterm compared to the fact that they are exposed either to cancer or to the treatments that are related. So I wanted to ask you exactly that if you feel that the main message that we can deliver to the oncologist community in general, but also to the parents and to the families that they are making a decision regarding the possibility of treatment, is that we can treat, we should treat. And probably the main objective, if you agree with me, is that we try to postpone the moment of the birth as long as possible, to allow for the development of these children.  Dr. Frédéric Amant: That is completely correct. I think when we started with this research, the general idea, the general practice was actually, well, we cannot treat. So we deliver the baby preterm, and typically, that was around 32 weeks because 32 weeks of pregnancy, that means that the baby is viable but still very preterm. But the baby is viable, but it's two months early. But that was generally accepted in the absence of any data on the safety for children. With the knowledge we have now that we built up and for which the paper we discuss now is like the last update of this follow-up, it shows, indeed, that we should not fear too much, and that indeed of cancer treatment during pregnancy, including chemotherapy, and that this is to be preferred rather than interrupting the pregnancy or having a preterm baby. Or what was done also is that the mother was not treated, and then the pregnancy was continued, for example, until 32 weeks of gestational age, and then the mother was treated. But all these alternatives are either suboptimal for the mother or suboptimal for the baby, especially if there is a termination of pregnancy. But even when there is no termination and preterm delivery, that is also not particularly good for a baby. So the best solution for all parties there is to treat during pregnancy, including chemotherapy.  And that is indeed the message that we need to bring, especially since the results confirm previous results and actually validate the previous results so, well, it adds to the solid results, actually, and that is really reassuring. And what we also need to say here, and although this is not really part of this paper, is that there are also not more congenital malformations because that is also a concern of many doctors, that actually these drugs are designed to kill rapidly dividing cells. We know they pass the placenta, they will go to the fetus, although in a bit lower dosages. But many people were scared about the increased chance for congenital malformations, and we know that this is not the case on condition that we give the chemotherapy after the first trimester. If you give chemotherapy during the first trimester, you will have an increased risk of congenital malformation. So that is a caveat that we need to take into consideration that it is possible, but mainly during the second and the third trimester. But of course, surgery, oncological surgery and even radiotherapy during the first trimester is possible. So it is only the chemotherapy, which is not possible during the first trimester. This is what doctors and patients need, that there is scientific data saying that this is possible, and that's why we are very happy that we could report on that and that the data validate the previous findings on this topic.  Davide Soldato: And I think that one of the concerns that were also associated with the administration of chemotherapy, particularly with anthracyclines, was kind of the concern that there will be some effect on the cardiac function of the children born from these mothers. Well, it's not actually the object of this specific paper, but you previously also published data that were reassuring also regarding cardiac function. But one other thing that I wanted to ask you, you said before that there were lower verbal intelligence scores from babies that were born from mothers who then died, especially in the first part of the life of the baby. And also, there were some signals that some of these babies, especially those who were born preterm or that lost their mother very soon, were in need of remedial care.  Although you say that once we arrive at the nine-year development, probably the development is going to be normal, but do you think that this kind of environment and social factors and difficulties in general in the family once we arrive to that stage of development could also lead to some differences for these babies? So more related to the social situation and loss of the mother than from the treatment that they received or that they were exposed to. And do you think it's important in general that we continue to follow up these now children also to kind of give an indication or somehow to raise attention on the fact that despite the cognitive outcomes, they are good, we still need to give social support or this type of help to these families?  Dr. Frédéric Amant: Yeah, I think that's an excellent remark, excellent question because it's true. I wanted to say at the first session, the first part, but when I was talking about the predictive value of our results, they are very strong, and we can actually already now exclude that also, in the long term, chemotherapy on these cognitive factors will not have an effect. And that in the meantime, when the children grow up, the new external factors, in fact, become more important than the antenatal exposure. It is the social environment. Children will smoke, will use drugs, will drink alcohol, psychological traumas, and so on. So these are more likely to influence the further development of the children. And that's why I think, and the older the children are, of course, the more likely that it is that these external factors will play a role, so that will be more and more difficult to really disentangle all these external factors related to antenatal development.  On the other hand, we also control for this, and we control for the maternal and the paternal education. We look at the education level of the parents. So this is all included when we analyze this, and it is actually interesting because now you refer to it. In fact, children do, well, or the intelligence outcome correlates to the maternal education. The paternal education is, in fact, less important in this. So just to underscore the fact that we look into this, so that will be maybe a bit more difficult to really explore in the future. But the future examinations, on the other hand, will give us more insight into, for example, fertility, the adolescence of the children, and their sexual secondary characteristics as maybe as a biomarker of fertility, which is not always the case. But at least it would be reassuring if we see that these sexual secondary characteristics develop normally and also, maybe later on, the increase on cancer development.  Until now, these are theoretical concerns, but today we have no indication that this is actually true. So we think we definitely need to further explore that. But again, this is theoretical because some children now are 12, 15, 18 years old. They are not part of the analyses. But we have seen the children already. The results are in the data set, and we have no indication of more cancers. And we have no indication or the patterns at least, do not report to us that these biomarkers for fertility, let's say, the secondary sexual characteristics, are actually delayed or absent from the information we have from the children, older children. So the adolescents and their parents, we have no indication that there is a problem. So we have no mention that they are worried on these topics. So from that point of view, this is also reassuring. But of course, this is not hard science, but this will be part of the future analyses. The reason why we don't have these analyses now is that the children, of course, need the time, and they need to grow. So we have to follow them up. But what we tell in our clinic is exactly what I say now is that from the non-scientific data, but from information from our patients, that we have no indication that there is a problem.  Davide Soldato: And of course, in the context of the study, you mentioned before that one of the previous reports was actually kind of a confrontation between these children that were exposed and normal controls. Do you plan also to continue the follow-up for the controls to have sort of normality to confront these children too? Dr. Frédéric Amant: Actually, now you refer to a sensitive point, to be honest. In the ideal world, we would do that to check the controls. But we see that it becomes a logistic problem to follow all these children and that we, to be honest, lack the resources to have such a large group of psychologists, not only to follow up all the children that were exposed to cancer treatment during pregnancy, but at the same time a control group. It's not only the existing cohort that we follow up. The cohort is fueled by new cases, and all our cases that are born in Leuven or in the Netherlands, in Prague, and in Milan, all the new cases are added to this cohort so that multiplied with a control becomes a really large group of children. So in the future, it will become impossible. Well, we will not have the resources to have to follow up this large group. And we will more focus on certain populations of drugs where we don't have so much information, cytotoxic drugs where the numbers today are too small. And we will compare the results with standard results that we would expose in that population, in those children from that country. And well, that is also a very reasonable approach and this is the approach we will need to apply in the future. Maybe in a subset of children, we will use controls but that will really depend on the scientific question. Davide Soldato: Yeah, probably for some data where we have less information gathered in the general population, maybe that would be a subset that we could explore a little bit further. In your opinion, do you also think that this prospective study will give us in the future also information that goes a little beyond the cytotoxic type of treatment? Also, referring to new kinds of treatments that could potentially enter in the clinic, I know there is also the problem of exposing these women to drugs that we don't know actually what they give in terms of safety for the children. But do you think this could be something that could also be explored in this type of study?  Dr. Frédéric Amant: I think what this study shows overall, is there is insufficient research in pregnant women. And it is always like ‘drugs - cannot give them to pregnant women because it's potentially toxic.’ Of course, I can understand the worry, but on the other hand, what we have shown actually is that we have investigated one of the most toxic drugs. When there is uncertainty, I mean, we took really the drug where we would expect huge problems with children and there it not to be so bad as we thought. Really. I've seen letters, I've seen doctors that told me babies will be born like monsters if you give chemotherapy. That was the idea at least of some people, of specialists, I mean, well-educated people. And then we can basically reverse that idea for that particular class of drugs. 50% of pregnant women take some kind of medication, and for most of these medications, it has not been investigated what is, in fact, the effect on the children. So I think that our research opens the door that we can also look in another way to other terminal conditions that need treatment and that we can really add to more data, and that it underscores the potential, not only the importance, but also the potential to investigate on this. So this is on a general idea, it shows that it is possible. Of course, when we then again focus on cancer treatment, there's a whole tsunami of new drugs, targeted drugs, the immunotherapy drugs. So we have to be also very clear, transparent that our research here mainly focused on chemotherapy. The number of mothers that took any other of these novel treatments is actually very low and they are not part of this cohort because that was nine years ago. Nine years ago, actually, there was no immunotherapy yet. There were some targeted treatments, but very limited. So that is definitely, let's call it a weakness of this study that we cannot report on that. Nevertheless, we have some data from other studies with a shorter follow-up, but very limited. So that becomes really a challenge, actually, the whole new drug class of drugs because they are small molecules, they're more likely to cross. And it will then really depend on what is the target of that drug. And if that target is also available in the fetus while it is likely that the fetus will also suffer from that. But if there is no target at the fetal site or if the molecule is too big, then there will not be a problem. So, the individualization will be much more important in the future.  Also because many of these drugs are actually more and more used in the adjuvant setting. When we started this study, these drugs were used only in the metastatic setting, recurrent disease. That is the clinical situation where women do not become pregnant. But now they're moving more forward into the oncological treatment and also the adjuvant setting, so children that are more likely to be exposed to these drugs. So that is an avenue for future research that we also want to further investigate.  Davide Soldato: Yeah, of course. And just on a personal type of question, was there something specifically that led you to this type of research in general, in cancer in pregnant women? Because as you said, there is not so much research in it. It's difficult to do because– Well, it's not something that is so uncommon. But of course, it's more uncommon than several other topics in cancer research. So I was just wondering if you could tell us a little bit if there was something specifically that led you to this type of research.  Dr. Frédéric Amant: Yes, indeed, there is such a thing. I did not have such an idea, just out of my mind. And actually, now we go back nearly 20 years ago, 2004. At that time, we were actually scared to give chemotherapy. We really hoped we would not see these patients because we did not exactly know what to do. And then, I was confronted with a patient with cervical cancer. She lost her first pregnancy when she was 20 weeks far in her pregnancy. And now she was diagnosed, second pregnancy, with cervical cancer. And actually, she was referred to do a radical hysterectomy to remove the cancer, the uterus, and the baby. And actually, she approached me and she said, “Listen, I was diagnosed.” She was asymptomatic. So she was diagnosed thanks to the pregnancy. So she said to me, literally, “I had an earlier diagnosis thanks to my baby, so I have more life chances thanks to my baby. So I want to do everything to save this pregnancy because it is my only option, my last option to become pregnant. And I'm happy to take any risks.” Because, of course, we discussed that we are unsure that there was little evidence on this. So we had a really open, transparent discussion on that. But we said there are options. But if you say unsure, that means that she may take a risk, then she said, “Well, I'm happy to take that risk because I want to give my child also a chance because it's thanks to my child that I also have an extra chance.” So that's actually where it started. So that's 2004, we started to look into the literature, two big things actually. To some extent, chemotherapy had been given, but really the number of cases was very small. But importantly, the children were born normally. So there was also some evidence that it was possible, but there was no really no long-term data. So we said to her, listen, the data we have is when they're born, they do well, but we cannot say anything more than that. So that was particularly to that patient.   And secondly, it really showed us the complete absence of knowledge on that, on all the aspects. There were no prospective studies. We did not know how many chemotherapy crossed to the child. We did not know the long-term follow-up of the children. We did not know, for example, the dilution of chemotherapy because mothers get chemotherapy, the chemotherapy is diluted. What are the effects on the maternal outcome? Because that is also important. So many unresolved questions that, at that time, I decided to put a lot of energy into this project.   But to answer your question, it started with listening actually, that is also an important message, listening to a patient and trying to help the patient and to be open for her question. And to elaborate on that, I was very happy to work in a group that was also that was actually a young group of young students and young registrars that were also passionate about the topic and helped me to investigate this topic. And together, actually we treated the mother successfully and well. The rest is history. Davide Soldato: I think that from where it started, you really actually helped us, a whole community of oncologists and of patients, to really receive the best treatment, the best option for the mother, for the baby. And now, with this manuscript that you published also gives us reassuring data that in terms of cognitive development, of general health, outcomes, of cardiac toxicity, there is all the possibility to give these treatments and to do well for the mother and at the same time for the baby. So thank you for your efforts in this really underserved research topic.  Is there anything else you would like to add?  Dr. Frédéric Amant: Well, maybe one general comment is that the diagnosis of cancer during pregnancy is not an emergency. It is always very confronting, and well, many physicians do not have a large expertise on that. And my advice would be that it's not an emergency. There is time to ask for an opinion, to ask for advice for your colleagues, and even to refer the patient. It's what we see. There is a diagnosis of cancer during pregnancy, and it's urgent. Everything needs to go quickly. And I understand this, and this is psychologically explainable. But it is better to take time, go for advice, allowing you, together with the patient, to make the right decision.  Davide Soldato: Thank you very much for this final remark. I think it's really important to deliver this kind of message that if we are unsure, especially in this type of situation, it's okay to refer, it's okay to ask for a second opinion. And thank you again for agreeing to be with us. Dr. Frédéric Amant: Thank you, Davide.  Davide Soldato: So this is Davide Soldato in this episode of JCO Article Insights. We discussed with Dr. Frédéric Amant the results of the manuscript titled ‘Cognitive and Behavioral Development of 9-Year-Old Children After Maternal Cancer During Pregnancy: A Prospective Multicenter Cohort Study’. Thank you for your attention, and stay tuned for the next episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Show Notes: Like, share and subscribe so you never miss an episode and leave a rating or review.   Article   Cognitive and Behavioral Development of 9-Year-Old Children After Maternal Cancer During Pregnancy: A Prospective Multicenter Cohort Study    Find more articles from the March 10 issue.  

Dr. Shannon Westin and her guests, Jessica Star and Dr. Ahmedin Jemal, discuss how the COVID-19 pandemic affected cancer screening in the US in 2021. TRANSCRIPT The guest on this podcast episode has no disclosures to declare.  Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours. I am your host, Shannon Westin, the social media editor for the JCO and Gynecological Oncologist at MD Anderson. And it's my pleasure to welcome you to our next episode, which is “Cancer Screening in the United States During the Second Year of the COVID-19 Pandemic.” And please note the authors have no conflict of interest.   I'm joined by two of the authors on this important work. First is Jessica Star, who has an MA and an MPH and is Associate Scientist II for Cancer Risk Factors and Screening Surveillance Research at the American Cancer Society. Welcome.  Jessica Star: Thank you for having me.  Dr. Shannon Westin: Of course. And we're also joined by Dr. Ahmedin Jemal, the Senior Vice President for Surveillance and Health Equity Science at the American Cancer Society. Welcome.  We're so excited that you both are here, and I'm hoping that we'll have a really lively discussion about your important work. This paper was published online on February 23, 2023, in the Journal of Clinical Oncology. So let's level set. We'll start—Jessica, can you talk a little bit about how the COVID-19 pandemic initially impacted cancer screening in the United States?  Jessica Star: So the COVID-19 pandemic disrupted the delivery and receipt of routine preventative services, and that included cancer screening. What we've seen from a lot of 2020 data that has been published is that cancer screening declined during that first year of the COVID-19 pandemic. One of those papers includes a paper by the American Cancer Society led by Stacey Fedewa. And many other studies also reported similar declines, including for breast, cervical, prostate, and colorectal cancer screening. However, some of these papers, by the end of 2020, it appeared that screening rates were starting to rebound back to pre-pandemic rates. And so that was sort of the interest in looking at that 2021 data now. Dr. Shannon Westin: And what did you hypothesize? Did you think that these data were correct? Like, did you think that we were going to start seeing an increase in screening in the second year of the COVID-19 pandemic, or what were your suppositions? Jessica Star: Yes, I think we kind of hypothesized or hoped, based off of what we were seeing from the 2020 data, that we would start seeing more substantial increases as we were getting into 2021. Based off of those declines during the first part of the pandemic, we were really wanting to see individuals coming back into screening now that stay-at-home orders had sort of been reduced and now that individuals were going back to screening more frequently. Dr. Ahmedin Jemal: I might add that the motivation for this screening, in addition to what Jessica said, is that the previous studies were based on representative US populations, either based on claims data or state-specific population-based studies. They were not based on nationwide population-based study. That's why we used the NHIS, National Health Interview Survey, which is a US population-based study, to look at whether screening in 2022 has returned to the pre-pandemic level.  Dr. Shannon Westin: Yeah, why don't we get into a little bit more detail here? I would love—Jessica, can you talk a little bit more about the National Health Interview Survey? I get the idea of why you all used it, but can you tell our listeners just a little bit more about that database? Jessica Star: To go off of what Ahmedin mentioned, The National Health Interview Survey is a nationally representative cross-sectional household survey of the United States population that is generalizable. And that survey is housed by the National Center for Health Statistics in the Centers for Disease Control, and they report on cancer screening biyearly. So we have data from 2019, and we have data from 2021. And the next increment of the National Health Interview Survey that we'll have for cancer screening is in 2023.  Dr. Shannon Westin: And then talk a little bit about which cancer types you all focused on when you're looking into this hypothesis, that potentially screening was being increased.  Jessica Star: So we focused primarily on breast, cervical, colorectal, and prostate cancer screening. And some of the reason behind this was because of data availability. The NHIS only provided those four—receipt of those four screening types, as well as when we were looking at the data previously from that 2020 data, we were seeing a lot that were focusing on some combination of breast, cervical, colorectal, and prostate cancer screening. So we wanted to continue that work into the second year.   Dr. Shannon Westin: And then let's cut to the chase. What did you find? Did you prove or disprove your hypothesis?  Jessica Star: We mostly disproved our hypothesis. Our team found that past-year screening for breast, cervical, and prostate cancer screening decreased in 2021 compared to that 2019 level, with decreases largest primarily among non-Hispanic Asian persons. And this translated to a population-weighted estimate of approximately 1.1 million, 4.4 million, and 700,000 fewer eligible individuals receiving breast, cervical, and prostate cancer screening, respectively. However, we did find that colorectal cancer screening actually remained stable between 2019 and 2021, and part of this can be attributed to an increase in stool testing that offset a decline in colonoscopy testing. Dr. Shannon Westin: Interesting. So people doing things from home allowed them—and I think we all got really good at that during the COVID-19 pandemic, is what actually can we do at home and be functional? That makes sense. Were you surprised at this? I know, as a gynecological oncologist, I was a bit disappointed to see the lack of cervical cancer screening and a bit surprised at the rest. What were your thoughts? Jessica Star: I guess, upon more reflection and seeing that colorectal cancer screening had remained stable and sort of the reason why colorectal cancer screening rates had remained stable, it wasn't entirely surprising. It seems that many people were still hesitant to get screening done in the office or in hospital. And also, considering that many individuals had lost their jobs during the COVID-19 pandemic, many might not have been insured in the same method that they were previously, and so they might have hesitated to be screened as well. Dr. Shannon Westin: That's a great point. Medical coverage is so tightly linked to the work that we're doing. I hadn't even thought about that. That is a great point.   Now, you mentioned briefly about the largest decrease in the non-Hispanic Asian population. Did you see any other kind of associations based on race, ethnicity?  Jessica Star: We did. We also saw some declines for both Hispanic and non-Hispanic Black persons. But we particularly pointed out the decline for non-Hispanic Asian persons because it occurred for all three of the cancer screening types that we saw decline, so for breast, cervical, and prostate cancer screening, whereas for Hispanic and non-Hispanic black persons, they might have had a decrease in one or two screenings but not all three. Dr. Shannon Westin: That's interesting. I bet there's a lot to explore there to try to understand why we would see such discrepancies across the different race ethnicities.  Now, we talked a little bit about how screening might have been improved for colorectal cancer having at home. So what's the lesson here that we can maybe utilize to direct guidance to other screening programs? Jessica Star: The lesson here, which will also have a bit of a caveat to it, is that home-based screening is effective at least getting in that initial screening for when there are healthcare disruptions, whether it's because of the COVID-19 pandemic or even thinking about environmental disasters or all of those different things. But the important thing to note is that once you are screened for colorectal cancer using, for example, like, a home-based stool testing, if you have a positive test, you would need to go in for that follow-up colonoscopy, so you still would need that in-office visit. It does allow a lot of people to get screened, figure out that they're negative, and then not have to proceed any further for those individuals.  Dr. Shannon Westin: Yeah. I wonder, do you have the opportunity to look at data to see how many of those people, if they found something, if they had a positive test then went on to get that next step? I'm sure not from this type of survey.  Jessica Star: Not from this study. From other literature that is already out there, it seems that the estimates are quite low for follow-up colonoscopy. So that's kind of the caveat there is that there would still need to be follow-up to be fully screened if you have an abnormal test. Dr. Shannon Westin: There are some really interesting opportunities to potentially do at-home cervical cancer screening. One of my colleagues is working very hard to try to get that out. And I think you’re bringing up a really big elephant in the room of what will need to be addressed, because it’s going to be something similar where, if you have a positive screening test and then you don’t go to that next step, then you’ve lost the opportunity there. Jessica Star: Yeah. And that's one of the things we did touch on a little bit in the paper, was about cervical cancer screening, since that is an area where there is a home-based option. But since it hasn't yet been approved by the FDA, it hasn't been able to be approved as an appropriate screening method moving forward. But that is definitely an area where we suggest further research sort of comes in to see about allowing cervical cancer screening to also have that home-based option.   Dr. Shannon Westin: So not what we were hoping to see, with the decrease in the screening across three of the major cancer types. What do we do? How do we address these findings? How can we make an impact? Jessica Star: So I think there’s many different areas that can allow for an impact. Clinicians and healthcare professionals should be playing a major role in the return to screening campaigns by recommending screening to each of their eligible patients according to screening guidelines, with that special emphasis on non-Hispanic Asian persons and other historically underserved groups. And I think another area is just continuing to put out research on this topic and continuing to follow up to see about how cancer screenings are continuing to progress as time goes on. This is looking at the second year of the pandemic, and we have data from the first year of the pandemic that's already been published by other people. And we need to sort of keep following it because, in the short term, this problem of delayed cancer screening might lead to late-stage diagnosis, but in the longer term, that can correlate to poor survival and increase mortality as well.  Dr. Ahmedin Jemal: Yeah. I might add one point to what can be done to what already Jessica said. Insurance is a major determinant of access to care, which includes the screening. But we have about 27.5 million, close to 30 million elderly adults who are uninsured. Especially if you look at the expansion of Medicaid, there are 11 states that haven't yet expanded Medicaid. So I think lawmakers can work to expand Medicaid to all populations—to income populations—low-income populations, not all populations. Dr. Shannon Westin: I think you bring up a good point. Policy is really important here, and we've seen this across cancer outcomes. And there's been a lot of really nice data in those states that expand Medicaid that we see improvement in mortality and surgical morbidity and so many things. And so it's a great point. I don't think I've ever heard it referenced towards cancer screening, but there's an opportunity there with policy to improve those numbers as well.  Well, great. I'm so grateful to the two of you. This was—it’s such an important work, and really disproving hypotheses is a good thing, because if we just assumed everything was getting better and didn't act accordingly, then we would be really negatively impacting our patients and potentially with our heads in the sand. So this work was so important, and I'm really grateful for you all to take the time today to have a chat with our listeners.  So listeners, thank you for being here. Again, this was “Cancer Screening in the United States During the Second Year of the COVID-19 Pandemic,” published online February 23, 2023. Thank you for listening to JCO After Hours, and please do check out our other episodes. And we'll see you next time.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Dr. Shannon Westin and her guests, Dr. Michael Atkins, Dr. Adil Daud, and Dr. Gary Schwartz, discuss a definitive work: The DREAMseq Trial. TRANSCRIPT The guests on this podcast episode have no disclosures to declare.     Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast that gets in-depth on articles that have been published in the Journal of Clinical Oncology. And it is my great pleasure to be your host. I'm Shannon Westin, GYN oncology, and I serve as the social media editor for the Journal of Clinical Oncology.   Today, we're going to be discussing a very exciting article describing “The DREAMseq Trial—ECOG-ACRIN EA6134, Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients With Advanced BRAF-Mutant Melanoma.” This article was published in the JCO on January 10th, 2023.   And I am joined today by the lead author, Dr. Michael Atkins, who is Deputy Director, Georgetown Lombardi University Hospital, and Scholl Professor and Vice Chair of Oncology at Georgetown University Medical Center. Welcome.   Dr. Michael Atkins: Thank you. Nice to be here.   Dr. Shannon Westin: In addition, we are also accompanied by two experts in the field, Dr. Adil Daud, Professor in the Department of Medicine at the University of California San Francisco, and Director of Melanoma Clinical Research at UCSF Helen Diller Family Comprehensive Cancer Center. Welcome, Dr. Daud.   Dr. Adil Daud: Hi, great to be here.   Dr. Shannon Westin: And with Dr. Daud is Dr. Gary Schwartz, the Division Chief of Hematology Oncology and Deputy Director of the Herbert Irving Comprehensive Cancer Center in Columbia, New York. Thank you for being here.   Dr. Gary Schwartz: Delighted to be here.   Dr. Shannon Westin: So I'm surrounded by experts, and I'm very excited as a GYN oncologist to hear all of what you all have learned in melanoma because we're always excited to take that back into our field. So I think first, though, for those of us that aren't melanoma experts, Dr. Atkins, can you just level set for us and tell us what was the standard of care for melanoma when you began this study?   Dr. Michael Atkins: Sure. Well, first of all, this was a study for patients with BRAF V600 driver mutations in their melanoma, which represents about 50% of the patients with metastatic melanoma. And at the time the study was launched in 2015, two BRAF/MEK inhibitor combinations were FDA approved and shown to produce significant progression-free survival and overall survival benefits relative to BRAF inhibitor monotherapy. In addition, combination checkpoint inhibitor therapy with nivolumab and ipilimumab was shown to be superior to ipilimumab and, in particular in patients with BRAF-mutant melanoma, also to nivolumab monotherapy based on the results of the CheckMate 067 study, leading to its FDA approval. So we had these two regimens there that were approved. Of note, despite the many debates and attempts to garner real-world evidence at the time—the study actually reported out in 2021—marketing data showed that half of all patients in the US with metastatic BRAF-mutant melanoma were receiving BRAF/MEK inhibitors, and only one-quarter received nivo-ipi as initial therapy. So there remained a confusion throughout the course of the study as to which regimen was best in the US and around the world.   Dr. Shannon Westin: Tell me, what led to the current study? Was it really trying to drive at that very question?   Dr. Michael Atkins: These were the best treatment available at the time. And they really had changed melanoma patient outcomes in ways that we could have only dreamed about just five to 10 years prior, when median survival for patients with metastatic melanoma was six to nine months. Hence, the DREAMseq trial, this doublet, randomized evaluation of advanced melanoma sequencing, was really an apt acronym for the trial. But we had these two regimens of BRAF/MEK inhibitors tending to display the overall survival curve, while immunotherapy tended to raise the tail. And at the time the study was launched, it was really unclear which treatment was preferred in general or for particular subsets of patients. And given that patients would likely have the option to receive both approaches, was there a preferred sequence? So the DREAMseq trial was a launch to address these questions.   Dr. Gary Schwartz: I can echo Michael's statement about that. There was also—having been at the beginning of immunotherapy and targeted drug therapy, the transformation of cancer medicine in melanoma was extraordinary. Over a very short amount of time, we transformed a disease that's incurable to curable. And I don't think anybody, at least not in my lifetime, that ever think we'd ever see—or I’d see that type of transformation. But the debate in the community was what should be the first therapy. Should it be a targeted drug combination targeting RAF and MEK for BRAF-mutant melanoma, or should it be immunotherapy? And actually, there was a trend favoring immunotherapy, I think, at the time of the start of the study. It was actually an unresolved issue that many of us were continuing to debate up to the publication of this data, which certainly has now solidified the role of immunotherapy as a starting point for patients with BRAF-mutant melanoma.   Dr. Michael Atkins: Thanks, Gary.   Dr. Shannon Westin: I would love for you—because it is a complex design, and I feel like a lot of times, as drug developers, we're often discouraged to do too many lines in a row. And I was just so intrigued at how well this was laid out to really understand those very questions of superiority as well as sequence, which we don't often assess. Dr. Atkins, will you just summarize the design so that all of the very smart researchers on the line can utilize that for their own cancer types?   Dr. Michael Atkins: Yeah, it was complicated to execute, but the design was pretty simple. Patients with treatment-naive BRAF-mutant metastatic melanoma were stratified according to ECOG performance status and LDH normal and high and randomized in step 1 to receive either combination nivo-ipi induction for 12 weeks, followed by nivo monotherapy maintenance for up to 72 weeks—that was arm A, and that was standard of care for that regimen—or dabrafenib-trametinib continuously, and that was arm B. And if patients experienced disease progression and met the step 2 eligibility criteria, they were able to cross over to the alternative sequence: arm C, dabrafenib-trametinib, or arm D, nivo-ipi. And we followed the patients and chose two-year overall survival as the primary endpoint.   Dr. Shannon Westin: And we kind of got a little hint. So what was the primary finding?   Dr. Michael Atkins: Yes, because of the anticipated distinct shapes of the overall survival curves, with the BRAF/MEK inhibitors tending to have their benefit early and the immunotherapies tending to raise the tail of the curve, we thought there'd be non-proportional hazards and that the overall survival curves might cross. And therefore, we chose as a primary endpoint two-year landmark overall survival, with an estimate that the nivo-ipi first sequence would have a 70% overall survival rate compared to 50% for the dab-tram first sequence. And with 300 patients enrolled and 270 evaluable, there was about a 90% power to show this difference in two-year overall survival rate, with a two-sided type one error rate of 0.05.   Dr. Shannon Westin: And it met its primary endpoint?   Dr. Shannon Westin: Yes, the study was opened in July of 2015, and it was set up that there would be Data Safety Monitoring Committee meetings after the first 100 patients were accrued every six months and that the data cutoff used for the fourth interim Data Safety Monitoring Committee meeting, which was a median follow-up of a little over two years, 265 patients had enrolled in step 1—those were evenly split between the two arms—and 73 had enrolled in step 2, with nearly two-thirds of those being on arm D, second-line nivo/ipi. And the two initial arms were balanced for most of the characteristics and was randomized for the important characteristics.   And from an efficacy standpoint, once again, we chose landmark two-year overall survival as a primary endpoint. And the overall survival curves for the combined sequences showed the anticipated biphasic pattern; they actually crossed around 10 months, and 100 patients had died, with 62 of them on the sequence beginning with dab-tram. And the two-year overall survival rate was 72% for patients who started on nivo/ipi and 52% for those who started on dab-tram. And that was a pretty significant difference; P equals about 0.01 by log-rank test. And so this 95% repeated confidence intervals, along with the 20% difference in overall survival, ranged from 3% to 38%, and the O'Brien-Fleming boundary had been crossed based on this estimate. Interesting, as we published, the three-year overall survival difference was even greater, approaching 24%. So that was the main study endpoint. And because the Data Safety Monitoring Committee felt that that difference was clinically significant even though we had only had about 59% information, they recommended at that point that the study be closed early and that patients who were on arm B, dabrafenib-trametinib, be given the option to cross over to immunotherapy before disease progression.   So that was the primary endpoint. I'm going to pause there. There were some secondary endpoints that I think were interesting, but maybe Gary or Adil have comments about this.   Dr. Shannon Westin: I hope they do, yeah. I'm going to give over my podcast hosting to you.   Dr. Adil Daud: Mike, congratulations on that study. I mean, that's transformative. I mean, I think there was a feeling, like Gary was saying, that immunotherapy might be better in the long term. But I remember a lot of discussions, and I think you answered them in 2015 or 2014 and 2013 because you've been working on this design for a while, that the people who were treated with BRAF inhibitor therapy were just different. And a lot of people would say that when somebody walks into the clinic, the folks who are BRAF-mutant, they just have rapidly progressive disease, like something really bad is going on. And that's why the results on BRAF/MEK inhibitor therapy just looked different than immunotherapy. Immunotherapy was for slower-growing tumors, and I think your study kind of puts maybe a different spin on that, basically suggesting differently. Would you comment on that?   Dr. Michael Atkins: Yeah. So, Adil, I think early on, people thought that the BRAF/MEK inhibitor was for patients who had rapidly progressive disease, and you needed to get a response to get the disease under control. But over time, as those studies were followed out, it appeared that the BRAF/MEK inhibitors tended to work best in patients who had less aggressive disease—performance status 0, M1a or b disease, and normal LDH. And so it was still confusing as to who should get which therapies. And when you compared the results using retrospective data between those who got immunotherapy and those who got targeted therapy, it was really difficult to be sure that these were the same patient population. So the only way you could really know whether immunotherapy was truly better was to do prospectively randomized studies where the two arms were balanced, which is what we set out to do in DREAMseq.   Dr. Adil Daud: Yeah, I think there's a lot of areas in oncology where people think whether you should give somebody a CAR T-cell or whether you should give somebody myeloma therapy or—people think, well, these are just totally different. Or in melanoma, I think, the TIL therapy, there's this question about, can you really compare that to anything else? And I think your study, which perhaps wouldn't be done by a pharmaceutical company and perhaps wouldn't be— outside of the cooperative groups, I feel that it's hard to really do a study of that type.   Dr. Michael Atkins: I agree.   Dr. Gary Schwartz: Yeah. First, I want to say congratulations on really an extraordinary study, Michael. I think it really answers some critical clinical and biological questions that have been subject to debate in the melanoma and the medical oncology community for the last five or more years.   There were a couple of things that surprised me. One was the fact that patients that started on dab-trame, when crossed over to immunotherapy, the outcomes were pretty poor. And that was a biological outcome, I guess, we kind of thought about. But this study certainly suggests that there's something about prior targeted drug therapy that may affect outcome and immunotherapy. And also, the other thing that was surprising was the number of dropouts that developed and couldn't cross over because of the rapid progression on the first-line study. Do you want to comment on both of those points and maybe share some thoughts about what that means for the medical care of patients who get this type of treatment?   Dr. Michael Atkins: Sure. First of all, response rates were similar between the step 1 regimen and for dab-tram, whether used in step 1 or step 2. In contrast, as you said, nivo-ipi appeared to be less effective after progression on dab-tram than in the first line. It was like a 46% response rate in the first line, and about 30% in the second line. The median PFS in the first line was about 11+ months, and in the second line, was only about three months. And I think there was some feeling in the community—probably wishful thinking and also based on what I think are some flawed preclinical and translational studies—that BRAF/MEK inhibitors might cause some immunogenic cell death and cause new antigens to be expressed and activate the immune system, be synergistic with immunotherapy given afterwards, while I think other data suggested that the resistance mechanism to the dabrafenib-trametinib was immunosuppressive, leading to upregulation of VEGF and things like that.   So this result suggested that immunotherapy didn't work as well in the second line. There are probably several reasons for that. It could be biologic changes, which I think we don't pay enough attention to when we think about what we're doing in the first and the second line. But also the type of patients who progressed on BRAF/MEK inhibitors. when you stop those drugs, the disease tends to accelerate. Many of them probably had subclinical CNS disease, and it was just not a good time for them to be going on immunotherapy, while in the front line, you didn't have to deal with those type of issues. And with regard to crossover, one of the things that we looked at as a secondary endpoint in this study was feasibility of doing the crossover. Because in clinical practice, we found that if you waited until disease progression on BRAF/MEK inhibitors and then tried to cross them over, oftentimes, patients progressed really rapidly, and you weren't able to get the immunotherapy in to large degree, while in patients who got immunotherapy, they had a lot of toxicity often, which caused them to stop therapy. And if they had toxicity at the time they were progressing, it might be complicated to add new drugs in.   And so I think the community was a bit surprised that only about half the patients were able to successfully cross over. But I think that's reality, that if you use these drugs to progression and then have eligibility criteria, which you have to have in a clinical trial for patients to go on the second-line treatment, you're going to have a lot of dropouts. One of the major reasons for dropouts on dab-tram was progression in the CNS, and dabrafenib-trametinib doesn't work as well in the CNS as it does systemically, while immune therapy actually appears to work as well for patients with asymptomatic or undetected CNS metastases as it does systemically. And I think that was an important reason why immunotherapy was better.   Dr. Gary Schwartz: I've looked at your paper now multiple times, Michael, and I can't think of any reason why anybody would want to start a targeted therapy for BRAF-mutant melanoma. I mean, I think this really becomes a definitive study declaring that immunotherapy is where all medical oncology should begin in the treatment of BRAF metastatic melanoma. Is that too much of a statement to make, or would you agree with that as well? I've been trying to think of all the reasons why not to give immunotherapy first. I can't think of one now, after your paper, that would suggest otherwise.   Dr. Michael Atkins: Well, I've been chastened by a lot of reviewers, as you know, to say that these results only definitively apply to the patients who were eligible for this study. And patients who had poor performance status or active brain mets or who required steroids and needed to be in the hospital or had to have a response were not eligible for this study. And so I think there are some patients where the disease is just on fire, where you may need to give BRAF/MEK inhibitors to try to cool it off before you start immunotherapy, particularly if patients need to be on immunosuppressive drugs to control edema in their brain, or because of bone mets pressing on the spinal cord or things like that, I think that it's important to have that other option. But as soon as you can, as soon as you've created enough window to get patients off immunosuppressive drugs or improve their performance status enough so that they can be an outpatient, you probably should switch to immunotherapy and give them the chance for a long-term benefit.   Dr. Adil Daud: I have doctors call me outside of academia and say, “Hey, I've got a patient walking in. I'm trying to decide, should I do the triple therapy, or should I do…”—which triple therapy in melanoma refers to dabrafenib plus trametinib plus a PD-1 drug like pembrolizumab or, in some cases, like a PDL-1 inhibitor—and they're questioning whether that's an appropriate place to start. Or sometimes people say, “Well, what about doing a sandwich regimen where we start off with dabrafenib-trametinib and then switch over to something else without waiting for progression just to give people…” And I give a long-winded answer to that, but I'm curious to hear what you think, what you both think.   Dr. Michael Atkins: So my view is—I've always thought, based on some of our early translational studies, which were presented at ASCO and hopefully we'll be able to publish soon, that the BRAF/MEK inhibitor data that showed that there was an influx of immune cells and potential synergy was actually an artifact, that it was not increasing immune cells in the tumor microenvironment, but actually loss of tumor cell in the tumor microenvironment that was causing the impression that the tumors were more inflamed. And I felt that when it came to immunotherapy, BRAF/MEK inhibitors were not ipilimumab and were not going to add to the benefit that we see with immunotherapy of durable responses the way you can see with nivo/ipi.   So I’ve stayed away from those triplet regimens, and I think we’ve seen with the studies that have been published so far that they tend to have sub-additive benefit when you add an anti-PD-1 to BRAF/MEK inhibitors. You see some prolongation of PFS, but you don’t see the same tail of the survival curve. And even at two years, the tail of the survival curve for those triple regimens is below where it is for nivo/ipi in the BRAF-mutant population all the way out at five years. And the nivo/ipi population—I'm talking about the progression-free survival curve—and that nivo/ipi population can still get BRAF/MEK inhibitors if they progress. So I think that triple regimen, I can't think of a patient where I would use that. But the sandwich regimen, as I was just describing, may be useful in some patients who just aren't in appropriate shape to start with immunotherapy.   Dr. Gary Schwartz: Now, I would agree with Michael. I think the clinical trial data would really discourage the use of triplet therapy. They really lean—again, the benefit of triplet therapy for all the published papers we've seen so far in that area. But I guess you're right. The idea, if you have one of those patients that comes in and who's really on fire with rapidly progressive disease, on steroids, and needs a very quick benefit, perhaps initiating targeted therapy first for a short time would be reasonable in the treatment of those patients. But beyond that, I really think there probably are not going to be many exceptions to starting immunotherapy first because your data, to me, strongly would suggest that starting targeted therapy is going to diminish the benefits of immunotherapy to follow. And that, to me, is an important take-home point of the study and sort of validates some of the preclinical data. I mean, depends what you look at. But there is preclinical data suggesting that MEK inhibition will diminish T-cell responsiveness, and I think this supports that biological effect. So I think we have to be cautious about upfront targeted drug therapy now and have to find what are those opportunities where it may be appropriate. But I think they're really diminishingly few.   Dr. Michael Atkins: And I would just emphasize the flip side of that, which is that targeted therapy is equally effective in the second line for patients who don't respond to immunotherapy. And I think that was also a critical component of why the immunotherapy first sequence was better than the targeted therapy first sequences. You had better salvage.   Dr. Gary Schwartz: That’s a very good point.   Dr. Shannon Westin: Well, I personally just want to thank the three of you. I learned a ton today, and I fully intend to take that back to the work that we're doing in gynecologic malignancies, combining immune therapies and targeted therapies, and I hope our listeners will do the same.   Further, I agree with you, Dr. Schwartz. I think this is a practice-changing study. I appreciate you, Dr. Atkins, in being a little cautious. I appreciate the editors that reviewed it as well. But this is as clear a definitive trial as we can get and a testament to your hard work through the cooperative groups, which we all know can be a struggle in itself to get this type of trial through. So congratulations again.   Dr. Gary Schwartz: And I think the lessons learned in melanoma are going to be applicable to all solid tumors. So melanoma is about so far ahead of many other tumors, but what we learned here isn't just impacting melanoma, but will impact all cancer medicine. And I think that what's so important about this trial is that lessons learned here really are broadly based and have clinical applications to many patients getting immunotherapy, targeted drug therapies today. So congratulations, Dr. Atkins. I think you hit a home run on this one. The medical oncology community is indebted to you and to your group to making this possible. And thank you for bringing it to JCO as well. I think that itself speaks to the success of the journal and the impact these types of studies have on reaching a large segment of the medical oncology community.   Dr. Michael Atkins: Well, thank you very much, Gary. I do want to emphasize the point you made, that I think this result does impact how we think about the use of targeted therapies or chemotherapies or antiangiogenic therapies in other tumors in coordination with immunotherapy. And I'm sort of on a mission to make the point that if you want to get the most benefit out of immunotherapy, you should give it first, and you should give it unencumbered by other things that might interfere with its activity.   Dr. Gary Schwartz: I think that's the last word, Shannon.   Dr. Shannon Westin: I believe it is. I believe it is. Thank you all so much for being here. And thank you to our listeners for being here for another episode of JCO After Hours. Again, we were discussing “Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients With Advanced BRAF-Mutant Melanoma: The DREAMseq Trial—ECOG-ACRIN EA6134,” published in January 10th, 2023, in the JCO.   Please do check out our other podcast offerings. You can check them out on the JCO website or anywhere you get your podcasts. Until next time, be well.     The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

In this JCO Article Insights episode, Emily Zabor summarizes two articles from the February 20th, 2023 Journal of Clinical Oncology issue: "Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non–Small-Cell Lung Cancer: The Phase III POSEIDON Study" by Johnson, et al  and "The POSEIDON Trial: Will Secondary End Points Change Our Clinical Practice?" by Remon, et al. The Original Report by Johnson, et al describes results of the Phase III POSEIDON clinical trial. The accompanying editorial by Remon, et al discusses the findings of a significant progression-free survival and overall survival benefit for the combination of tremelimumab plus durvalumab plus chemotherapy as compared to chemotherapy alone, which were secondary endpoints in the trial. TRANSCRIPT Emily Zabor: Welcome to JCO Article Insights for the February 20, 2023, issue of JCO. I’m your host, Emily Zabor, JCO Biostatistics Editorial Fellow.  Today, I will be providing summaries for two articles. The first article, titled ‘Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non–Small-Cell Lung Cancer: The Phase III POSEIDON Study,’ by Dr. Melissa Johnson and colleagues, describes the results of the Phase III POSEIDON clinical trial. POSEIDON was a randomized Phase III clinical trial in patients with metastatic non-small cell lung cancer. The trial had a three-arm design to evaluate the efficacy of tremelimumab plus durvalumab plus chemotherapy; durvalumab plus chemotherapy; and chemotherapy alone in a first-line treatment setting. The two immunotherapies were selected for study because of their complementary mechanisms of action. Tremelimumab is an anti-CTLA-4 antibody which can diversify T-cell responses and lead to increased tumor infiltration. Durvalumab is an anti-PDL1 antibody which can enhance T-cell function. Chemotherapy is still an important treatment option for early disease control and potential for immune priming. Patients in the POSEIDON trial were randomized to the three arms with equal allocation. The co-primary endpoints for the trial were progression-free survival and overall survival for the comparison of durvalumab plus chemotherapy vs. chemotherapy alone. Then, a hierarchical multiple-testing procedure with a gatekeeping strategy was used across the primary endpoints and key secondary endpoints. Gatekeeping procedures are a way of controlling the type I error rate across multiple groups of null hypotheses that have a hierarchical structure, meaning that some of the hypotheses are considered more important than others. In this case, the plan was to first test for differences in progression-free survival and overall survival between the durvalumab plus chemotherapy and chemotherapy alone arms. Then, if either of those tests had a significant p-value so that the null hypothesis of no difference between groups was rejected, tests for differences in progression-free survival and overall survival between the tremelimumab plus durvalumab plus chemotherapy and chemotherapy alone arms would be conducted. Additional levels of testing could be conducted for other secondary endpoints following significance at the previous level. These types of gatekeeping procedures are a rigorous way of controlling the type I error of the entire study at 5% while still allowing multiple tests to possibly be conducted. The efficacy analyses were conducted in the intention-to-treat population, which included 338 patients on the tremelimumab plus durvalumab plus chemotherapy arm, 338 patients on the durvalumab plus chemotherapy arm, and 337 patients on chemotherapy alone. The median follow-up among those without an event was 10.3 months for progression-free survival and 34.9 months for overall survival. The findings for the co-primary endpoints were that progression-free survival was significantly improved with durvalumab plus chemotherapy versus chemotherapy alone, with 12-month progression-free survival rates of 24.4% versus 13.1%. There was no statistically significant difference in overall survival, with 24-month overall survival rates of 29.6% versus 22.1%.  Because progression-free survival was significantly different in the durvalumab plus chemotherapy versus chemotherapy alone arms comparison, according to the hierarchical testing procedure, the study proceeded to compare efficacy between the tremelimumab plus durvalumab plus chemotherapy and chemotherapy alone arms. Both progression-free survival and overall survival were significantly higher for the tremelimumab plus durvalumab plus chemotherapy arm, with 12-month progression-free survival rates of 26.6% versus 13.1% and 24-month overall survival rates of 32.9% versus 22.1%. The tremelimumab plus durvalumab plus chemotherapy arm had higher rates of grade III or IV treatment-related adverse events and immune-mediated adverse events as compared to the other two arms. The rates of grade III or IV treatment-related adverse events were 51.8%, 44.6%, and 44.4%, and the rates of immune-mediated adverse events were 33.6%, 19.2%, and 5.1% for the tremelimumab plus durvalumab plus chemotherapy; durvalumab plus chemotherapy; and chemotherapy alone arms, respectively.  This paper also reports on a number of subgroup analyses of overall survival comparing both the tremelimumab plus durvalumab plus chemotherapy and durvalumab plus chemotherapy arms to chemotherapy alone to examine consistency of effect across subgroups of patients. The results were found to be generally consistent across subgroups according to sex, age, tumor PD-L1 expression levels, histology, planned chemotherapy regimen, smoking history, race, ECOG Performance Status, and AJCC disease stage at diagnosis. Notably, patients with less than 1% PD-L1 tumor cells had no difference in hazard of death on durvalumab plus chemotherapy versus chemotherapy alone with a hazard ratio of 0.99, but had a reduced hazard of death on tremelimumab plus durvalumab plus chemotherapy versus chemotherapy alone with a hazard ratio of 0.77. But the study was not powered to conduct statistical tests for the subgroups, so no p-values are reported, and no strong conclusions can be drawn from the subgroup analyses.  Dr. Johnson and colleagues conclude that durvalumab plus chemotherapy significantly improved progression-free survival as compared to chemotherapy alone, and tremelimumab plus durvalumab plus chemotherapy significantly improved both progression-free survival and overall survival as compared to chemotherapy alone. The authors suggest that adding a limited course of tremelimumab to durvalumab and four cycles of chemotherapy provided long-term survival benefits to patients with metastatic non-small cell lung cancer and may represent a new first-line treatment option. The second article, titled ‘The POSEIDON Trial: Will Secondary End Points Change Our Clinical Practice?’ by Dr. Jordi Remon and colleagues, is an editorial related to the first article just described. In the editorial, the authors discussed the findings of a significant progression-free survival and overall survival benefit for the combination of tremelimumab plus durvalumab plus chemotherapy as compared to chemotherapy alone, which were secondary endpoints in the trial. Recall that the POSEIDON trial had two co-primary endpoints of progression-free survival and overall survival for the comparison of durvalumab plus chemotherapy to chemotherapy alone, and the secondary endpoints were only evaluated since the co-primary endpoint of progression-free survival was found to be significant.  Dr. Remon and colleagues note that while there was no head-to-head comparison of the durvalumab plus chemotherapy and tremelimumab plus durvalumab plus chemotherapy arms, the tremelimumab plus durvalumab plus chemotherapy regimen had only a modest increase in progression-free survival and overall survival rates, but much higher rates of immune-related adverse events as compared to the durvalumab plus chemotherapy regimen. The authors suggest that following this trial, we still don't know what subset of patients would benefit from a dual immunotherapy treatment approach or what is the optimal duration of such treatment protocols. Recall that in POSEIDON, while efficacy was estimated in pre-planned subgroups, the study was not powered to detect effects within subgroups, so no statistical comparisons were made, and therefore no definitive conclusions could be drawn about whether a particular subgroup did or did not benefit from either of the experimental arms.  The authors point out that many combinations of immunotherapies have been studied for patients with advanced non-small cell lung cancer, and that there is likely little benefit from further studies where new drugs are added to current protocols in unselected patients. The authors emphasize that new predictive markers are urgently needed, especially given the financial toxicity associated with the use of immunotherapies. They propose that the study of such markers should be at the forefront of future trials. That concludes this episode on the articles ‘Durvalumab With or Without Tremelimumab in Combination with Chemotherapy as First Line Therapy for Metastatic Non-Small Cell Lung Cancer: Phase III POSEIDON Study’, and the associated editorial, ‘The POSEIDON Trial: Will Secondary Endpoints Change Our Clinical Practice?’  Thank you for listening, and please tune in for the next episode of JCO Article Insights. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  Show Notes: Like, share and subscribe so you never miss an episode and leave a rating or review.   Articles Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non–Small-Cell Lung Cancer: The Phase III POSEIDON Study   The POSEIDON Trial: Will Secondary End Points Change Our Clinical Practice?   Find more articles from the February 20 issue.

Dr. Shannon Westin, Dr. Ezra Bernstein, and Dr. Nadir Arber discuss increasing cancer prevention and early detection with a one-stop-shop comprehensive cancer screening center. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, our podcast where we get in-depth on manuscripts that have been published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN oncologist and social media editor of the JCO. And I am thrilled to be discussing this very interesting paper entitled “Data From a One-Stop-Shop Comprehensive Cancer Screening Center,” focused on asymptomatic screening. And this very important work was published by these two authors who are joining me today. We have Dr. Nadir Arber, professor of Medicine and Gastroenterology, head of the Integrated Cancer Prevention Center, head of the Cancer Prevention section of the European Society of Medical Oncology at Tel Aviv Sourasky Medical Center in Tel Aviv, Israel. And we're also joined by Dr. Ezra Bernstein, Fulbright fellow and researcher at the Integrated Cancer Prevention Center that we're going to be discussing today at Tel Aviv Sourasky Medical Center in Tel Aviv, Israel. And he's also, impressively, a resident in internal medicine at the New York University, so he's a gentleman of many talents and quite busy. Welcome. Dr. Ezra Bernstein: It's great to be here. I had a slow clinic day. Dr. Shannon Westin: Oh, I was going to say I'm impressed you, as a resident, could find the time. So we're really excited to have you, and you certainly have a bright future ahead of you as an oncology practitioner. So let's get started. I think certainly most of our listeners are quite familiar with the benefits of cancer screening. But I think it would be great if you all could level set and review the benefits at the patient level as well as at the healthcare system level. Dr. Ezra Bernstein: Sure. So I think, kind of breaking it down, on the patient level, the scientific community has made incredible progress over the last several decades in not only the understanding of the biology of cancer, but also that's translated into the treatment of cancers, from genomic sequencing to targeted therapy, which you now have specific small molecule inhibitors for specific mutations in each cancer. But despite all these incredible improvements and advances and the ability to treat many cancers, the greatest prognostic factor is still often the stage of diagnosis because the chances of survival and the chances of complete cure increase dramatically if the disease is detected in its earlier stages. So earlier detection and diagnosis can greatly reduce mortality, it can increase treatment effectiveness, and ultimately improve the quality of life for the cancer patients. On a healthcare system level, often when you're doing screening, you're discussing cost-effectiveness. And so the thing about the healthcare system, which we didn't really address in our paper–we initially were going to, but we think we're going to do a follow-up paper on this–the cost of cancer care is very high. In Europe, the total cost of cancer care in 2018 was $199 billion. And then I think the last data I saw was the US, in 2015, the total cost of cancer care was $183 billion. So, on a healthcare system level—and those are just the costs of cancer care; there's tons of other costs that go into when patients have cancer: lost wages… So I think that it's crucial not only for the patient but also for the healthcare system to help catch these cancers earlier. Dr. Shannon Westin: Yeah, I completely agree. I think we have such great guidelines on how we should be screening our patients. I think there's a number of different areas where providers can look to understand what they should be doing with the patient in front of them. What do you think are some of the barriers of implementation of this guideline-based cancer screening? Dr. Ezra Bernstein: That's a crucial question. We have the guidelines, especially in the US; we have our grade A recommendations: colon cancer, cervical cancer. We have our grade B recommendations: mammography. And lung cancer. So a big hurdle, especially in the US now with the recommended screenings at this point, is just getting people to do it. You look at the US, and for Pap smears, it's pretty good; 80% of the population is up to date with PAP smears. Mammography, a little bit less, low 70s. And then colon cancer screening, a little bit less. So how do we get these up, and what's the barriers? And that's kind of the idea behind the Integrated Cancer Prevention Center is it’s cost, it’s time, and it's also awareness. And this kind of gets into a little bit of the theory for what kind of created the Integrated Cancer Prevention Center is the idea that if you do a one-stop-shop approach where patients come in in a single visit and they get screened for all the recommended cancers, so they don't have to do multiple appointments, they don't have to take off work multiple times, and they can get it all done at once, that automatically leads to 100% compliance for those screenings that they do during that day. So that was kind of the theory behind it is you're able to remove a lot of the barriers to the implementation of the guideline-based cancer screening. The other thing is awareness and just making sure that patients are aware. I think it's actually great timing with this paper. They haven't done it so much lately, but the NFL, the National Football League, they were actually running a campaign for the first few games of the season where—you know, you have millions and millions of American viewers—it was called Intercepting Cancer, and they were highlighting the importance of screening and prevention. They gave a link, which is great, but it really just links you to your providers in your area to then go ahead and screen individually. That initiative was important in getting more awareness, but still, there's the cost and the time issues that are still barriers. Dr. Nadir Arber: Let me just emphasize what Ezra brilliantly says. He said that the best therapy of cancer is prevention, so increase early detections. I’m a gastroenterologist, so I'm fairly aware of preventions. I do colonoscopy, I found the polyp, I take it out, I prevent colon cancer. In other cancers, it's not that obvious, especially colon cancer. But then to detect it at an early stage, it means when the patients have no symptoms. When there are symptoms, mostly—not all, but mostly—it's too late. And then, when somebody feels good and well, it is not acceptable, it's not possible to go to all these different facilities and to have the referral. You want to go to screen for colon cancer, you go to your GP, who sends you to a gastroenterologist, you get the colonoscopy, then you come back, go to another GP, then you have to screen for prostate cancer. So you ask him, “Can you send me to a urologist?” They send you to a urologist. And they send him for a PSA and then free PSA and the rest of it. And then, if you do it on one stop, this is the only way that is feasible, for maybe the five major or six major cancer screening, there is no doubt and no questions. But then, with Ezra, we have learned that there is more than that. It's not only screening, but it's also case finding. Patients come to me for different reasons. They came to the center to be screened for skin cancer, breast cancer, colon cancer. So let's just tell him, “Can you open your mouth?” And then five minutes, not more than that, an oral surgeon checks your mouth. It is not cost effectiveness to call the patients to come to check, but he's coming for another reason. This is what you call case finding. People are not that aware about the difference between screening and case findings, and I would like to emphasize before I let the floor to you, so I'm not speaking about cost-effectiveness; I’m speaking about cost saving. It saves money. It does not cost; it saves. Actually, I was in Singapore when maybe I was invited to Singapore by the Singapore government. They heard about my concept and invited me to speak, and like we have just said, and that it's going to be published in the JCO, in the journal. And they told me—and they were very impressed—“We are going to do it because it's going to save money for us.” And I said, “But how you are going to implement it?” They said, “We are a democracy; we cannot force the people to do it, but we are going to offer them free of charge. Free, because we understand that if they do, the government are going to save money.” But if they offer it free of service, free of charge, and then somebody does not want to do it and he has cancer, it is his problem. It's like somebody has a car, buying a new car. He's not obliged to make insurance for the car, but if he doesn't do it and something happened to the car, he cannot come to the government or the insurance company or his spouse and complain. It's his problem. I think when you understand it, and we understand that it's cost-saving and it's a win-win situation, then we can make a big step ahead, and this is the way to go. Dr. Ezra Bernstein: I think Professor Arber brings up a very interesting point that I'm just going to make real quickly when he talks about kind of the case findings and the screening for something like oral cancer and skin cancer, which aren't currently grade A or grade B recommendations by the USPSTF, but in the context of a one-stop shop, it kind of changes the game a little bit. It's one thing to go to your dermatologist once a year in terms of screening for skin cancer, but if you're already at a one-stop-shop center screening for skin cancer, screening for thyroid cancer, and things which aren't currently—the thyroid is a little bit different, but screening for certain cancers aren't currently recommended for because they're not cost-effective, it changes the game a little bit in the concept of the unique setup that Professor Arber started. Dr. Nadir Arber: And at the same times, we also measure blood pressure, we measure sugar, hemoglobin, A1Cs, and other things that are known, but not only for cancer, but the patient is scanned when he's there. And also, if we found something—and we have the data, between 1% to 2%, we do find cancers—then we can help the patient to solve it on the spot because he's in the hospital, so we can arrange whatever he needs. So the patients like it. They appreciate. They know that they're in safe hands. And if you like, “I need to do ultrasound. I have some very suspicious legion,” I can do it on the spot. Vaginal ultrasound, Pap smear, now we do it for HPV, DNA. So everything is on the spot, and we give solutions if something happens. People need—they found something or anything, so we can do everything. For this is the way of modern medicine. Ezra and myself have been working for many years. But eventually, it's going to catch up because this is the right things to do. The modern medicine, the way we see it in the future, is turning from sick care to health care. This is the way to go. This is one of these when we are advancing the technology and everyone is health conscious. Dr. Shannon Westin: I really appreciate you kind of giving that laundry list of all the things you're doing because I do think you're exactly right, that people are doing a better job around the kind of the most common screening tests. I'm a gynecologist by trade, so Pap smears are part of my daily activity. But I think mammograms, Pap smears, colon—I think that's more common. But this is a great way to kind of get screening for all of those other things. Like, I know a friend who just got diagnosed with an oral cancer, and it's like nobody's screening for those things. And you're right, Ezra, where they say that it's not cost-effective to have a visit just for that, but if you can encompass it all in one visit, it just makes so much sense. So I think that that takes us into the current study. Can you kind of just take us through briefly the design and your outcomes that you looked at? Dr. Ezra Bernstein: Yeah. So it was a retrospective analysis of over 17,000 patients that have visited the ICPC, the Integrated Cancer Prevention Center, between 2016 and 2019. And as Professor Arber was saying, patients come in, they're mailed a questionnaire beforehand, they ideally fill it out before, but they'll then meet with an internist or an oncologist. And they'll go over the questionnaire, they'll go over family history, risk factors, and then it will be really a tailored screening exam for that. They'll get the classic recommended screenings based on if they're due for a mammogram, if they're due for a Pap smear, and then from there– Do you want me to go through in detail or just kind of overall? Dr. Shannon Westin: I think overall is fine, yeah. Dr. Ezra Bernstein: Overall? Okay. So they do their screening test, they’ll get some blood work done, and then if there's anything abnormal, then as Professor Arber was saying, the great thing is you get worked up right there. So they'll get TFTs, thyroid function tests. If those are abnormal, then they'll indicate a thyroid ultrasound needs to be done. They do all their screenings, all their testings. Most of it is done there. Professor Arber, do they do the biopsies there too if there needs to be a biopsy? Dr. Nadir Arber: Yes, obviously. But what is Ezra also referring, we are trying to do precision medicine. When somebody is coming to us, like you said, the woman, so we are measuring her Tyrer-Cuzick score and to see, if it is high, then we send her to do an MRI, if it is above 20%. Dr. Shannon Westin: So what were the outcomes that you measured in the study? Dr. Ezra Bernstein:  So, after they did all the screening, our main outcomes were the number of malignant lesions detected and then also what stage were they detected. Basically, if the cancer was found within a year of a visit to the ICPC and it was found as a direct result of the screening done that day or if there were recommendations for follow-up that then led to a successful detection, we counted that as a malignant cancer that was successfully detected through the ICPC. Dr. Shannon Westin: What about the results? Were they as expected? How did your detection rates compare to kind of, say, the general population? Dr. Ezra Bernstein: A successful cancer screening program is always going to have a shift in detection of cancer to earlier stages, which is exactly what we saw, which was great. We then compared it to the Israeli general public over a similar time period, and the percentage of cancers found at a metastatic stage at the ICPC, that was lower for all cancers. Just going through: Colon was 20% versus 46.2% in the general populations. There was no metastatic, cervical, or uterine cancer found. Prostate was 5.6 versus 10.5, lungs 6.7 versus 11.4, as well as renal, which isn't recommended we screen for, but that was 7.7 versus 10.3. Dr. Shannon Westin: That's so incredible. I guess the other thing I thought was really nice that you did is looking at patient satisfaction and making sure—we're very much focused on patient experience and satisfaction right now in medicine. So what were your findings there? Were the patients satisfied with the process? Dr. Ezra Bernstein: Yeah, so this is something that we started doing towards the end of the study period. So we really had respondents from 2019. There was about 1300 patients who responded on a Likert scale, 1 to 10. The average response was 8.35. So it's really good response. I try to go back there whenever I can, and it's always bustling. People are coming back. Professor Arber can speak—he's interacting with the patients every day. But talking with just friends who have heard of it, every time I bring it up, “Oh, that's amazing. We love that program.” Dr. Shannon Westin: Were there any limitations or weaknesses to the mechanism? Dr. Ezra Bernstein: The main limitations and weaknesses were that it was a one-arm study; it was not a randomized controlled trial, whereas randomization would control for generalizability as well as other confounders. And as with all cancer screening, there's the issues of the lead time bias, the concept that cancer is detected earlier through screening, but the length of time a person survives with the cancer does not. So survival time is falsely lengthened. There's also time bias, which is the idea that more indolent and less aggressive diseases with longer survival times are more likely to be detected through screening, artificially inflating survival time. So that's always present in cancer screening. In addition, the most reliable measure for determining the efficacy of a screening program is cancer-related mortality rates, and that's from the time of randomization as opposed to the time of diagnosis. And given the study design, that's just something that we weren't able to do. And any successful screening program such as ours is going to have the natural shift in the incidence of cancer to an earlier stage. But some of that can be attributed to overdiagnosis, the diagnosis of indolent diseases that are never going to actually cause harm, which has been heavily studied in the case of breast cancer with mammography. But it's not something that can be really proven; it's just more—overdiagnosis is more of a theory, and it can be hypothesized. So you're going to have overdiagnosis, you're going to have lead time bias, you're going to have a length time bias with any screening program, but in particular with ours, I think it's mainly the randomized control trial aspect, which is the gold standard. Dr. Shannon Westin: Yeah, that makes sense. Okay, well, and then the final—let's give a call to action here. So how do we implement this more broadly? What's kind of necessary to get something like this up and running? Infrastructure, personnel, yeah? Dr. Ezra Bernstein: So to implement this intervention more broadly, you really need the want from the general public and whoever's going to help implement this. And I think we're starting to see that with, as I mentioned, the recent program that the NFL is running about intercepting cancer. And then, to actually implement it, I'm going to leave some of it to Professor Arber, who did an amazing job setting up this program. But I think it makes the most sense setting it up within a hospital setting because you'd need certain imaging modalities within a clinic. And then, depending on which specific cancers you're screening for, you're going to need specialists able to screen for those cancers. Primary care, they can screen for skin cancer, but really, it should be someone with more training, dermatologists, to do that kind of screening. But Professor, I don't know if you want to jump in and talk about what you think it would take to set it up. I know you did an amazing job setting it up. Can't imagine the amount of work and coordinating. Because at the clinic in Tel Aviv, you have many different specialists coordinating every day. It has got to be quite difficult. So I don't know if you have anything to add, professor. Dr. Nadir Arber: I think everything in medicine, in order to be successful, has to be simple. We are physicians. We are simple people. And this is a way that you are able to do this screening. Because first, from economy, it's cost saving. It doesn’t cost money for the government, for the health providers, but also for the patients. If somebody feels well, there is no way that he will go all this saga of going to the GP and have this referral to five, six specialists. And when we understand also the issue of cost and case finding on top of the screening, then we understand that this is the only way that this screening program—when people are feeling healthy, no symptoms, the only way that once a year, they can afford it. If I break my leg or have a rectal bleeding or have a chest pain, I go to the special physician because I have symptoms. But if I have no symptoms, then only once a year, I would like to go to a special place which has all the expertise which the GP cannot provide and then to implement it. This is the only way, and this is simple. And we are happy that you took the lead, and with this initial project, that should be multiplied everywhere. This is the only way. Now we understand that the best therapy of cancer is prevention or at least early detections. And also, Ezra maybe mentioned that we also teach for lifestyle modifications. If needed, we are doing genetic testing; that is going to be very important. I don’t know if Ezra mentioned that we are checking for this polymorphism in the APC genes that we have shown in the [inaudible]. Carriers of this APC can have double the risk of having cancer. Dr. Shannon Westin: Well, this has been such a fascinating discussion, and I'm just so glad that you both had the time to spend with us today to review this. I think this is an incredible intervention, and I really do hope that we can mimic this across the States and across the world. So, again, listeners, this has been JCO After Hours. We're discussing “Data from a One-Stop-Shop Comprehensive Cancer Screening Center,” focused on asymptomatic screening. We're so glad that you joined us today. Please do check out our other podcasts on the JCO website. Be well. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

Dr. Shannon Westin and her guests, Dr. Paul Frankel, Dr. Judith Karp, and Dr. Robert Maki discuss how to better inform patients of the risks involved in phase 1 clinical trials. TRANSCRIPT Dr. Shannon Westin: Hello, everyone, and welcome to another episode of the Journal of Clinical Oncology After Hours podcast, where we do a deep dive on manuscripts that are published in the Journal of Clinical Oncology. We're so excited to have you all here today. I am your host, Shannon Westin, GYN Oncologist at MD Anderson Cancer Center, and it's my great pleasure to serve as the social media editor of the JCO and the host of this podcast. Today we are going to be discussing a very important manuscript titled “Ethics and Clinical Research: Improving Transparency and Informed Consent in Phase 1 Oncology Trials”. And I'm joined today by several of the authors, as well as one of our editors that helped to review this paper. But before I start, I'll note that none of our authors have any conflicts of interest to disclose. And with that, I'd like to introduce our guests. First is Dr. Paul Frankel. He's a research professor at the Division of Biostatistics, Department of Computational and Quantitative Medicine, at the City of Hope National Medical Center. Welcome. Dr. Paul Frankel: Hello and thank you. It's a great honor to be here today. Dr. Shannon Westin: Also with Dr. Frankel is Dr. Judith Karp, who is Professor Emerita of Oncology and Medicine at the Johns Hopkins University School of Medicine in Baltimore, Maryland. Welcome. Dr. Judith Karp: Thank you. And I echo exactly what Paul said. Thank you for having me. Dr. Shannon Westin: And then finally, our esteemed Associate Editor of the JCO, Dr. Robert Maki. He's a professor of hematology and medical oncology, a physician leader in developmental therapeutics, clinical leader of the Sarcoma program at the University of Pennsylvania. Dr. Robert Maki: Hi, Shannon. Thanks for having me on the program. Dr. Shannon Westin: Well, it's awesome to have this star-studded group of guests. We are going to try to cover as much details about this important paper as we can in a short period of time. But I encourage you also to check out the JCO to read the paper in full. So first, let's level set. As we start this discussion around phase 1 trials and ethics, maybe, Dr. Mackie, can you start by giving the basics of just phase 1 trials just to make sure everyone's on the same page? Dr. Robert Maki: Sure, absolutely. Since we have people who are listening from different walks of life, that's for sure. Clinical trials in cancer run anywhere from phase 1, 2 to 3. There are also such things as phase 0 and phase 4 trials. But the primary ones we'll discuss today are phase 1 trials. These are the initial tests, be there a brand-new drug never tested before in people, or it might be testing a new combination of treatments, or it might be looking at an already approved drug or an experimental drug in a new population of patients. Let's say you wanted to take a look at a drug in an elderly population. There aren't any data about that in people who are, let's say, 80 or older, and that would constitute a phase 1 trial. The idea of the trial is to start with low doses of a medication and increase the doses in a systematic way, tracking the side-effects that occur with treatment, and then come to an answer as to how you should move forward with the medication in future trials to determine whether the drug is actually active or not and in which setting. The important point, I guess, in that sense is that a phase 1 trial isn't necessarily looking at whether a drug is useful or not, really just looking at the toxicity of the agent or new combination or new setting overall. Dr. Judith Karp: If I could add one thing to that, and I think this is something that has evolved—well, it's evolved over the last 30 years, but in terms of practicality and application, it's really over the last 10 years, roughly speaking. It's also, I think, the opportunity to identify potentially informative biomarkers through a series of pharmacodynamic studies. I'm an old leukemia doctor, and so I've had that capability, if you will, with our diseases because they're so accessible. But I think there's been a new emphasis on that over the last decade. And it's an important one because it becomes a tool for stratifying in phase 2 and ultimately for identifying, hopefully, in a prognostic fashion, who is potentially likely to respond versus not. And if it's a versus not, then you go in a different direction once you got a bunch of—or if you're lucky enough to have a bunch of different directions. Dr. Robert Maki: It's a really important point about looking at so called pharmacokinetic and pharmodynamic markers. How long is the drug staying in the body? What is the body doing to the drug? What is the drug doing to the body? Judith is right on the mark. You can get leukemia cells right out of the body, oftentimes take a look at them directly, whether you're actually hitting the target you think you're hitting. This is a really great place to—and it's often mandatory to get pre- and post-treatment biopsies, even in solid tumor patients, to know if you're actually hitting your target of interest. So, yeah, if you're not achieving that much, then you shouldn't really be moving the drug forward. Dr. Shannon Westin: I agree. And it's so critical because, as we've seen, you know, to your point, Dr. Maki, about the true goals of a phase 1 trial, I think we've done a lot better job of trying to ensure there is efficacy or trying to clarify for whom we are getting efficacy. And I think we all are aware of several drugs that have gotten approvals from an extended so-called phase 1, right? An appropriately selected population. And certainly that's something new over the last five, six, seven years that we've been able to do that. But things like PARP inhibitors in BRCA-mutant populations and TRK fusion inhibitors like Larotrectinib and others in those with NTRK fusions just come to mind kind of quickly. And even more so, we're seeing these focus drugs, right, that are focused on abnormalities in a specific—Exon, like the G12C inhibitors and things like that. So it is interesting to see how drug development is kind of changing in the phase 1 space where we're trying to move that efficacy potentially up earlier and earlier, just to Dr. Karp's point about that biomarker development. So I think it's a really exciting time. Okay, so the next piece I wanted to just make sure, again, to ensure that we're all on the same page, is these are very common trials, I'd say, and certainly the foundation of drug development. Do one of you want to give an estimate of approximately how many phase 1 trials are ongoing currently and maybe how that's changed over time? Are we seeing more phase 1? Less phase 1? About the same? Dr. Paul Frankel: Yeah, I can take a look at that. The number of phase 1 studies that are currently accruing patients today in oncology is around 4500, something like that. I think there's 4451 open clinical trials and phase 1 clinical trials in oncology today. If you look at, let's say, in May of this year, there was 4263. So you're seeing it's increasing. But if you want to look at really the increase, you can look at between 2000 and 2010. There were a little bit over 5000 phase 1 clinical trials that had started in that period, that 10-year period. If you look at the next 10-year period, 2010 to 2020, it's over 10,000 that started. So the number of phase 1 clinical trials is very large, and it's increasing at a rapid rate. And these do set, as you mentioned, the foundation for all the studies that subsequently follow. Dr. Judith Karp: It's very interesting to me that Paul has these numbers in his head. I am not as quantitative as Paul, but we have these increasing numbers of trials, and yet the percentage of patients who go on those trials has not increased at the same rate. There's still that gap where now for children with leukemia—actually, for children with cancers, it's 90%. 90% of those children go on clinical trials. But for adults, it's still around 8 or 10%. It's unfortunate. Dr. Robert Maki: It's a really good point. There really should be more adults being put on clinical trials. But by the same token, not every adult is appropriate for a clinical trial. Let's say you have—there are things you can do that are clinical trials that aren't treatment either. And if it's data collection or patient-reported outcomes, something that we really don't have a lot of information of in a broad manner, there certainly are clinical trials, even if you're getting standards of care in which patients can be enrolled. So you're certainly speaking to a group of people who espouse and promote clinical research wherever it can be done. Dr. Paul Frankel: These clinical trials, I think, are often the best opportunity that patients have. And even though we're going to be talking about issues with consent and other issues with regard to phase 1 clinical trials, they still remain the best option for patients in almost every situation, if you can get on them. Dr. Judith Karp: Yeah. I just think of them as… Dr. Shannon Westin: Yeah, and I think we could have a whole ‘nother podcast of how to expand an exclusion criteria to allow for those patients, but maybe we'll bookmark that for another episode. Paul, you kind of started mentioning, I think, the last place to level set before we get into a little bit more detail from the paper that you all wrote is from regards to informed consent. Can one of you, or more than one, review the importance and challenges of this process for our listeners? Dr. Judith Karp: I’ll take a stab at that one. I think the importance of informing a patient, however well we can do it, of what we expect to happen and what we know and what we know we don't know is a very important part of the contract between the physician and the patient. And it's really a partnership, especially for phase 1 trials, where we really know so little. And what we do know is that the patient—these are for treatment trials. We know that there is no therapy widely available for that patient that's going to do that patient any good. So we have to enter into a partnership with the patient to say, “We're going to try something. We know this little bit. We don't know this huge amount.” And so I think that that's really the importance, just ethically, to have the patient be informed. In terms of the challenges, I think that—this is certainly not politically correct, but were I on the receiving end, on the patient end, and somebody gave me a 35-page document to read, I would not for many reasons. In some ways, it's too much information. Most patients are not, by definition, medically sophisticated. That's one. Two, they don't want to read 30 pages. They're either going to sign it, or they're not. And it's confusing. And, yes, you can say to a patient, “Look, take this home, read it, come back in a week, call me in a week,” whatever. There are many instances, certainly in the leukemia field, where you can't do that. You don't have that luxury. So I think that that is a real challenge that we really haven't addressed. And in the good ol’ days when all of us physicians really sat down and talked to the patient, then I think that the challenges were much less. And I think that that's key. Dr. Robert Maki: Yeah. I mean, Judith, AML over age 65. You're not going to get most people into remission, and you've got a captive audience because there they are with low counts. And what are you going to do next? We all, in our research, want to follow the Belmont report. We want to respect people. We're looking for studies that offer beneficence, that do no harm. We can't really do no harm a lot of the time, but we can at least minimize harm. And I think it's where the consent process kicks in. And justice, the third tenet of the Belmont report, being sure that we're using well-considered procedures as part of the research. All those are part of those beautiful words that you used, “partnership” and “contract,” that I think are really important in developing that bond with the individual patient who you're going to treat is super critical. Dr. Judith Karp: Yeah, absolutely. And in some senses, the only real informed consent is if the patient has been through it before. Dr. Shannon Westin: Right. Dr. Paul Frankel: So one of the things making it even more challenging, all these challenges exist throughout. And one of the focuses of our paper is that there's been an increasing trend to use designs that specifically target toxicity rather than limit toxicity during the dose finding of the phase 1 study. And so that introduces a whole ‘nother aspect to the consent process. So if you look at those studies, the most common toxicity target, as noted by others, is a 25% DLT rate. And if interpreted directly, that means that these risk-targeting designs, they claim to aim to find the dose where one in four patients are expected to experience a severe or a life-threatening adverse event in the first cycle of therapy, which is usually 28 days. And that's despite dose modifications. And further, most of these designs consider it a positive feature if a large percent of the enrolled patients are treated near the target. Now, whether this is really what the physicians want or not is separate. But one way or the other, what we have noted in our paper is that our collective experience that the actual toxicity target, the targeted risk, whether it's 20%, 25%, or even 33%, is not disclosed to the patient in the initially submitted consent forms that we see. That is a fundamental change in the way we've designed studies, but it requires that we adapt the consent process to this very challenging problem. Dr. Judith Karp: Along those lines, you're talking about toxicity. Any treatment that targets a non-itchy skin rash has got to be a lot less toxic than a drug that is targeting refractory ovarian cancer or leukemia or what have you. And the disease itself is toxic. So I think there has to be a way to approximate and weigh those toxicities, the toxicity of the treatment versus the toxicity of the disease, because the disease is not benign. Dr. Shannon Westin: One of my mentors, Dr. Razelle Kurzrock, used to always say, “The worst toxicity is progression of cancer.” And I completely—that's a very wise woman. But I think it's a really good point. And I think, just to kind of summarize what you all were saying, if we're targeting a certain toxicity level, we just need to make sure that patients are aware of that. And many of them might be willing and would probably be willing to take that for that potential benefit and things they might get out of it, but we need to be more transparent on that kind of individual protocol level. Would you say that’s…? Dr. Paul Frankel: That’s the critical thing is to be transparent about these things. And certainly certain different treatments which have maybe more curative potential, certain types of diseases, they’re going to be more amenable to a higher toxicity threshold. But it depends on the intent of the therapy, and these need to factor into the decision of what's being used, what kind of target and kind of design is being used. That's kind of part of the issue of transparency is once you get that in front of the patient and the physician and they discuss it, you're likely to get people to agree if it's at least a reasonable target. Dr. Robert Maki: The toxicity targets up from some of these Bayesian designs, oftentimes they're kind of guardrails to ensure there's not too little or too much toxicity on a trial. I think people are using more of the rules-based designs, this risk-targeting design, than the classic three plus three simply from the inability to come up with an adequate dose-escalation scheme using three plus three simply from the fact that you're just looking at the prior three patients. If you look at a lot of the kinase inhibitors that have been approved over time, even when they’re FDA approved, drugs like lenvatinib or cabozantinib, even in the phase 3 trials, patients had to have their dose reduced two times out of three. And it really speaks to something went awry in the development of these agents if they really were looking for a 16% DLT rate in a classical sense, which is what you get from that three-plus-three design, one out of six people. It's pretty crazy that two thirds of people in a larger population need that dose reduction. So perhaps by putting better guardrails with one of these rule-based designs, we’ll actually end up with a schema for treatment of a patient that ends up being more appropriate. Dr. Judith Karp: It would be very interesting, actually, to examine how often we're wrong. It might be very easy. 100% of the time, I would imagine. But how often the so-called RP2D turns out not to be that. And even with phase 3 trials, you never really know a drug until it's out on the street and thousands and thousands and thousands have been treated with that drug or combination. Paul, maybe that's our next study. What do you think? Nah, I can tell you don't like it. Dr. Shannon Westin: This is kind of getting at what Project Optimus is trying to do, right, is getting away from that idea that we have to get to the max dose and instead look at long-term tolerability. And yeah, Robert, I've given quite a bit of lenvatinib and pembrolizumab in my clinic to patients with recurrent endometrial cancer. You can see that that max dose is not the ideal dose for a lot of patients. Now, there are some patients that tolerate just fine, but 70% grade 3/4 toxicity is legitimate, and making sure we're protecting patients from that is really critical. And I want to cover a few more things before we wrap up. I guess we've talked a little bit about what to do on an individual protocol level. Do you all have some recommendations about what can be done at the research/enterprise level to kind of address the issues that we've been discussing today? Dr. Paul Frankel: One of the issues is, if you look at, let's say, clinicaltrials.gov, you'll see that there's very few studies that have both a model consent form or the protocol on clinicaltrials.gov. And I think if you look at all the clinical trials, the number that have both, you can count on one hand. So the question is whether or not there's a way to systematically evaluate whether the consent form is appropriate, whether the target is reasonable, that kind of thing. And it's very hard to do when you don't have a way to assess that information in a systematic way. So one thing that can happen is that the registries could require a model consent form where they could ask for it, encourage it, one way or the other. It's just a simple document. The other thing that they can do is make sure that the protocol summaries, if the design uses a DLT targeting method to at least state what the target is in the protocol summary, that would help quite a bit. And then you can go through and see if this is reasonable or if this has been communicated in the consent form in particular. And so that's one thing that can happen on the enterprise level that would help considerably. Dr. Judith Karp: The only thing I would add to that is that I think a model consent form, a template, is it's surprising that it hasn't been done yet, although, as you say, it's not easy with all of these studies being done by government and pharma and other enterprises. But that has to be modulated for the disease that’s being targeted and for the drug. You can't have the same thing for cell cycle cytotoxic agents and immunotherapy because they're totally disparate. And you can't have the same thing for leukemia and breast cancer. The pathogenesis may be the same, but the phenotyping is not. So that's the only thing I would add. Dr. Robert Maki: The patient population involved as well can certainly impact that. Greater or poorer performance status, susceptibility to complications, all that figures into that consent form. So it's not an easy thing to prepare, at least in a coherent way that a patient is going to understand, especially, as you were saying there, with a 40-page tome that reads at somewhere between grade levels 11 and 14. How do you expect a patient with, let's say, an 8th or 9th grade reading level to fight their way through that if they really wanted to understand the side-effects. It's kind of like the teacher in the Charlie Brown cartoons: “Wah wah wah wah, wah, wah, wah, sign here.” So there are many challenges. Dr. Paul Frankel: There's no question that this is a minimum requirement. Having a written consent form is just an absolute minimum. But the conversation that needs to take place, the communication, that's a whole ‘nother level that I think the physicians are better able to address. But it's just the minimum requirement to have something in the document, and it doesn't make the document longer to communicate the targeted risk in some of these studies. There's really no extra effort that's being asked. I mean, the model consents exists. The DLT targeting is stated in the protocol. It's all fairly simple. Dr. Robert Maki: Yeah, it'd be another line or two, wouldn't it? It's just saying here's what our expected rate of toxicity is. And uploading, whether you're a cooperative group, whether you're an industry, whether it's an investigator-initiated trial, some sort of redacted consent form makes a lot of sense. You may not have to have the grid of activities, which oftentimes is now included in one of these cumbersome documents, but at least the description of the treatment and the toxicity would be at least something everybody could agree to. Dr. Judith Karp: Yeah, some kind of a precede or a FAQs, frequently asked questions. What is this? Why are we doing this? Very simple. Dr. Robert Maki: And that's now mandated, I think. They said at NCI, they insist that we have a summary of the trial, and one page or page and a half at the beginning of that long document. That, to me, has been incredibly effective, as have been things like a little drawing of patient and going one randomization and things like that. Simple means can really be powerful, especially on those first two pages before the eyes glaze over. Dr. Judith Karp: Exactly, yeah, a little CONSORT diagram or something like that, very nice, schema. Dr. Shannon Westin: This has been a really awesome discussion, and I think the bottom line is we need to increase our transparency. And it seems—I don't know, after this discussion, I feel like it's a pretty straightforward ask. Are there any downsides to being transparent? I know we've already talked a little bit about patient burden and how we don't think that would add much to that piece. Dr. Judith Karp: The fear that might exist, that, “Oh, my God, if we really tell them what we're going to do, they're not going to do it. They're going to say no.” I don't think that's realistic. I think patients, especially for phase 1, we're dealing with a population of people for whom there is not a reliable, effective therapy available. These patients know that. Many times they've been through rounds and rounds of chemotherapy or immunotherapy or surgery already. So many patients say, “Just give it to me, and I'll sign it.” And you say, “No, no, no, you must read it.” So they say, “Okay, I'll read it. Where do I sign?” Dr. Robert Maki: Done. Exactly. But it's a really important point that I'd also like to highlight, that phase 1 trials aren't just for the patients with performance status 3, very sick. You can certainly impose those earlier in a patient's course, especially in situations where there is not a randomized trial, for example, showing evidence of survival benefit. Short of that, I tend to be more aggressive about putting patients in earlier lines on phase 1 trials simply because it provides more options for them. Dr. Judith Karp: Yes, and I think a good example, as you had brought up, Robert, earlier, the older patient with AML, maybe a myelodysplasia-related AML. There are lots of things you can do, but none of them work. And so is it an opportunity to look at improving the hypomethylating agents where you get a 25% response rate, not much in terms of complete remission, and a year survival, maybe a year and a half survival. Can you improve on that if you add a drug that interrupts the survival pathway targeting BCL? Can you do that? The answer has been yes, but the only way to get there is to do the phase 1 trial initially and then move up the trial schema. Dr. Robert Maki: To your question, Shannon, though, the administrative burden is a small one. It’s uploading a document, adding a little bit more to a consent form. It should not be a deal breaker, I would think. Dr. Paul Frankel: There's plenty of burdens on the research team. We certainly don't want to increase that at all, and I don't think this does. One of the questions you mentioned are the downsides of transparency, but some of the upsides also: by having the physicians have more discussion with the patient on some of these issues in a more transparent and lay language, I think, increases the understanding between the physician and the patient. And the physician can take that back to the statistician who's designing the study with the physician and say, “Hey, maybe we need to reconsider this.” There's some upsides in a variety of ways. Transparency and discussion are only going to be improving the ultimate product. And we certainly don't want to find drug doses that end up being a program drug death or unnecessarily hurting patients. Either one are totally unnecessary and unacceptable. Dr. Shannon Westin: Well, great. I think you've made a very clear call to action. I think the last question is how do we get this done besides raising awareness and just kind of setting the bar, right? Because I know, coming from my standpoint as a clinical trialist, it's not something we think to put into the informed consent as we've transitioned to this more risk-targeting type of trial, which I think, as you mentioned, is becoming much more common and over, like, the three plus three and things like that. How do we implement this? Too big of a question? You’re like, “You tell me.” Dr. Judith Karp: We, as physicians, have removed ourselves from patients in so many ways. And how do you get it done? You sit down with the patient. And listen, I'm no saint, and none of us are saints, and we all have other things that we have to do, and there are—you know, we're pressed for time and this and that the other. But much of this, yes, full transparency, you have a 20%, a 25% chance of having a dire consequence. That doesn't mean that you will. If you do, it's 100% in you, right? But there's got to be a communication part that goes with it. That's personal. You can't just do it on paper. You need to do it on paper, but you gotta do it with people, too. Dr. Robert Maki: And the discussion point around potential toxicity, all of the visits, extra visits you might have to make, what extra work you might have to go through, versus, let's say, supportive care only if you are at that point. That is an incredibly important point to make to patients, that you really have exhausted many therapies. Is it best just to go with supportive care for whatever time is left? Because this certainly is rolling the dice. You're going to have some side-effects. And what's the chance of benefit in a phase 1 trial? I think that it's higher now these days, simply from the ability of immunotherapy to intervene on so many different diseases. For example, our success rate is higher than the 5% that's quoted previously, but it's not a home run in any case. And we don't want to take away hope, but we also don't want to give false hope. And I think with Paul's paper and your paper have really pointed out how important it is to have that discussion around the degree of toxicity you might have to expect. Dr. Judith Karp: Absolutely. Absolutely. Dr. Shannon Westin: Well, great. I just want to thank you all for such a lively discussion. I learned a ton, and I hope that our listeners did, too. I do want to remind our listeners to check out this paper, “Ethics and Clinical Research: Improving Transparency and Informed Consent in Phase 1 Oncology Trials,” published in the JCO. And also check out other episodes of the JCO After Hours podcast to learn more. So thank you all again and have a wonderful day. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

In this JCO Article Insights episode, Davide Soldato summarizes two articles from the January 10th, 2023 Journal of Clinical Oncology issue: “Low-Intensity Chemotherapy for Early Breast Cancer in Older Women: Results From the Prospective Multicenter HOPE Trial” and “Inflammation and Clinical Decline After Adjuvant Chemotherapy: Results From the Hurria Older Patients Prospective Study .” Both articles report on clinical outcomes of elderly patients treated with chemotherapy for early-stage breast cancer. TRANSCRIPT Davide Soldato: Thank you for joining JCO Article Insights. I'm Davide Soldato. Today I will be providing summaries for two different articles focused on elderly patients treated for early-stage breast cancer. Both articles are reported from the Hurria Older Patients With Breast Cancer Study. This study is also known as the HOPE Study, and it was a multicenter, prospective, study of patients aged 65 years and older treated with current standard (Neo)adjuvant chemotherapy regimens for early-stage breast cancer. The study captured several detailed geriatric clinical and treatment data from 500 patients that were recruited between September 2011 and May 2017 in 16 sites across the United States. The first article is titled ‘Low-intensity Adjuvant Chemotherapy for Breast Cancer in Older Women’. In this article, Dr. Sedrak and colleagues used data from the HOPE Study to investigate the incidence of chemotherapy administration with low relative dose intensity, associated risk factors, and relationship with survival outcomes. Previous data already showed that the receipt of chemotherapy with a low relative dose intensity is associated with inferior survival outcomes, and the commonly used threshold to define a low relative dose intensity is 85%. And this same threshold was used inside of the study that I am reporting. Elderly patients that are treated with chemotherapy are at higher risk of receiving chemotherapy with low relative dose intensity because of toxicity. However, previous data on the topic was mainly retrospective in nature and reported heterogeneous rates of low relative dose intensity up to 75%. And also, little information was available on risk factors and on the impact on survival outcomes. So, considering the paucity and the quality of the previous data and the potential clinical implication for survival outcomes, results of the HOPE Study are extremely relevant to clinical practice as they provide novel insight on the topic from a prospective multicenter study. In the analysis that was reported in the January issue of JCO, the authors excluded patients with HER-2 positive disease, those receiving nonstandard chemotherapy regimens, and those with upfront chemotherapy dose reduction. The final analytic cohort included 322 patients with a median age of 70 years, 44% with stage II, and 22% with stage III disease. Docetaxel and cyclophosphamide, and anthracycline-based chemotherapy, and this one, either alone or with subsequent paclitaxel, were the most commonly used chemotherapy regimens. Additionally, 85% of patients received a primary prophylaxis with G-CSF. Relative dose intensity was variable in the study. More than half of the patients received full course chemotherapy with 100% relative dose intensity. However, the incidence of low relative dose intensity in the HOPE study was still 21%, thus identifying a subset of patients who received chemotherapy with a suboptimal dose intensity. The rates of low relative dose intensity were higher for patients receiving either anthracycline-based chemotherapy and those with a planned treatment duration over 12 weeks. The authors developed a multivariable logistic regression model with stepwise selection to identify risk factors associated with low relative dose intensity. The results of this analysis showed that an age higher than 76 years, administration of anthracycline and CMF-based regimens, and a physician-rated Karnofsky Performance Status under 90 were associated with higher risk of low relative dose intensity ranging from 3 to 5 times greater compared to reference categories. Then the authors realized another model where they used the previously mentioned three variables, but they also adjusted for relevant clinical characteristics, including age, stage, liver and renal function, and also previous cardiovascular disease. And in this model, the three variables that were observed previously— age, type of chemotherapy, and Karnofsky Performance Status—remained significantly associated with higher risk of receiving chemotherapy with a low relative dose intensity. Finally, the Authors evaluated the association between a low relative dose intensity and survival outcomes, specifically breast cancer-specific mortality, non-breast cancer-specific mortality, and overall survival. Patients who received the chemotherapy with a low relative dose intensity had a significantly lower overall survival, and this association persisted even after excluding patients older than 76 years. A higher risk of both breast cancer and non-breast cancer mortality was observed in patients with low relative dose intensity chemotherapy. However, the number of cause-specific events was too low to obtain statistical significance for both these endpoints. In conclusion, the study by Dr. Sedrak and colleagues provides several relevant information for clinical practice. First, the HOPE study demonstrates that the administration of chemotherapy to elderly patients while maintaining an appropriate relative dose intensity is feasible. However, 1 in 5 patients received chemotherapy with a low relative dose intensity. So the results of this study reinforced the need to identify upfront patients most likely to require dose reduction. And these patients should be proactively supported during the administration of chemotherapy to ensure that appropriate toxicity management can reduce the risk of low relative dose intensity. Second, in the study, the authors observed a significant association between a low relative dose intensity and the CARG and CARG-BC scores. These scores were previously validated to predict chemotherapy toxicity. The presence of this association is important because it suggests that these validated scores can be used routinely in clinical practice to identify patients that might benefit from a comprehensive geriatric assessment to optimize comorbidities treatments and assure optimal delivery of chemotherapy. Finally, longer follow-up will provide the opportunity to establish if the higher mortality that was observed in the HOPE study in patients receiving chemotherapy with a low relative dose intensity is consequent to the low chemotherapy efficacy or to a clinical decline that might be consequent to chemotherapy itself. I will now move to the second article titled ‘Inflammation and Clinical Decline After Adjuvant Chemotherapy in Older Adults With Breast Cancer’. This article was published by Dr. Ji and colleagues, and it describes a secondary analysis of the HOPE study. In this specific manuscript, the authors wanted to evaluate the potential predictive role of baseline inflammatory biomarkers on the risk of clinical decline after administration of chemotherapy. In the HOPE study, the authors collected information on frailty stages, pre and post-chemotherapy using the Deficit-Accumulation Index (DAI): this is a 50-item scale that evaluates deficits in physical activity of daily living, instrumental activities of daily living, psychosocial status, nutrition, frequency of falls, number of medications, comorbid conditions, social support, and laboratory values. The inflammatory biomarkers that were evaluated in the current study were CRP and IL-6, and their levels were determined on pre-chemotherapy blood specimens. Using the deficit accumulation index score, patients were categorized pre-chemotherapy as being robust, pre-frail, or frail; this is important because previous studies already demonstrated that there is a significant association between this categorization and morbidity and mortality outcomes in older adults. The primary outcome of the study was a chemotherapy-induced clinical decline that was defined as a decline from a robust stage pre-chemotherapy to a pre-frail or frail status after chemotherapy. The overall analytic cohorts included 295 robust women. The median age was 69, 62% of patients had stage II or III disease, median number of comorbidities was 1.9, and mean BMI was 28.5. One in 4 older women included in the study experienced a chemotherapy-induced decline in frailty status, so this means that they transitioned from a robust status pre-chemotherapy to a pre-frail or frail status after chemotherapy. This decline in frailty status was more frequent among patients with a higher BMI, those with more comorbidities, and those with stage II and III disease. Additionally, the patients who experienced chemotherapy-induced decline had higher baseline levels of both IL-6 and CRP. Univariate analysis also showed that patients with high IL-6 and CRP had a threefold higher risk of experiencing chemotherapy-induced decline in frailty stages. This association between higher inflammation and the decline in frailty status remained significant in a multivariable logistic regression analysis that was adjusted for relevant clinical and demographic characteristics, including age, stage, race, education, BMI, breast cancer surgery, anti-inflammatory medication, and number of comorbidities. Specifically, the results of these models showed that patients who had both high CRP and IL-6 at baseline had a threefold higher risk of experiencing a decline in frailty status. So, in conclusion, this study shows a significant association between systemic inflammation and a decline in frailty status in elderly patients receiving chemotherapy for early-stage breast cancer. From a biological perspective, these higher levels of systemic inflammation might be a direct byproduct of a more advanced biological aging following the accumulation of senescent cells. There are several intriguing future perspectives that come from this study. First, if validated in additional cohorts, these findings might lead to higher treatment personalization thanks to the identification of patients at risk of clinical decline based on clinical characteristics but also on systemic inflammation. And these patients could be then proactively supported during chemotherapy to try and reduce the appearance of the clinical decline. Second, we know that inflammation is a potentially targetable pathway, and previous data obtained in breast cancer patients showed the potential of behavioral, exercise, and dietary interventions in modulating systemic inflammation. So, based on this new information, if validated in additional cohorts, future research should then evaluate if this interventions can be used to treat and eventually prevent the decline in frailty status in patients with high baseline systemic inflammation before receiving chemotherapy. This is Davide Soldato in this episode of JCO Article Insights. We discussed two publications: ‘Low-intensity Adjuvant Chemotherapy for Breast Cancer in Older Women: Results from the Prospective Multicenter HOPE Trial’,  and the second one, ‘Inflammation and Clinical Decline After Adjuvant Chemotherapy in Older Adults with Breast cancer: Results from the Hurria Older Patients Prospective Study’. Thank you for your attention, and stay tuned for the next episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    Like, share and subscribe so you never miss an episode and leave a rating or review. Articles Low-intensity Adjuvant Chemotherapy for Breast Cancer in Older Women Inflammation and Clinical Decline After Adjuvant Chemotherapy in Older Adults With Breast Cancer Find more articles from the January 10 issue.

Dr. Shannon Westin discusses ways to ensure continued employment for cancer patients with her guests, Dr. Cathy Bradley, Dr. Tina Shih, and Dr. Robin Yabroff. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast for the Journal of Clinical Oncology where we get in-depth on manuscripts that have been recently published in the journal. Today, we're going to be talking about a Comments and Controversies article titled “Ensuring Employment After Cancer Diagnosis: Are Workable Solutions Obvious?” This was published online November 3, 2020. And I'm thrilled that we're accompanied by all three of the fantastic authors of this manuscript, including Dr. Cathy Bradley, who is professor and Associate Dean for Research at the Colorado School of Public Health and Deputy Director of the University of Colorado Cancer Center. Welcome, Dr. Bradley.   Dr. Cathy Bradley: Thank you.   Dr. Shannon Westin: We're also joined by Dr. Tina Shih, who's professor chief of the Section of Cancer Economics and Policy in the Department of Health Services Research, the Division of Cancer Prevention and Population Sciences, at the University of Texas MD Anderson Cancer Center in Houston. Welcome. And then finally, we have Dr. Robin Yabroff, who's Scientific Vice President of Health Services Research at the American Cancer Society.   Dr. Robin Yabroff: Welcome. Thank you.   Dr. Shannon Westin: We're so excited to have the three of you, and I know this is going to be a lively discussion and such a timely and important topic that I really just don't think enough has been done in this area. So you guys are to be congratulated.   So let's start by level setting. How many survivors are of working age and may consider work continuation during treatment?   Dr. Cathy Bradley: Yeah, we don't have a perfect estimate of that. We know there are just over 18 million survivors, and half, maybe even 60%, are working age and possibly employed during their survivorship time.   Dr. Robin Yabroff: And I'll add to that and say that there are also a lot of informal caregivers who were taking care of patients receiving cancer treatment who are of working age. And so that includes spouses, children, and parents. Dr. Cathy Bradley: Excellent point.   Dr. Shannon Westin: It does bring up a good point because I think sometimes with this type of research, we're so focused on the survivor themselves. But when we really look at the definition of survivorship, it includes the caregivers and the people that are participating in the care of the actual patient.   Well, why don't you guys talk a little bit about some of the benefits of work continuation to cancer survivors? Like, why should we be even thinking about this?   Dr. Cathy Bradley: Yeah, I think there are a number of reasons. I mean, the two obvious, of course, are income and insurance. Income, in order to continue their daily lives, but also health insurance to continue their treatment and surveillance. And that health insurance is not just for them, but it's also for their dependents and for their entire families and sometimes for their caregivers and others as well. So there's being able to preserve income, and insurance is critical to cancer survivors, as it is to all of us.   And then there are all the other benefits of work, of continued career growth, to continue quality of life, that interaction, social interaction with others, and a sense of self-worth and identity that many of us have wrapped up in our jobs.   Dr. Tina Shih: Yeah, and I think the other issue to think about is income also tied to your retirement savings. So you don't want to stop your earning ability, so that makes continuing working also important. And then also to have a sense of achieving something so that you wouldn't be continuously thinking about only cancer treatment, but there’s other aspects of life.   Dr. Shannon Westin: Yeah, I think what I've seen in my practice is that another benefit of continuing to work is they're not just focused on themselves as the patient. And I think you got at that a little bit with that idea of self-worth, but it's also a distraction, right? Like, not sitting at home thinking about what's going on with my cancer, what's the next step in my treatment. It's kind of just keeping your mind busy with other things. I also wonder if when we talk about chemotherapy brain, if continuing to work and stimulate your mind and things like that could potentially be helpful in that setting as well. Like, we tell patients to do puzzles and things like that, but staying busy at your job and pushing the envelope there sometimes could seem to be beneficial as well.   So I guess I want to back up a little bit and just see what kind of led you all to be interested in this area. What were the kind of inciting experiences that led you to start to explore this work?   Dr. Cathy Bradley: For me, it was just an observation over time and growing up and seeing people around me who had to make incredibly stark choices, whether or not to continue, to be diagnosed with a serious illness but not be able to get care without that health insurance. So it's a very stark choice that they have between being able to continue to work or take time off to care for their illness during this very acute phase. And that just struck me as such an important thing that we needed to shine a light on, that as we make advancements and treatment and early detection—and the thing with early detection is that you’re going to pick up more people who are working age with cancer, and their source of insurance is their jobs. So looking at this stark choice, it just seemed critical to start to study these questions systematically and, as I said, shine a light on this issue.   Dr. Robin Yabroff: For me, I had the experience of my mother being diagnosed with cancer when I was in graduate school, and I was fortunate that I was working and I had a supportive employer. But everyone in my family, including my father and my sisters, were able to take leaves of absence with paid sick leave that allowed us to step up and care for my mother. But I realized that we were coming from such a place of privilege in having paid sick leave. As Cathy said, for many people who don't have the opportunity to continue working, it's a really stark decision. And then I'll also be a little bit of a fangirl; I saw Cathy give a talk a while ago, and I was so fascinated with her research related to this topic, so I approached her afterwards and asked if we could work together.   Dr. Cathy Bradley: You are too kind.   Dr. Robin Yabroff: I won't say how long ago it was, but it was a long time ago.   Dr. Tina Shih: I think, for me, I was trained as a labor economist in my Ph.D. program, and after that, I keep on wanting to connect cancer studies with labor market studies, but there's really not good data on that. So I'm also an admirer of Cathy’s work, like she’s able to build that connection. And, of course, it's been a lot of fun working with these two really accomplished researchers.   Dr. Cathy Bradley: It’s been the best collaboration for the three of us to work together.   Dr. Robin Yabroff: Absolutely.   Dr. Shannon Westin: I love these cross-institution collaborations, and not even just institution, obviously, the ACS—well, I guess it's big enough to be an institution. But it really is inspiring to me because I think a lot of times we tend to collaborate within our own institution or within our own group even. So you all really have created a model of success here.   So, getting back to work continuation, what are some of the gaps of knowledge that we have in this area, and why do they exist?   Dr. Cathy Bradley: I think Tina said it best. There’s just no good data sources out there. We’re not like Scandinavian countries that can link our health system with our employment data and link it all up and understand what’s going on, that this area, generally—I mean, from my studies—require primary data collection. And other studies. There are some surveys that are out there. Robin’s done a great job publishing in this area using secondary data. We just don’t have a single data source that ties it all together. So that is the biggest challenge in studying this area and leading to our gaps. We don’t know which treatments lead to fewer or more side-effects. Work effects are not studied in clinical trials; they’re not recorded in medical records. There’s so much that we just don’t know, that we can’t say, and that providers can’t have a conversation with their patients about how a particular treatment course will affect their ability to work.   Dr. Tina Shih: I think, to add to that, like for people who also are in the working age population, there’s no equivalent data to see in Medicare. So a lot of time, you have to kind of guess what’s happening with the cancer stage. A lot of time, you can only know what cancer patients have, but that kind of limits your ability to dig deeper into: Are they getting the right chemotherapy, or are they getting the right treatments? Because you don’t really know at this stage.   Dr. Robin Yabroff: I’ll just reiterate what both Cathy and Tina already stated, which is really the lack of comprehensive data, not only about cancer and the clinical details of treatment and diagnosis but also about the type of jobs that people have. So, many times, we know whether or not they had a job, but not how long they‘ve had it, how many hours they work a week. And so a lot of our data from national surveys are really pretty limited for exploring any of the longitudinal effects of the cancer diagnosis on work, which we think are really important, not only for patients but also for their informal caregivers and family members.   Dr. Shannon Westin: So I think I might know the answer to this based on what you all are saying, but how do we overcome these gaps to be able to increase research in this area?   Dr. Cathy Bradley: I think creating that data infrastructure and collecting the information is what's critical. And we know that providers and patients don't—not all of them have discussions about employment when they go in to make treatment decisions, that that's often not part of that shared decision-making about going forward, the employment component, and the patient is kind of left trying to figure it out. And I just think there are more opportunities to create that data infrastructure to stimulate that discussion and to have follow-up.   Dr. Tina Shih: And I want to add to that to say that a lot of time, the information we want to collect about employment, patients, they have the information. I think they would be willing to provide that information. I think the information is not as sensitive as, “Hey, what is your income level?” or things like that. I think we should be able to collect that information with really high-quality data just by asking patients.   Dr. Robin Yabroff: And I want to reiterate the importance of having longitudinal information about employment over time. Some people may take a brief or extended leave of absence from work while receiving cancer treatment, but what happens when they return? And what does that mean for career development and mobility and how they return to a fulfilling work life for both the patients and the family members? So, as Cathy said, many providers don't discuss employment and job tasks and things like that with patients.   And I think another advantage—and I don't remember if we mentioned this, but another advantage of these discussions is tailoring treatment so that patients will be most likely to complete the recommended treatment. Because you can imagine a situation where someone who is being treated for cancer cannot get time away from work and doesn't complete their treatment, or they can't get time from work because they don't have paid sick leave and they need the income and they can't complete their treatment.   Dr. Tina Shih: I want to add to that point being one of the studies we look at young women. We looked at the age of kids, and then we noticed that among those with lumpectomy, about 1 in 5, 20% of women, actually did not have radiation therapy follow-up after lumpectomy, so that's a big problem. And so that also reflects—you need to tailor your treatment based on your patient's needs.   Dr. Robin Yabroff: Yeah, I remember that study, Tina. I thought it was really clever, where you were looking at newly diagnosed patients with breast cancer who received breast-conserving surgery but did not complete the radiation treatment. And so thinking about childcare is really important too.   Dr. Cathy Bradley: Transportation, all of those things that play into treatment completion, especially for people who are employed and trying to balance their jobs with their treatment. And I think the scenario Robin laid out of someone taking leave and then coming back, but you also have the other scenario where people just try to gut it out and do everything at once and then later become the same. So this longitudinal data and understanding what's going on and the impact of whether or not they complete, as Tina has shown earlier and women in my studies have reported, they will miss treatment before they miss work if it jeopardizes their health insurance, especially if they have children. Going back to Tina's point, if they have kids and those kids are dependent on them, they are not going to risk health insurance and their family's wellbeing.   Dr. Shannon Westin: We see this quite a bit with patients with cervical cancer. Obviously, it's a problem across all cancer types, but there especially seems to be quite a bit of burden amongst survivors of cervical cancer. And they're required to have daily treatment for six weeks. And we know best outcomes occur when that timeline is kept very tight. And when we have multiple missed radiation treatments and the timeline extends out, say, past ten weeks, then you see worse outcomes. And so we definitely are living this every day in the clinic.   How can workplaces support survivors? Because I feel like a lot of what we're talking about is that fear of losing their job, that need to keep insurance. So what are some strategies or some suggestions, I guess, we should make to workplaces to help support their survivors?   Dr. Cathy Bradley: Of course, having benefits like paid sick leave and those things are critical. And being flexible, offering accommodations, flexible work schedules of when they come in and when they leave or if they're able to do their work in off hours or remotely, those things are all helpful. We've moved into more of a remote environment since COVID; those things can be very beneficial. But for somebody who does a job where that's not an option, I think there are other kinds of accommodations that employers can make. And being respectful and understanding of a patient who is going through this and valuing them as an employee, maybe not necessarily as a survivor, but as an employee who's dealing with something, that's pretty critical. And I'll let Robin speak for the caregiver component.   Dr. Robin Yabroff: As usual, you read my mind. That's exactly what I was going to say. The importance of offering paid sick leave and health insurance coverage for the patient and also for the informal caregivers and also those accommodations, because frequently informal caregivers are responsible for getting patients to and from treatment, which, when you think about daily radiation, for example, making sure that that caregiver has time away from work is also important.   Dr. Tina Shih: And I think the other issue is to be emotionally supportive for your workers so that they know they don't have to be afraid of losing their job after completing cancer treatments. Or if they have to take more sick leave than they have, they might be able to borrow some sick leave. Having cancer patients in small businesses is stressful for business owners. But I think that's just something that they need to think carefully about, not make cancer patients feel like you are increasing my company's premiums because you have cancer.   Dr. Cathy Bradley: Building off of what Tina just said, taking the long view. It's not a short-term thing, where let's take the long view. This is a valued employee who is going to continue to contribute to the company, to our organization, long term. Take the long view here, not make it so hard on them in the short term.   Dr. Shannon Westin: I love real strategies, and I think certainly those are things that people can do on the local level. We certainly need to discuss policy as well. It's hugely lacking.   What are the next steps, do you think, we could do from a policy standpoint to improve the lives of our survivors?   Dr. Cathy Bradley: I think there are a number of things that we can do: I mean, having health insurance outside of the employer-based mechanism as an alternative, having paid sick leave for someone who is ill as well as those who care for them, having a policy of accommodation. Currently, the ADA, or Americans with Disabilities Act, while it covers cancer survivors, it does not cover their caregivers. So there are things that we can do to extend. And then there are policies that are in place that are just cumbersome. You see this, I'm sure, in your own practice. For a person to qualify for disability benefits, it takes a year. Being able to do that quicker, expedite it. That's a huge deal. That's a protection we have in place that is just extremely cumbersome to use, such that by the time a year goes away, the patient could have passed away but yet still need those benefits for the family and income prior to that happening.   Dr. Robin Yabroff: I'll also add that we talked about occupational health and rehabilitation in our Comments and Controversies piece and the importance of making sure that health insurance coverage extends to occupational health and rehabilitation to ensure that patients can successfully return to work.   Dr. Tina Shih: I think, on the provider side, there might be things that providers can do to kind of somehow accommodate working population’s schedule. I know this kind of adds to providers' burden; they might have to open evening clinic or weekends. But I think, for working population, they really cannot afford to be not at the office for the type of job. I think this kind of arrangement would be very helpful.   Dr. Robin Yabroff: Yeah. And I think for providers to be asking patients about their employment. Like, what type of job do you have? What types of job tasks do you need to do on a daily basis. Do you have health insurance coverage through your work, or is it through someone else in your family, or do you not have health insurance coverage at all? And then, importantly, do you have paid sick leave, and what types of accommodations will your employer offer you? And I know Cathy's done some really interesting work thinking about how patients can talk with their employers about work and what their options are.   Dr. Cathy Bradley: Yeah. Opening the discussion would be a huge step forward to figure out what kind of referrals they need, what kind of letters need to be written for employers. How can they expedite the process to get patients what they need rather than have it be an afterthought?   Dr. Tina Shih: And I think if this is too much for providers to take on, then I think mitigators can also share some of the workload or research nurse. I think those are information you can collect on patient intake.   Dr. Shannon Westin: Great. So I guess the final question I have for you is what are your next steps? Where does this go next?   Dr. Cathy Bradley: I think we have a number of things that are ongoing. I'm involved in a study now with the team here at the University of Colorado, the Total Worker Health Team, and they're looking at the impact of interventions with providers, the oncology care team, for things that they can do to be more supportive of the patient who is undergoing treatment. So it's a really unique perspective of how they apply Total Worker Health concepts to the oncology care team. And that study is just getting underway and hopefully will provide guidance for the oncology care team of how to interact with the patient in order to provide the support they need. I think it's somewhat of a black box, everyone being well-intentioned but not having the data to support them.   So that's one study that I'm involved in currently, and then the three of us are always looking at policies and implications and what's the downstream effect. Tina did some great work on looking at the impact on the financial hardships and long-term impact on people who are diagnosed with cancer, how it extends well into retirement. And I think understanding those impacts and being able to communicate it is an important role that we play as a team.   Dr. Robin Yabroff: I'll also add that we have other things underway, sort of thinking about the impact of disruptions in employment for any period of time or for any reason and what that means in terms of development of financial hardship. And thinking about outside of the cancer diagnosis, how the cancer diagnosis affects employment and then affects development of financial hardship later. I think it’s a really important area, especially as there is more attention to medical financial hardship broadly. Many researchers I know are actively interested in the topic.   And then I'll also add, so we're talking about research, but I'm increasingly interested, and hopefully can work with Tina and Kathy on this, in benefits managers and how those decisions are made for employers. Many employers take up a set package of benefits to offer for their employees without carefully considering what it means for patients with cancer and their caregivers—so thinking a little bit more about the decision-making process that employers have and thinking about the benefits they offer their workers.   Dr. Tina Shih: So as a data geek, I think I'm still trying to figure out a way to collect the claims data with short-term disability and then to see can I figure out who took short-term disability and came back and what happened to those people? And it's been a difficult task because not many data collect those information. That goes back to the data infrastructure issues, that we really need to have better data to understand working-age cancer patients.   Dr. Shannon Westin: Well, thank you all so much. This has been incredibly fascinating. I learned so much. I just want to thank all three of you, Dr. Bradley, Dr. Yabroff, and Dr. Shih, for your exciting work, and I hope that we can continue to make strides in this area.   And just thank you to all of our listeners. Again, this has been a JCO After Hours on “Ensuring Employment After Cancer Diagnosis: Are Workable Solutions Obvious?” published online November 3, 2022. Please do check out our other podcast offerings on the JCO website, and we will see you next time. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Shannon Westin and Dr. Stephanie Graff discuss a revision to the famous "Simone's Maxims" and the broader nature of intersectionality. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, where we get in-depth on articles that have been published in the Journal of Clinical Oncology. I am your host, Shannon Westin, a GYN Oncologist, and Professor at MD Anderson Cancer Center, and I'm honored to serve as the Social Media Editor of the Journal of Clinical Oncology. Today, we're going to be discussing the very important work called “Understanding Modern Medical Centers: Beyond Simone—Intersectional Maxims for a New Era.” And this was published online in the JCO on September 27th, 2022. And joining me to discuss this important work is Dr. Stephanie Graff, who is the Director of Breast Oncology at the Lifespan Cancer Institute at the Warren Alpert Medical School, Brown University. Welcome, Dr. Graff. Dr. Stephanie Graff: Thanks so much for having me. It's going to be fun to talk about this piece with everyone. Dr. Shannon Westin: Yeah. It's a great piece of work. And before we start, I will just note that all participants have noted no conflict of interest for this manuscript. So, let's get down to it. I want to level set. What were Simone's Maxims, that you just revised, and why did they matter? Dr. Stephanie Graff: Yeah. So, Dr. Joseph Simone, who is a legend in oncology, and our revision of his work is truly in respect of what he did, not in any way meant to be anything less than that. So, in 1999, Dr. Simone published, in Clinical Cancer Research, this piece that would famously come to be known as Simone's Maxims, and the official title was, “Understanding Academic Medical Centers.” And that list of, you know, sayings and circulated truths have really sort of been this commonly quoted list of things that people talk about in medicine as just the truth of what it takes to sort of cut it, if you will, in the world, especially in academic medicine, but just medicine in general. Like, one of the famous ones is "Institutions don't love you back." And I think that you've probably heard these and maybe not even realized that you were quoting or hearing Simone's Maxims, but they're pretty ubiquitous in the world of academic medicine and, in particular, oncology, because Joseph Simone was an oncologist. He actually went on to write a book. There's a text called Simone's Maxims as well that's much longer than the Clinical Cancer Research piece. We didn't have a book in us yet, so we just started with updating the original manuscript. Dr. Shannon Westin: That's so great. And it's so funny when I was younger--I don't know if I'm still young or not, but there was things that we said, and I had no idea where they came from. So, I bet that a lot of our listeners are saying the same things, like, "Oh, that's a Simone's Maxim." So, I guess the question is now why did your group set out to update these? Dr. Stephanie Graff: I think if you look at the list of authors, a bunch of the authors have had recent career changes. And so, it actually started as just sort of this casual conversation about how for many of us who have recently undergone career changes, that some of these maxims don't hold true for us. The list of authors is a group of very intersectional physicians in our identities--and I know you'll ask me a question in a moment here about what exactly intersectional means. But, you know, I think that Dr. Simone wrote Simone's Maxims at a time when Medicine was more homogeneous, and so, some of the Maxims that he wrote represent the more traditional values of medicine, what medicine looked like in 1980, in 1990. And I think medicine in 2022, 2023, 2033 is just continuing to evolve and change shape. And so, it's important that we reframe the truths of what it takes to foster a successful career, create successful working environments for the modern workforce. Dr. Shannon Westin: I think this is so critical, and we're seeing it across a number of different fields, not just medicine. We're seeing it in politics and policy and other places. So, why don't you just make sure that all our listeners do understand this concept of intersectionality and how it applies, you know, in medicine and feminism and other areas? Dr. Stephanie Graff: Yeah. And that--shout out to our co-author Edith Mitchell. Dr. Mitchell very quickly said, "Well, we have to start the manuscript by defining intersectionality if we're going to include it in the title because a lot of the readers won't even be familiar with the concept of intersectionality." So, it's included there in the maxims. Intersectionality was first introduced in 1989, and the definition is this nature of social categories, like race and class and sex and gender and the way that they overlap, so that I'm not just white or Christian or a farmer's daughter or a woman, but I'm all those different things, and that creates my intersectional identity. And obviously, there are millions of different intersectional identities, because we have all of these different facets of our personality, of our identity, that come together. And as medicine gets more diverse, which I believe makes us stronger, we'll see more and more complexity in the intersectional personalities, intersectional identities, of the people working in healthcare. Dr. Shannon Westin: Thank you. I couldn't have said it better myself. You know, the other question that comes up as we start seeing more diversity in our workforce, and I mean, frankly, in our patient population, how do you think that that understanding about diversity and the accentuation of our diversity helps improve the success of medical organizations? Dr. Stephanie Graff: Oh, gosh. There's like a million examples. I think that-- ah, Shannon, there's so many different examples I can quote. So, I think that you know, there's a study that looked at patients coming into the emergency department having heart attacks. And if they were female patients cared for by female doctors or female patients cared for by male doctors, that had an impact on their risk of death. Not surprisingly, it was the women patients cared for by male doctors that were the most likely to die and the female patients cared for by the female doctors that were the most likely to live, telling us that when there's this concordance, this understanding between patient and physician, that it improves outcome. But that could be corrected if the male physicians had more female partners. So, just that understanding of relationships, that exposure to more people, more female physicians, increased male physicians’ ability to care for female patients or communicate with female patients, it just increased confidence, our collective confidence. And that's been proven in other settings too. But that's just one sort of great example. The McKinsey group has shown how financial performance improves with gender diversity and ethnic diversity. And that's been shown, not just in healthcare, but in numerous different business environments. And if we think about, you know, as an oncologist, as a clinical researcher, if I imagine that innovation is improved by diversity, imagine that translating into better clinical trial outcomes with a more diverse workforce. And the outcomes that the McKinsey group show, ethnic diversity drove a 35% improvement in financial performance, which is huge. And again, that's at a time when the oncology workforce is really struggling with everything from, you know, recruitment to trials, staffing, revenues. That would be enormous if we could derive that sort of performance. So, I think that there's a million different ways to illustrate what diversity could do, whether it's make us better or stronger or more confident or provide better care, and it's been shown in a million different ways, in a million different contexts. Dr. Shannon Westin: Well, you're convincing everyone, I know. I think we'll get into some of the kind of more nitty-gritty details of the manuscript. I want to be very clear; I think all our listeners should absolutely 100% read the entire manuscript because it's so critical. But let's try to hit some of the major high points. And I say this all the time, and I'm going to take your line, but which one's your favorite? What do you think is the most important one? Just like you would totally tell me which of your children is your favorite, right? Dr. Stephanie Graff: I can't possibly pick a favorite. That's completely impossible. I really like--one of the Maxims that we have is, "Everyone's time and voice is valuable. Institutional leaders must respect time and encourage diversity of thought." Originally, Dr. Simone had a maxim that said, "Members of most institutional committees consist of about 30% of people who work despite other pressures and 20% who are idiots, status seekers, and troublemakers." And we changed that to say, again, "Everyone's time and voice is valuable. Institutional leaders must respect time and encourage diversity of thought," as a way of saying that, you know, I think that in 2022 and beyond, we're getting to a place where it's important that we find better labels for people than idiot and troublemaker and that we reach beyond that to identify how we can help everyone find an environment to be successful and that we fill the working corners of our cancer centers, the working corners of our hospitals, healthcare systems, clinics, with the people that are excited about the work that needs to be done. And, you know, not all of us are gonna want to run clinical trials. Not all of us are going to want to do quality improvement projects. Not all of us are going to want to do five straight days of clinic. Not all of us are going to want to do--insert the day-to-day grind of whatever it is that needs to get done to make a cancer center function. But somebody somewhere loves that little thing. And it's important that we work together to accomplish what needs to be done for best care of the patients that we're honored to take care of. And so, we have to respect that time, respect that voice, and work to connect people with the thing that drives them. Dr. Shannon Westin: I think that one, how you just ended there, kind of touches on one of the ones that really grabbed my attention, which was the original maxim that was, "Leaders are often chosen primarily for characteristics that have little or no correlation with successful tenure as a leader." And instead, as an intersectional maxim, you all changed it to, "Leaders should be chosen for their ability to inspire." That really spoke to me because it's exactly what you said.  That leader has to work to inspire people to do what they love within each piece of that, you know, department or division or hospital or organization or whatever. You can't expect everybody to do the same cookie-cutter thing, but help inspire people to be behind the mission and do what they love as part of moving that hospital organization forward. I thought that was really perfect. Dr. Stephanie Graff: Yeah. And we've too often seen, you know, in academic medicine especially, that we equate a really high h-index or a really successful history of grant funding with leadership. And those aren't the same skills, right? Like, you could be a really fantastic researcher and not a really great person at organizing a team of people to run a cancer center. And you might have both skills, in which case, wow, congratulations. But I think that it's important that we look at the job in front of us and select for that, rather than assuming that all of the same skills fill every single job because that's just not true. Dr. Shannon Westin: I think that, again, I know I said this already, listeners, but please, please run, don't walk, to read the whole paper and get more information. On our last note, one of the things I really loved about this paper was you really provided some clear reforms really to help improve physician wellness. Can you maybe summarize some of those reforms that could improve intersectionality within healthcare organizations? Dr. Stephanie Graff: Yeah. Those are all in Table 2. So, again, I hope you guys all grab the paper and give it a download and pin them up somewhere and think about them. I think that some examples are, you know, to really promote intersectionality, which means that you've got a lot of diversity in characteristics across your cancer center, which is going to be things like gender, race, introverts, extroverts, researchers, clinicians. You really have to have very clear metrics that are shared and discussed. And so, you might need to publish benchmarks for things like median RVUs or come up with a group incentive structure, so that whether you’re a person who is in clinic less and publishing more or in clinic all the time and publishing less, you can work together to be flexible collectively, and then everybody can be contributing to that greater team environment. I think it's really important that if you want to grow intersectionality, that your search committees and your leadership interview strategy undergoes unconscious bias training. There's still not really great strategies to make sure that we're 100% pursuing a no-bias environment in our workplace, but there is evidence that unconscious bias training can be effective to help us recruit a more diverse workforce. And that's the simplest strategy - is if you're going to be putting a search committee together, have everybody do an implicit bias training and work together to select candidates that don't necessarily fit what feels like your traditional mold, and then find strategies, once you've hired into your organization, to partner your new employee, new physician, new hire, for maximum success in that workplace. Another important thing is, as you're growing diversity in your organization, is to make sure that you're creating opportunities to give everybody a voice. You should be looking at who's being invited to speak and making sure that that's representative and diverse. You should be considering changing up strategies. One of the examples I often give is that, when we have a problem and we do brainstorming, where you bring everybody in a room and they shout out, "This is what I think we should do," what happens is you get the loudest extrovert or the most powerful person at the table who just gets their way. And it's far more effective to do brain writing, where you have everybody write down the three or five or 10 things that they think might work, and then you read those out in a neutral way, because then, everybody's voice and everybody's idea gets equal play in a neutral way that allows you to elevate those ideas independent of the other bizarre, irrelevant hierarchies that may exist in your system and can really elevate some of those diverse voices and ideas in your organization. Those are just some of the examples that are listed. Dr. Shannon Westin: Yeah. Listeners, there's a ton of very clear frameworks that you could potentially implement tomorrow in your organization if you want to strive to improve the intersectionality. Well, the time always goes so fast. It has been so great to speak with you, Dr. Graff. Thank you so much for being here. Dr. Stephanie Graff: It's such an honor. I hope everyone gives it a read and comes up with the next iteration and update together with us. Dr. Shannon Westin: Perfect. So, again, readers and listeners, this was, “Understanding Modern Medical Centers: Beyond Simone—Intersectional Maxims for a New Era,” published online in the Journal Clinical Oncology, on September 27th, 2022. And we are so thrilled that you came to listen to JCO After Hours. Please go check us out on the website and see what other podcasts you've missed.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Shannon Westin and Dr. Mustafa Raoof discuss the paper "Medicare Advantage: A Disadvantage for Complex Cancer Surgery Patients." TRANSCRIPT Dr. Shannon Westin: Well, hello, everyone, and welcome back to another episode of the JCO After Hours podcast, where we get in-depth on articles that have been published in the JCO. I am your host Shannon Westin, and it is my pleasure to serve as the Social Media Editor for the Journal of Clinical Oncology, as well as a Professor in GYN Oncology at The MD Anderson Cancer Center in Houston. And today, I am very excited to be discussing a paper that was recently published in the JCO called “Medicare Advantage: A Disadvantage for Complex Cancer Surgery Patients.” And I am accompanied today by Dr. Mustafa Raoof, and he has no conflicts of interest to disclose. He is an Assistant Professor in the division of Surgical Oncology, Department of Surgery, and an Assistant Professor in the Department of Cancer Genetics and Epigenetics at the City of Hope Cancer Center. And there, he is a Surgical Oncologist with expertise in hepatobiliary and pancreatic cancer, and I'm thrilled to have him here today. Welcome, Dr. Raoof. Dr. Mustafa Raoof: Thank you. It's a pleasure to be here. Thank you for inviting me. Dr. Shannon Westin: Of course. And thank you for your incredible work. We're going to get right to it. This is, I think, a really timely and important paper because I think we are always trying to understand how the insurance coverage or the medical coverage that our patients have here in the United States impacts their overall quality of care. So, first, let's level set for the audience. Can you describe the basics of Medicare Advantage, which is what you explored in this paper, and how common is this coverage in the United States? Dr. Mustafa Raoof: So, Medicare Advantage is the privatized aspect of Medicare, and what we know is that since the 1970s there were some private plans that were part of Medicare. But really at the turn of the century, 2000 and onwards, Medicare Advantage has gained a lot of popularity. And this is where the government basically pays a lump sum cost for a beneficiary to private insurance companies to manage Medicare. And so, it's a privatized product. And the idea there is that it's supposed to be an all-encompassing product for the beneficiaries, and the biggest advantage, initially at least, was that there was an out-of-pocket maximum, so patients are not subjected to extreme financial stresses. The cost that was paid to Medicare Advantage plans per beneficiary were in the order of somewhere between 800 and $900 per beneficiary, per year. This was a little bit higher than what would have been the cost to Medicare, but that was to gain a lot of momentum into getting the private insurance interested in the plan. And then subsequently into that, there were a lot of incentives that were set for these Medicare Advantage plans based on some measures of quality, to kind of incentivize the quality products from this private insurance. And so, that's kind of the lay of the land for what the Medicare Advantage plans are. Now, in terms of, how popular are they? I think this has grown significantly over the last 10 years, especially, 46% of all Medicare beneficiaries nationally are part of this Medicare Advantage plan, and it's not one plan, every private insurance company has their own offerings. But a significant majority, I think it's estimated that more than half, and even, you know, going beyond 10 years, the majority of Americans will be insured by these Medicare Advantage plans. Dr. Shannon Westin: That's incredible, and certainly, that means this work that you did has such great impact with the number of patients that are going to be impacted. Can you give the listeners a little bit of an idea of how Medicare Advantage coverage might differ a little bit from the traditional? I know you mentioned the out-of-pocket costs, and that it's run by different companies, but any other kind of discerning features? Dr. Mustafa Raoof: Yeah. So, with the Medicare Advantage plans, as I mentioned, you know, there's an out-of-pocket maximum. In addition, vision and dental plans, as well as gym memberships are included as part of the plan, to kind of provide a holistic plan to the older Americans. And then, one of the things that kind of stands out is that what is the downside to Medicare Advantage plans from a company that is providing this kind of a product, and so, they have to cut costs somewhere. So, I think the main downside to patients would be that their options, in terms of specialist care, will be limited because the networks are generally narrower. There is a variability in different plans as to how big and small their networks are, but they could be more restrictive, and if a potential beneficiary is not aware of that, they could lose out on seeing some doctors that they would've otherwise wanted to see. Dr. Shannon Westin: Okay. That totally makes sense. And so, I guess the next natural question is, what led you to explore the impact of this coverage Medicare Advantage on patient outcomes in surgical practice? Dr. Mustafa Raoof: Yeah. So, as somebody who sees patients with advanced cancer, I think a lot of Medicare Advantage beneficiaries are caught by surprise at the time when they're seeking out care, and they think that they have Medicare, and they should be able to seek whatever care that they would like. Whereas, you know, when they contact their provider, they're told that they have to go to a certain doctor in a certain network. And the shock that this is, as a secondary shock, in addition to the shock of a cancer diagnosis and needing a surgical intervention. So, early on in my training, I had seen some of that, and, you know, I really wanted to delve deeper into helper based problems, is: does it even matter if they go with different specialists, as long as there is some quality to that? And so, I started looking into the quality of the Medicare Advantage network from there on. Dr. Shannon Westin: That leads us directly into your study. Why don't you give us a rundown of the design, and how you wanted to achieve those objectives that you just discussed? Dr. Mustafa Raoof: So, leading up to the study, we had a publication in Annals of  Surgery that looked at what do the networks look like for these Medicare Advantage plans. And that kind of information is hard to find. As you could tell, a lot of patients don't even know if a certain hospital will be covered by their insurance. And so, through a collaboration with Gretchen Jacobsen who studies this as well, they had compiled data on the networks for different hospitals, and for different plans in LA County, as to which hospitals were covered. So, we looked at that, and we found that a lot of these Medicare Advantage plans don't have access to high-volume hospitals, which was our way of measuring quality. And so, that kind of set the tone for this, and then we wanted to ask if there is a difference in outcome between patients who are insured by Medicare Advantage versus those who are insured by traditional Medicare. Medicare Advantage data has been a little bit tricky to obtain for a lot of folks that I think it wasn't released because of data quality issues. We were a little bit lucky, in that we had access to the California Cancer Registry dataset, which includes all patients diagnosed with cancer in California, and that data was linked to discharge data from inpatient hospitalizations. And so, one of the categories that is collected is patients' insurance, whether it's Medicare or not, and whether it's managed or not. So, with that, we thought it was the perfect opportunity to ask a very simple question, and that question is, what are the differences in terms of access to high-volume surgery or quality cancer surgery, and what are the impacts on the outcome for the two different kinds of insurance plans? So, the design is a retrospective cohort analysis, and we included all patients who were undergoing elective inpatient cancer surgery. We selected some index cancers, and we realized that it's not comprehensive, but we wanted to give it a go with some of the more common cancer diagnoses. So, we included lung, colon, and rectal, and then we also included some high complexity operations such as esophagus, stomach, pancreas, and liver, and we included all data from 2000 to 2020. And in terms of the primary objective of the study, we wanted to look at hospital mortality, so we looked at the association between 30-day hospital mortality, but we also looked at complications, readmissions, and failure to rescue. One of the other objectives of this study was to look at the association between insurance stipend, access to care-- we defined access to care in several different ways. Because there's no singular definition, we said access to care would be somebody getting access to cancer surgery at a Commission on Cancer-designated hospital, or NCI-designated cancer center, or a high-volume hospital, as defined by other authors previously, or a teaching hospital. So, we used several different definitions to kind of see if there is association between insurance and patients’ access to care. Dr. Shannon Westin: And let's hear it. What were the results? How did Medicare Advantage compare to traditional Medicare? Dr. Mustafa Raoof: Given our previous work on MA networks data, this was not a surprise, but when we saw that for all of the cancers that we looked at, there were significant barriers to access, in terms of getting to an NCI-designated cancer center, or a high-volume cancer center. So, no matter how we looked at it, we felt that there was a significant disparity in getting to these specialist hospitals, which we associate with quality of cancer surgery. But what was interesting in a major finding of the paper was that for certain cancers, for example, gastrectomy, pancreatectomy, and hepatectomy, we found significantly increased early-day mortality for those operations. And so, for example, for gastrectomy, there was 1.4-fold higher mortality, for pancreatectomy 1.9-fold, and then for hepatectomy, 1.4-fold. So, these are tangible figures in-- you know, the idea is that if somehow  we can improve access to high-quality surgery within MA plans, to match that of traditional Medicare, which is not ideal still, but I think just by doing that, we could impact, potentially reduce cancer deaths from surgery itself. Dr. Shannon Westin: So, I was struck by the fact that there was a difference between the outcomes you mentioned - stomach, pancreatic, liver surgery, and colon cancer. You know, why do you think there might be a difference? Dr. Mustafa Raoof: That's a great question. So, I think colon cancer surgery has-- I wouldn't say it is low-complexity, but it's intermediate-complexity. And I think as a surgical workforce, a lot of surgeons who may or may not be trained with fellowship specialization, they are able to do a really good job of colon resection, and so, there are many high-volume surgeons that do not actually sit in NCI-designated cancer centers or CoC-accredited hospitals, and they're doing a really good job. And so, I think we see that the impact of access is less in colon surgery, and I think that may explain why that is. Dr. Shannon Westin: We've looked at this, and I know you said that you picked some common cancers, and I know you did that because, you know, I'm a GYN Oncologist, so I was definitely interested in outcomes here. We definitely see that, in especially ovarian cancer surgery, which is rare, is that high-volume centers matter. And it can be a comprehensive cancer center, or it can just be a really high-volume center that draws a lot of ovarian cancer, it doesn't necessarily have to be a cancer center. So, that certainly makes a lot of sense. I guess the next question really is what happens next for this work? Like, what can we do to make a difference here? Dr. Mustafa Raoof: So, just reading the landscape on health insurance, I think there's significant incentives for Medicare Advantage plans. So, I think that is going to exist, and I think that will be in the future. I think the important aspect will be to ensure the quality of Medicare Advantage plans. And I think the data that is presented in this study, we hope that it will shed some light, and give a voice to patients who are dealing with a situation where they need complex cancer surgery. And we also hope that there would be some transparency when patients are signing up for the insurance plans, they should be able to say, "Okay, well, with the Medicare Advantage plan, we are getting this quality of cardiac care, this quality of cancer surgical care", and I think that should be an important component. You know, some Medicare Advantage plans may excel in one aspect of care, for example, you know, Alzheimer's care or cardiac care, but may do poorly in cancer surgery care, or cancer care in general. So, I think those are some of the things that the policymakers will need to balance and incentivize. Medicare Advantage plans are really great at cutting utilization because they manage healthcare effectively, but it does introduce some sort of inefficiencies in the system where everything requires a prior authorization; a lot of physicians are familiar with that - a patient needs life-saving surgery, and the authorization is nowhere to be found for two, three weeks, four weeks, and that's a really difficult problem for the patient to go through, and their caregivers. It's a difficult time for them. So, I think those inefficiencies can be mitigated as long as those who require cancer surgery are seen as a distinct population who need timely access to high-volume surgery. I think modifying MA plans in a better way to reflect that, will be the future. Dr. Shannon Westin: Yeah. We've seen this come up on the podcast multiple times as we're talking about inequities and quality of care. You know, it's on us as physicians and practitioners to interact with our policymakers. We've not always been really good at that, but I think this type of work that you've done really helps us have that objective data that we can bring to these policymakers so this change can be enacted. Well, thank you so much, Dr. Raoof. We really appreciate you taking the time being on the podcast. And again, for our listeners, this was a discussion of “Medicare Advantage: A Disadvantage for Complex Cancer Surgery Patients,” and we were with the first author, Dr. Mustafa Raoof. Please make sure you check it out, and please feel free to check out our other podcasts on the JCO website. Until next time, this has been Shannon Westin, with JCO After Hours. Have a great day.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement.  

Shannon Westin, Pamela Kunz, and Rachna Shroff discuss the lack of gender equity on oncology industry advisory boards. TRANSCRIPT  The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of the JCO After Hours podcast; our podcast where we get in-depth for articles in the Journal of Clinical Oncology. I am your fearless leader, and host, Shannon Westin, the Social Media Editor for the JCO, as well as a Professor of Gynecologic Oncology at MD Anderson Cancer Center. And I am so excited to introduce our two guests today. We are going to be discussing the article from the JCO, 'Where Are All the Women in Industry Advisory Boards?' And none of my guests have Conflict of Interest related to this work. So, first, let me introduce Dr. Rachna Shroff, she is from the University of Arizona, Tucson. She's not only the Interim Chief of the Division of Hematology/Oncology, she's the Associate Dean of Clinical and Translational Research, and Associate Professor of Medicine, the Chief of the Section of GI Medical Oncology, and the leader of the GI Clinical Research team. And somehow, we got her on this podcast. I don't know how she had the time. Welcome. Dr. Rachna Shroff: Thank you. So excited to be here. Dr. Shannon Westin: She is the first author on this paper, and she's also accompanied by the last author on this paper, Dr. Pamela Kunz, from the Yale School of Medicine, where she serves as Associate Professor of Internal Medicine, the Director of the Center for Gastrointestinal Cancers at Smilow Cancer Hospital, and Yale Cancer Center, the Chief of GI Medical Oncology, and the Vice Chief of Diversity, Equity, and Inclusion in Medical Oncology. Welcome. Dr. Pamela Kunz: Thank you. Really excited for this. Dr. Shannon Westin: I have to step up my game, man. This is an esteemed panel here. So, we're going to get right to it. I think this is such an important topic because you know, we've been seeing quite a bit of focus on gender equity in Oncology, I would say, really over the last five years, really, especially - yay. Where do you all see the biggest gaps? Like, what are we missing? What do we need to do? Dr. Rachna Shroff: Well, I'm happy to chime in, and I know that Dr. Kunz has her thoughts as well, but I agree with you. I think the first step to trying to address these gaps is just opening the conversation, and I think we have made tremendous strides in that regard. In terms of gaps, I mean, half of the reason that we even started thinking about this topic was really related to research, and opportunities for clinical trials, clinical research, drug development, and where women can try to increase their visibility and their opportunities. And the honest truth is, some of these things we see day-to-day when we see the number of women at the podium presenting pivotal trials, and the number of women that are lead authors on practice-changing papers. And that, I think, is really an area that needs to be talked about. And then, we need to work on the opportunities for solving these problems and coming up with solutions with everybody around the table, all of the key stakeholders engaged. Dr. Pamela Kunz: I completely agree. And you know, I think that because Dr. Shroff and I are both in the clinical trials space, you know, she and I have talked about this, and I think that industry-sponsored clinical trials are certainly one space, national clinical trial network trials are another space that we are also trying to move the needle, and I think that we really all have a collective responsibility in whatever we're doing to really try to ensure equity and representation, both of women, but also underrepresented minorities. And I think that the way I really like to personally think about this is, as Dr. Shroff said, if we can diversify the people who are leading the science, whether it's clinical trials, basic or translational, our science will in fact be better. We will ask more innovative, creative questions, and our patients will benefit from it. We will have more, I think, health equity because different people will be thinking about how to do the science. So, it's really critical and I think it's something that it is really exciting. I agree with you, Dr. Weston, that it's, "Yay," that we're having some recognition of this. And I think really step one is collecting data, benchmarking, figuring how we can do better. Dr. Shannon Westin: Yes. And I think that's a really nice segue to get into kind of what led you to explore this current area of focus around advisory board participation, and why that matters Dr. Pamela Kunz: Dr. Shroff, should I tell the story? Dr. Rachna Shroff: I was going to say, "Should we share our story?" Dr. Shannon Westin: Oh, I love a story. Yeah, definitely. Dr. Pamela Kunz: Oh, it's a good story. It's a good story. It involves Dr. Brian Alexander, who is one of our co-authors in this and is at Foundation. So, I was invited to participate in a Foundation Advisory Board, this was now, probably two years ago. And I have, as a practice, I now ask, "Who else is on the Advisory Board, and who is chairing the Advisory Board?" Because I've ended up, as I'm sure Dr. Shroff has as well, on advisory boards where I'm the only woman. And so, I've just as a policy, tried asking, and then I will also nudge if I notice that there's not great representation of women. And so, this was one of those times, and there were no other women advisors invited, and I objectively had a conflict, so I could not attend. And this was before I even knew Brian. I was like, "I'm going to email the CEO and the COO of Foundation." And I did, and immediately got a response. And in fact, really to Dr. Alexander's credit, he called me the next day and said, "We can't let this happen. How can we be part of the solution? We have some other fantastic industry partners intentionally as part of this author list, and I think we're really eager to try to partner in this. I think it takes an academic-industry partnership to try to move the needle here." So, I think it took some real vulnerability on Dr. Alexander's part to say, "We need to do better and to really do a deep dive." Dr. Shroff, any comments on that? And then you and I started texting, I think. Dr. Rachna Shroff: Yeah, No. So, similarly, I was asked to participate in I think, the same advisory board, but I also had a conflict, which is why Dr. Kunz did not see that I was one of the invitees. And so, that's how we started talking about it. And I agree. I think what was truly admirable was, of course, not just the immediate responsiveness, but the, "Let us be part of the solution." Like, "What can we do intentionally to try to shine a light on this?" And then, "What can we do to help find solutions?" But you know, I think it was interesting because once Dr. Kunz and I started talking about it, I also mentioned to her that I have had the privilege because I work in a very small research space of cholangiocarcinoma, that I have had the privilege of participating in an all-female advisory board. And it was again, a very purposeful creation and composition of an advisory board in partnership with industry and myself. I helped chair that advisory board, and it was night and day in terms of the way that the advisory board ran, the way in which there was engagement and participation. And so, we kind of started talking about, "Well, what if we started coming up with these types of solutions, and how could we flip the script and be able to see positive impact?" Dr. Shannon Westin: I'm an advisory board participant myself, in a predominantly female-driven cancer, and a female-dominant physician, and still, we have a long way to go in GYN oncology as well. I'm often the only woman at the table, and so, I'm so grateful to your leadership for kind of calling this out. I guess before we get too much into your paper, I want to be mindful for listeners that maybe don't participate in these advisory boards, can you give us a little bit of a rundown with what happens at these tables? Dr. Pamela Kunz: Dr. Shroff, I'm happy to let you start if you want to. Dr. Rachna Shroff: Okay. So, you know, advisory boards are typically composed of anywhere from five to 15, 20, sometimes participants. And usually, the composition is what are historically called KOLs. So, people who are thought of as thought leaders in a specific space, and advisory boards are typically organized by an industry partner, and that partner decides on the question, the question that they want the advisors to address. Oftentimes, it's related to a drug that they are developing, and it could be as early as, you know, "How do we design the initial clinical trials,” to “How do we bring this to a phase III, and to the FDA, and to market?" So, it can be anywhere along the continuum of drug development. And the advisors are basically often given some, maybe a little bit of pre-reading and homework, but we basically come together. Pre-COVID, we came together in person, I think since COVID, it's been a little bit of a mix in terms of virtual opportunities as well as in-person opportunities. And it's anywhere from three-hour up to full-day, if not a day and a half of discussions in a room where the company, or the sponsor is asking very specific questions in terms of helping pick our brains and ask us to help develop their drug, and trial design, and help them focus their efforts in a very specific manner. Dr. Pamela Kunz: Yeah, maybe I'll add to that. So, the KOLs that Dr. Shroff mentioned are Key Opinion Leaders, and I think what's really interesting-- and I certainly learned more about this process in the course of writing the paper, but Key Opinion Leaders are really selected on the basis of metrics that are themselves biased. So, it's number of podium talks, number of publications, number of times you've maybe chaired a prior advisory board, or participated in an advisory board, or been on a steering committee, or PI’ed a clinical trial. And I think as our audience likely knows, many of these metrics were themselves skewed and there are disparities to many of these metrics, I think, as Dr. Shroff mentioned in the beginning. And I think the other really interesting thing is that companies don't often have standardized ways to approach or track who they are inviting to their advisory boards, and the composition of advisory boards, and they are often, sometimes third parties will often organize the advisory board. So, it really has historically not been done in a very intentional or deliberate way. Dr. Shannon Westin: Those are really great points, and I think we're seeing it all the time. I also think that it's kind of like that idea, like the rich get richer, right? And so, it's on us to some degree too. As we rise and become the lead authors, and are the chairs of the steering committee, and that's what I heard you say, Dr. Shroff, is like being very mindful about who you select, or who you ask your industry partner to select. So, I think there is a role there. I completely agree with you that calling attention to this is going to make it-- because it can't just be a couple of people doing it. It needs to be a widespread movement. I guess the next question-- we've talked a little bit about how these boards are selected. How does the lack of women at the table impact the patients? How does it impact the women themselves? Like, why does this matter? Dr. Rachna Shroff: Well, I mean, I can start with the latter in the sense of how does it impact the women? And it's like you said, the rich get richer. And so, I think because these advisory boards are often the first place that trials are discussed and or developed, those advisors tend to lend themselves to having pivotal roles in the trials that are being designed. And pivotal roles include Global Steering Committee participation. And Steering Committees are formed usually at the get-go of a clinical trial, and typically authorship for the subsequent publication, and or presentations, are determined by the Steering Committee composition. And so, if you don't have a seat at the table at the advisory board, you are more than likely not going to have a seat at the table on the Steering Committee, which then leads to not necessarily being at the podium, and or the first or senior author on the subsequent publication. And so, unfortunately, it's very much a snowball effect in terms of not being able to have women participate along the continuum of the development of a drug or a therapy in a specific disease site. And then of course, those things potentially impact the advancement of the woman in terms of her career, right? Because at the end of the day, there are still very somewhat outdated, promotion and tenure, things that are looked at, including authorship, and lead and senior authorship, and platform presentations, and how many practice-changing studies you've been involved in. And so, if you don't necessarily start at that advisory board, you may have that impact affect your ability to get promoted and advance in your career as well. And then, Dr. Kunz, I'm sure you'd love to talk a little bit about the other. Dr. Pamela Kunz: I agree. I think you really painted a nice story of like this massive domino effect that not being at that first table has on a woman's scientific opportunities, and really on their career. And so, I think that it's really trying to help create opportunities for women. I will also-- we may get to talk about this a little bit later, Dr. Westin, but really women and underrepresented minorities and really looking at sort of the intersectionality of gender and other underrepresented characteristics, because I think we really also want to indicate that we need really a diversity of all types of voices on these advisory boards. Dr. Rachna Shroff: And I just will say that, you know, just like Dr. Kunz mentioned that there's something to be said because the more diversity of representation we have at the table, the diversity of thought there is in clinical trial design. And to your question, Dr. Westin, smarter, more innovative, more equitable, and more accessible clinical trials will inevitably come out of diverse voices that are helping to design that trial. Dr. Shannon Westin: Yeah, and I think that's what we want, right? There's obviously two major issues here. We want women to succeed so they can do more research and help our patients, and we want our patients to have the best possible outcomes, and get the best drugs, and have access to them across all types, you know, no matter where they are or where they're from. So, we've touched on those two critical issues. I do want to expand a little bit. Do you have information of how this lack of gender parity may intersect with traditionally disenfranchised groups? You were kind of starting to get at this, I think, Dr. Kunz. Dr. Pamela Kunz: I can certainly touch on that. I mean, I think that this concept of intersectionality was actually coined by a law professor, Kimberlé Crenshaw, and it really speaks to the fact that a number of underrepresented characteristics when experienced together, those individuals can experience an extra burden of discrimination. And I think we can see that, where whether they're women of color, or who have other underrepresented characteristics such as disability, et cetera, really don't have a voice at the table. And I think we need to be especially mindful of that. And I think that we want to be certain, I think that we know that our patients, certainly there are a number of health inequities, health disparities, and I think that if we can have more diverse voices designing trials and being really mindful of how we accrue more underrepresented minority patients to clinical trials, how we design eligibility criteria that aren't unintentionally exclusive, there really needs to be, I think, a revolution of how we think about being more inclusive in our clinical trial designs so that we get answers that are reflective of our diverse populations. Dr. Shannon Westin: Now let's hit where the rubber meets the road. There's an issue, right? What do we do? What can we do? Dr. Rachna Shroff: Well, I think, like I said, shining a light on it is obviously the first step. And when we went to write this paper, we realized the paucity of data that is out there, quantifiable data for us to kind of support certain comments and anecdotal thoughts that we had. And so, I think the first step is to be able to partner with industry. And I know that that has a little bit of a taboo component to it when we talk about clinical research and academia, but the honest truth is that the only way we're going to be able to come up with solutions, is by having everybody on the same page about the fact that we need to remedy this. And so, I think we talk in our paper, about a number of actions that companies and sponsors can take in terms of just intentional leadership, and asking for those that are involved in designing and planning advisory boards to strive for equity. But also, to your point about rubber meets the road, more hard data. How can we better quantify where we're at? And what benchmarks and milestones we want to hit in terms of equity and diversity across the board, not just gender. And that way, the companies have milestones to hit and know how far a way they have to go. I think that's really the first place to start. And then, you know, there are small things that can be done. Again, just like I said, we had this all-female advisory board. I mean, creating spaces for women where they may be able to engage more or differently with industry so that they are better known, and develop relationships with the companies so that for the next advisory board or the next Steering Committee, their names are at the top of these people's minds, I think is really, really important. But I'm sure Dr. Kunz has some other thoughts as well. Dr. Pamela Kunz: Yeah. No, all of those are great ideas. So, I completely agree that step one is collecting the data, and I think that's easier said than done, and I think it requires just this incredible intentionality about it. And I'm going to be really bold. Like, what if we required advisory boards to have like 50% women and a certain number of underrepresented minorities? We're doing that on certain committees, on kind of university settings. What if they were required to publish those in the accompanying papers? Or what if that was required to be on: clinicaltrials.gov? And I think that it requires probably some centralization of how companies track their advisory boards, because I think what we also learned is that they're often not tracked centrally. It may be one person in one disease group organizing one advisory board, yet in the rest of the company, it's not really coordinated. Or again, a third party may actually be doing it, and the company may have no idea. So, some real intentionality around the organization and composition of advisory boards. I loved Dr. Shroff's example of sort of the all-women advisory board. Another example, and I think one area of also disparity is that junior physicians are not often invited to advisory boards, so therefore we get like the same old voices. Often, that limits being innovative and creative. And so, I was part of an advisory board for junior faculty where I actually helped moderate it, but we invited what we, you know, called ‘rising stars’  and that was really fun. I don't know Dr. Shroff or Dr. Westin if you remember your first advisory board. It's really scary. I think you don't know what to say, when to talk, how to be a good contributor. And so, I think at this advisory board, we gave some tips on how to be a good advisor, and I think there are lots of really great opportunities that I think our industry partners would, I think, find really compelling. Dr. Shannon Westin: Yeah. That's an awesome point because when you first start, it's not just like they're senior voices, they're also sometimes the loudest voices. You tend to, at least I did, tend to kind of just sit back and take it all in, and then have maybe some small conversations and a few times like pipe up. But I agree. Well, this has gone by super-fast, and has been incredibly engaging and educational. I guess the last question I have for you all is, what's next for you guys? What are you doing next in this work? Dr. Pamela Kunz: That's a good question. I mean, Dr. Shroff and I need to talk about that. But my goal from this is to really spread the word. So, I thank you, Dr. Westin, for inviting us to this podcast, that's part of that. I'll give one example of something that I did with one of the other co-authors. So, I spoke at the Medical Affairs Professional Society meeting, which is an industry-related meeting, but really just to get the word out to medical science liaisons we all work with. So, I think we need to figure out how to really partner, and I think to Dr. Shroff's point, this can't be taboo. This has to be something that we really work on together. I think there are other arenas, as we'd said, like National Clinical Trial Network trials, investigator-initiated trials of really diving deeper into how we can create opportunities in those spaces as well. Dr. Shroff? Dr. Rachna Shroff: And I think that we can even go-- obviously, partnering with industry is going to be key, but some of the other things that Dr. Kunz and I have been doing, and/or are working on, is partnering with everybody that sees the need for this. So, to her point about the NCI and the NCTN, and increasing representation for leadership across the NCI-sponsored studies. ASCO has been amazing in terms of their commitment to increasing diversity at the podium. I mean, they do a great job with their educational programming, but they're really interested in, "How can we increase diversity in terms of the scientific programming?" You know, "How do we make sure it's not just nine oral abstracts with eight men and one woman? What can we do to increase that representation?" And so, I think it's going to require, like I said earlier, all of the stakeholders to buy in, and to work together hand-in-hand to figure out how we can come up with those solutions. And I think myself, Dr. Kunz, and a lot of other people are very much committed to being those bridges and bringing all these people together. Dr. Shannon Westin: Well, you've inspired me to do the same, and I intend to recruit all the women in GYN oncology to help me. Well, thank you both so much. This was such a great podcast, and I hope everyone learned a lot. Thank you all listeners, for tuning in to JCO After Hours. Please go to our website and check out our other podcast offerings. This podcast was about, 'Where are all the Women in Industry Advisory Boards?' Please go read that paper and learn a ton. Take care.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement.  

Dr. Shannon Westin discusses germline genetic testing in gastrointestinal cancer with Heather Hampel and Dr. Matthew B. Yurgelun.   TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours. This is our podcast where we get down in the nitty-gritty of articles that are published in the Journal of Clinical Oncology. I am your fearless leader and host, Shannon Westin, the Social Media Editor of the Journal of Clinical Oncology, as well as Professor of Gynecologic Oncology at The University of Texas, MD Anderson Cancer Center. And I am very excited to bring two guests in today to discuss a review article that was published in a special series on, 'Precision Medicine and Immunotherapy in GI Malignancies,' back in June of 2022, and this is, 'Point/Counterpoint: Is It Time for Universal Germline Genetic Testing for All GI Cancers?' And please note that our participants have noted no Conflict of Interest. So, without further ado, let me welcome our guests. First is Heather Hampel. She is a Cancer Genetic Counselor, and the Associate Director in the Division of Clinical Cancer Genomics, and a professor in the Department of Medical Oncology and Therapeutics Research at the City of Hope National Medical Center. Welcome, Heather. Heather Hampel: Thanks so much for having me. Shannon Westin: We're also accompanied by Dr. Matthew Yurgelun, he is a Senior Physician in Medical Oncology at the Dana-Farber Cancer Institute, the Director of the Lynch Syndrome Center, and Assistant Professor of Medicine at Harvard Medical School. Welcome. Dr. Matthew Yurgelun: Thanks for having me. Shannon Westin: And we have all decided we were going by first names. So, audience, don't be alarmed. Okay, let's get right into it. So, this is a really great review. I learned a ton and I think, you know, just to kind of get back to basics, I think we've been seeing an increase in the use of germline genetic testing across a number of different cancer types. As I mentioned, I'm a gynecologic oncologist, certainly this is something we're doing for patients with ovarian cancer. What are the reasons this has become so widespread across all cancer types? Heather Hampel: Matt and I probably agree on this one. I will, but I'll say you a couple of reasons, and see if Matt has any to add. I think that 2013 marked a major turning point in the field of cancer genetics for a couple of reasons. One was; the advent of next-generation sequencing, so that we could do multiple genes at the same time for a lower cost. The other was that that was the year the Supreme Court struck down the patent on BRCA1 and BRCA2, which allowed lots of different competitors into the market to offer sort of these pan-cancer panels, including, BRCA1 and BRCA2, among other genes. And the price has dropped precipitously since then, giving better access for patients. The competition, I think, has been good, so that a lot of the laboratories now will offer out-of-pocket maximums of $250. And then, we've seen a lot of research. Because of that, I think, where we've just done pan-cancer panels on different solid tumor cancers, just to determine what the prevalence of mutations is, all of this is sort of leading to, I think, just greater use of germline genetic testing across the board. I don't know. Matt, what do you think? Dr. Matthew Yurgelun: No, I fully agree. This is an example of the more you look, the more you find, and I think we've seen that both in the studies that have been done looking at multi-gene panel testing in virtually any setting across different cancer types and then I think people who use these in clinical practice, whether they are genetic counselors, oncologists, gastroenterologists, gynecologists, primary care physicians, I think as people have become more experienced and more comfortable using them in routine practice—I think it's not an uncommon phenomenon for those of us who use these to find things that were somewhat unexpected, which kind of naturally leads to the question, "Well, what else might I be missing if I'm not doing these tests further and wider?" What's made it a little bit difficult is that this is an example of testing that's become available commercially before we really understood how to use it. And so, we've been figuring a lot of this out kind of on the fly a little bit. Shannon Westin: Yeah. I think it brings up, and not to get too nitty-gritty right from the beginning, but to me, it brings up the whole idea around variance of uncertain significance, right? I think we've really struggled with this on the GYN space, and I don't know how common that is for you all in the colorectal space, but we get answers, we don't know how to tell a patient what to do with that information. And in fact, we've personally seen people get risk-reducing surgeries, probably not appropriately in response to these variants. Dr. Matthew Yurgelun: It's a real phenomenon, and it's the other side of the more you look, the more you find. You know, you end up finding a lot of these variants of uncertain significance. I think we've become a lot more comfortable and maybe even cavalier about them as panel testing has become so widespread. But there are data out there, and not to mention just anecdotes of people who are potentially being harmed by these variants of uncertain significance, as you said, whether it's through unnecessary surgery, whether it's even just psychological burdens and harms that come from the angst of those uncertainties. So, it is important that we be thoughtful about just how to use this technology. Heather Hampel: And really it is, "the more you look, the more you'll find." So, on a panel of about 50 genes, there's about a 30% rate of finding a variant of uncertain significance, increase that panel to 80 genes, you're up to probably a 40 to 50% chance of finding a variant of uncertain significance. A panel of 150 genes, maybe an 80% chance of finding a variant of uncertain significance, and it becomes almost the rule and not the exception. So, this is where genetic counseling becomes really important in terms of having people understand that these are sort of common, and usually, not anything, and setting expectations so that people don't over screen, or overreact, or get in a situation where they're mismanaged. And this is one of the things that Matt and I go back and forth a lot about when you start to think about testing all-comers because if you're testing all-comers, you kind of have to give up pre-test genetic counseling and kind of move to a post-test genetic counseling scenario more for the positives, or people with a strong family history or concerns. And I know Matt worries, and I do too, that that's where we've risked these variants of uncertain significance getting mismanaged, particularly in centers that aren't as used to dealing with cancer genetics. Dr. Matthew Yurgelun: I would just add one more concept on that. We’re probably also, in the case of some of these larger panels, dealing even with genes of uncertain significance. At the end of the day, it's the commercial laboratories in many cases that are really setting the agenda on some of these panels as far as choosing which genes to include or not to include, and a lot of these genes are genes where the link to cancer risk is sometimes very preliminary. Shannon Westin: Those are some great points. I think just to kind of take a step back, since the paper’s in GI cancers, and I want to make sure we have—we have a mixed audience out there, so I want to make sure we level set. So, can you tell us the current standard of practice for germline testing in GI cancers? What are you looking for specifically? What are some of the things that you know are of certain significance? Heather Hampel: Currently, the NCCN guidelines recommend that all pancreatic cancer patients be offered germline genetic testing. And what is very new in 2022 is that there's now a consideration recommendation that you could consider offering germline genetic testing to all colorectal cancer patients. That is logistically much more challenging than offering germline genetic testing to pancreatic cancer patients because there are so many more of them. And it comes with a page of caveats of things that you need to think about before you would consider offering testing to all colorectal cancer patients. And then, I'd say among the rest of the GI cancers, you're going to be offering testing in cases of early onset, multiple primaries, maybe three affected’s on the same side of the family with cancers that could go together in a family, and raise a red flag that there could be hereditary, diffuse gastric cancer comes to mind when you think of the stomach, certainly, polyposis is an indication for testing as well. But for most of the GI organs, you're going to need early age, multiple primaries or some family history. The one clear exception being pancreas, and now, a lot of debate about colorectal. Dr. Matthew Yurgelun: And I would just add to that from some of Heather's own seminal work. Tumor testing is often used to drive a lot of this in day-to-day practice. Certainly, the presence of microsatellite instability, and/or mismatch repair deficiency. This isn't limited to GI cancers, obviously, but it is where we often think about it the most. But any finding of mismatch repair deficiency in microsatellite instability should really strongly trigger strong consideration for germline testing, at least for Lynch syndrome, which is often, at least a way in the door for germline testing a bit further and wider. Shannon Westin: Yeah, that's kind of what we've done in endometrial cancer, and it's definitely a less expensive way of kind of getting at that, and we use those same Amsterdam criteria for the full germline outside of that. But that's really how we've gotten to universal testing for endometrial is using the less expensive protein testing, you know, as a trigger to break down the door. Heather Hampel: But it's not necessarily less expensive anymore. So, that's where things are getting a little challenging. You know, at most hospitals, if you're going to do four immunohistochemistry stains, you're going to take whatever they charge for IHC times four, then you're going to have a reading fee for the pathologist times four, and believe it or not, that adds up pretty quickly, and can become a test that's $1,500+, compared to potentially a $250 germline panel. I find it an odd situation for me to be in, who I've spent 20 years of my career advocating for universal tumor screening for Lynch syndrome. But I do feel that we really need to relook at the cost-effectiveness analysis now that the cost of germline genetic testing has gotten so low, and we need to think about what we're missing with universal tumor screening. So, yes, it will detect most of the cases of Lynch syndrome, and it should detect anyone who could benefit from immune checkpoint blockade therapy. And those are very important points, and I think that's the reason we're never going to go away from tumor screening. But it's not going to detect mutations in any other cancer susceptibility gene. And that's what you risk missing if that's your only approach. Shannon Westin: Those are some great points. Again, bringing those of us that aren't GI experts, up to speed, what's the overall incidence of these germline genetic abnormalities in GI cancers? What are we looking for? Dr. Matthew Yurgelun: I think it depends on which cancer you look at, and it also depends a little bit on even just how you define the prevalence here. Where it's been a little bit difficult, or where it's been kind of moving goal posts is that the panels that we're using in day-to-day practice are getting bigger and bigger, and certainly, the panels that are being used in a lot of the studies that are examining this are getting larger and larger. And as far as the number of genes being tested-- and not surprisingly, as you test more genes, you find more stuff. We make a point in the paper that some of the older studies, these are all still relatively new studies, but some of the older studies that have looked at gene panels of say, 30 genes or fewer, you actually find germline prevalence rates that are maybe 10% or lower across most of the GI tract malignancies. But as you start getting into panels that are 50 genes, 60 genes, 100+ genes, that's when you start getting these prevalence rates that are 15%, 20%, almost across the board. But the prevalence is only part of the story, in my opinion, it's a matter of what you're finding, in addition to how many people you're finding stuff in. Because you know, finding a diagnosis of Lynch syndrome, finding a BRCA1 or BRCA2 abnormality, things that are high penetrance, clearly actionable that we understand reasonably well, I would argue is much more impactful than finding something like a monoallelic MUTYH pathogenic germline variant, which arguably has very little clinical significance for the person themselves, and is honestly, much more common than some of these other things too, and drives up some of these prevalence rates. Heather Hampel: I agree, Matt, completely. And I struggle myself, sometimes, with how people should report out the incidence of mutations in series like this because when you include those MUTYH heterozygotes, you include your APCI 1307Ks, you're padding the numbers, but are you finding something that's going to really make a major management change for that family? I don't know. The one thing though that has stuck with me as I look at this is that it appears that people who meet the criteria for testing aren't much more likely to test positive than people who don't meet criteria for testing. And as a genetic counselor who, you know, loves to take family histories, and for years, liked to believe that if I took a good family history, and assessed it, I could pick who was going to test positive appropriately, it's been a little bit of a dash to the confidence to see rates of positivity that are pretty similar in the patients who don't meet criteria. And I think that's been a challenge for all of us. So, if we could pick these cases well, it would be one thing, but I don't think we can all the time, outside of Lynch syndrome. Lynch syndrome, I think we can pick, to a large degree, through tumor testing more than family history. But the non-lynch genes are much harder to predict based on age of diagnosis, family history, or any other clinical criteria. Dr. Matthew Yurgelun: I totally agree, and for me, that's what moved the needle a handful of years ago with pancreatic cancer in particular, in my own mind, is that it was becoming quite clear that you could find some of these with clinical criteria or even just clinical intuition, but there were a lot that were just being missed. We were looking at age of diagnosis, we were looking at family histories of BRCA-related cancers, and family structures being what they are, in many cases, you know, the fact that pancreatic cancer, even in the setting of some of these germline variants is often diagnosed well after age 50, and often after age 60, or even after age 70, you know, our usual clinical criteria just weren't working. Shannon Westin: I think you kind of already started touching on this, but I'd love to get a little bit more, you know, what would be the additional benefits to doing this universal testing? I think one of the things you just mentioned, like, not being able to completely pick the right people to test. I mean, this is exactly why we started doing this in ovarian cancer is because, more than half of the women that were testing positive BRCA, did not meet the age criteria, they had no family history to note, you know. So, we were missing tons of people. What are the other things we can gain from universal testing? Heather Hampel: I think that's a key one. I think another one that Matt and I agree on is that from that proband there, are all those at-risk family members who get to benefit because of the cascade testing that begins from that first person who gets diagnosed in the family. And those are often unaffected at-risk people who you can really keep from getting cancer in the first place, and make a major impact in their health outcomes. So, not wanting to miss a potential hereditary family, and that ability to get to those at-risk family members, I think is a major benefit. I think the one that hasn't really panned out yet in GI, and I'll leave this to the oncologists in the room, is a change in treatment. But I think it's coming. I hope it's coming; we'll see what research all you oncologists can do. But I think that what moved the needle on ovarian and pancreatic was the fact that we had mutations in the homologous repair deficiency pathway, leading to a change in treatment, and the use of PARP inhibitors that just hasn't born out in GI cancers yet, outside of pancreas. And the one thing that you do see a treatment change for is mismatch repair deficiency, which you can find by doing IHC for the mismatch repair proteins or MSI testing, so, you don't really need the germline panel. In fact, some people with Lynch syndrome don't have an MSI-high tumor, and won't benefit from immune checkpoint blockade therapy. And so, I feel like that's the one benefit that maybe hasn't been fully realized in GI cancer, but I hope it will one day. I don't know. Matt? Dr. Matthew Yurgelun: No, I agree. I think the therapeutic actionability has been one that we've been hoping for more than what we've actually seen in real-world practice, the big exception being PARP inhibitors for pancreatic cancer. But even there, I think so far, the benefits have been maybe a bit more modest than people would've originally hoped for. I agree, I think the therapeutic benefits are ones that we're still trying to work towards. Shannon Westin: Yeah, and you kind of got around this before, and I think this is what we're experiencing in some of the gynecologic malignancies is like, not every gene is created equally. You know, we originally thought, "Oh, any homologous or combination gene will do. We could do PARP for all," and then realized, "Actually, no, it's probably just BRCA, maybe PALB2, RAD51." So, I think it's exactly like what we're seeing in honestly, frankly, across precision medicine, right? Where it's like, not every PI-3-kinase mutation will lead to benefit from a PI-3-kinase inhibitor. So, I think the science got ahead of us, or we got ahead of this science, and so, I do think that that's where the struggle is. Because I think once you've got therapeutic actionability, it becomes a no-brainer. And then, you've already hinted at this, but I just want to be really clear for everyone listening, why shouldn't we do it right now? What's holding us back from universal germline testing for everybody in GI cancers? Dr. Matthew Yurgelun: You know, I think if it were a perfect world, then it would be a no-brainer - test everybody. The finances, as Heather alluded to, are in some ways kind of the least compelling argument against universal testing, that the cost of the germline testing itself has come down tremendously. But it's more than just the cost of the test itself, at least in my opinion. I mean, first of all, I think we've got massive work to do just to figure out the care delivery here. As it stands right now, roughly half of colorectal cancer patients meet criteria for germline testing, putting aside the recent update to the NCCN, which says, "consider testing for all individuals." But even if you just look at colorectal cancer alone, if you expanded germline testing to all-comers with colorectal cancer in the US, that's another 80,000+ new diagnoses per year in the US, who are all over age 50, have mismatch repair proficient tumors, have no striking family history, you know, where the odds of finding something truly actionable in my mind, is exceedingly low. Then you add in all of the other GI cancer types. You add in the literal millions of GI cancer survivors that are out there, and you're talking about bringing this testing to a whole lot of people. On top of that, there's really all of the uncertainties and nuances that come from the testing itself, as we were talking about at the beginning of the chat here. Whether it's variance of uncertain significance, whether it's genes where there's really no link between the gene in which they have a germline variant and the cancer that they were ultimately diagnosed with, or whether they're genes we don't understand or don't have clear-cut management guidelines for, it's really all the unintended consequences in some ways of a lot of what we're doing. And I think too often out there, whether it's from the patients themselves, or us healthcare providers, or combination of the two, there's this misperception that genetic testing is giving black and white answers to what's going on. There's a whole lot of gray here, as far as understanding what needs to be done with this. Yes, if we could test everybody and get them clear-cut answers, and then get their at-risk family members in for testing, the benefits would supersede all of these concerns, but I don't think the real world is as simple and straightforward as that. Heather Hampel: And I find myself just in the struggle between-- when I get in a room with people who discuss this, most people feel like we should be doing it, and the thing that's stopping us is that it's difficult. And that doesn't seem like a good reason to not do this. If it's the right thing to do, I think we have to figure out how to do it. And you think of, you know, Mary Claire King's Lasker Award talk when she talked about offering BRCA1 and BRCA2 testing to all women at age 35, population-based screening. And one of the things she recommended there was, not reporting out variants of uncertain significance. I realize it's a different situation when you're talking about population testing and healthy people, but are we doing more harm than good with reporting out variants of uncertain significance even in cancer patients? Whereas, you know, we could just ask the lab to let us know if anything ever got upgraded and avoid risking mismanagement of patients based on a variant that you know is likely benign. So, I think there are things we can do. We've been working on some of them, I know Matt has done a little work with mainstreaming in pancreatic cancer patients. I did as well, my former job, because that was sort of the first new tumor outside of ovarian where we needed to recommend all patients get seen by cancer genetics. And the wait time often in cancer genetics is too long, given the prognosis for pancreatic cancer patients, we had to kind of come up with new service delivery models. And there's some great data out there, people are using genetic testing kiosks in the waiting room, videos at the oncology clinic. We can get creative, and the trouble is, I think we're learning while we're doing, which is coming full circle in our discussion here, that's a hard way to do things. Dr. Matthew Yurgelun: I would just add on top of that, in my mind, the reason why not to do this, is really why not to do it. I think we can recognize that more germline testing is going to pick up more people with inherited risk to cancer. There's the unintended consequences, and we need to figure out how to deal with them. And as Heather said, just because it's hard, that shouldn't be a reason not to do it. At the same time, I think it's okay for us to recognize that this is where the field is heading, but to also recognize that we don't yet have all the answers, and to say, "Well, let's be thoughtful about it. Let's figure out how to implement these types of things, how to study them," because it's not going to be one size fits all. What works in a major tertiary care academic medical center is going to be very different from what works in other settings and for other populations. What works for English-speaking patients versus non-English-speaking patients is probably going to be very different. And I think there's all sorts of permutations when you start breaking it down like that. And I think it's okay for us to say, "Well, this is where the field seems to be going, but let's really be thoughtful about it and make sure that we're not doing harm in the short term just because we think it makes more sense to just test everybody in a shotgun approach." Shannon Westin: This has been great; I've learned so much. I was like trying to frantically take notes for thoughts of what we're doing in our clinic right now. I just want to thank my two guests. I think that I remain hopeful that we will get here. I think that you all outlined some really clear steps that we need to take to get there. And audience, I just want to thank you all for being here with us. Again, this was a discussion of, ‘Point/Counterpoint: Is It Time for Universal Germline Genetic Testing for All GI Cancers?’ Thanks again for joining us on JCO After Hours, and we will see you next time.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement.  

On this episode, our guests discuss how postmortem tissue donation can provide meaning to patients and their loved ones.   TRANSCRIPT Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours. This is when we get in-depth on articles that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncologist and Social Media Editor of the JCO. Excited to be here today to discuss a really awesome paper. It was a Comments and Controversies named “Postmortem Tissue Donation: Giving Families the Ability to Choose,” just published on August 26th, 2022. And I'm joined by a number of the authors. It's going to be a really incredible discussion. I'd like to introduce each of them, and then we'll get right down to it. First is Allen Gustafson. He is the founder of the Swifty Foundation, which he started with his son, Michael, who sadly died in 2013 of medulloblastoma. And this foundation really was the catalyst of the group Gift from a Child, which we're going to really discuss today. In addition, I'm accompanied by Dr. Angela Waanders, the Interim Head of Neuro-Oncology and the Director of Precision Medicine and Associate Professor at the Ann & Robert H. Lurie Children's Hospital of Chicago; Beth Frenkel, a Tissue Navigator at the Children's Hospital of Philadelphia; and Dr. Mateusz Koptyra, a Senior Scientist and the Director of the Center for Data-Driven Discovery in Biomedicine at the Children's Hospital of Philadelphia. So, thank you all for being here. I'm so excited to discuss this paper. I think this is something that our listeners are going to be really interested in and really want to move forward. So, welcome. Allen Gustafson: Thank you. Dr. Mateusz Koptyra: Good morning. Dr. Shannon Westin: So, let's get started. You know, postmortem tissue donation is so critical for research and improving outcomes for our survivors. I think the best way to start, I'd be very interested to hear how each of you got involved with this. And Allen, let's start with you because I think that your story is so important. Allen Gustafson: Sure. Thanks, Shannon. Well, as you mentioned, our son, Michael, died of medulloblastoma in 2013 at the age of 15, and probably about four months before he died, he knew his life was going to end. And he got the idea of donating his body to science, so they could use him to find the cure. And he used to refer to that as his master plan. So, obviously, that charge was put on his mom and I to figure out how he could do that. And although we were being treated by two excellent hospitals, one here in Chicago and one in Boston, they were not helpful in terms of helping us with his final wish. And so, it was really through Nancy Goodman from Kids vs Cancer and his pediatrician going above and beyond the call of duty that Michael was finally able to donate his spine and his brain, some of which was sent to Texas Children's and some of it was sent to SickKids. And it became both very meaningful for him as his life ended, and it was also very meaningful for us in terms of the important step we took as a family in our grieving and our loss of him. And as you mentioned, our work with the Swifty Foundation, really, his choice there was prescient, in that we didn't realize how important postmortem collection is for advancing scientific discovery, nor did we realize how important this could be for other families. So, it all started with his experience in terms of our journey with Gift from a Child. Dr. Shannon Westin: That's so incredible. I'm so glad that you chose to do this work. Dr. Waanders, do you want to pipe in? Dr. Angela Waanders: Yes. So, I think reflecting back, it really was a serendipitous moment in meeting with Patti and Al. I can still remember it was in 2016, I believe, at a Children's Brain Tumor Network annual meeting. I'm a Physician Scientist, a practicing Neuro-Oncologist, and at the time, I was in the laboratory trying to dissect out, why do children die from brain tumors. I was also taking care of children who were losing their battle. And so, a couple of years prior, I had been trying to figure out how to set up a postmortem or a research-based autopsy program. I knew from talking to some of my own families and helping to make it happen, it was really important and meaningful to them. But the logistics were beyond me as a single provider. You know, it really takes a lot of logistics going from the initial conversation, to how to make it happen. And so, one of my colleagues, Dr. Rishi Lulla, introduced me to Patti and Al. We realized we had a shared mission. And so, I've been very fortunate and grateful to be involved in this project. And, you know, including some of the comments from the paper, as well as meeting and talking with families, and seeing even the larger scope, families do want us to ask. This is meaningful for many families. And it's a really special moment for me as a provider in any of the autopsies that I help to coordinate with our Tissue Navigator, Melissa Williams, at our hospital, we do try to have a follow-up conversation with families when they are ready, and those conversations are just so meaningful. I have several stories of things that I hadn't even imagined would be meaningful to families. And so, to me, this has really been something that wearing both hats as both a physician, and a scientist, that is one of my projects, and things that I've been involved with that I think will have the biggest impact when I look back at the end of my career. Dr. Shannon Westin: I completely agree with you. Dr. Koptyra, I'd be interested to hear your perspective of how you got involved with this. Dr. Mateusz Koptyra: Hello. So, working as a scientist at Children's Hospital of Philadelphia, I actually had the privilege of also working with Dr. Angela Waanders here at CHOP. And part of my scientific effort was really focused on utilizing biospecimens into research. And specifically in the lab, we are generating two more models which can be used in wet bench research that specifically relates to cell lines or xenograft models used in science to explore tumor biology, novel therapeutics, et cetera. And at that point, Angela actually introduced me to the Gift from a Child program. And initially, I offered my assistance, but quickly realized how working with the Gift from a Child program and with Swifty Foundation, adds additional meaning to our daily work in the laboratory. So, from initial assistance, I quickly became fully engaged in the process of tissue banking, processing, and model generation out of specimens we received on their website. Until today, I'm leading that effort on the laboratory side here at CHOP. Dr. Shannon Westin: Thank you. And then Beth, I think we'd be interested to hear your perspective as well. Beth Frenkel: So, thank you very much for having me. I started my career as a funeral director. I did that for about 10 years or so before moving into organ and tissue transplant. My job, specifically, was advocating with our community and our healthcare partners to make sure that every family was given the opportunity to donate, to help others. What really got me into my job here with Gift from a Child is that my mom was diagnosed with an inoperable brain tumor, and there were no treatment options for her at all. And so, after her death, it really led me to start researching brain tumors and to see the lack of treatments, not only for some adults, but for all of these kids. So, that's what really made me seek out this opportunity with Gift from a Child, and to work with all of these wonderful people to try to help these kids find better treatments and cures. Dr. Shannon Westin: You all have such incredible stories, and it's so inspiring to see people take terrible things that have happened to you and make it into something so much more positive. So, I'm so inspired by all of you. I know personally as a surgeon and a physician, I sometimes feel really uncomfortable approaching the idea of postmortem tissue collection with patients. So, I think one important aspect of it is—you know, of course, we've talked a little bit about the positive impact on research, but can you all speak a little bit more about how family members actually may benefit from this practice in being offered this opportunity? Allen Gustafson: I'd be happy to start. I think I can speak both from a personal experience, as well as from the many families we've spoken to and surveyed. I think the number one reason families want to make this choice is to help other families. I mean, it's the one bit of light that can come from perhaps the darkest time a family is ever going to go through. I know that's what prompted our son, Michael, in his words, to help as many as he can. And as we talk to other families, that is their principal reason for giving, as well as certainly to create a legacy for their child. As I mentioned, our son was older, so it also gave him some personal meaning at the end of his life. And helpful in the grieving process, both to know that your loss may be benefiting another, but also the researchers that have received Michael's tissue have been keeping up with us in terms of publications that his tissue has helped fuel. And there was even a protocol change in how recurrent medullo is dealt with that Michael's tissue was a part of. So, again, to know that is so gratifying for the family. Dr. Shannon Westin: I think that just knowing that and hearing that from personal experience should, hopefully, help our practitioners that are listening feel more comfortable with approaching it. The consensus conference that you all discussed in the paper, how did this come to be? What drove that discussion and where people ended up? Angela, if you want to tackle that? Dr. Angela Waanders: I can take this question. So, the consensus meeting in 2018 happened in Philadelphia when I was still at Children's Hospital of Philadelphia. It came out of a conversation with Patti and Al. We really wanted to dive down deep into understanding what barriers existed. I knew from the clinician side, it's uncomfortable. It is a really difficult question to broach, and so, we thought that from hearing from families-- and we specifically chose a mix of families that were able to donate and those who were not able, or who hadn't been asked, and it's a meeting that will forever stick in my head, just the moments and things that I would not have imagined. And I think for all of us who were involved, the families that did not have the option to donate, or who weren't asked, I think the quotes and the comments from those families were the most memorable. To kind of step back a little bit in how I became involved in this too, it's trying to make sense of the nonsensical. I mean, children should not die from brain cancer, and children should not die from brain and spinal cord tumors. We are uncovering the biology, the past decade has been really exciting from a biology standpoint, but having matched specimens from the time of diagnosis to time of death, will really answer crucial questions, which are, why do children die? And so, as clinicians, we just kind of need to get out of our own way, get out of the discomfort of asking, and, I think this is something that our generation of physicians are modeling. Another big aspect of this too, and I think this came out of the consensus meeting in 2018 and is important to continue to illustrate and emphasize; tissue that's taken, you know, this precious tissue, this precious gift, the mandate is to share it broadly. So, we did develop standard operating procedures so that we can try and make cell lines, we can have matched tissue for DNA and RNA extraction, protein extraction, we can look at areas of tumor, areas that don't look like tumor. And with the understanding, this tissue will be shared as broadly to every laboratory who is studying brain cancer or something relevant, and that the findings from this precious tissue will also be redeposited or shared again. So, this really is a legacy of life and celebrating the life of these children who've lost their battle. Allen Gustafson: If I can add one thing on the consensus meeting that the other great thing that came from that, we wanted to query families about how clinicians should talk to them, or what's the best way to talk about this very sensitive subject? And we were right at the beginning of our Gift from a Child, creating the program. And so, our website and our materials have all been influenced by the input of these families. And so, we created these to help clinicians with this very difficult conversation. And that consensus meeting really helped us understand as best we can understand any individual family, how to communicate this very, very sensitive subject at such a very difficult time in their family's journey. Dr. Mateusz Koptyra: If I can add something as well, I actually had this privilege during, and after that conference to provide a tour for some of these families around the laboratory, and kind of refers to us into your former question a bit, but I was able to show the biorepository where the tissue is stored as well as laboratory and some cell lines and models, which we created in the laboratory. And one thing which was really striking and filling, and in words which were shared by those families, the fact that some of donated tissue, some of these families actually already donated tissue, that some of those tissues are within this biorepository, that some of the cell lines we have might be specifically from the tissue from their children, brought this almost like continuity of their life and the second meaning to family's life, just by possibility of being together in this laboratory and seeing that those models work. Talking about investigators who actually share those specimens had exactly the same effect, bringing this kind of closure to the fact that this tissue still brings meaning on a daily basis. Dr. Shannon Westin: It's wonderful. You know, Allen, I wanted to kind of expand a little bit on something that you started talking about around “best practices for requesting” because I really do think that's a huge-- one of the huge barriers is that we feel uncomfortable as clinicians in asking. And so, I'd be interested to hear a little bit more about what are the best ways to approach this, and to give these families this opportunity. Allen Gustafson: Well, I can certainly give the parent point of view on this. First, I would say that our Oncologist and the healthcare team helped us make difficult decisions throughout Michael's cancer treatment and had a lot of very difficult conversations with us. And so as a family, we would see this perhaps as another difficult conversation to have in the journey of our son's cancer. And again, I would encourage physicians to think about it like that, because they are quite practiced in having difficult conversations with family members. I think the best time that obviously, this conversation would be received by a family is when it becomes clear that our child is not going to survive their cancer, or perhaps when they enter into hospice. Again, it's such a difficult time for us. And it may be the case that we don't respond particularly well to what the clinician has to offer. And I know, you know, throughout Michael's cancer journey, I wasn't always at my finest hour with my Oncologist in terms of my response to what he had to tell me. So, that certainly may be true here as well, but again, I think the more important thing here is that it's really the family's choice to decide. And like other choices that are made throughout our child's cancer journey, we deserve to make an informed consent about that. And so, this is another opportunity, I think, for those of us whose children don't survive their cancer, to make another important informed consent. Dr. Shannon Westin: Thank you. Angela, you've done this so much. I would love to hear your perspective from the other side. Dr. Angela Waanders: So, with asking, it's a big thing of, this is a cultural change too. On an individual level, when I'm talking with one of my own families that I'm guiding through a cancer journey, I usually bring it up at the time when we're talking about, "Your child's cancer may still be treatable, but it's not going to be curable." And so, opening up the conversation to what is important to you, what is meaningful to you as a family, knowing that the cancer will ultimately take your child's life. And so, during that part of the conversation, I usually bring it up as an option and say, “You know, one thing that I have found that some families find very meaningful when they know that their child is dying from cancer, is to donate, and we do have a research-based autopsy effort.” I go into just a very brief description of it, and I read the room. Some families you can tell, like they are too shocked, too overwhelmed, to even broach that conversation. And so, I say, "You know, we can talk about this at a later time." Or if it seems like it may be a hard “no,” initially, just not interested at all, or just it's not a topic that they want to broach at that time, I do say, "You know, let's keep the conversation open, and I may bring this up again later, or please feel free to bring it up to me again later." One of the key messages we try to convey is to try and do things beforehand, if at all possible, and also explain the process once a family expresses interest. Because it is foreign, it is unknown. As Beth was bringing up earlier, you know, with her prior experiences with Gift of Life, there was a time in the US when organ donation was unfathomable. And now I think for many of us, it is just a commonplace, it is something we automatically state. So, it would be very nice for us to have that cultural change within our field, within Oncology, within Medicine in general. An important part though is, when I ask, I know I can make it happen. And I think too, for many physicians, many clinicians, and this is where the Gift from a Child program has been so important and really a game-changer in making this happen, is I know when I ask, and I bring up the conversation, that I can make it happen. And that is one thing we truly try and convey to any clinician who expresses interest. We talk with them, “Here's the process, this is what you need to do, and this is how we can make it happen." So, I think from both getting out of my own way of the discomfort of asking the question, modeling the behaviors with our trainees, I do oftentimes have our fellows, or our residents in those meetings when I'm having these difficult conversations. And then also just conveying and making sure that logistically we know we can help make this happen. Dr. Shannon Westin: Great. Beth, I don't know if you have any thoughts kind of from the Navigator perspective. I'd love to hear. Beth Frenkel: Yeah, sure. I definitely agree with Angela that I think when we're dealing with clinicians, one of their biggest concerns is that it's going to be a lot of work for them. And that's when the role of the Tissue Navigator takes over, is that we don't need a lot of involvement from the family clinician, they aren't as involved as they would like to be, but that's our job, is to coordinate all the logistics. We work with the families, we work on getting consents, we take care of any kind of processing of the tissue, shipping. So really, what we're looking for from the clinician is the referral. We're just looking for them to bring up that topic with the family and give them the opportunity to make an informed decision about if they would like to donate their child's tissue. Dr. Shannon Westin: Great. And then Allen, you mentioned something and I was interested in this overall, you know, you said that the researcher kind of was keeping you in the loop and letting you know what the tissue was utilized for. Is that pretty standard as far as accountability, or what measures are in place to kind of keep families in the loop? Allen Gustafson: When we started this, one of the values here for us was that the researchers who would receive our children's tissue would be excellent stewards of that tissue. And one way, in our mind, to ensure that excellent stewardship is transparency. And so, as a family member, we can stay abreast-- and again, this is not for every family member, but most family members do choose to want to know what's happening with their child's tissue, in terms of how it's being used in the lab, how it perhaps is fueling a study or a publication, and God willing, perhaps improving treatments for future children. So, that is really an important aspect of this whole process. Dr. Shannon Westin: Great. Dr. Angela Waanders: And Shannon, we have families, from my experience, that they kind of make it a yearly thing. Like, on the child's birthday, they'll reach out and ask, "Hey, is there any update on how my child's tissue is being used?" Or maybe they were just thinking about it one day, and they'll send an email and ask, "Hey, can you give me any updates?" So, the donation isn't finished after the actual autopsy is complete, we develop a relationship with these families that lasts forever. And they can feel comfortable to reach out at any time with any questions, or if they want an update. And I think that's also a way that the Gift from a Child program is so different from any other postmortem donation program. Dr. Shannon Westin: It really is so inspiring, and it makes me want to figure out how to do this and within our own field. I think the time is flown by, and I'm so grateful to all of you. I think the last piece would be just to make sure that everyone listening, where can families learn more about the process, and what's the best way for also clinicians to check in on what you all are doing? Allen Gustafson: Probably the easiest way to do that is through the website, which is: giftfromachild.org. There, you'll be able to find all the information you need, to get in touch with the Navigator. Families have access to a 24-hour hotline that they can call at any time. And their call will be answered within 24 hours, and that hotline works for clinicians as well. So, that would be the best place to start, I think. Dr. Shannon Westin: Well, thank you. Thank you all so much for all of your work and this amazing paper. And I hope everyone does go and check it out again. Again, we were discussing; 'Postmortem Tissue Donation: Giving Families the Ability to Choose', published this month, August 2022 in the Journal of Clinical Oncology. Thank you all for tuning in, and please make sure you like and subscribe. And we'll see you next time. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement.  

Dr. Westin and Dr. Justin C. Brown discuss how physical activity can improve disease-free and overall survival in colorectal cancer and its potential application across all cancer types.   TRANSCRIPT   The guest on this podcast episode has no disclosures to declare. Dr. Westin: Hello, everybody, and welcome to another episode of JCO After Hours, the podcast where we get in depth on recent manuscripts published in the Journal of Clinical Oncology. And it is my great pleasure today to tell you we're going to be talking about a really important manuscript: “Physical Activity in Stage III Colon Cancer: CALGB/SWOG 80702 Alliance Study.” And this was published in the JCO on August 9th, 2022.   All participants in the podcast have no conflicts of interest.   And I am very excited to welcome the first author on this important paper, Dr. Justin C. Brown. He is the Director of the Cancer Metabolism Program and Assistant Professor in Cancer Energetics at the Pennington Biomedical Research Center at Louisiana State University.   Welcome, Dr. Brown. Thank you for being here. Dr. Justin C. Brown: Thanks so much for having me. Dr. Westin: So, this is some really important work, and I think we're starting to see more and more really objective data around the importance of physical activities. But before we get too far down the road, I do want to level set because this was a study in colon cancer. So, just because we have a really mixed audience, give us a quick bit of information about the standard treatment for colon cancer and where we are with survival outcomes. Dr. Justin C. Brown: Yeah. So, for most patients with early colon cancer, they'll get upfront surgery. And then a subset of patients who have high-risk features for recurrence, or have positive lymph nodes or tumor deposits, will get three or six months of chemotherapy. And outcomes have improved over time for this population, but there is still a lot of heterogeneity, in that, some patients do better than others. And you know, a lot of patients ask as they finish therapy or as they're starting therapy, "Are there things I can do that potentially could improve my outcomes?" And so, we think that this data will provide physicians with a lot of really important information regarding the benefits of physical activity during chemotherapy, as well as after therapy, for patients with stage three colon cancer. Dr. Westin: Okay, that's great. And so, again, continuing on that level-setting piece, before this study, what did we know about the impact of physical activity on outcomes in colon cancer? Dr. Justin C. Brown: So, we knew that there was some association between physical activity during chemotherapy and after chemotherapy with disease-free survival and overall survival. There have been studies that have linked those two things. There was some uncertainty about, what is the best exercise or physical activity prescription? And so, a lot of the current recommendations before this study basically said encourage patients to avoid sedentary behavior, encourage them to be as active as they can be, because some activity provides benefits over no activity. But for the patient who really wanted the specifics of how much should I be doing, when should I be doing it, what types of activities should I be doing, should I avoid certain things, the evidence was really absent. And so, what this study provides is a lot of important clarity for both physicians and patients about the types of activities that can maximize their disease-free survival and overall survival. Dr. Westin: I think that's so important because you're exactly right. We all have those patients that you give them a vague, and they're like, "No, I need instructions. I need to know how much time. I need to know what I'm doing." And it can be really frustrating because—I know personally, I'm like, "Well, this is what I do.” And I'm like, is that enough? I have no idea. So, this is really important work.   And before we get into the specifics of the work, can you just give our listeners a little information? Do we know anything else about physical activity in other cancer types? Like, beyond colon cancer, is this something that's broad-based across everybody?   Dr. Justin C. Brown: Yeah. So, there is emerging observational evidence that physical activity after diagnosis of early breast cancer, of early prostate cancer, is associated with improved disease outcomes, so disease-free survival, overall survival; that's observational data. We do have randomized clinical trial data on other quality of life endpoints and biologic endpoints in a variety of tumor types. And we know that patients who engage in physical activity or exercise during and after treatment tend to have better quality of life, they have less fatigue, they have improved physical functioning, they have reduced inflammation, improved insulin sensitivity. So, there's a variety of short, medium and potential long-term benefits to being physically active after your diagnosis of cancer. Dr. Westin: Perfect. And how did you end up here? What made you interested in this work? Dr. Justin C. Brown: So, my story dates back all the way to 2002. So, my father died from metastatic colorectal cancer. Dr. Westin: I'm sorry. Dr. Justin C. Brown: No, no, it's okay. I mean, if that didn't happen, I wouldn't be here today. And so, he is with me every day. And, when he asked his physician, "Is there anything I can do to improve my long-term outcome?" This was 2002 before we knew how patient lifestyle factors really improved or impacted disease outcomes. And so, my whole life's mission has been focused on trying to empower cancer survivors, so people from the point of diagnosis on, with information about how the choices they make outside of the oncology clinic have a profound impact on how they feel, function, and survive. And so this has come full circle for me because now I'm able to generate evidence that hopefully will inform clinical practice about how patients who are exactly like my dad and wanted to know what they could do to improve their outcomes, we now have the data that we can provide more precise recommendations about what patients might consider doing to improve their long-term disease outcomes. Dr. Westin: Great. Wow. It's so inspiring, and again, I am sorry for your loss. But I'm glad that you're really transitioning it into positive things. So, let's help everybody understand first just the overall design of the trial that you utilized, the CALGB/SWOG 80702 clinical trial. Dr. Justin C. Brown: Yeah. So this trial was a two-by-two factorial trial, and it randomized patients to three years of Celecoxib; the anti-inflammatory drug, or three years of placebo. And that was the primary analysis. The primary hypothesis was that Celecoxib would improve disease-free survival versus placebo. And that paper was published by my mentor, Jeff Meyerhardt, in JAMA last year. And that analysis showed that Celecoxib did not improve disease-free survival over placebo. The other factor of the two-by-two design was a randomization to three months of FOLFOX therapy, 5- fluorouracil and oxaliplatin, or three months of FOLFOX. And that analysis contributed to an international pooled consortium called the IDEA Consortium. And that analysis was published in 2018 in New England Journal of Medicine, and the follow-up overall survival analysis was published in Lancet Oncology in 2020. And that showed that while overall, three months of FOLFOX was not inferior to six months, there were some lower-risk patients that achieved good disease control with a shorter regimen of chemotherapy. And so, that has changed practice, and now there are certain lower-risk patients that are getting treated with three months of FOLFOX chemotherapy instead of six months. But patients with high-risk features still continue to get six months of therapy. That was the primary questions that that study was designed to answer: the Celecoxib versus placebo and then the contribution to the international pooling project to answer the question of three versus six months of postoperative therapy. Dr. Westin: Well, that's a really clever design. And then I love how you have an additional question built in here. So, why don't you explain how you incorporated your exercise objectives and also what this nested cohort design is? Dr. Justin C. Brown: Yeah. So, this is a unique opportunity to leverage an ongoing clinical trial to conduct an observational study. So, what we did is, about midway through chemotherapy, we asked patients if they wanted to participate in a lifestyle substudy. And if they chose to participate in the lifestyle substudy, they were asked questions about their physical activity and their dietary patterns and how much they weighed. And we measured those things midway through chemotherapy, and then we also measured them again about six months after patients finished their chemotherapy. And so, what this allowed us to do is to leverage all of the amazing resources that were put into place in the randomized clinical trial—that is, a homogenous patient sample, uniform treatments—and systematically ascertain disease outcomes to answer a question in an observational setting—that is, "Does physical activity relate to disease-free survival and overall survival?" So that is the nested cohort within the larger randomized clinical trial. Dr. Westin: Okay, perfect. And then just tell us how you measured the physical activity and the questionnaire that you utilized. Dr. Justin C. Brown: Yeah. So physical activity was measured by a self-reported questionnaire, and the questionnaire is included as a supplement to the JCO paper. So, if people are interested in using this questionnaire, it is available. And it asks 10 different types of physical activities, and it asks the frequency with which those activities are done in the past two months. And using the answers that the patients provided, we were able to calculate which patients were more physically active versus those that were less physically active. And we were also able to understand were the activities that they participated in more vigorous or less vigorous. So, it provided us with a lot of important details regarding the types of physical activities that patients reported during and after chemotherapy. Dr. Westin: Great. That's so interesting. And then, of course, we know diet is important, right? So, you did assess diet as well in this group. You want to give us a little bit of detail on that? Dr. Justin C. Brown: Yeah. So, we measured diet with what's called a Food Frequency Questionnaire, and it asks a series of questions regarding habitual dietary intake. And we know that people who are more physically active tend to be more mindful about what they eat. And so, that's an important confounding variable in trying to understand the relationship between physical activity and disease-free survival. So, we measured diet using that questionnaire. At the same time, we measured physical activity during and after chemotherapy. And that was included in our analysis so that we can attribute the association that we observed to the physical activity per se. Dr. Westin: Okay. And how often did you assess these time points? I'm sorry if I missed it. Dr. Justin C. Brown: So, we measured physical activity and diet two times. We measured it midway through chemotherapy, and then about six months after patients finished their chemotherapy. Because we know that activity, as well as diet, changes from when patients are being actively treated to after they finish their systemic therapy. Dr. Westin: Okay. Perfect. Great. All right, so let's hear it. What were your primary findings? Dr. Justin C. Brown: So, the benefit for the simple messaging is that any activity is better than no activity. That is, if patients need to know the bottom line, my advice is that they find an activity that they like to do and they do it for the rest of their life. For patients who want a little bit more precision, we can think about physical activity on a spectrum of intensity. So the examples I would give a patient is we can do walking, we can do jogging, and we can do running. And jogging is more intense than walking, and running is more intense than jogging. And so, if you decide to do more intense activities, you don't have to do them as much in a week. If you choose to do walking, you need to do more walking than if you choose to do running. And so, this will help to clarify what types of activities are beneficial. So, some people might choose to play tennis, which is a vigorous activity, one day a week. And that would provide them—from our analysis, that provides them with a disease-free survival and overall survival benefit. If a patient says, "My joints are too old and too achy that I can't play tennis, but I can walk around my neighborhood," then we know that those patients may need to do a little bit more activity, maybe a 20 to 30 minutes a day, three to five days a week, in order to achieve a meaningful disease-free survival benefit. So, this helps us to understand with a little bit more precision what we should be advising patients. And if patients say, "I can't do this” or “I prefer to do that," that helps us to have evidence-based recommendations about what is likely to be beneficial and worthwhile to improve their long-term disease outcomes. Dr. Westin: It's so awesome. And I think it's so great to have just very clear guidelines that we can give our patients. I know I've said it already during this podcast, but every time I—because I think we all get so frustrated with these vague recommendations, like, "Okay, drink water, eat healthy." You know, really, I want bullet points of what I can do. Now, we talked a little bit about some of the findings in other cancer types that were already existing. So, can we extrapolate your findings to other cancer types? Dr. Justin C. Brown: I think there is a reasonable expectation that our findings can probably generalize to early-stage breast cancer and maybe to prostate cancer. And the reason I say this is because these are tumor sites where there is existing evidence that being more physically active is associated with improved long-term disease outcomes. Now, the specific magnitude of benefit, I'm not sure if that will generalize. But I do think that this study provides a framework to start thinking about how we can understand the specific characteristics of physical activity that might be more or less important in terms of maximizing long-term disease outcomes. Dr. Westin: That is perfect. So, tell me, what are your next steps with this work? Dr. Justin C. Brown: So, one of the findings that this study reported was that patients who were more physically active during their chemotherapy were more likely to receive more of their planned chemotherapy. They had a higher chemotherapy RDI. So, some of us on this paper have been very fortunate that we received funding from the National Cancer Institute to launch a Bayesian Adaptive Trial of exercise, aerobic exercise, during chemotherapy, and the primary study endpoint is chemotherapy relative dose intensity. So, what we're going to be able to do is to understand, in a randomized clinical trial setting, does different doses of aerobic exercise have a causal effect on improving chemotherapy RDI? Because one of the hypothesized mechanisms through which we think physical activity may improve disease-free survival and overall survival is it enhances a patient's ability to tolerate systemic therapy. And so, we have the funding. We are in the process of planning that study. It should begin later this year, and that will provide us with concrete randomized evidence to understand if exercise during chemotherapy for colon cancer has a causal effect and can improve adherence to systemic therapy. Dr. Westin: That's outstanding. And can our listeners potentially participate in that? Are you looking for sites? Dr. Justin C. Brown: So this study will be launched at Pennington Biomedical Research Center, where I am, in Baton Rouge. This study will also take place at Kaiser Permanente, Northern California, so if there are people on the West Coast listening, as well as at Dana-Farber Cancer Institute in Boston. And so, we are part of a larger consortium of four studies that are trying to understand the benefits of both exercise as well as nutrition and their role in impacting how patients feel, function, and tolerate anti-cancer therapy in a variety of cancer sites. And we are focused on colon cancer, specifically. Dr. Westin: Well, that's great. I hope our listeners will get involved. And those of our listeners that are survivors, you heard some very clear data on what you can do to help impact your overall survival, as well as quality of life. So, I hope you’ll implement that. Thank you again so much for being here, Dr. Brown. The time just flew by. And again, for the listeners, this was the JCO manuscript published August 9th, 2022, “Physical Activity in Stage III Colon Cancer: The CALGB/SWOG 80702 Trial.” And until next time, we'll see you at JCO After Hours. Take care.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.  

Shannon Westin, Francesca Gany, and Theresa Hastert discuss the topic of food insecurity among patients with cancer. TRANSCRIPT Dr. Shannon Westin: The guest on this podcast episode has no disclosures to declare.   Hello friends and welcome to another episode of JCO After Hours, your podcast to get more in-depth on some of the amazing work that has been published in the Journal of Clinical Oncology.   I am thrilled to be here today with two fantastic investigators and researchers who are going to discuss a paper that is titled “Food to Overcome Outcomes Disparities – A Randomized Control Trial of Food Insecurity Interventions to Improve Cancer Outcomes.”   This was published online in the JCO on June 16, 2022. We're joined by the principal investigator Dr. Francesca Gany, who is the Chief of Immigrant Health and Cancer Disparities service at the Memorial Sloan Kettering Cancer Center in New York City.   In addition to Dr. Gany, we're also joined by Dr. Theresa Hastert, who's an associate professor in Population Science in the School of Medicine at Wayne State University in Detroit. And she published an editorial that went along with this article named “The Potential of Cancer Care Settings to Address Food Insecurity.” This was published in the JCO on July 1st, 2022.   Welcome, ladies. So excited to hear about this work.   Dr. Francesca Gany: Thank you! It’s great to be here.   Dr. Theresa Hastert: Thanks so much for having me.   Dr. Shannon Westin: So, what we're seeing more and more of is oncologists getting into other areas of expertise. For a long time, we've all been involved with treatment trials, and we've started getting into survivorship and health services. But I think that we really are realizing there are other issues for our patients that affect their cancer care and outcomes.   So, first, I just wanted to level set and see if maybe Dr. Gany, you can kick us off, can you define food insecurity and just kind of briefly discuss the prevalence patterns in women and men that are diagnosed with cancer?   Dr. Francesca Gany: Sure! So, food insecurity is essentially not enough access to food to help you maintain your health. And that could come from a variety of reasons, including not having enough money to buy food, living in a food desert, where there's not availability of food and other factors that could make food inaccessible to you.   This potentially has a tremendous impact on health. We see that with folks with cancer and folks who don't have cancer. We know with cancer patients, it's a particularly difficult issue because of the increased nutritional demands that come with a cancer diagnosis, the need for special diets, and decreased absorption of nutrients for certain folks. So, it's especially important that our cancer patients have access to enough healthy food, so they can have the best cancer treatment outcomes possible.   Dr. Theresa Hastert: I can add a little bit about the prevalence of food insecurity more broadly. So, in the US population, about 4% of Americans have what's called very low food security. So, that's where people actually reduce the amount of food they eat because they have a lack of money for food.   And by contrast, in previous work among cancer survivors, that number is closer to about 15% in sort of population-based studies and much higher in certain select patient populations.   So, if you're in an under-resourced population, and as some of Dr. Gany’s previous work has cited figures of more like 55 to 70% of cancer patients and survivors with low resources can be food insecure and not have enough money for food.   Dr. Francesca Gany: All of this has, of course, worsened with a COVID pandemic because just food insecurity rates have gone up overall and we have certainly seen an impact on our patients in the cancer centers in which we work.   Dr. Shannon Westin: And you can imagine with the high costs of drug pricing and all of the other issues around coverage of cancer care that people are having to make those types of decisions between food and shelter and basics and getting their treatment for their cancer, their treatment for their other related comorbidities. Am I on the right track?   Dr. Francesca Gany: Absolutely! In fact, we did a study that specifically asked patients whether they were not purchasing medications in order to be able to feed their families. And a very high percentage of them, up to a third of patients, said that they were foregoing some of their cancer meds in order to be able to feed their family.   We asked it the opposite way as well, whether purchasing their cancer meds meant that they were unable to feed their families and unfortunately, it was a similar percentage for those food insecure patients.   So, it has a tremendous impact on fully engaging in cancer treatment, and also being able to take care of one's family which of course is so important to our patients.   Dr. Theresa Hastert: So, in Detroit, we're in Michigan, which expanded Medicaid. So, in the work that we do predominantly among African-American cancer survivors, we find that most Americans are able to access care, like with the expansion of Medicaid, people are able to get treated for cancer. Paying for drugs is another thing but we still have a lot of food insecurity among this population. About 15% of our cancer survivors, African-American cancer survivors in Detroit are food insecure.   So, it's not an insurance issue in the sense. They have Medicaid coverage and they're able to get cancer care, it might not cover every out-of-pocket expense, they still have food insecurity. So, broadening insurance is not necessarily enough to help people avoid some of these follow-on impacts.   Dr. Francesca Gany: Yes! One very important issue is that looking at food insecurity at a moment in time with our patients is not enough because we know that as treatment progresses, financial hardship also progresses – financial toxicity of the cancer treatment.   So, it's really important not to do just an initial screen for food insecurity and for other social determinants of health because food insecurity is certainly a window into other essential needs that have to be met, but it's really important that we don't just ask once, but that we ask in an ongoing way because we know that as time goes on, it only gets worse.   Dr. Theresa Hastert: That's so important. I've talked to several providers who have these issues with patients, where it's the people who are sort of more middle class who are going into cancer and be like, ‘I'm fine, I’m fine, I’m fine” when first asked if they need assistance. And it's not for several weeks or months when they start racking up out-of-pocket costs, and then suddenly, they realize they're not fine. It can become very delicate also because people are used to being self-sustaining, and financially independent, and they're used to being able to maybe help other people who have financial needs to donate to charities and things like that. And there can be a shift for people when they realize, ‘’Oh, no, now I need assistance.’ That can be difficult for people to grapple with. And it's so important to keep checking in with patients throughout their treatment experience to see how they're doing.   Dr. Shannon Westin: I think this is really a great segue into kind of getting into the nitty-gritty of the publication. I would love for you, Dr. Gany, to give our listeners a little bit of information around the trial, the patient population that you chose, and the intervention arms.   Dr. Francesca Gany: Sure, I’m happy to do that! So, we started when we first saw the high prevalence of food insecurity among the patients, we were working with that are partnering with safety net institutions, we knew that we needed to do something.   And so, we did a study and we looked at emergency food resources in the top 50 zip codes that our patients lived in and then we did site visits, etc, to these emergency food resources and saw how inadequate they were for our cancer patients. They were inadequate because they didn't have medically tailored foods. Often, they didn't have culturally tailored food choices. Their hours of operation were very short and with all of the appointments that our patients had to keep, it made it really hard for them to reach the pantries. They weren't that geographically accessible so that was a deterrent to patients.   So, we realized that we have to do something that was much more convenient for our patients that would address their medically tailored food needs. And also, the difficulties they might have traveling to another site to get food.   So, we started a medically tailored food pantry of one initially, in which we partnered with a local food bank for New York pantry site that was close by to the hospital and worked with them around food choices for our patients, etc. And would work with them to pack the bags at their site and then we would bring the bags over to the hospital.   We found with our patients that there was tremendous uptake of this service, and tremendous appreciation and they reported improved quality of life and improved ability to get on with their cancer care.   This grew to now 15 pantries in both safety net facilities and also Comprehensive Cancer Centers because there are a sizable number of people in Comprehensive Cancer Centers, as you know we've been discussing that are also food insecure.   So, we had 15 pantries, but pantries - they’re a great piece of the solution - but we didn't feel that they were enough of the solution because even though they were medically tailored and patients had some choice, they didn't have total choice in what they were getting. And especially with cancer care, people's food preferences shift, etc. And what they need to be healthy shifts.   So, we explored two other options of home grocery delivery service where they would get to pick what groceries came to their home, and having the groceries come to their home eliminated the issues that come up certainly with having to carry heavy bags, etc.             It was some choice that this gave them but the windows of delivery were a little bit of a problem for the patients because sometimes the food delivery services would be coming at a time that didn't work for the patients.   And then, the third option was a voucher system, where people get basically a debit card, and they can buy whatever they want within, no alcoholic beverages, etc, but whenever they want to purchase with that voucher card. And we accompanied that with education around healthful food choices, nutrition during cancer, etc, which was translated into a number of different languages.   So, those ended up being three pieces of the arms of the study. The pantry had become pretty much the standard of care in all of the facilities we were working in. So, that was one arm. So usual, customary care. And then, we added to that because it was in the sites that we were at, we added a voucher arm as well.   And in the third arm, it was a home grocery delivery arm. Those were the three arms of this randomized control trial. All of the monetary amounts were the same for the three arms. So, the grocery bag cost the same as the amount they were given in the debit card, which costs the same as the home grocery delivery pretty much, or it was at least equivalent nutritional content and food content. So, those are the three arms of the study.   Dr. Shannon Westin: Great! Well, just cut to the chase and let the group know what did you find?   Dr. Francesca Gany: So, we found that after six months of participation, the voucher plus pantry arm had the greatest treatment completion rates, 94%, versus the home grocery delivery, 82.5%, versus the pantry alone, which was 77 and a half percent.   So, tremendous differences between these three arms. All three arms saw a significant improvement in food security status but those were the treatment completion rates across the arm.   We also looked at quality of life and depression symptoms across the arms at 6 months, and across all arms, patients had fewer depression symptoms in follow-up. And improved FACT-G quality of life scores. But the statistically significant differences were actually found in the pantry and the delivery plus pantry arm for both of those measures.   Dr. Shannon Westin: That is so interesting and so exciting to see this type of intervention making a difference for our patients. Was there anything that surprised you about your results?   Dr. Francesca Gany: So, the one that was a little surprising was why the quality-of-life results did not exactly mirror the treatment completion rates. And we are assuming that that has to do with the fact that with the pantry, there's a lot of in-person interaction with staff and with the home grocery delivery, actually, because many of the patients found it a little bit tricky to order the grocery deliveries online, they also had a fair amount of staff interaction. Whereas with the voucher, there was less of that.   So, perhaps that explains that we're not sure and we're doing a much larger randomized control trial now in which we're going to look at that. One really great finding was that around food choices and healthy food choices with the voucher because we wanted to look at that, we were controlling what we gave to patients with the pantry arm, and we were controlling that to some extent with the grocery delivery, especially because we were ordering with them.   But we were very interested for the voucher arm and across the board, people made very healthful choices with the voucher. Again, they all were accompanied by nutrition education, etc. And interestingly, limited English proficient patients and patients who were born abroad had the healthiest food choices.   So, this was a great way to intervene with all patients who were food insecure. And we saw that it had a tremendous impact equally regardless of country of birth, language, etc. And great extra finding that there were healthful food choices and that was especially true in immigrants and in folks who have limited English proficiency.   Dr. Shannon Westin: Great. It's so exciting. I think though, it brings up the obvious question that seems like a ton of work. So, how do we operationalize this in our clinic? How do we screen patients? How do we work with our cancer center directors or our clinic directors to be able to provide these types of interventions? Sorry, I know it sounds like it's a million-dollar question.   Dr. Francesca Gany: This screening is simple. For these studies, we use the 18-item USDA Food Security screener. That's a longer instrument but we wanted to make sure we use that for this study. But in actual clinical practice, the two item screener works. And we are working now on one question specifically for cancer patients that we're finding is also quite sensitive and quite specific, and that does not take a long time at all.   We should be screening everyone. We should be screening in an ongoing way. We should be tracking this as a very important patient outcome. What does take longer and which is a little bit daunting to folks is that once you find food insecurity, you need to treat it.   And so, we do a lot of work around how to treat food insecurity and how to treat it efficiently. In the end, I actually think that the food voucher is going to be the way to go because it requires less staff time. And people are used to paying for groceries with debit cards, and with cards, and that has not been an issue at all for our patients. And I do think from a clinical operations perspective, from a policy perspective, and from an insurer’s perspective, this should be part of the workflow. The vouchers are a really easy way to do it. We’ll of course have more data when the larger trial is done.   Dr. Shannon Westin: These points are so important around needing to be able to address food insecurity when you find it. The screening is very simple and providing food to somebody else is much less so. And it can actually be harmful to screen for something and then not do anything about it like that could actually increase patient's distress if you're making moves like you're going to help them and then don't, it can actually be harmful.   But I was wondering, Dr. Gany, if you could talk a little bit about how you got this off the ground, functionally speaking, at the beginning. Like, if somebody wanted to do something similar for their own cancer survivor, with their patient population, what kinds of steps can people be taking? Who did you work with? Did you get any pushback? Are there any lessons learned that you could share with people?   Dr. Francesca Gany: Yes, so I think there are more and more pantries actually now that are being implemented at cancer sites. So, I think that there is broader buy-in now on the systems part.   So, I think that's a little bit less of a heavy lift than it might have been a few years ago. We were in a very receptive place. They were really happy that we wanted to help the patients this way and were very facilitative.   And so, we partnered with a food bank for New York Food Pantry at our initial site, and we partnered at other sites, and then we became a food pantry site ourselves so that we could have access to as many varied products as possible, so that we could put together bags that were tailored, etc. And so, then patients could pick the items in the pantry that were tailored.   The couple of issues that arose was this one was a space issue, especially in New York City spaces at such a premium and the clinics were really worried about even giving over a closet. So, in one pantry, we have a few drawers in the conference room, and we pull everything out when we get there. We have a cart and we wheel it around, and we wheel to a spot, etc. So, we take care of it that way.   At another site, we keep everything in the basement. When we came to where there was more space, we wheel it up to the cancer clinic. Some sites had more space and that was great, we could set up the pantry to be permanently there and displayed.   The other issue that concerns sites was food safety, food management, vermin, etc. So, all of our folks are trained in food safety, food handling, and food storage, so that we store it in the safest way possible. And so, that there were no issues around that. So, that has really worked out.   One other thing is we've also introduced an intervention at some of the sites of food navigators. So, not only do they help patients with the pantries, etc., but they also work with folks around what are some of the other resources they can access that'll work for them in their communities near their home that have the right foods for them, etc. And that's helped. This was not in the study, but this is just in our clinical operation for this. That has helped as well.   Dr. Shannon Westin: It's so great. It's such a lot of work and it seems so essential. I think it's really going to be on us to take it back to our institutions and determine what works. I loved your line about it seems like the vouchers might be our best. I think we really need those kinds of real-world solutions that we can actually bring back to implement.   I guess my other question is, is there a role for policy change here? Is there something we can do kind of on a more national level to address these things rather than it being at the individual practice and institution levels?   Dr. Francesca Gany: Oh, my God, yes! That is our hope from these studies that at the healthcare system level, the insurer level, and then the broader policy level in New York. For instance, some of our patients are undocumented immigrants. So, they have less access to food programs that others might have access to such as SNAP.   By the way, we saw the same food insecurity rates in SNAP participants as we saw in non-SNAP participants because the benefits are not that hefty in SNAP, but that is an aside.   But for undocumented immigrants, let's say, when in New York when they are diagnosed with cancer, they are eligible for Medicaid for the treatment of emergency conditions. So, such an easy thing to do would be to do a food insecurity screener when you were doing the emergency Medicaid eligibility, and then help people right into a food program, a voucher program.   When we think of the costs of the vouchers, in this study, the costs were a little bit more than $200 a month. For the vouchers, the staff time does not cost that much. And when one thinks about the cost of cancer treatment, of cancer care, and what a teeny drop in the bucket this is compared to the cost of cancer treatment. This should be a no-brainer for policy folks because it is so little money compared to the bigger outlay with so much impact.   So, that's one example of how we see it rolling out in a policy arena. When you're screening for Medicaid, for the treatment of emergency eligibility, you ask a couple of food insecurity questions or the one we’re hoping to roll out and if somebody's food insecure, it’s just they automatically got the food voucher.   Dr. Theresa Hastert: I think, well, ultimately, being able to have people in with policy-level solutions for this would be amazing, it would be a huge step. In the meantime, I really think it is going to be a lot of individual people and individual cancer centers trying to connect the people in front of them with the resources that they need.   And in order to do that, I think we’ll really make the biggest progress when we do get buy-in, we get champions higher up in the cancer centers. When cancer center leadership takes it up and helps smooth paths, and when funders put efforts behind it, and I think they're doing this increasingly, put efforts behind addressing social needs among cancer patients and survivors, and also our accrediting agencies in terms of tracking, ‘Are you not only screening people? Are you hooking people up with resources?’   And of course, there's a balance between cancer centers that are set up to diagnose and treat cancer but if our patients are dealing with all these other issues, we need to be doing what we can to help address those issues so people can recover from cancer, can go on to live healthy, happy lives, could have the best outcomes.   Dr. Francesca Gany: Definitely. And some natural allies, the cancer centers, our folks in nutrition services, because they totally know how important it is for people to have access to nutritious food during their treatment. So, they're great allies, social work depending navigators, and community helpers depending on how the institution is structured. But it has not been hard for us to find champions at any of the sites that we've been at despite the space issues, etc. But we're super flexible. We make it work however we have to so that the site feels that it's value-added and that it's not interrupting their clinical flow.   Dr. Shannon Westin: This was great. Ladies, thank you so much for your expertise and for giving us some really, I think, concrete things that we could potentially do back in our institutions. And thank you to all of our listeners.   Again, we were discussing  ‘Food to Overcome Outcomes Disparities – A Randomized Control Trial of Food Insecurity Interventions to Improve Cancer Outcomes.’ published online in the Journal of Clinical Oncology on June 16th, 2022. We're so excited that you took the time to listen, please check out our other episodes and check back soon for a new episode of the podcast. Have a great one, y'all.   Dr. Francesca Gany: Thank you!   Dr. Theresa Hastert: Thank you.     The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.    

Dr. Shannon Westin discusses the topic of climate change in the operating room with Dr. Anaeze Offodile and Dr. Elizabeth Yates.   TRANSCRIPT   The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hey everybody! Welcome back to JCO After Hours, a podcast where we get a little bit more intense, a little bit more specific about articles that are published in the Journal of Clinical Oncology. My name is Shannon Westin, and it is my honor to serve as the social media editor for the JCO. I'm an associate professor at the University of Texas MD Anderson Cancer Center and a gynecologic oncologist. Today, we are going to be discussing a really exciting paper which was published in the March online JCO. It's a Comments and Controversies piece called, “Prescriptions for Mitigating Climate Change-Related Externalities in Cancer Care: A Surgeon's Perspective.” I have several guests with me today, none of whom have any conflict of interest. The first is Dr. Anaeze Offodile, who is an assistant professor in the Department of Plastic Surgery, as well as in the Department of Health Services Research at the University of Texas, MD Anderson Cancer Center. He also serves as the Executive Director of Clinical Transformation at MD Anderson. He is the senior author on the paper, so he will have a lot to offer here. But we're also accompanied by Dr. Elizabeth Yates, who has the title of clinical fellow in surgery at the Brigham and Women's Hospital in Boston, but tells me she's a rising PGY 4 resident, which makes it even more impressive that she is already published on the role of the surgeon in climate change. And so, we're so honored to have her with us today to share her perspectives as well. Welcome both of you. Thank you for being here. Dr. Anaeze Offodile: Happy to be here. Dr. Elizabeth Yates: Thanks so much for having us. Dr. Shannon Westin: So, I'm definitely someone that has been interested in climate change for some time, and living in the state of Texas, does what I can to rally the political climate here. But I was really intrigued because I never really thought of it in terms of what we do in the operating room. So, I'd love for each of you to give just a little bit of background on your careers and how you kind of got involved with this idea of climate change and environmental sustainability here in the operating room and in medical care? Do you want to start, Anaeze? Dr. Anaeze Offodile: Liz can start first. Dr. Elizabeth Yates: Absolutely! So, I actually came at it from an interesting perspective, I have always been interested in issues of resource distribution and disparities. And when I was in medical school, I started to think about these issues pretty deeply, especially because my younger brother was at the University of Michigan at the same time as I was, studying Environmental Science for his undergraduate and kept nagging in my ear about this problem of climate change and why I wasn't thinking about it as a doctor. And with my kind of ongoing interest in disparities, I came to realize and become compassionate about the role that climate change will play in driving the existing disparities that we see both nationally and globally. And I realized that nobody was really talking about it yet, at least in the surgical field. It had started to permeate some of the medicine and subspecialties, but really, there wasn't a conversation in our world yet. It became all the more relevant to me because I did see this dual relationship where not only do the downstream factors of climate change, like heat waves and major storms, impact our patients' access to care and their outcomes, but on the flip side, we contribute to climate change, because the delivery of surgical care, particularly in high-income countries, is so energy intensive and so wasteful. And so, I felt like if any clinician has a role in this space to really lead and change the narrative, it would be us as surgeons. Dr. Anaeze Offodile: It’s really interesting to listen to Liz’s journey to this issue, which affects all of us. I came at it from the micro level, bottom-up level. So, when I was a fellow about four years ago, under the mentorship of Nancy Perrier, we launched and have since scaled, I don't know if you're aware of this, Shannon, so the 'Know Your Costs' program. For the audience, this is a project at MD Anderson where we really try to minimize cost variability and waste in the operating room by providing a feedback tool to surgeons that sort of made them more conscious about the spending directly attributable to disposable supplies, implants, devices in the OR. One direct outcome of the project that we found was that actually narrowing the variability in these disposable instruments, supplies implants surely had no impact on the outcome, but also got sort of the cost structure of what we do in the OR down. So, that's the value-based care proposition. And in doing this work as I dug more into literature, I learned as we so highlighted in the article, my co-authors and I, that actually the perioperative environment is a major driver of waste in the hospital setting. I think that recognition certainly led to this work, which we're very glad that JCO looked upon favorably to champion. Dr. Shannon Westin: Yeah, I love 'Know Your Cost'. My fellows make fun of me, because I always take the electrosurgery devices, they're the cheapest. And they're like, ‘Oh, you're using the Costco version!’. And I'm like, ‘You know what? We're reducing costs. So, just hold it a little bit longer there, and you're gonna be fine.’ So, I was really struck by one of the first sentences out of the gate in your commentary that the healthcare industry accounts for roughly 8.5% of total GHG emissions in the United States, the most in the world in per-capita and absolute terms, I mean, to me, that was so eye-opening within the first few sentences. What are some of the other major takeaways that you hope that readers of the JCO get from this piece? Anaeze, I think we can start with you and then I'd be interested to hear your perspectives as well, Liz? Dr. Anaeze Offodile: So, I will say, a couple of high-level, and I can touch on the sort of specific prescription that we put forward, but I think the big takeaway is, one, is healthcare has a certain moral imperative to keep our contributions to sort of environmental sustainability, greenhouse gas emissions, to control that, there's a moral imperative to this work, right? One, climate change effects are differential. So, the vulnerable populations, like Liz said, tend to suffer the worst. So, when you think about communities and countries in the global south, they bear the brunt of this, not industrialized nations. And number two, our activity directly maps to greenhouse gas emissions. And as surgeons, the relationship is much more direct. So, carbon-intensive procedures like the robot, the perioperative environment, and the supplies, the waste, and the supply chain that sort of feeds into that. So, those are the things high-level that I want to call out. And many ways this paper is intended to start a conversation that will be ongoing amongst the community, the academy, and I'll say in both surgical and medical respect: to what extent do we take ownership of this problem and contribute to the meaningful solutions of the problems? And I can certainly talk about some of the recommendations we put forward, but I think that's the key takeaway. Dr. Elizabeth Yates: Yeah, as not an author, but a reader of this paper. I really thought it summarized the high-level ideas, and really did serve as a conversation starter in the best way. What I really liked, and I try to strive for in my own work at our hospital, and we implement sustainability initiatives, was the perspective that you took coming from more of a cost-saving perspective initially, because I think people have a misconception if they do ever think about sustainability and care delivery, that somehow quality has to be compromised for sustainability - to go green, you have to do less - and that's not necessarily true. And you really highlighted a lot of opportunities in the four domains you emphasize in this paper about how you can change the way your system works, or the choices you make, for the devices you use or the energy supply, without actually compromising outcomes for patients, that we can maintain a high level of quality that makes them smarter choices for our systems to also be more sustainable. And then a lot of the time there are cost savings. It could be a triple win but we just need to put more time and effort into the surgical world thinking about these issues. Dr. Anaeze Offodile: Liz, thank you so much. What we tried to articulate was, there is no trade-off between planetary health and value-based care and high-quality care. I think those two are actually synergistic, and certainly mutually reinforcing. So, that's the one thing we tried to do. I'm glad it came out to push forward. Dr. Shannon Westin: I was joking about our bipolar use and such, but that's really what I'm trying to teach our fellows is that you can do the right work with an instrument that doesn't cost as much. And in this case, the robot is perfect. I was reading that as a robotic surgeon who also does laparoscopy and I thought, ‘Gosh! When I'm making these decisions, this is such a trickle-down effect.’ And so, I really do think that I'm interested in strategies to offset those things. Because sometimes, for us in gynecologic oncology, the robot is a superior tool as far as visualization and also surgeon back pain and such. But you really have to understand that trade-off or what else you're impacting. So, I guess, what can we do with the framework of this piece in mind, what can the clinical care providers really do across the country to meaningfully address climate change and improve overall healthcare sustainability? Dr. Anaeze Offodile: So, I will talk from the surgical perspective and maybe I'll point to Liz for a broader outlook on this, but we touched on four main buckets or domains of sub-activity. So, one is the OR environment, right? Thinking about the type of anesthetic gasses that we use, thinking about energy efficient lighting, thinking about the heating ventilation AC, HVAC, can we sort of bake in preventative maintenance on a scheduled time, and using things called setbacks. So, for instance, don't have it run overnight when no one is using the OR. For the most part, there are always emergency cases, but when there's low foot traffic, like nighttime, could we not have the HVAC running during that time period. So, some things like I'll say, low hanging fruit that we can do in respect to the OR environment. And as we think about building new ORs in new hospitals, let's bake in sort of an environmental impact assessment as you sort of commissioned these new environments. So, that's one. Number two, the supply chain and thinking about streamlining the disposables, the gowns, the implants that we use, and really thinking about the procurement and sourcing of these things, taking a climate change lens to picking vendors, picking partners, almost sort of requesting an audit for these vendors with respect to how they create these goods that are sort of being engineered for the environment. The third thing is actually waste. And thinking about sort of the amount of waste that comes from the cost of surgical care – Can we lean more towards reusable as opposed to disposables? Can we think about reprocessing devices sort of like, the world is a circular economy now? Can we think about those types of initiatives with respect to waste? And the last two are value-based care, specifically thinking about low-value surgical care, really that's another way of saying activity that doesn't track to meaningful clinical outcomes. So, that activity, if we're to reframe it , creates carbon that worsens our greenhouse gas emissions, but doesn't track to any meaningful benefit to patients' society. So, low-value care, de-escalating that, or de-implementing that certainly could help with our greenhouse gas profile. And lastly, COVID has been a major force in functioning telemedicine. Can we think about telemedicine in a way that optimizes traffic, and transportation, while keeping cost structure down and thinking about greenhouse gas emissions? So, those are the four or five main elements that we've sort of proposed in our paper. I'll say pieces of this can be contextualized in a medical context. Waste can be put in the medical oncology lens as is virtual care, and as is low-value practices. So, that's how we thought about it for this paper. Dr. Elizabeth Yates: It really nicely summed up the categories of areas for implementation. So, I think I'll keep my comments focused, one, on what does it mean to actually implement that kind of work, and then scale back and what can we do, as you highlighted more broadly as clinicians. But as someone who's really started this work, and we initiated what we call 'Watching Our Waste' program across our procedural spaces at our hospital, and working with my mentor, Dr. Winn who’s a vascular surgeon has been really beneficial, because having a clinical voice start to push and champion these ideas, is really meaningful. And when it doesn't come from the administration or top down, it feels a lot more homegrown, and people accept it a lot more quickly on the clinical side, rather than an eco-green team being purely administrators and people who work behind desks. You know, having boots on the ground, saying that this is important, and champion ways to integrate it into our workflow without compromising efficiency or quality of care has been really meaningful. And for anyone who's starting these initiatives, I would say the gateway for anyone who wants to really tackle this, I would recommend a waste audit. Just start with your floor, your OR, whatever your clinical area practice is, your outpatient clinic, and see what kind of waste you make in a day. The efforts you put towards that in terms of meeting your environmental services people, meeting Environmental Affairs, going through the trash, understanding what your use of various supplies is, gives you so much information and such a strong foundation as an easy thing to do as a first step and you'll know where to go from there. It'll really guide your next steps. And as you scale out, and if you get more involved in this work, what I've come to find is the administrators are looking for a clinical voice. There's the policy being pushed at a national level, to start really looking at healthcare and its carbon emissions, and there isn't a lot of expertise, and making sure that this kind of effort and these policies and the implementation of more sustainable practices align with clinical care is a priority and a growing one at the hospital level. And they need clinical voices to actually understand how this is going to work and move this forward and in an effective way. So, if you're interested, I would just highlight that this is an opportune time to get involved. Dr. Anaeze Offodile: Can I make one somewhat controversial comment, I hope it’s not that controversial. You know, Shannon, as you think about the demographic shifts in the next 15 years, millennials will be the dominant healthcare workforce and the dominant patient population, right? And as you think about awareness, I will say, as you go down in the age levels, I'll say anxiety, apprehension, and more optimism increase as you go down. So, as this population ages into the workforce and the patient mix, I will reckon that they'll begin to demand more of these initiatives from their health systems, both, like I mentioned, first of all, the moral imperative, but also, as most hospitals are the biggest employers in most towns in this country. So, I think there'll be a clarion call that gets louder and louder and louder and louder. So, in many ways, I think beginning to think about these issues now is probably the way to go. And in many ways feels inevitable to me. Dr. Elizabeth Yates: There's some great data to back that up. If anyone's interested, the Yale Center - I have no affiliation, this is a purely altruistic endorsement - but the Yale Center for Climate Change Communication has really impressive data that completely backs up everything that Anaeze has just said, he couldn't be more spot on. Dr. Shannon Westin: So, we need to be focusing on this. And I guess, balancing on that kind of thinking of the upcoming generation, clinicians, and patients, is there an opportunity to build a career that is a balance between climate change and clinical care? Dr. Elizabeth Yates: I sure hope so! Dr. Shannon Westin: Liz, this is your thing, right? Dr. Elizabeth Yates: There better be! Dr. Shannon Westin: But how do we operationalize this better? Is this something that should be part of the medical school curriculum? Where can we make an impact? Obviously, you all are doing this great work, but how can we get beyond our centers? Dr. Elizabeth Yates: I think one of the things I've learned in my two, kind of, research years during my residency, and really focusing deeply on this topic, is that there's a real dearth of data-driven work in this space both on quantifying the impacts of climate change downstream on our patient outcomes. And on the flip side, how to make surgical care or medical care more sustainable broadly. There are methods that are incredibly applicable to this space. One that many sustainability providers will know about is called lifecycle analysis, where you can actually quantify your impact on carbon emissions with different changes in which products you buy, and how you implement your systems. And being able to produce that kind of data for our clinical providers, whether it be in your outpatient clinic, or in the OR, so you can make more informed choices that align quality with sustainability is a really important next step. And understanding how to implement that kind of research needs a clinical voice. It can't just be these kinds of environmental practitioners who don't have a sense of how clinical care works on a real day-to-day basis. So, having an increasing number of providers who are interested in this overlap to inform that research, I think, I sure hope, is going to be a valuable contribution to the academic literature because I'm slowly building my career upon it, and it's quite the gamble. Dr. Anaeze Offodile: No, it's a pretty safe bet, Liz. I think as a clinician, academic or community-based, late early career at this point, so the way I think about moving forward will be one, Liz just talk about scholarship, right? Both empirical data-driven work, as in thought pieces, like the JCO paper that has a policy inclination, I think we need much, much more of it. And there's increasing activity in this space, but nowhere near commensurate with the gravity of the problem. So, that's number one. I think number two is actually just advocacy, right? In the same way that surgeons are very compelling and effective advocates for gun violence, for COVID, and related science for health equity. I do think there's a huge space for physicians, surgeons, medical oncologists, and primary care doctors in this space from an advocacy standpoint. I think some of the more productive arguments have touched on the fact that, typically in healthcare, the largest employers, I mean, healthcare is, paid on the year, almost 20% of our GDP, of our economic output, is a huge chunk of US healthcare, so, we have viable legitimacy to sort of have this bully pulpit on this issue. That's number two. And number three is about clinical practice. I think one thing about climate change is the ultimate tragedy of the commons, right? So, I'm like, how can one person make a difference? I think if everyone has a position, nothing's going to happen. I think the key thing is that we all begin to move in this direction, as I like to say, ‘Incremental change is not insignificant change.’ There's certainly the proverbial 'burning platform' right now on this topic. I think as we begin to have our clinical practice, each of us individually be more aligned either from an adaptation standpoint or mitigation standpoint, where we're sort of reducing greenhouse gas emissions. I think that is a huge, huge benefit to us for future generations. So, let's hope with the three main ways practice, advocacy, and scholarship get built into our careers. Dr. Shannon Westin: Yeah, not to get into a total mentoring conversation here but Liz, there's a huge opportunity for policy and through our own home organization, ASCO, there's a policy fellowship, there are lots of opportunities that I think that you'll find your academic career could be supported by. So, just a little off note. Dr. Elizabeth Yates: I’ll preview the recruitment. Dr. Shannon Westin: So, we'll talk about some inspiration as we close this conversation. You guys have kind of peppered this throughout, but maybe just summarize a little bit, what are you doing in your own practice, as well as in your lives, like out of hospital lives to contribute to these efforts? Dr. Elizabeth Yates: I try to live my life with a perspective of sustainability kind of in every aspect, but with an informed perspective because I really do believe that quality of life, just like the quality of care, does not need to be compromised in order to be green. And so, being really informed about what choices in your life and your actual career have a true impact, and an impact that can scale is really important. So, do I try to buy the least plastic that I can? Certainly. Do I kill myself to be completely waste-free? I do not. I try to amplify the need for these kinds of interventions across my own little local network, both socially and wider in my own career. And as I've started to pull this into my workplace, I was apprehensive about what the kind of reaction was going to be from pushing a sustainability perspective. I've been really pleasantly surprised and impressed with how many people in our workplace already, like me, are doing what they can at home, and just don't know how to start in the workplace, especially in a hospital. And so, being that champion, and having that voice to start, wherever you are, whether it be a small project or a big policy initiative, whatever you can take on, I would say is kind of the inspirational next step and as you see the reaction of your colleagues, I hope, like me, you will continue to be inspired to do more. Dr. Shannon Westin: Great! Anaeze? Dr. Anaeze Offodile: So, I'll lead off with a plug. I read this book called The Uninhabitable Earth by David Wallace-Wells. And I thought that book is the most compelling argument that we just think about climate change. It really created a sense of urgency within me. It came out about two and a half, maybe three years ago – compelling read. So, I'll just sort of start off with that. There are many sources that are available now, I think the National Academy of Medicine, they have a grand challenge and a national collaboration on decarbonizing the US healthcare sector, and they have a bunch of resources on their website. So, I'll certainly point many people to that. What I do in my day-to-day life and the way I've thought about this is what behaviors can I entrench in the long term. I think human beings, physicians, in particular, I'd say, we're high resistance pathways, old habits tend to come back to the surface. So, I've really focused in the last few years on embedding certain climate-sensitive practices in my life that I hope to continue moving forward. So, one of them is a) I drive less. Now, it's not super easy in Houston, Shannon, as you are aware, but I happen to live near the light rail. And for the last nine months, I've been taking the train in, every morning to work to and fro. That allows me to zone out. I put a podcast on, ASCO podcast, After Hours. Dr. Shannon Westin: Love it! Love it! Dr. Anaeze Offodile: So, that's one. Number two is just easy. My purchasing choices have a climate lens. So, in many ways, you could say what you buy reveals your preferences like nothing else. So, when I buy a new radio or a new TV, I look for the sticker that says EPA certified. It's a little thing but it's something that I'm able to maintain for the last 2-3 years now. So, I'll say, being informed, changing my commuting habits, I curtail my spending habits, also like the ways I'm just really embedding this into my daily life. Dr. Shannon Westin: That's great! I think there are so many great resources that you guys have mentioned, so, I hope our listeners will check it out. I will put a plug in. I love to compost. It’s super easy to do, and you can use it to grow food and beautiful flowers. And so, that is something that my husband and I have been doing for years now. So, another simple little thing. I mean, you can get everything online. It's magical. So, alright guys. Well, this has been incredible. I have so enjoyed getting to chat with both of you and I hope our listeners have the same feeling. Just as a reminder, this article can be found online in the March version of the JCO, “Prescriptions for Mitigating Climate Change-Related Externalities in Cancer Care: A Surgeon's Perspective.” Many thanks to my guests, and you all have a great day. I hope to see you next time. Dr. Anaeze Offodile: I’m happy to be here. Thank you so much for having us. Dr. Elizabeth Yates: Thank you so much!   The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product service, organization, activity, or therapy should not be construed as an ASCO endorsement.    

Shannon Westin, Veena Shankaran, and Scott Ramsey discuss the issue of financial toxicity among low- and middle-income cancer patients.   TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Westin: Welcome to JCO After Hours. I am your fearless leader, Shannon Westin, the editor for social media of the Journal of Clinical Oncology, and it's my great pleasure to bring you another episode. Today, we are going to be talking about a paper published in the January 7th version of the JCO called “Risk of Adverse Financial Events in Cancer Patients: Evidence From a Novel Linkage Between Cancer Registry and Credit Records.” And none of the participants have any conflicts of interest. I am joined by two amazing people. First, let me introduce Dr. Veena Shankaran. She is a physician in the Seattle Cancer Care Alliance, professor in the Division of Medical Oncology at the University of Washington School of Medicine, and co-director of the Hutchinson Institute for Cancer Outcomes Research at Fred Hutch Cancer Research Center. Hey, welcome. Dr. Shankaran: Hi, Shannon. Thanks for having me. Dr. Westin: I'm so excited to have you. And she's joined by her colleague, Dr. Scott Ramsey, who is a professor in the cancer prevention program in the Public Health Sciences Division at Fred Hutch and the director of the Hutchinson Institute for Cancer Outcomes Research at Fred Hutch. Welcome, Dr. Ramsey. Dr. Ramsey: Shannon, great to be here. Dr. Westin: This is such an exciting paper and so very timely. We've been certainly hearing—I wouldn't say a lot but more and more about financial toxicity over the last few years, I'd say very appropriately. So, let's start with the basics. Let's make sure we level set. Can you educate our listeners on what financial toxicity is and what it means for patients with cancer? Dr. Shankaran: Yeah, absolutely. I can start. Financial toxicity, I think, is a relatively recently recognized complication, if you will, of cancer treatments. And really, I would say over the last decade or so, the literature has just sort of exploded describing kind of the various aspects of this big problem. I think one conceptual model that sort of helps me understand financial toxicity was developed by Robin Yabroff and Reggie Tucker-Seeley that really describes financial toxicity is that trifecta of material, financial hardship, kind of what we think of as out-of-pocket expenses, debt, the money that you pay to get cancer care. The other aspect is sort of the indirect coping mechanisms related to the cost of cancer care, like forgoing treatment, forgoing surveillance, cutting back on treatment-related cost concerns. So, more of the behavioral aspects. The final aspect is sort of the psychosocial-psychological aspect of financial hardship, which is really just the distress related to how am I going to pay for all of this? How is this going to affect my children and sort of our financial well-being? It's a big problem, a broad problem that touches on a variety of issues and also affects families and caregivers too. Dr. Ramsey: I would add that financial toxicity really got into the literature probably seven or eight years ago. The term itself was coined by an oncologist, Yousuf Zafar, at Duke University. He told me he actually heard it from a patient who, when he was describing all the toxicities of cancer treatments, the patient said, ”Well, don't forget financial toxicity.” And so, that's how the term, according to Yousuf, was coined. He published a series of case reports on patients who experienced financial toxicity. And our group did a study where we linked federal bankruptcy records to the cancer registry and found about a 65% higher risk of bankruptcy among cancer patients. We also did a subsequent paper looking at mortality among cancer patients who went bankrupt compared to cancer patients who did not and found excess mortality. So, we do have evidence that severe financial toxicity, i.e. bankruptcy can actually affect survival. And now, since that time, there have been other papers that have looked at quality of life, adherence to therapy and have found those as adverse impacts as well. Dr. Westin: Well, that makes sense when you're looking at that trifecta. I hadn't heard that. That was really educational for me. But looking at the ways that patients cope with this issue and actually foregoing their cancer treatment. And I think I've certainly heard about that in terms of like diabetics, like maybe taking their insulin every other day versus every day. You could see where we would see something similar in a patient with cancer. Do we have any data to know how common this is across our patients with cancer? Are there specific cancers where we see this more commonly, or is this kind of every cancer type is at risk? Dr. Shankaran: The non-adherence aspect? Yeah, I mean, I think in the studies that we've done, it hasn't been reported terribly commonly by patients. So, probably on the order of 7 to 10% of patients in the studies that we've done, though you have to imagine it's much, much more common and prevalent, particularly in cancers where people are taking oral cancer therapies, and these tend to be associated with a lot of high out-of-pocket costs, these drugs that go through the prescription plans. Actually, I mention a few papers that have been published over the years by Stacie Dusetzina, who's a wonderful colleague of ours, who's looked at how changes in copay, not even by a lot of money, but just slight increases in copays for these oral cancer medicines can significantly impact not only adherence to prescriptions that have been built, but whether or not people actually fill their prescriptions. Dr. Westin: Wow, that makes sense. So, what led you all to this particular work that's described in the paper in the JCO? Dr. Ramsey: As I mentioned, we had this bankruptcy study where we linked federal bankruptcy—and bankruptcy is an extreme form of adverse financial outcome. And I think our interest was, well, what happens with less extreme forms of adverse financial outcomes. And that led us, I think, to search for ways to characterize less severe forms, and Veena and I have done surveys over the years where we've asked patients, but it's very hard to define something that's on a population-wide level. So, we came to this idea of using credit report data and that led to a very long journey—I think it was about a two-year journey—to get one of the credit reporting agencies to agree to allow us to link their database with the cancer registry in our state. Dr. Shankaran: I always laugh when we talked about the study, because I feel like we've spent years—I mean, two years might be right, Scott, but in my head, it feels like closer to a decade—just trying to make this happen, because it was a long process trying to link the credit records to the cancer registry data. And to add to what Scott already said, part of our motivation for doing this is that there have been a lot of studies that have used survey-level data and where we've asked patients to describe what their financial burden is, and it's substantial. Sunny reports anywhere from 30 to 75% of cancer patients report financial hardship. These surveys, they're subject to interpretation, whether patients understand the question being asked. There's bias in terms of who participates in a study in the first place. And so, our feeling was, can we be a little bit more methodical in trying to understand what the impact is and looking at measures that—almost everyone has access to credit on some level or the other. So, it's a very kind of standard way of looking at people's financial status to use credit data. So, that was our goal in trying to understand, as Scott said, at a population level, what is the impact? Dr. Westin: One, that's brilliant, and that makes total sense. And anytime you can get population-level data, as opposed to the kind of trying to get people to answer questions and give you details, is always ideal. But I loved your aside about the two-year process because we have trainees listen to this or young investigators, and it's always good for them to understand sometimes the amount of time that can come—and this is obviously a really high-impact paper and so important, but even when we're doing just simple retrospective studies, the amount of time sometimes that goes into it, I love that kind of background, just to tell people it's okay if it takes a long time. It's still going to have an impact and still going to be important. That's a great segue into just really a review of some of the methods that you used for the study, what were your primary outcomes, and how you laid everything out. Dr. Shankaran: Yeah, so we essentially went to the credit agency—TransUnion, in this case—and asked them to provide us with a long list of credit attributes that we were able to link with the cancer registry. And there were many, many items that they gave us of credit data, of which we went through them all and really tried to understand the financial literature, the landscape of what credit measures are important, what indicates kind of this spiraling down towards bankruptcy, what happens first, what happens next? And so, with a lot of guidance from the economic literature and the folks from the credit agencies, we defined three categories of financial hardship that we looked at. The first one was what we categorized as severe financial hardship, which we described as inability to pay the bills as evidenced by third-party collections or charge-offs, which are basically kind of like collections where it's not worth it to the creditor to actually collect on it. The next is the kind of more of the impacts on or events that suggests potential action against a person's property. So, tax liens, delinquent mortgage payments, on to the most severe kinds of financial hardships, actually losing a home through foreclosure or repossession by the bank. And so, we took individuals with cancer, matched them by age and sex to individuals without cancer, and essentially looked to see how common these events were in the cancer population versus the non-cancer population, and then controlling for confounding factors that could also influence this association between cancer diagnosis and financial hardship. We found that cancer patients had a significantly higher, 71% greater risk of adverse financial events than individuals without cancer. Dr. Westin: That's so interesting and then can you take us through the bottom line of what y'all found? Dr. Shankaran: Well, the bottom line is that when you take people with cancer and similar people without cancer, cancer diagnosis has a significant impact on risk for major credit events that are likely to have, we think, long-term impacts on people's financial health. And that's a problem, and this does not seem right, and it should not happen that people who develop a disease, for the most part, no fault of their own. I mean, this is a major health shock that leads to potentially severe and long-term effects on people's financial health. Dr. Ramsey: And overall, the excess risk for any of these adverse financial outcomes was about 71% higher for the cancer patients compared to the non-cancer patients. Dr. Westin: Wow. That's an incredible number. I read your paper, but still hearing it just is incredible. So, what can we do? What recourse do we have here? How can we help support these patients? Dr. Shankaran: Well, I think you touched on this a little bit earlier, Shannon, which is that, how do we screen people for financial risk in the first place? How can we identify those who are most likely to develop these adverse events? I wouldn't say that screening everyone's credit score and credit status is really feasible at the clinic level, but our hope is to use these data along with other studies we've done to see if we can develop risk scores to try and predict those who would be most likely for these kinds of severe credit impacts. I think, in addition to screening, what we're really thinking about a lot, and I'll let Scott add to this in a second, but is what can we do at the clinic level to help avoid financial hardship. And we've been doing a lot of work on developing financial navigation interventions, which is essentially kind of like patient navigation, where you're trying to get people to their appointments and get them there on time, but really instead of navigating the logistics, navigating more of the financial aspects. So, hooking them up with resources for copay assistance or lodging, transportation, in the hopes that kind of comprehensively addressing all the financial aspects of care can help, ultimately, people stay on treatment and live better, have better outcomes. Dr. Ramsey: Yeah, and I'd add that I think the immediate things that we can do for patients—Veena outlined very well—screening people to find out people who are financially fragile, getting those folks to financial counseling services so that they can adjust their spending and saving so that they can withstand what could be months or years of excess costs due to cancer. It's worth noting that a lot of people don't choose to enter cancer, and they come with the financial situation they have, and some are well off, and some are very tenuous. And in order to prevent people getting into a disastrous situation, having someone look at their current situation is critical, and we've worked with a bankruptcy judge who says often it's the people that are kind of in the low or middle income that are at the biggest risk for falling because they have expenses that we all have, cable bills and car payments and everything else. And they don't think about adjusting those when they have cancer because they don't think this is going to be an issue, and pretty soon the added expense of paying for cancer care and the loss of work and the caregiving needs pile on to all the other expenses, and before they realize it, they're in serious trouble. It's much harder to get out of trouble at that point than to try to adjust your expenses to accommodate what's going to be a long journey for many people with cancer. Dr. Westin: What about more globally? I think that you addressed kind of at the clinic level. What about from an advocacy standpoint? Drug charges are the elephant in the room here, right? And I think one of you mentioned copays. I feel like we do quite a bit of targeted therapy in GYN oncology with PARP inhibitors and now lenvatinib and pembrolizumab, and it's just such a wide range. I have patients that have $0 copays and patients that it's going to be $2000 dollars a month or even more. So, how do we level that? And how can we advocate to our lawmakers to try to reduce the bonkers costs right now of targeted therapies and novel drugs in America? Dr. Ramsey: Well, I think it'd be easy to blame the pharma companies and the high price of drugs, but it really is a multifaceted problem. And I personally think we do need to have some policy discussions about what we can do to address this because it's so prevalent. I should add that it goes beyond cancer.  People with other chronic diseases surely suffer the same problem. But yes, the drugs are very expensive. But there’s also the insurance plans have copay and deductible structures that really are beyond the means of many Americans. I mean, as we mentioned, in the paper, a federal reserve study found that only 40% of US households could afford a $400 unexpected bill in their average life. And we know that's going to happen in probably the first week of a cancer diagnosis or more. So, I think the insurance needs to be restructured to address the fact that people can't afford the out-of-pocket costs that are part of the insurance system right now. I also think physicians need to have some role in this. Most of us don't prescribe thinking about the cost and its impact. In situations where there is an option between different regimens, one which would have a bigger out-of-pocket burden and one would have less, if we know the patient's financially fragile and the outcomes are similar, it's worth having that conversation to try to protect our patients. So, yes, the prices of drugs, we need to address that, but we also need to address insurance coverage. And as providers, we need to be mindful of what we're prescribing and how that impacts patients. Dr. Shankaran: I'll just add to what Scott said. I think one of the key things that we need in order to accomplish that goal of trying to be mindful about what we're prescribing is understanding what the costs are. So, there's very little cost transparency. You probably can't tell your patients that you treat how much the drug is going to cost them until you run it through the billing coordinator or people try and pick up the medication at the pharmacy or the bill comes to their house. So, we have not good strategies in place to be able to identify the cost in real-time and also the cost of alternatives. So, it's only helpful that we can adjust our decisions and include cost information in the shared decision-making process so long as we actually have that information. So, I think that's kind of part of the problem. I totally agree with everything Scott said, and will just add the way insurance works is that you pay more for things that are expensive for the most part, and you reach a cap at some point, which is one of the many good things that came out of the Affordable Care Act is that there are at least limits on how much you can spend over the course of a year for most insurance plans. But that limit is around $13,000 for a family over the course of a year. And given what Scott just said about how much liquid cash that most households have—it's $400 or less in most households in America—that's going to be really hard for most people to cope with. Dr. Westin: Well, thank you both. That went by so fast, and I really appreciate how in-depth you were able to get in a really accessible way, especially for somebody like me, who is just a novice at this and actually has been known to say, “I'm blissfully unaware of the cost of that,” which now I'm thoroughly chastened and will work very hard to expand my understanding so that my patients are in a better situation. So, thank you both for all of your hard work in this area. Really, really appreciate everything you've done and can't wait to see what comes next. And with that, I think we'll close this episode of JCO After Hours. Thanks to all our listeners, and we will see you next time.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Shannon Westin and Virginia Sun discuss the JCO article "Patient-Reported Outcome-Based Symptom Management Versus Usual Care After Lung Cancer Surgery: A Multicenter Randomized Controlled Trial"   TRANSCRIPT Speaker 1: The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello everyone. This is Dr. Shannon Westin, your JCO Social Media Editor here with another episode of Journal Clinical of Oncology After Hours Podcast. So excited to bring you in depth discussion on some of the amazing studies and manuscripts that have been published in the JCO. I am joined today by Dr. Virginia Sun, who's Associate Professor in the Division of Nursing Research and Education and the Department of Population Sciences Education at City of Hope. Dr. Shannon Westin: She has 17 years experiences as an oncology nurse, four years experience as a nurse practitioner, before becoming a full-time nurse scientist. And her research program is meant to develop and test interventions to improve patient and family-centered care and outcomes, specifically on cancer surgery and cancer survivorship populations. And what better person to have with us today as we're discussing the article, Patient Reported Outcome Based Symptom Management Versus Usual Care After Lung Cancer Surgery, a multi-center randomized control trial by Dr. Dye and colleagues. So welcome, Dr. Sun. So excited to chat with you today. Dr. Virginia Sun: Thank you so much for the opportunity to be here. Dr. Shannon Westin: So let's get right into it. I think this article caught several of the editors' attention, because it really is an exciting [inaudible 00:01:42] into how we might take care of patients after surgery. And as a surgeon myself, I was completely intrigued so I can't wait to get your perspective. So let's start off first, the author's note that patients with lung cancer have a high symptom burden after surgery, as a non lung cancer expert, can you walk those of us through a typical post op course and some of the issues that might be experienced by these patients? Dr. Virginia Sun: Sure. So, I think symptoms is something that probably all of our patients who just underwent surgery experience. But for our patients with lung cancer, some of the common symptoms would include pain. I think pain is one of those universal symptoms that many of our patients experience after a procedure. But particularly for this population, they would also experience shortness of breath, of course, because anatomically there were certain parts of their lung that were removed as part of the procedure. Dr. Virginia Sun: Cough is something that they would experience regularly as well. And I think sleep disturbance is one of those general symptoms that all of our patients may experience. And also just emotionally, the anxiety perhaps, and the stress may continue probably in the immediate post op timeframe when they just transition home. And then also the functional decline, also happening along with the fatigue. Many of our patients, although we get them up and out of bed as soon as possible, as a nurse, I know that's generally sort of our responsibility in the post-op recovery period. Certainly fatigue and the functional decline is something that our patients will experience in this population as well. Dr. Shannon Westin: Certainly many of those are universal across what we see in patients in the postoperative period. But I know personally, and I'm sure you could speak to this as well, we're busy post op, right? Especially whether you're rounding in the hospital, or you're seeing patients in post op in the clinic, I don't know how much we really get super deep dive into a lot of these symptoms. So I think that's what makes this work so important. So I'll just have you, if you could, briefly discuss this study design that was performed by Dr. Dye, and Dr. She, and their colleagues. Dr. Virginia Sun: Sure. So the intervention is really patient report outcome based symptom management. And this is done by way of alerts and completion of the MD Anderson Symptom Inventory, which is very well known symptom inventory tool well validated within this population as well. And also when patients share that information after surgery, and while they're recovering in the hospital, that will prompt an alert. So there were predetermined thresholds by way of the symptom score. So if a patient on the trial that reported a four to 10, which is generally a moderate to severe intensity for a symptom, and that will trigger an alert to the surgeon and the surgical team for management purposes. Dr. Virginia Sun: Now, in terms of this trial, the investigators chose several very relevant symptoms to focus on for this population to assess. And that would include pain, fatigue, cough, shortness of breath, and sleep disturbance, although the MD Anderson's Symptom Inventory does cover more of symptoms and beyond those as well. And in addition, I think, to the surgeons in response to the alerts, there were also other management, I think, that were triggered from the alert itself. So there may have been other services that were triggered as part of the intervention. But the first line of response to the alert were from the surgeons for this particular trial. Dr. Virginia Sun: So the patients after they were discharged home continued to provide, I believe, twice weekly symptom information by way of completing the MD Anderson Symptom Inventory. These are all done electronically, and then the alerts I think were continued. And this was done up to four weeks post discharge. And they also did include on data that's collected in the pre-op setting, I think, one baseline, and then after post-op there were several data collection time points. In the hospitalization period I believe it was a daily symptom report, and then after they return home in the first four weeks, it's I think twice a week. Dr. Shannon Westin: I think it's perfect to have a way to automatically alert the surgeon and their team. Because again if we just don't have time to engage on that level with the patients on.... Can you imagine every day your team having to call? Just the amount of operationalizing that that would take, it would just be bonkers. And so I love this because I'm already kind of thinking tick, tick, tick in my mind, "Okay, how would I incorporate this to the patients of mine that are in the postop setting?" So tell us, should I do that? What are the benefits of incorporating patient reported outcomes into the post op care? And then of course, were there any negatives to the strategy? Dr. Virginia Sun: Sure. I think we have quite a bit of evidence now by way of patient report outcomes guided management. This was done in many different settings, I think primarily starting in the chemotherapy setting, but now more and more in the surgery population as well. And so I think first and foremost, it's a great way to make care more patient centered, right? Everything is driven by the patient's needs. And everyone may be presenting different symptoms at the same time, even though there are common symptoms that we may see from patients with lung cancer after surgery. But it makes it really personalized and relevant to each of the individual patients. Dr. Virginia Sun: Another way I think about it is sort of the proactive versus reactive approach of postoperative care. In most settings, perhaps, I don't want to say all, but certainly in most settings our approach to postoperative management, while the patients are at home and in the community, I think are more largely reactive. So most of the time we may... We have information that we give to patients, "If you are having any symptoms, or you're meeting any of these criteria where you have a fever or anything like that, please call us." And many institutions may have a phone number that patients can contact during business hours or after hours. Dr. Virginia Sun: But this approach gives patient an opportunity and places to contact us when they're experiencing challenges. But it relies on the patients, right? So it's still the patients who need to remember that, "Oh, I need to call when I have these things." In most situations unfortunately, it may be a little too late. We may get a phone call from patients or families when it's kind of at a crisis mode and we need to bring them in or they need to be you readmitted. So I think the patient reported outcomes approach to me is more of a proactive way. Dr. Virginia Sun: The patients share their information with us at certain time points, during the perioperative setting or postoperative setting. And the healthcare team and oncology team, the surgical team, somebody on that team is the one who is monitoring or getting the alerts from this team, and then we proactively contact the patients to perhaps assess and manage. So I think another way that I kind of tend to look at it is that, the responsibility is really on the healthcare team to sort of act on the patient's information rather than sort of more of the reactive approach, where we wait for patients to call us when they're having pain issues, when they're having sleep disturbance issues, or shortness of breath issues. By that, it kind of makes also for a more patient centered approach too that patients have a way communicate with us and they know that someone is on the other end that will be reacting. Dr. Shannon Westin: Well, and I think some of the symptoms that you're covering, I feel like patients will call for, "Oh, gosh, I'm really short of breath, or my pain is uncontrolled." People feel really comfortable with that. But some of the other things like, "Well, I'm not sleeping that well," or some of the other things that could be precautious to a worse issue, exactly to your point, they may not call early on, and then you get behind the eight ball and you're in a really serious situation. Dr. Shannon Westin: So I do. I like this and I like that they know, "Okay, there's someone on the other end of this. I'm not just shouting my issues out into the ether. Someone is going to hear this and respond." And then conversely, the care team is prepared. They know, "Okay, these are coming in and these are the triggers. These are the thresholds at which we're going to mobilize what. Okay, we're going to get pulmonology involved for this, so we're going to bring the patient into clinic to have them look at a wound," or whatever. I think to me, this makes so much sense. Do you see any negative? How's the burden on the patient, I guess, is one obvious question. Dr. Virginia Sun: From this trial, we see that the investigators did assess and try to examine sort of the burden on both the patients, and I believe the surgical team as well. And the patients were very favorable in their response in terms of the system, because it's another way for them to communicate with the care team. Especially for our surgery patients who were before surgery at home, right? There may be had been some visits, but they're mainly out of the community, and in the home setting. And then of course, when they're discharged after. Dr. Virginia Sun: So one of the things I think we should think about is, this is of course.... And this is a great study but it's done in, I would think, a different healthcare system. So this is a study out of China. And so is it replicable, perhaps, within the United States Healthcare System, where there may be differences in terms of when we get patients into the OR versus sort of the care that's provided after. And who will be monitoring this information? It's great to see that the surgeons, and I think the data from this trial shows that on average, it took them three minutes to manage some of the symptom alerts, which is great. Three minutes, it's actually really, really amazingly quick, right? Dr. Shannon Westin: That's incredible for that. Dr. Virginia Sun: I know. Dr. Shannon Westin: Well, which Is great. Dr. Virginia Sun: But is it possible for example, within a healthcare system in the United States? And of course within the United States different healthcare systems have different systems too. And so it's identifying who are the people that are going to be receiving this information, and then are there resources for them to be able to react in a timely fashion? And then communication processes in place with the surgeon and the surgical team, if there is a need. Because I think that would be helpful in terms of these types of information, these types of trials, being helpful for surgeons in surgical teams to make decisions about care. Should we be bringing the patient in a little bit earlier, for example, for the first post-op visit or do we need to see them a little bit more often? Dr. Virginia Sun: The other thing I think that would be very important for us to think about, is the digital health and the digital technology disparities. Technology is great. Being able to capture symptoms in a remote fashion electronically and in a relatively quick fashion is great. But we also, I think, need to be mindful of the fact that, what is the comfort in terms of using these kind of programs and devices, and does everyone have access to this? During the pandemic we've heard a lot about Telehealth. We use Telehealth quite often. And Telehealth has great potential. But Telehealth and digital health can also create disparities. And so, I think we just need to be mindful of the population. And perhaps be mindful of the fact that not all patients and families will come with the knowledge in relation to using mobile applications, or technology based programs. And just have those support systems in place, so that we can make things at equitable, right? And that everyone will be able to access these kind of systems to communicate with their surgical team. Dr. Shannon Westin: That's a great point. And I could see something around the fact that for the patient population that maybe doesn't have the devices necessary, needing to kind of lend out devices to the patients, and make sure that the nursing staff or medical assistance can counsel the patients. Then they should walk them through the process. So yeah, I could see where that would be a place where making sure that it was generalizable to the population here and equitable will be essential. The other thing, and this may be completely off base is, for us and I think for you all as well, we use quite a bit of enhanced recovery. We have a pretty elaborate enhanced recovery program request. Really all of our surgical services. And I noticed that wasn't something that was mentioned in this particular article. I don't know if that's something that they were doing. Do you think that that would have an impact in any way on these findings, or if there's a way to incorporate this into some type of enhanced recovery pathway? Dr. Virginia Sun: I think definitely. Perhaps the more long-term, if there is a need to do more long-term remote monitoring when patients are out in the community, or more frequent timeframes in terms of follow up. A lot of this work can also be thinking about what does the data mean? And how can this data not only drive sort of the symptom management piece, but is there a way for us to utilize this data perhaps at the very beginning, as part of that ERAS program, right? In terms of being able to identify those who may need a little bit more communication, or monitoring after they're discharged home. So I don't see this as replacing the ERAS program, I see it as something that could potentially enhance, and perhaps really be able to bring in that program and that approach where we are able to see what's happening to our patients when they're in the community, or at home while they're recovering. So I see it as an augmenting rather than a replacement, if you will. Dr. Shannon Westin: Well, and I think that's really how enhanced recovery has been. I feel like when we first started, we had some of the basics and then we added on, "Okay, let's reduce opioids and let's send less opiates home. And okay, we're going to inject the incision." So I feel like that's what's great about that pathway is you can keep kind of adding to it. And I guess that leads to my final question. I can't believe how quickly time has passed. This discussion went fun. What do you think ultimately this study is going to mean for clinical practice? Do you think this is ready for Prime Time or kind of what are next steps for us here in the states, or our colleagues in Europe? Is this something that we can start doing? Dr. Virginia Sun: Sure. Great question. So I think definitely there's pretty strong evidence now within oncology care that remote monitoring, whether it's symptoms and other approaches, definitely has a benefit. Our patients appreciate the opportunity to communicate with their care team this way. And it's beneficial for the clinical team as well to understand what's happening to our patients out in the communities, and especially for surgery patients, when they're recovering. In terms of whether it's ready for Prime Time, I think we definitely need to maybe replicate a trial like this within the United States or a European healthcare system, and really be able to understand who are the key stakeholders in this process, right? The patients, the surgeons, the surgical team, or nurses, or other team members that are going to either be monitoring this data or benefit from the data that's being collected from patients in terms of guiding the clinical care. Dr. Virginia Sun: I think it would be important to understand the processes a little bit better in terms of who's responding, and then what happened during these encounters? For example. What are the things that we're hearing from patients? So that within a system or within an institution, we can understand what are the resources needed to have a program like this take place, but also understand more from the patient and the surgeon, surgical team perspective, in terms of how this could benefit care. Dr. Virginia Sun: And then also I think the other piece, I think would be important for us to think about is, beyond symptom monitoring, are there other, perhaps, information that would be worthwhile to remote monitor or collect from patients? For example, for surgical population, perhaps functional recovery is something that is quite important. And so is there some other data that we could incorporate beyond sort of the subjective reports? Which are very important, but is there a way perhaps to think about subjective and objective measures combined together? And really be able to understand what it means in terms of the data that we're collecting. Dr. Virginia Sun: And then also, what types of symptoms data, for example, and other kinds of data that we absolutely should collect versus everything under the sun, right? That is going to be most helpful in terms of informing care for our patients. This is because by way of thinking about burden, we can collect data. I think the technology's there to collect data as much as possible, but how we use it and what does that data mean, we still need to understand a lot of that work. And so I think bottom line, no doubt, this is something that's beneficial from the patient's perspective, and the cancer care delivery surgical team perspective as well. But understanding a little bit more about the stakeholders' perspectives and the details of the care, I think, will make it much more efficient and more successful, perhaps, in terms of implementing into standard of care. Dr. Shannon Westin: Great. Wow. Well, thank you so much. This was an awesome discussion and I know our listeners will be intrigued and hopefully are planning some trials of their own to explore these patient reported outcomes. So, listeners, thank you so much again for tuning in to JCO After Hours, and we will see you again next time. Speaker 1: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.  

Dr. Shannon Westin and Dr. Antonio Di Meglio discuss the issue of fatigue among cancer survivors.   Transcript [MUSIC PLAYING] Speaker 1: The guest on this podcast episode has no disclosures to declare. Shannon Westin (Dr. Westin): Hello, everyone. And welcome to another episode of JCO After Hours. This is our podcast where we get in depth with different authors and experts about wonderful manuscripts that are being published in the Journal of Clinical Oncology. And today it is my great pleasure to be accompanied by Dr. Antonio Di Meglio, who is a Medical Oncologist and a Physician Scientist at the Breast Cancer Survivorship Research Program in Gustave Roussy in France. So welcome, Dr. Di Meglio. Dr. Antonio Di Meglio (Dr. Di Meglio): Thank you so much for having me here today. Dr. Westin: We're so excited to have you. We're going to be talking about your article, which is due to be published January 21, 2022, in the Journal of Clinical Oncology titled “The Development and Validation of a Predictive Model of Severe Fatigue After Breast Cancer Diagnosis: Toward a Personalized Framework in Survivorship Care.” And before we get started, I would just note that none of the guests have any relevant conflicts to disclose. With that, let's get into it. I was so excited to read this paper because this such a critical problem for our patients. And I'm a gynecologic oncologist, but this goes across all—surgical, medical, any field that we could even think of. So why don't you start off by telling us what led you to explore the problem of cancer-related fatigue? Dr. Di Meglio: Cancer related fatigue is one of the most troublesome and prevalent symptoms among cancer survivors and including breast cancer survivors. So several reports reported on the prevalence of cancer-related fatigue reporting up to 50% of patients in some studies with fatigue after cancer and the end of treatment. But what we know is that at least one in three cancer survivors experience fatigue symptoms at some point over time. In addition, we do know that fatigue is particularly distressing and impactful as it can impact on daily living and functioning and overall quality of life. Also, there's an important impact on social function and return to work after cancer and adherence to oral therapies, especially in the age event setting in breast cancer survivors. Finally, we also know that fatigue is often inadequately addressed and often neglected because of lack of time, lack of resources. Definitely, we should do more in the clinic for our patients struggling with fatigue. Dr. Westin: This is such an important issue. I think the elephant in the room here is how do we grade this and how do you advocate for a busy clinician in the clinic seeing 30, 40, 50 patients in a day. How do we really assess this? What's the best way to determine if somebody has cancer-related fatigue or is at risk? Dr. Di Meglio: Thank you for this important point. In clinical research, we do have a number of instruments that we can use to grade fatigue, including the European Organization For Research and Treatment of Cancer, Quality of Life Questionnaires that are the questionnaires that we used in our study. These are instruments that our patient reported. So we really can hear patient voices and patient perspectives in terms of their own symptoms. And some of the items that we use, for example, for cancer-related peak do not take much time to be asked also in a basic clinic. For example, we did use the EORTC QLQ Questionnaire C30 to score global fatigue. So we basically asked patient three questions: whether they needed to rest, they felt weak, or they felt tired, typical week. And these gave us the score of what we called global fatigue. There's also other instruments and companion models that we can use to assess more specifically dimensions of fatigue, including the physical, emotional, and cognitive dimension of fatigue. It is true that in our busy day in clinics, this may not be easily implementable. But what I believe is that if we never ask patients the right questions, patients will never tell us the right answers that we can proactively use to address the symptoms. So even just assessing fatigue in a general way, asking whether their energy levels changed over the past weeks, if they know that any change that was related to the treatment or any tiredness that was not really related to their usual activities or that was impactful on daily activities, this should trigger clinicians to ask more and more and to find solutions for the problem. So just ask the questions, even though the assessment may not be comprehensive and extensive, but this can be very important and meaningful for the patients. Dr. Westin: I think that's a really critical point because using validated instruments is obviously our aspirational goal and our attempted standard of care, but on a day in and day out clinic, it can be hard to have patients filling out a survey or something that may take a longer time. So I think that's a critical point is pull out these critical questions so that you can identify these issues and address them for your patient. When we're talking about grading fatigue, say in the clinic, would you recommend maybe choosing one? How long do these types of assessments take? Is this something feasible for a busy oncologist in clinic? Dr. Di Meglio: So definitely our study calls a little bit for the implementation of these instruments that are being used in mostly in clinical research over the past decades, also in the clinical practice. These are patient reported instruments that really can give us a sense of how impactful fatigue is in daily living and functionality. And when we grade fatigue using this instruments such as the EORTC scores, we can really capture fatigue that is defined as severe, meaning fatigue that really impacts on quality of life and needs to be absolutely addressed by clinicians and needs interventions urgently. Dr. Westin: That makes a lot of sense. Why don't we get into a little bit more around your study using these specific instruments? Like what was the patient population? Run us through that. Dr. Di Meglio: So this study was performed using CANTO data. CANTO is a longitudinal cohort of breast cancer survivors. Patients that were initially diagnosed with Stage 1, 2, and 3 breast cancer. It's a French cohort that enrolled patients across 26 centers in France starting in 2012. And at this point, the cohorts included over 10,000 patients, and this study was performed using a first split of the cohort for the development models that included around 6,000 patients overall, and then 3000 patients for the validation of these models. So the availability of data of fatigue was really the driver of the patient population that we used for this study. So we used all available questionnaires of EORTC QLQ-C30 therapy, to which we assessed our primary outcome of interest, which was global fatigue. CANTO has a first assessment at baseline, that is a breast cancer diagnosis, meaning before the initiation of any cancer treatment. Meaning surgery, chemotherapy, radiation therapy, therapy of any type. Then we perform longitudinal assessment at one year, two years, four years after diagnosis. There is a fifth assessment at five years after diagnosis for which data are not mature yet, but for the present study, we use data until four years after diagnosis. So our interest was to understand which are the risk factors for severe fatigue, primarily at two years after diagnosis. Then we also developed and validated models for severe fatigue at four years after diagnosis. So our interest was to identify a population of patients that since diagnosis can be flagged as being at high risk of developing severe fatigue after diagnosis and of course after treatment for breast cancer. This is a population of early-stage breast cancer survivors. So I really want to highlight that these models were developed and validated for survivors that are free of cancer at the time of fatigue assessment. So whether they experience cancer recurrence, metastasis, second cancers, they exit cohort. So this is purely early stage survivors of breast cancer. Dr. Westin: Thank you for that clarification. And I think it is important to really focus in on these populations because we are going to see differences in the occurrence of fatigue across patients that are actively receiving treatment in the continuum of recurrence or later in survivorship. So thank you for that clarification. I think that that really makes a lot of sense. And this is a population that's extremely large and very critical to our management. So why don't you tell us a little bit about what were some of the factors that you found to be associated with severe fatigue in your cohort? Dr. Di Meglio: So our models allowed us to identify a number of factors that are risk factors for severe fatigue after breast cancer diagnosis. So first of all, the most consistent and the strongest factors that was identified as associated with post-treatment fatigue was pre-treatment fatigue. So patients that are already severely fatigued at diagnosis have much higher likelihood of reporting severe fatigue also years after diagnosis. This was identified as a risk factors also in previous literature as it may set stage for post-treatment fatigue because maybe there are biological disruptions or bio-behavioral disruptions that are already present at the moment of diagnosis. So they keeping there and they put patients at higher risk of post-treatment fatigue. In addition to this, we found that clinical factors such as younger age was associated with high risk of fatigue after treatment. And there are also behavioral risk factors.  Patients that are current smokers at the time, active smokers at the time of the diagnosis, as well as patients with a higher body mass index. They are all at higher risk of persistent, severe fatigue after diagnosis. Finally, we also identify concomitant symptom clusters that are associated with a higher risk of severe fatigue. And these include emotional distress and particularly anxiety, insomnia. So sleep disturbances and pain at the moment of diagnosis. These are the risk factors that emerged for the models of severe fatigue at year two after diagnosis. But when we look further in to the risk factors of fatigue at year four after diagnosis, we consistently identified premenopausal status that is very consistent with younger age and also received of hormonal therapy. So our assumption was that longer these patients are into hormonal therapy, the higher the risk of severe fatigue becomes. So even though our models at Tier 4 are to be considered exploratory, we believe that they give us an additional insight into which treatment related factors would be associated with higher risk of fatigue. Dr. Westin: You'll have to forgive me because my knowledge of early breast cancer is very minimal. So for these patients, did any of them receive chemotherapy and was that at all relevant or is this a population that generally got maybe surgery and hormonal therapy? Dr. Di Meglio: So in the population that we study and consistent with the stage distribution, over 50% of the patients received chemotherapy. Almost 80% and more received hormonal therapy. So we really investigated the impact of all treatment types on the risk of fatigue. And we did find a differential impact of different treat modalities on the risk of fatigue.  I liked this in the paper because this is Year 1 model while our main interest was Year 2 after diagnosis models. But we did find an impact of chemotherapy on the risk of fatigue at one year after diagnosis, meaning the closest time point that we have to the end of primary treatment, including chemotherapy. And this effect seems to produce over time, and we don't find it in models at Year 2 and Year 4 anymore. So it's less consistent and it's not confirmed invalidation models. In contrast, the impact of hormonal therapy was much stronger at Tier 2 was confirmed at Tier 4. So this gives us the sense that the longer patients are on hormonal therapy, the higher risk of severe fatigue becomes for them. And this is also consistent with previous data from other literature. For example, Pat. A Ganz in The Mind-Body Study had demonstrated that hormonal therapy can delay the recovery from treatment-related symptoms that are usually associated with chemotherapy. And in a previous study using the CANTA cohort, we also had found an impact of hormonal therapy on the recovery of symptoms and functions that usually get better over time, for example, emotional function or future perspectives whose recovery seems to be delayed among patients that receive hormonal therapy. Dr. Westin: Well, this is great, understanding who might be at risk and trying to identify these patients. I guess the natural question is next. Like what do we do? What are our available options to treat cancer-related fatigue or even prevent it? Dr. Di Meglio: I think this is a great point and that definitely leads me to trying to understand and to explain what is the implementation of our models in clinic. So what we envision would be a clinical care setting where our models would aid clinicians to be more aware about the problem of fatigue and about ways that we have to better describe fatigue among our patients and better identify its risk factors. So let's imagine that we have an incoming new patient in our clinic and we assess the risk of severe fatigue in this patient after treatment. By assessing risk factors, we also assess fatigue at the moment of diagnosis. And we do know that in this analysis, we found that almost 25% of patients present already with severe fatigue diagnosis, and a patient like this needs to be already treated for the symptoms that he or she is reporting. So we do have now available interventions to treat fatigue when it's already present. So first of all, increasing physical activity. We also have psychosocial interventions, including cognitive behavioral therapy and psychoeducational therapies that we know that work for cancer-related fatigue and some mind-body interventions, such as yoga demonstrated some activity for cancer-related fatigue. Other approaches include mindfulness based approaches or acupuncture that can be offered to patients that already present with severe fatigue and diagnosis, particularly also the assessment of all concomitant conditions, such as nutritional imbalances should be performed in detail at the moment of diagnosis. In contrast, we might find a patient that doesn't have symptoms of severe fatigue at the moment of diagnosis, but definitely our models can increase the awareness of the risk factors and highlight a way to recognize symptoms that can hurl out the onset of fatigue and facilitate the management of risk factors and the referral to dedicated consultations or to dedicated specialists that can take care of such risk factors. In fact, the majority of risk factors that we identified are modifiable, such as we can address as tobacco use. We can address overweight and obesity as well as we can address specific symptom clusters that usually come in conjunction with fatigue, sleep problems, pain, emotional distress. We do have interventions available for all these symptoms. Of course, there is an important question there arises here, that is by addressing all three factors, is fatigue preventable at this point. I am not sure that we have the answer yet for this question at this point, but definitely by addressing risk factors, by addressing behavioral problems, we are addressing survivorship problems in a more comprehensive way. That is the direction in which survivorship care should probably go today. So as next steps, definitely we should look towards the implementation of risk models in clinical practice towards planning more meaningful prevention trials for problems such as cancer-related fatigue. And in addition, I believe that cancer-related fatigue is just an example of very common and prevalent and distressing symptoms that are not often taken care of or sufficiently taken care of in the clinic. So this can serve as a case study, as a model to expand our no also of other symptoms and of other survivorship issues that our patients and survivors may face. Dr. Westin: Well, I just want to commend you. These are really such exciting work, and I know it's something that will be implemented in the breast cancer community but also beyond. And I'm hoping that some of our other cancer-type survivorship experts are listening right now and getting inspired by your work. So we can look at this in other tumor types and really help implement this across the world. So thank you so much again for your amazing work. Thank you so much for taking the time to meet with me today, and best of luck in moving this forward. Dr. Di Meglio: Thank you so much, Dr. Westin. It was great to be here with you today. Dr. Westin: Thank you so much to all our listeners. We are always so grateful that you tune in and we can't wait to bring you discussion of our next manuscript. Have a great one. [MUSIC PLAYING] Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

Dr. Shannon Westin, Dr. Abby Rosenberg, and Dr. Reshma Jagsi discuss the timely issue of diversity, equity, and inclusion in the field of oncology.   TRANSCRIPT [MUSIC PLAYING] SHANNON WESTIN: Hey, everyone and welcome to JCO After Hours, the podcast that gets a little bit more in-depth about some of the articles and amazing research that have been published in the Journal of Clinical Oncology. I'm so excited to be with you today. And more importantly, I'm very excited to talk about this amazing manuscript, which is called "Picture a Professional-- Rethinking Expectations of Medical Professionalism Through the Lens of Diversity, Equity, and Inclusion." And this was a Comments and Controversies article that was just published in October of 2021. And I am beyond thrilled to be joined by Dr. Abby Rosenberg, who was the lead author on this manuscript. And she is currently an associate professor in the Division of Hematology-Oncology, as well as in the Division of Bioethics and Palliative Care at the University of Washington School of Medicine. She has a number of different amazing accomplishments, including being the director of Palliative Care and Resilience Lab at the Seattle Children's Research Institute, the director of Pediatrics at the UW Cambia Palliative Care Center of Excellence, and the director of Survivorship and Outcomes Research in Pediatric Oncology at the University of Washington. In addition, she is our ASCO chair of our Ethics Committee. Welcome, Dr. Rosenberg. So excited to have you. ABBY ROSENBERG: Thanks for having me. Happy to be here. SHANNON WESTIN: And in addition to Dr. Rosenberg, we're also joined by one of her co-authors, Dr. Reshma Jagsi, who is the deputy chair of radiation oncology, the Newman Family Professor of Radiation Oncology, and the residency program director and the director of the Center for Bioethics and Social Sciences at the University of Michigan. You guys, we're going to spend this whole podcast just talking about how amazing the two of you are. Thank you so much for being here. RESHMA JAGSI: Thanks for having me. SHANNON WESTIN: So let's get into it. I'm really excited about this paper. I think it's super timely and certainly something that we've all been, I think, dealing with on a day-to-day basis and also reading about and really trying to get better at. So can you tell us a little bit-- and we'll start with you, Dr. Rosenberg-- about what first drew you to this work, how you got involved and, really, how you became passionate about it? ABBY ROSENBERG: Yeah, happy to. I think just, as you said, Dr. Westin, there is this ubiquity in the experiences, in particular of women and folks of color in medicine, where we feel discriminated against, and we feel like we don't belong. And we know from some really great data from the National Academies of Sciences that 50% of women in med school, for example, experience discrimination before they graduate. And when we educate them about what microaggressive and sexist behaviors can actually look like, that number goes way up. And most women, in particular, say that they're willing to, quote, "pay this price" for being in medicine because they believe in the work, and they believe in the mission. And for me, this was really personal. Because I was one of those people, too, until I got to the point in my career where I noticed how my mentees and people who reported to me were being held back. And that, to me, made me feel like there was something I really needed to do now as an advocate and mentor to try to change the system so that more women and people of color could be successful in our field. SHANNON WESTIN: That's great. And then how did you get involved Dr. Jagsi? I'd love to know how the collaboration came about and also about your passion for this work. RESHMA JAGSI: Thank you. Yes, so both Dr. Rosenberg and I have had the privilege of chairing ASCO's Ethics Committee. And I think, to both of us, this is a fundamental matter of professional ethics. And there's really two reasons that this is so centrally and fundamentally an ethical issue. And so one of them is that human beings have a duty to resect the dignity of other human beings. And this is a situation in which we are not treating one another with due dignity. And then, of course, there's also really important consequences when we do fail in that duty. And so it's important because we share a professional mission here to promote the highest quality of patient care, to educate those who are following in our field, and to do the scholarly research to discover advances that will ultimately benefit patients and society in the future. And all of those missions are enriched when we have a diverse workforce. So this is really squarely in the lane of ethics. And so when Dr. Rosenberg proposed this article, I was just more than delighted to be included in this work. SHANNON WESTIN: And it's so important for us, as women. And I am not a woman of color, but especially as we cross all of these different groups to really elevate each other and to move the message and put it out there and make sure that people feel OK bringing these things up and understand that they're not alone, I think that's, to me, that resonated so much, with both of you saying this. Like, we've all experienced this and some of us don't even know we're experiencing it, right? Because it's just, oh, this is the way it's always been. This is the price you pay. It's the price of doing business. And I'm so grateful for people like you all that are kind of not afraid to step up and step out so that our trainees, and even pre-trainees-- people that are considering coming into the practice of medicine-- will know that this is a safe space. Because I think that's the issue, right? So I'm so grateful to you. I think, for me, it's been very interesting across these last few years, especially in the idea around #MeToo, which I know was not a new idea but certainly became very much a focus over the last three or four years. This focus on diversity, equity, and inclusion has really become, I think, a welcome change amongst a number of professions. Can you speak a little bit-- and I'd be interested on both your takes, and feel free to interact-- but can you guys speak on why we've been slow to take this on in medicine? Is it just that kind of-- gosh, I'm going to offend some people-- old, white male kind of leading the way and keeping us from doing this? Or what's been the hold-up here? Nobody wants to-- they're like, whoa, Shannon. Whoa, Shannon. RESHMA JAGSI: I have some thoughts if you want me to go. I'm yielding to you because this is really your thing. ABBY ROSENBERG: No, you go. RESHMA JAGSI: This might be a landmine, so let me go first. [LAUGHTER] No, it's totally fine. Because I think that there are very good reasons that medicine has been a conservative profession, that we've had strict hierarchies. It makes sense. You're in the operating room, you really want one person to be in charge. You need a captain of the ship. There's a lot of reasons that many of our traditions sprang up the way that they did. But they have made us a field within which individuals rise to positions of leadership. There's relatively little turnover. We've not embraced, for example, term limits in the way that many other academic fields have. And so there has been this tendency for people who have certain shared lived experiences to be able to react to the things that they've experienced but perhaps not to have as much familiarity with those things that they haven't experienced. And so I think that's one of the challenges that we have. SHANNON WESTIN: Dr. Rosenberg, do you have anything to touch on or add there? ABBY ROSENBERG: I totally agree. And thanks for launching that grenade for us. [INAUDIBLE]. [LAUGHTER] I think that change is hard, and change takes a lot of time. I'll share sort of a minor anecdote, but bear with me. When I started to really try to speak about this publicly and move the needle, my father was very ill. And he actually died during the year that I started this own crusade at my workplace. And my father had been this big civil rights activist back in his day. And I was talking to a colleague who said, oh, your dad would be so proud of you. And he said, what do you think your dad would say? And I said, you know what my dad would say is how silly it is that I thought I could make this dramatic change within a matter of months. Because it takes years and years and years to really do that. And I think where we are in academic medicine is years behind everybody else. And we're watching this change happen and this culture change happen in other industries, and we're trying to catch up. But within our own culture, it just takes a lot of time. Because there is this real institutionalized history, as Dr. Jagsi was describing, of the way we've always done it. I will also name, to just be even more provocative, that the people who have the power of influence, the people who have the power to really make those changes, are the very people who I think wrongly perceive it as a loss of their power to diversify and change the way we do it. And that's really threatening to people who can make those changes with us. And so the additional barriers we have as a grassroots community that's trying to make change becomes really hard when it's not ubiquitous from the bottom up and the top down that people are trying to be change makers themselves. SHANNON WESTIN: I think that's a great point. And I guess that kind of leads to my next question. How do we overcome this? How do we help those people in power understand what the benefits are to focusing on diversity, equity, and inclusion? And also, how do we overcome that existing bias in medicine that is affecting not only our professionalism standards but also, frankly, the care of our patients? We know that this is a clear indicator of poor outcomes for our patients, not only in oncology, which, obviously, is where we all sit, but across a number of different fields. I'm just asking you to solve all the world's problems in this podcast. ABBY ROSENBERG: Yeah. Well, Dr. Jagsi mentioned some of this. I think if you go back to it needs to be top-down and bottom-up. The top-down piece is we need leaders who look like the workforce. People cannot aspire to belong if they don't see that they belong. And so things like term limits, our abilities to promote and ensure that the tippy-top levels, and every level in addition, is really representative of the diversity of the workforce we want. That's really important. But then, from the bottom up, we need to be bringing people in. We need to be working extra hard to make sure that folks who have been historically marginalized with fewer opportunities are given the additional opportunity and resources they need to succeed in medicine. And so the system, to go back to our previous question, why it's so hard, it's not easy. I mean, all of us know going through our medical training and getting to where we are is really, really difficult. And every step along the way, there are so many obstacles. And what we need to be doing is supporting those who are bringing diversity in to ensure that they continue to succeed. RESHMA JAGSI: Yeah, I love the way that you've approached this with the top-down and the ground-up for culture change. And just to add to some of the things that we can do from the top down, in addition, we can provide sponsorship. We can be intentional about that, not exhibit homophily and simply think of the person that reminds of us of ourselves when we were younger when we have the opportunity to give someone a chance to shine. We can be absolutely intentional about developing mentor networks for individuals, recognizing that simple hierarchical dyads tend both not to be effective and not to be safe. We should be thoughtful about implementing unconscious bias training. Certainly, there are some that don't work. But Molly Carnes at the University of Wisconsin has actually developed some within medicine that can be very effective. And again, I'm saying this all from the top down because this is not about fixing the individuals. The top-down bit is that we have to change the structures, right? We're not fixing individual human beings. We're fixing systems. We need to develop transparent, consistent, criterion-based hiring, promotion, compensation processes. And then, from the ground up, we need to develop our allyship behaviors. I had a very smart trainer come to our department about a year ago who talked about how we should approach allyship development in the same way we approach behavior changes in other areas. There's people that are pre-contemplation. They're not really sure they want to be an ally yet or don't even know that allyship is a thing or necessary. There's people who are in contemplation who'd like to be allies. They're not sure exactly how to do it. There's people who are actively trying to be allies and even become advocates for change but need more support. And we need to meet people where they are in that behavior change wheel so that we get that ground-up cultural transformation at the same time that we're changing the system. ABBY ROSENBERG: As we're talking, I'm sitting here, realizing that we're talking about the larger problem of diversity in medicine. And I did want to get back to this idea of what professionalism in medicine is and how the two are related. Because that's sort of what we endeavor to do with this project. And it gets more granular and more opaque at the same time. So the granularity is part of that progression of success is this thing that we call professionalism, which is hard to measure. Sometimes it's like are you accountable, are you honest, do you communicate well? But they're these super-nebulous things-- are you a good person, essentially? And I think we all want to be those people. The folks who are judging professionalism, the folks who are grading it, so to speak, especially as we're trainees, are not necessarily consistent with how they assign good or bad professionalism merit. And what we want to do with this project, we wanted to focus on this particular aspect of how to improve the diversity of our workforce and the success of a diverse workforce by sort of naming this problem. And what Dr. Jagsi is saying is, I think, the accountability of how we record professionalism, the accountability of how we say, no, no, no, that wasn't actually professional behavior and therefore, you are not necessarily representing what we want as the best of our field, those kinds of behaviors and those kinds of metrics have not really been established in medicine. And I think that's the particular needle we were trying to move with this paper. RESHMA JAGSI: And that's where the brilliance is in the title that Dr. Rosenberg developed for this piece-- "Picture a Professional." Because when we're trying to assess, are you a good person, really, what we end up doing is deciding, do you look like a good person? I mean, we literally look at appearances rather than behaviors. And I think that she just so hit upon such an important point there. SHANNON WESTIN: Yeah. And you all mentioned that those biases are, again, the way medicine was originally-- what was the face of medicine-- the white male. And now that the face has changed, how can we also adjust what we picture? Also, I've heard this before, but when I was reading the paper about the children that were asked to draw a professional or draw a physician or a scientist and what that was back in the '60s and what might it be now? I know in the 2010s, it was still overwhelmingly male. And I think that speaks to a bigger problem. That speaks to a larger issue. So now the question is, how do we change that picture in the minds of people that are hiring and promoting physicians and medical professionals? I think that's what I took away. And I felt this table was so-- I was like, wow, how did they even figure this out? Because it's so granular and so specific. And I feel like that is really the marching orders that I got from this paper is how do you take these types of descriptions and apply them when you're looking at candidates and when you're looking at promoting within your institution. And I'd just be interested to hear your thoughts. I know that really wasn't a question. I'm just so inspired by kind of what you were able to do in this short piece. ABBY ROSENBERG: Oh, yeah. No, thanks, Dr. Westin. I'll start because when we were developing this, we were actually looking up, how does professionalism get defined in different places? And it is super vague. It's super different in different places. There are some really outrageous, frankly confined, if not racist and sexist, things out there that say, you should dress like this. And it's very white patriarchal standards. But most places have these nebulous things, like the American Medical Association, which is what we pulled down. And I actually have the paper in front of me. Because it's sort of like, "Refrain from supporting or committing crimes against humanity." I mean, really? Is our benchmark that you didn't commit a crime against humanity? [LAUGHTER] SHANNON WESTIN: It's a pretty low bar. ABBY ROSENBERG: That is so bizarre to me. But OK, fine. So let's say we all endorse that we are not going to commit a crime against humanity. How do you actually measure that? And so what we wanted to say is, actually, what we should be doing is holding ourselves accountable, being responsible for what we think represents our field in medicine. And in this new era, as we are becoming more and more aware of the importance and the value of diversity, equity, and inclusion within any workplace, we need to really come up with ways to translate "refrain from this badness" to "do good." And so we thought, what if we instead said, we're going to demonstrate an intolerance of bias. You have to actually show that you are willing to speak up, that you're willing to interrupt it when it happens, that you are investing in the skills development to be that kind of inclusive leader or workforce member. And those are actually measurable things that we can say, as far as folks are going along in their training and their career development, are you meeting these particular benchmarks? Do we see that you are demonstrating these particular values that we all hold so dear? RESHMA JAGSI: It's that type of specification that makes it so useful. And I'm just so grateful, Dr. Rosenberg, for you taking this on. Because I really do think that this document is, as you said, Dr. Westin, something that is concrete and can be useful to people who are in the position of assessing professionalism as a competency, for example, as I do, as a residency program director. SHANNON WESTIN: I think that's what we're lacking, right? Because it has been this idea that's so nebulous. And I think we've all had experiences where your hair is too big or your skirt is too short or you're whatever-- you're too quiet, or you're too loud, or you're too pushy. I mean this is what we get judged based on. And I think I just was so pleased with how clear and how measurable each one of those things were. And some of them weren't even related to diversity or equity, like applying evidence-based best clinical practices, acknowledging medical errors, that type of thing-- conducting rigorous research and disseminating your results. This spans well beyond DEI. But it's rooted in overcoming those issues of bias. So I really just was so impressed with this paper. And I think that it really does bear getting this out here. Obviously, everyone listening right now loves the Journal of Clinical Oncology and is thrilled to hear the novel research that's presented there on a weekly basis. But I really do think we should be thoughtful about how else we can get this information out here. And I'm just interested to see, are the invitations just flooding in now? Are you preparing a dog and pony show to go out to disseminate these practices and these ideas to the world? ABBY ROSENBERG: So Dr. Jagsi has been so kind and effusive, I'll just put that back on her. She is really a hero to so many of us as an advocate for women in medicine and has been such a role model for how do you do this work, how do you do this advocacy, how do you get this message out there, and how do you persevere, to be totally honest. Because I think what happens is folks will have a story. They'll have an experience. They might share it. They might not. And then we get kind of smushed back under the rest of the burdens of our work and the hardness of change-making so that folks just stop trying and they stop talking about it. And then the cycle repeats itself. And so what I have learned from working with Dr. Jagsi is that you can't stop talking about it. You do have to continue to get back up on that soapbox, share this message. And every single time that I do, the number of people who reaches out to me to say thank you is overwhelming. And that tells me two things. Number one, we still have a lot of work to do. And number two, we are doing real good by continuing to distribute this message and remind people that, no, they're not crazy. This is actually real and that together, we can make a really meaningful change. RESHMA JAGSI: Thank you. I really can't say more than that, other than blush. But I am so grateful that I've seen, over the years that I've been studying these issues and speaking about these issues, the number of people who are doing thoughtful, rigorous research into these issues and taking the platform and having the courage to speak up about experiences they've had, to provide that vivid detail, that personal stories can provide that dry data simply cannot. That's the power of the #MeToo movement. It's showing people that they're not alone. It's encouraging people who haven't had these experiences to understand what it is like. And it really does, then, motivate us to change. And I think it's a great time right now for us to be doing this kind of work. I really do see change. And so we may have been a little slow in coming to it. And we may be the field that, in the National Academies Report on the Sexual Harassment of Women in science, technology, engineering, mathematics and medicine, we may have been the worst field of everyone they studied. But I have faith that we can actually have the fastest trajectory towards positive change, as well, and we can become exemplars. SHANNON WESTIN: That's great. Super inspiring. And I hope that our ASCO leadership are listening to set this up as a educational session at the next ASCO and really also figure out how we can get these very granular and very specific ways to improve our inclusivity in medicine over the next few years. So I am so grateful to both of you, Dr. Rosenberg and Dr. Jagsi, for spending the time with me. And I hope that we can have a podcast, maybe, in a year or two, talking about all that we've accomplished and a celebratory podcast, perhaps. So with that, thank you all so much for listening to JCO After Hours. And see you next time. [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. For more original research, editorials, and review articles, please visit us online at jco.org. This production is copyrighted to the American Society of Clinical Oncology. Thank you for listening.

Dr. Shannon Westin, Dr. Michael Gnant, and Dr. Kathy Miller discuss the results of the PALLAS trial.

Dr. Shannon Westin, Dr. Kirsten Beyer and Dr. Jennifer Griggs discuss how mortgage lending bias and residential segregation intersect with cancer disparities and survival outcomes.   TRANSCRIPT [MUSIC PLAYING]   SHANNON WESTIN: Hello, everyone. My name is Shannon Westin, and I'm an Associate Professor at the University of Texas MD Anderson Cancer Center in the Department of Gynecologic Oncology and Reproductive Medicine. And I currently serve as the Social Media Editor for the Journal of Clinical Oncology. And we're starting a brand new podcast series to try to bring really exciting research that's being published in the JCO to you, and I'm so excited to kick off this series with a group of very accomplished women who are covering something that I don't think a lot of us don't know very much about. So I'm really excited to learn a ton over this next few minutes. So it's my pleasure to introduce Dr. Kirsten Beyer, who is an Associate Professor in the Division of Epidemiology in the Institute for Health and Equity as well as the Director of the PhD program in Public and Community Health at the Medical College of Wisconsin. We are also joined by Dr. Jennifer Griggs, who's a Professor the Department of Internal Medicine, Division of Hematology Oncology, as well as a member of the Institute of Health Care Policy and Innovation at the University of Michigan. She does predominantly practice taking care of women with breast cancer. Welcome, doctors. JENNIFER GRIGGS: Thank you. KIRSTEN BEYER: Thank you very much. SHANNON WESTIN: So we're talking today about the manuscript "Mortgage Lending Bias and Breast Cancer Survival Among Older Women in the United States" that Dr. Beyer published just this month in the JCO. In addition, Dr. Griggs and her colleague Dr. Pleasant were invited to participate in an editorial called "Contemporary Residential Segregation and Cancer Disparities." So let's get into to what was covered. So I think for me, the lowest hanging fruit here, Dr. Beyer, is understanding what exactly is redlining, because that was one of the critical exposure that you were assessing amongst these women with breast cancer. KIRSTEN BEYER: Thank you, Dr. Westin. Yes, redlining-- I think most people think about redlining as being a historical practice, where mortgage lenders would essentially draw red lines around particular neighborhoods and then not lend mortgages in those areas, regardless of whether or not the applicant for that mortgage was otherwise qualified. So it's generally thought of as a historical practice. But what we've done in this study is to look at some more contemporary data and create a new measure that we think represents contemporary redlining, maybe not in the legal sense in terms of housing discrimination. But this measure represents essentially the odds ratio of denial of a mortgage application for a property in a local neighborhood as compared to the metropolitan area as a whole. So we're really looking to see which areas of our US cities are systematically denied mortgage applications. By denying those mortgage applications, they are suffering from disinvestment, and I would argue structural racism is guiding a lot of that practice. SHANNON WESTIN: So can you explore that a little bit more with us? And how do you find that type of data? Where do you get this information about these denied mortgages? How do you get into the different covariates like race, ethnicity, things like that? KIRSTEN BEYER: Sure. So I think a little history lesson is important first. Between the historic practice of redlining and today, there have been a number of major laws that have been passed in the United States really to try to overcome housing discrimination. Some of the most important ones are-- in the Civil Rights Act of 1968, there was something called the Fair Housing Act, and that act prohibited discrimination in the sale, rental, and financing of housing based on race, religion, and national origin. And since then, they've added a few more protected categories. And then right after the Civil Rights Act of 1968, there was something passed called the Home Mortgage Disclosure Act. And this act was essentially to bring transparency to mortgage lending in this country. The idea was that we were requiring public disclosure of loan-level information about mortgages that were lent in the country. And the goal was to shed light on lending patterns, including those that could be discriminatory. And so the HMDA data-- it's commonly referred to as "hum-duh." That HMDA data has been collected then since 1975. And that database evolves over time, but we use that data for 2007 to '13 to really try to understand what are the mortgage lending patterns in our US cities in terms of their spatial distribution. And so there are a number of covariates that we were able to control for there. There are some things that we're not able to control for. I'm excited that the HMDA database has recently improved, and there are some new variables that are going to become available in the coming years. So what we did with the HMDA database was to calculate an index of redlining, so an odds ratio of denial of a mortgage application for a property in a specific neighborhood compared to all the properties across the metropolitan area. And so it's an area-level measure, a neighborhood-level measure. And then we put that measure into a statistical model to see what happens to women diagnosed with breast cancer if they live in redlined areas compared to if they live in other areas. And so we were able to control for a number of other factors, including race, including tumor characteristics, age, stage at diagnosis, and then to see what is the added effect of redlining over and above the things that we already know impact survival. So what we found was that women living in redlined areas in the United States were more likely to die faster after breast cancer diagnosis than women living in other areas. We also found that among people living in redlined areas, there was a discrepancy in terms of the race and ethnicity of those women. So 79% of Black women, 57% of Hispanic women, and 34% of white women lived in redlined areas in our sample. SHANNON WESTIN: That's so interesting, because I think we've all read and seen across a number of different cancer types how race and ethnicity can be associated with worse outcomes. So I think you're starting to scratch the surface of why that might be. Now, do we think that is there an association with other factors like socioeconomic status or insurance or anything like that? KIRSTEN BEYER: Yes, I think those are really good questions. Not all databases contain all of the information we would like. But in SEER-Medicare, which is the database we use, we know that all of the women have health insurance because it's a linked database with cancer registry data and then Medicare claims data. So health insurance wasn't a factor here, but we certainly know that it could be a factor in a larger sample of women across the age spectrum. And I think when you get into questions of socioeconomic status, you also have to think about, as opposed to statistically controlling away the effect of socioeconomic status, what is the mediating effect? Or what is the explanation? What factors explain the relationship between redlining and breast cancer survival? So I think that's where we'll see a lot of the important explanations for how does redlining contribute to survival. SHANNON WESTIN: Thank you. I think you nailed it right there, because finding a problem is, of course, important, but then what do we do next? Dr. Griggs, I thought your editorial was just so great at providing context for this issue, and I was wondering if you could expand a little bit more on this idea around residential segregation and how it impacts outcomes for these patients. JENNIFER GRIGGS: Thank you very much, and thanks for including me on this great podcast. It's so important to understand that place matters more than race, and we've known this for quite a while. So that area-level factors are associated with environment-- for example, pollutants, safe water, safe places to play, safe places to exercise, transportation fragility, for example, a robust public transport system. We know that neighborhoods that are in redlined areas are more likely to be policed in different ways, which takes children from school being suspended at higher rates. There's less educational investment, but Dr. Beyer mentioned this disinvestment in neighborhoods basically has shutters all the way down. It shutters from childhood all the way to how we age and access to healthy food. We know redlined areas are associated with poor markers of diabetes control, and if you take somebody from an area that's a poor neighborhood that's segregated and give them a voucher to live in a more affluent area, that markers of diabetes improve and weight goes down. So just to think about this, that the impact of where we live affects things that we think of as personal behavior-- like, what we eat or how we control our diabetes. There are, of course, implications for access to high-quality health centers when we think about people sort of locked into certain neighborhoods, all that goes along with that, including wealth. Wealth is probably one of the biggest predictors of health and not being able to have the wealth associated with home ownership decreases economic stability. And we know these things like allostatic load or stress, sometimes called wear-and-tear effects, are associated with things like tumor biology and breast cancer. We see more triple-negative breast cancers in areas where there's more allostatic load. So imagine, we think about race as this fixed-- sometimes people even construe race as a biologic construct, when really, of course, it's a social construct that has systematically-- our systems have been put in place so that even the legislation, Fair Housing Act, can't be overcome, as shown in Doctor Beyer and colleague's paper. In other words, despite legislation, we continue to see mortgage lending bias, which we've termed contemporary redlining. Yet, we think of race as this fixed, deterministic way of describing people and explaining differences and outcome. So this kind of work is really important when we can show the effect of place independent of race and if we can show that there has been systematic construction of something so important as residential segregation. What this does is it drives us to really a call to action. A lot of ideas in there, but basically, showing where people live being associated with their outcome in breast cancer-- and this has been shown in other cancers, as well-- through pathways like economic stability and wealth, wear and tear on the body, and then to acknowledge the sad truth that things have been intentionally constructed structures. SHANNON WESTIN: I mean, I think this is really in line with a lot of what we're learning about our society and our country, the way we were educated when we were younger was that we did not always hear the truth about what really went down as this country was built. I think that you really touched on a lot of very critical points. And I think for me, a lot of times when we read about these racial and ethnic disparities, I feel like it often comes down to where people are like, oh well, it's just access to care, or lack of insurance, or they're just not focusing on these things. They're not educated. They don't know that these things are important. But what I hear the two of you saying is, it goes much deeper than that. So Dr. Beyer, I'd be interested to hear your thoughts on that with these areas. Should we be working on improving what is available to people in these areas? Or should we work on breaking down or both? KIRSTEN BEYER: Yeah, thanks, Dr. Westin. That's a great question, and it's a complicated one. I think Dr. Griggs mentioned housing vouchers. And so for example, when we are giving someone a housing voucher to move from a more vulnerable neighborhood, let's call it, to a less vulnerable neighborhood, that can improve health outcomes for sure. But we also know that there's a downside to that. Sometimes there are impacts on social support or mental health. And then on the flip side, if we are trying to improve neighborhoods themselves so that the people living in them can benefit from those enhancements, we often see that what happens is gentrification, when people who are living in those neighborhoods get displaced, and newer people, wealthier people, move in and take those amenities. So I think it's something that really requires close management with housing policy. And then I think another thing that I would add is that, as you mentioned, we're really scratching the surface. I think that's an important thing to emphasize. This is one aspect of housing. There are other aspects that are very important, like quality of housing and stability of housing, which is what Dr. Griggs mentioned. And I think it's also important to note that even if a person is denied a mortgage application because of a credit score, that credit scores, wealth, income, and many other things that are considered in the mortgage lending process are also affected by structural racism, as are things like home appraisals, mentorship, and eviction, something that we've certainly seen during the COVID-19 pandemic. SHANNON WESTIN: Wow, so thoughtful. I feel like I'm trying to take notes as fast as I can because I'm learning so much. I think we didn't hear about anything like this in our medical school and your PhD training. I don't know if you all got any type of background in this. Dr. Griggs, did you-- I mean, we never even scratched the surface with the impact of structural racism. And in fact, I think a lot of our medical education was founded in that structural racism. JENNIFER GRIGGS: I couldn't agree more, and I couldn't agree more with what Dr. Beyer said about things like housing vouchers, so I just want to acknowledge that it's not as simple as giving people a voucher, obviously. No, we are calling for structural competence. There are multiple calls that we teach medical students and current practicing clinicians and scientists the structures that have been put into place and that persist. So again, that intentionality that these systems were put in place through deliberate efforts, and it's only going to be through deliberate efforts that they're dismantled. And teaching people that individual behaviors are not predetermined or, frankly, learned. They cross multiple generations, and they reside within a place and the way not just a person, but an entire people, have been treated. And I do just want to say, although this may be new to a lot of us, that the lived experience of people who live in vulnerable neighborhoods and their life experience and their family's experience going back many generations make this not new news, right? This is old news. This is stuff people have known for generations that they're being systematically cut out of opportunities for advancement and for accumulation of wealth. So I think we just want to be-- I just want to be careful when I'm talking with my colleagues, my team, my research colleagues that this is not new knowledge. And we want to also be careful not to be parasites in a way on other people's suffering, that we want to be careful not to glorify our own ideas because number one, they're not our ideas. And number two, this type of work is the lived experience of people for many, many years, not just our neighbors and friends and colleagues. So there's so much harm that's been done, and we can celebrate advances and new knowledge, but I also think we want to focus on cultural humility and do a lot of deep listening and less talking and build trusting relationships with communities that are not about our career advancement but are really about fairness and justice. SHANNON WESTIN: I think that needs to be shouted from the rooftops, and I think it is a very careful balance, because we want this research to get out. We want to make sure people understand this. You're right. It's not new knowledge, but I think it's something that hasn't necessarily been highlighted in academic fields up until, like, the last few years, where I feel like we've started to see this. But you're exactly right. We can't just do the research and find the association. Now it's time for the next steps. And I'd be interested to hear from both of you, because, to me, there are several levels of steps that we can take. There's the local level, right? So what can we do for the patients in front of us? And then I'd be interested to hear what you all think about what do we do on the more institutional-- and by institutional, I mean, our entire country. Like, what can we do? How do we advocate for policies that will help to reverse these practices? I don't know Dr. Beyer, if you want to start. I know that was a really big question. What can we do when we're seeing patients in the clinic? Are there ways, or are there things we can offer or things that we can do on the local level that could help to address some of these disparities? KIRSTEN BEYER: Yeah, thank you, Dr. Westin. I'm not a medical doctor, but I work a lot with medical students. We have some pathways at the Medical College of Wisconsin, one on urban and community health and one on global health. And in those pathways, we do try to put forth a lot of this type of content and learning. But again, that's just a select number of students who end up getting that training. I think that structural racism is a fundamental force in our society, and therefore, it justifies a position in the core medical curriculum. I think since the murder of George Floyd, there has been a national consciousness that's been raised around this issue, that we should take advantage of that and try to push forward some core learning on structural racism for medical students. And then beyond that, I think as a patient, I can use the patient perspective. As a patient, I would want my physician to take into account my life context when providing clinical care. How hard is it for me to get to my appointment and to get there on time? How hard is it for me to find child care? How hard is it for me to obtain the prescriptions I need and maintain them with any significant cost at hand? So I think that awareness for physicians is really a first step. And then the last thing I would say is that doctors have power, and so I think it's the responsibility of those with power who are in the know about structural racism to leverage and use that power to make social change. JENNIFER GRIGGS: I really appreciate what you said from education to practice. I would add that an integrated health system would be able to think from prevention all the way up to health care. I feel like by the time people are accessing health care, a lot of other things have gotten in the way of their health, right? That's why we talk about social determinants of health. So I think we need to think about elevating the role of other people in the health care system. So even if you're in an individual practice, do you have access to a social worker? Are you including patient and family voices when you build your new office? We have transportation initiatives being made all over this country, and I know in Europe as well. So cities are being designed to undo transportation fragility and vulnerable neighborhoods. I can't emphasize enough the importance of asking communities what they need. It strikes me that the ivory tower is just that, right? It's very rarefied where we work. And to go into a community and say, this is what you need, feels-- which is not what you were suggesting, Dr. Beyer or Dr. Westin, but to start by listening and ask the communities what they need and then to provide it and to listen and not leave once the, quote, "problem is fixed." And I think the same is true nationally. We need to make sure that the administration's priorities actually bear fruit and soon, that we not kick things down the road and make compromises at the level of national policy. And as physician clinicians, those physicians who are listening, we should be going to the city council meetings when a new building is being erected. Is there going to be a consequence for neighborhoods in terms of things like gentrification? Cities have been constructed intentionally to isolate people, and we need to start undoing that, and cities are doing that. They're taking down freeways that divide the rich from the poor. I think we need to make sure as clinicians that we are speaking up about equitable and high-quality education for young people because we know your early life experiences and education are associated with health. Publishing work like Dr. Beyer's work, ASCO has a heavy advocacy arm. And as Dr. Beyer said, we have power. Inequities in power is what got us to where we are. So really, the burden is on those with power to speak on Capitol Hill and other places, local level, statewide level, to make change and to insist on it for the health of our patients and our communities. SHANNON WESTIN: That is so thoughtful and such a great call to action. And I do think there's a huge opportunity for members of ASCO to get involved. The advocacy is extremely strong. There are Capitol Hill days and committees, and now we even have their own political action committee, where we can work to lobby for patients and their health care. So I think that is a perfect place for us to end this conversation. I would like to give Dr. Beyer last opportunity to one-liner to sum up where we are and what we need to do next for those people that tend to fade in and out of these types of things. KIRSTEN BEYER: Sure. Thank you, Dr. Westin. I would say, to summarize, that the housing sector is actively revealing structural racism. This isn't a historic practice only. We are seeing structural racism in housing right now, and it's actively revealing both structural racism and economic disinvestment. And it's a very actionable policy target, so that we can mitigate those upstream determinants of health for the benefit of patients with cancer and with other diseases. And then I think as a final, I would say that there's a great quote from Matthew Desmond, who's a housing equity writer and scholar and activist. And he says, "A stable home functions as a secure foundation on which to build holistic and cost-effective health care." And so I think that's a great way of thinking about it from a practical standpoint. Housing is primary. It's an important foundation on which we build all the other things that we can do to improve people's health. SHANNON WESTIN: Perfect. Thank you both so much. Thank you, Dr. Beyer. Thank you, Dr. Griggs. And thank you, all of the listeners. We'll be back soon with a new podcast coming to a ear near you. JENNIFER GRIGGS: Thank you so much. KIRSTEN BEYER: Yeah, thank you very much. [MUSIC PLAYING] SPEAKER 1: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. For more original research, editorials, and review articles, please visit us online at jco.org. This production is copyrighted to the American Society of Clinical Oncology. Thank you for listening.

This podcast will discuss data from a phase II trial evaluating the dose-adjusted EOPCH-R chemo-immunotherapy regimen for the treatment of primary mediastinal B-cell lymphoma in children.   TRANSCRIPT [MUSIC PLAYING] LISA GIULINO-ROTH: This JCO podcast provides observations and commentary on the JCO article "Dose-Adjusted Rituximab Therapy in Children and Adolescents with Primary Mediastinal B-cell Lymphoma, a Multicenter Phase II Trial" by Burke et al. My name is Lisa Giulino-Roth, and I am a pediatric oncologist at Weill Cornell Medical College in New York. My oncology specialty is lymphoma in children, adolescents, and young adults. I have no relevant disclosures. Primary mediastinal B-cell lymphoma, or PMBCL, is an aggressive non-Hodgkin lymphoma derived from thymic B-cells. While previously classified as a subtype of diffuse large B-cell lymphoma, PMBCL is now recognized as a distinct clinical and pathologic entity. Unlike diffuse large B-cell lymphoma, PMBCL has a peak incidence among adolescents and young adults and is more common in females. PMBCL also shares many molecular characteristics with Hodgkin lymphoma, including alterations in JAK-STAT pathway signaling and amplification of the 9p24.1 locus, leading to upregulation of PD-L1. Adults with PMBCL have historically been treated on regimens designed for diffuse large B-cell lymphoma, which in the US was most commonly R-CHOP and radiation therapy. More recently, adult patients have been treated with a dose-adjusted EPOCH-R regimen, which is composed of dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab. This radiation-free approach is of interest, given this young and predominantly female population who are at risk for significant long-term toxicity from chest radiation. In a single center NCI-led study by Dunleavy and colleagues, dose-adjusted EPOCH-R was administered for six to eight cycles without radiation therapy and resulted in excellent outcomes with a five-year event free survival of 93% and overall survival of 97% among 51 adult patients. Pediatric patients with PMBCL have historically been treated on regimens designed for mature B non-Hodgkin lymphoma, which in pediatrics is most commonly Burkitt lymphoma or diffuse large B-cell lymphoma. These dose intensive multi-agent regimens include doxorubicin, high dose methotrexate, and intrathecal chemotherapy without radiation. Outcomes for children with PMBCL treated on these regimens are inferior to pediatric patients with diffuse large B-cell lymphoma treated on the same protocol. Children with PMBCL have a five-year event-free survival ranging from 65% to 75% in different international series. Given the excellent outcomes observed with dose-adjusted EPOCH-R in the adult NCI trial, an international phase II trial of this approach was conducted by two cooperative groups, The European Intergroup for Childhood Non-Hodgkin Lymphoma and the Children's Oncology Group. This single arm trial enrolled patients age 18 and under with primary mediastinal B-cell lymphoma. All patients were treated with six cycles of dose-adjusted EPOCH-R without radiation. The primary endpoint was event-free survival with events defined as any of the following-- viable cells in any residual mass after six cycles of treatment, relapse, progressive disease, secondary malignancy, or death from any cause. The four-year event-free survival from this trial would be compared with the event-free survival from historic controls, which was estimated at 67%. A total of 46 pediatric patients were enrolled between 2012 and 2016. All patients received six cycles of dose-adjusted EPOCH-R without RT. At a median follow-up of 59 months, there were 14 events, including four patients with viable cells in the residual mass at the completion of therapy, eight progressions or relapses, and two secondary malignancies, including one case of Hodgkin lymphoma and one case of acute promyelocytic leukemia. The event-free survival of the entire cohort at four years was disappointing at 69.6% with a 95% confidence interval of 55.2% to 80.9%. This was not statistically different than historic controls treated on pediatric mature B and HL regimens. Overall survival at four years was 84.8% with a 95% confidence interval of 71.8% to 92.4%. The authors acknowledge several limitations in the current study and challenges when comparing this study to the NCI trial. Not all patients adhered to the dose escalation rules, and 29% should have received a higher dose level in at least one course of treatment. Among the 10 cases of local relapse or primary refractory disease, five were noted to have a failure to dose escalate, including one patient with a clinical complication that precluded dose escalation. Comparing this trial to the NCI trial is challenging due to several important differences. Adults in the NCI trial were treated with six or eight cycles of dose-adjusted EPOCH-R based on the response between cycles 4 and 6. In pediatrics, eight cycles was not deemed appropriate, given the potential for greater than 600 milligrams per meter squared of cumulative doxorubicin exposure and concern for significant long-term cardiac toxicity at this exposure level. In addition, the NCI trial did not consider residual viable cells or secondary malignancy as an event, both of which were defined as events in the current pediatric trial. In a reanalysis of the pediatric data using the NCI event definitions, there was only a modest change in event-free survival with a four-year event-free survival of 73.9%. So where does this leave dose-adjusted EPOCH-R and the management of pediatric patients with PMBCL? In my opinion, there's no single superior regimen to treat pediatric PMBCL. Outcomes are similar across regimens. However, the toxicities are different. Dose-adjusted EPOCH-R offers significantly less short-term toxicity, but the potential for a higher cumulative doxorubicin dose compared to pediatric mature B and HL regimens. Regardless of the chemotherapy backbone, it is clear that for children with PMBCL, outcomes remain suboptimal, and further studies are needed to advance treatment. Given the rare nature of PMBCL and the peak incidence in the AYA population, combined pediatric and adult trials may allow us to evaluate novel agents and advance outcomes. Both children and adults with PMBCL may benefit from the incorporation of novel agents. Retrospective multicenter data from adults treated with dose-adjusted EPOCH-R have also failed to reproduce the excellent outcomes observed in the NCI trial. In two large retrospective series, adults with PMBCL treated with dose-adjusted EPOCH-R had a two- and three-year progression-free survival of 85% and 87% respectively. To advance outcomes in PMBCL across age groups, our team at the Children's Oncology Group in collaboration with Alliance and the National Clinical Trials Network is conducting a randomized phase III trial of the checkpoint inhibitor nivolumab in combination with chemo immunotherapy for adult and pediatric patients with PMBCL. Checkpoint inhibitors, including pembrolizumab and nivolumab, have demonstrated efficacy and PMBCL in the relapsed setting. And pembrolizumab is FDA approved for children and adults with relapsed PMBCL after two or more lines of therapy. However, these agents have not been evaluated in the upfront setting. In this trial, the treating physician will choose between R-CHOP and dose-adjusted EPOCH-R as the chemotherapy backbone. And patients will then be randomized to standard of care with six cycles of chemo immunotherapy alone or six cycles of nivolumab plus chemo immunotherapy. We are optimistic that this will define the role for checkpoint inhibition in the upfront management of PMBCL and work towards improved outcomes for both adult and pediatric patients. This concludes this JCO podcast. Thank you for listening. [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. For more original research, editorials, and review articles, please visit us online at jco.org. This production is copyrighted to the American Society of Clinical Oncology. Thank you for listening.

This podcast discusses the study, steroid dose reduction, practice experience, and guidance changes.   TRANSCRIPT [MUSIC PLAYING] ROBIN ZON: This JCO podcast provides observations and commentary on the JCO article-- "Do Steroids Matter: A Retrospective Review of Pre-Medication for Taxane Chemotherapy and Hypersensitivity Reactions," by Lansinger et al. My name is Dr. Robin Zon. And I am the quality oncology practice initiative lead physician for Michiana Hematology Oncology, an independent community oncology practice located in Mishawaka, Indiana. My oncologic specialty is general medical oncology. And I have a strong interest in breast cancer. This article is based on the premise that there exists significant variation regarding the prescribing practices of steroids for pre-medication to minimize the known hypersensitivity reactions associated with the taxanes paclitaxel and docetaxel. In fact, the authors remind the reader that initial clinical development of paclitaxel was delayed due to the notable hypersensitivity rate of 25% to 30%, as patients did not receive pre-medication. Subsequent trials used a pre-medication strategy of dexamethasone, diphenhydramine, and H2 antagonist, with a reduction of the reaction occurrence to 2% to 3%. As a result of the improved reaction rates in clinical trials with the use of a pre-medication regimen, both paclitaxel and docetaxel, FDA approved package inserts recommend oral corticosteroid pre-medication, 20 milligrams, 12 and 6 hours prior to the taxane administration. However, there has been no dose optimization to date. In fact, the authors note that lower dose regimens are routinely used in daily practice and may lead to increased risk of hypersensitivity reactions. Furthermore, steroids can cause multiple adverse effects if taken for extended periods of time, which can range from mild to moderate in their severity. This study reviewed steroid prescribing patterns in patients receiving the first dose of paclitaxel or docetaxel at Stanford Cancer Institute between 2010 and 2020. A total of 3,181 patients met criteria for analysis, with an 8.3% rate of hypersensitivity reactions. And the adjusted multivariate analysis, the authors found no correlation between the hypersensitivity reaction rate or the severity among the variables evaluated, except for the gynecology/oncology clinic patients who had an increased risk for hypersensitivity reactions overall with a hazard ratio of 1.34 and high grade hypersensitivity reactions with a hazard ratio of 2.34, and female patients who had a higher rate of hypersensitivity reactions overall with a hazard ratio of 1.26, but not high grade hypersensitivity reactions. The conclusion of the article is that neither dexamethasone dose nor route, IV or oral, correlated with subsequent hypersensitivity reactions. And that the recommended 40 milligrams dose of dexamethasone prior to taxane administration is no better than the 10 milligrams dose for protecting against hypersensitivity reactions. Therefore, the lower doses used in clinical practice is acceptable and even preferable to higher doses. Although the study authors point out that the strength of the study is the large data set reviewed, they also point out that this study was a retrospective analysis completed on first dose dexamethasone use and not on subsequent taxane exposures Additionally, the authors also point out that since there was no external validity, the results may not be generalizable to other patient populations treated at other institutions. For the remainder of this podcast, the commentary represents my opinion only and may not represent the opinion of this journal or its editors. First, I would like to commend the authors on this analysis, which addresses a very practical question-- do steroids matter. And is it possible to safely vary from the package insert? The work dedicated to collecting this data set does not go unnoticed. As the authors acknowledge, the prescribing practice patterns for steroid pre-medication does vary considerably across and within practices. Furthermore, the common references that practices use for treatment guidance, including NCCN and UpToDate, describe differing options. For example, the NCCN order template for weekly paclitaxel refers to using pre-medication of H2 blocker plus diphenhydramine and dexamethasone 10 milligrams IV with weekly doses, one to three, then may consider dose reduction of dexamethasone to 4 milligrams with weekly dose 4, and does not elaborate on further dose reduction. For Q2 or three-week paclitaxel dosing, the NCCN template follows the package insert. UpToDate also recommends 20 milligrams of dexamethasone orally 12 and 6 hours prior to drug administration with H1 and H2 receptor antagonists as a pre-medication regimen for Q2 or three-week treatment. However, for weekly paclitaxel, UpToDate offers consideration of a dexamethasone dose of 10 milligrams IV with H1 and H2 blockers, then tapering the glucocorticoid by 2 milligrams decrements after weekly dose 3 or 4, and can even discontinue the dexamethasone in patients without infusion reactions. For docetaxel, UpToDate suggests dexamethasone 8 milligrams orally BID for three days. To further confirm the practical world of dexamethasone pre-medication variability, in a straw poll within our practice and outside our practice, many providers do utilize the 10 milligrams dexamethasone dose for the first dose of Q2 or three-week taxanes, and reduce and then eliminate dexamethasone for weekly taxanes when feasible and have done so for many years, while other providers strictly follow FDA labeling. Importantly the reason providers are willing to de-escalate the pre-treatment medications for taxanes is that patients have less side effects and are grateful to have this drug reduced or even eliminated from their treatment. So the question asked and the knowledge generated by the study becomes extremely relevant as providers consider ways to de-escalate interventions, especially if patient outcomes are not placed at risk and quality of life can be improved. The next question relates to the authors' concern of lacking external validity and generalizability to other patient populations. In my opinion, it would not be feasible to conduct this labor-intensive data set collection and analysis at a multitude of independent community and academic sites. However, this could be an opportunity to query real world data platforms, such as ASCO's CancerLinQ, to look for steroid complications such as grade 3 and grade 4 events related to change in pre-medication strategies. But even real world databases may have limits based on the specificity of the query and the inadequate capture of adverse events, especially less severe toxicities, as this structure data may not be recorded in the electronic medical record. Finally, the most relevant question is whether practice and guidelines should change as a result of this data. As I have discussed, many practices have already made this initial dose modification, and even safely dose reduced beyond the scope of this data set inquiry. Therefore, I do think that initial dosing as suggested by this study should be more widely guideline adopted and that consideration for further reduction with additional taxane doses be based on practice-specific experience and guidelines. This concludes this JCO podcast. Thank you for listening. [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. For more original research, editorials, and review articles, please visit us online at jco.org. This production is copyrighted to the American Society of Clinical Oncology. Thank you for listening.

Improving care in vulvar cancer via the prospective Vulvar GROINSS VII study   TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Radiotherapy Versus Inguinofemoral Lymphadenectomy as Treatment for Vulvar Cancer Patients with Micrometastases in the Sentinel Node: Results of GROINSS-V II” by Oonk et al. My name is David Gaffney, and I am a professor and Vice Chair of Radiation Oncology at the University of Utah. I am also Senior Director for Clinical Research at the Huntsman Cancer Institute in Salt Lake City, Utah. My oncologic specialty is radiation oncology. I have no relevant disclosures to this study. The GROINS VII study is the successor trial of the GROINS V I trial. In the GROINSS-V I study, the authors demonstrated that omission of an inguinal femoral lymphadenectomy was safe in patients with a negative sentinel lymph node with an isolated GROIN recurrence rate of 2.3%. It also showed that with long term follow up a significant proportion of patients will recur. At 10 years local recurrence occurred in 39.5% of all patients. Although local recurrences are treated with curative intent, the disease-specific survival of these patients decreases significantly. It is important to ask if there is a dose response to radiotherapy in vulvar cancer?  GOG 101 was published in 1998 and employed a split course of radiotherapy to a dose of 47.6 Gy with concurrent cisplatin and 5-FU. The complete response rate was 46.5%. The subsequent prospective phase II randomized trial, GOG 205, was published in 2012 and employed 10 Gy more of radiotherapy with weekly cisplatin to a total dose of 57.6 Gy. This study demonstrated a 78% pathologic complete response rate. Hence, by adding 10 Gy, the complete response rate increased by 30%, indicating a steep dose response. Also, by way of background, a retrospective study from MD Anderson by Stecklein et al. published in 2018 demonstrated a 3-year actuarial groin control rate of 83% with high dose conformal radiotherapy with a median dose of 66 Gy to grossly positive nodes. These data demonstrate that radiotherapy can sterilize gross disease in select circumstances.   The GROINSS-V II study was a phase II prospective study in a rare disease, and sought to answer whether radiotherapy to 50 Gy could be an effective and less morbid alternative to inguinofemoral lymphadenctomy   Patients were accrued from 59 hospitals in 11 countries. Eligibility for this study were patients with tumors less than 4 cm, with  negative groin nodes on preoperative CT, MRI, or ultrasound. The primary endpoint was a groin recurrence rate at 24 months. A combined technique was used to evaluate the sentinel lymph node of lymphoscintigram and blue dye. Bilateral sentinel lymph node procedures were required for midline lesions. The radiotherapy was 50 Gy in 25-28 fractions with the field size to extend to the bottom of the SI joints, including the distal external iliac lymph nodes. Greater than 1700 patients were registered. One hundred sixty patients were found to have micrometastases, that is disease less than 2 mm, whereas 162 patients were found to have macrometastases. The median size vulvar lesion for patients with negative sentinel lymph node was 18 mm, 23 mm for patients with micrometastases, and 25 mm for patients with macrometastases.   Results at 2 years demonstrated an isolated groin recurrence rate occurred in 1.6% of patients that were treated per protocol with micrometastases. Whereas patients with macrometastases had an isolated groin recurrence rate at 2 years of 12.2%. For patients with macrometastases treated with radiotherapy, the groin recurrence rate was 22%. Whereas groin failure was 6.9% for patients who had macrometastases treated with inguinal femoral lymphadenectomy and radiotherapy. For patients with macrometastases, no groin recurrences were observed in 7 patients treated with chemoradiotherapy. Among the 1213 patients with a negative sentinel lymph node, an isolated groin recurrence occurred in 31 patients for a rate of 2.7% at 2 years. For the 56 patients who suffered a groin recurrence, 31 of them died of vulvar cancer for an overall survival rate of 39% at 2 years.   This trial also looked at morbidity of patients treated with inguinal femoral lymphadenectomy versus sentinel lymph node procedure plus radiotherapy. The lower extremity edema rate was 32% at 6 months versus half of that for patients treated with the sentinel lymph node procedure plus radiotherapy. It should be noted that IMRT was utilized in 19% of cases, and chemotherapy was utilized in 12% of cases.   This trial clearly demonstrated that in patients with a macrometastasis or disease greater than 2 mm within a groin node, radiotherapy is not a safe alternative to inguinal femoral lymphadenectomy due to a higher rate of groin recurrence, albeit there was no difference in disease-specific survival.   Management of patients with vulvar cancer is complex. Clinicians need to control the ipsilateral and the contralateral groin. The GROINSS-V II study gives us data on contralateral groin failures also. Overall, there was a very low rate of contralateral groin failure.   The subsequent study GROINSS-V III will evaluate patients with macrometastases and compare inguinal femoral lymphadenectomy versus chemoradiotherapy with weekly cisplatin and an elevated dose of radiotherapy to the groin with 56 Gy utilizing a simultaneous integrated boost technique. It will be quite interesting in years to come to discern if IMRT with more precise daily imaging and dose escalation together with chemotherapy will improve local regional control. Additionally, there may be select populations of node positive patients where intensification of chemotherapy, radiotherapy, or more extensive surgery may be useful. McAlpine and colleagues have demonstrated that cases of HPV-negative vulvar cancers had a markedly inferior survival rate with a hazard ratio of 0.35. It is also hoped that advance radiotherapy techniques such as IMRT will decrease longstanding morbidity such as lymphedema. The GOG prospective study 244 demonstrated no increase in lymphedema in gynecologic cancer patients where radiotherapy was added compared to surgery alone.   The study by Oonk et al. is a remarkable effort in a rare disease demonstrating that patients with micromets can be safely treated with 50 Gy and patients with macromets should be treated with an inguinal femoral lymphadenectomy. It will be very interesting to see if chemoradiotherapy with increased dose can improve local-regional control and provide a high quality of life for patients with macro mets in the GROINS VIII trial.    This concludes this JCO Podcast. Thank you for listening.

Dr. Lindsay Morton of the National Cancer Institute at the National Institutes of Health reflects on research findings by Øvlisen et al that leverage large-scale linked registries in Denmark to suggest that improvements in both chemotherapy treatments and assisted reproductive technologies have made it possible for more survivors of Hodgkin lymphoma to become parents.   TRANSCRIPT This JCO podcast provides observations and commentary on the JCO article “Rates and Use of Assisted Reproduction Techniques in Younger Hodgkin Lymphoma Survivors: A Danish Population-Based Study of 793 Patients and 3965 Matched Comparators” by Øvlisen and colleagues. My name is Lindsay Morton, and I am a Senior Investigator and Deputy Chief of the Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, at the Intramural Research Program of the National Cancer Institute at the National Institutes of Health. I am trained in epidemiology, and my oncologic specialty is in hematologic malignancies and cancer survivorship research. I have no relevant conflicts to disclose. The adverse effects of treatment among patients with Hodgkin lymphoma have long been at the forefront of oncology research. In the late 1960s, patients with Hodgkin lymphoma were some of the first to receive combination chemotherapy with a four-drug regimen called “MOPP,” consisting of mechlorethamine, vincristine, procarbazine, and prednisone. MOPP resulted in dramatic improvements in patient outcomes following diagnosis with Hodgkin lymphoma. But in subsequent decades, the toxicities of MOPP came to be understood, including both acute toxicities – most notably myelosuppression – as well as longer-term toxicities such as second cancers and sterility, especially in males. Around the same timeframe, long-term toxicities of radiotherapy also were increasingly recognized, which set off a search for effective Hodgkin lymphoma treatment approaches with fewer short- and long-term toxicities. I often think of how research on adverse effects in patients with Hodgkin lymphoma has been at the vanguard in cancer survivorship: this focus has helped to drive development of new therapies and changes in clinical practice. This has occurred in part because Hodgkin lymphoma is frequently diagnosed in early adulthood and patients now have such a good prognosis; this means there is a longer window in which to experience any long-term effects of cancer treatments, and patients face unique issues, such as impacts on fertility, which aren’t relevant for older cancer patients. In the paper accompanying this podcast, Øvlisen and colleagues present novel data on parenthood rates and use of assisted reproduction techniques in Danish patients with Hodgkin lymphoma. Importantly, the results of this study are very relevant to current patients because all the patients in the study were treated between 2000 and 2015 using standard treatment approaches that are still frequently used today. About one-third of the study population received radiotherapy plus 2-4 cycles of the combination chemotherapy regimen called “ABVD,” which consists of doxorubicin, bleomycin, vinblastine, and dacarbazine, and is the preferred front-line therapy approach for Hodgkin lymphoma patients in the United States. Another third of the study population received 6-8 cycles of ABVD, while in the remaining third, about half received either “BEACOPP” (a seven-drug regimen, which includes bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, and which is commonly used in Europe) or some other chemotherapy regimen. In this study, the authors compared the rates of parenthood in patients with Hodgkin lymphoma to individuals in the general population who were matched to the patients by age, sex, and parenthood status. Overall, the news was good: both male and female survivors of Hodgkin lymphoma had similar parenthood rates as the matched individuals from the general population. But the details of this bigger picture finding are really worth understanding because of their important impact on patients. In particular, a larger number of patients with Hodgkin lymphoma than the comparison individuals from the general population used assisted reproductive technology in order to become parents. Specifically, nearly 22% of male and 14% of female survivors of Hodgkin lymphoma used assisted reproductive technology compared with only about 6% of those in the general population. When the authors looked at various predictors of parenthood in subgroup analyses, one other finding stood out: male survivors of Hodgkin lymphoma who had received BEACOPP therapy had about half the rate of parenthood compared with other Hodgkin lymphoma survivors and the general population. In contrast, for female survivors, parenthood rates were similar among the different treatment groups, but the numbers of female survivors treated with BEACOPP was small, so we should be cautious about drawing conclusions for females. The results from Øvlisen and colleagues seem to reflect two important changes from previous studies, most of which included patients who were treated with older chemotherapy regimens, like MOPP. First, Hodgkin lymphoma treatments have continued to evolve, and adverse effects on fertility seem to be declining for the newer regimens. Second, of course, there also have been important advances in assisted reproductive technology, so that individuals who have trouble with conception initially can be helped by these technological advances. In addition to hearing this good news for patients with Hodgkin lymphoma, the way the authors collected the information for this study was also exciting because it was large-scale, long-term, and systematic. Most of the data on fertility in patients with Hodgkin lymphoma previously has come from clinical trials. Those data have been invaluable, and in fact, provided some of the first signs several decades ago that patients with Hodgkin lymphoma treated with MOPP could face fertility issues. But we also know that clinical trials often have incomplete information on outcomes that occur more than a few years out, which raises some questions about the validity or generalizability of the study results for those outcomes. In this report, the authors collected information on patients with Hodgkin lymphoma and the matched individuals from the general population from nationwide birth and patient registries. In countries like the United States, this study design would be virtually impossible because our healthcare system is fragmented – patients receive different types of care, like their cancer treatment and fertility treatments, in different places, and there is no easy way to link information on these different types of care for a specific individual. In this Danish study, the authors were able to leverage the centralized nature of the healthcare system in Denmark to capture not only all the information on the Hodgkin lymphoma treatments but also the birth registries and use of assisted reproductive techniques – connecting this information from different sources for all the individuals in the study. Because of the linkages that are possible among all these different sources of data, we are confident that the study provides complete, unbiased information even on longer-term outcomes. While this study demonstrates both the importance of long-term patient follow-up and the power of registries, it also highlights the need to continue efforts to reduce toxicities and improve outcomes in patients with Hodgkin lymphoma, particularly those diagnosed in childhood, adolescence, or young adulthood. Fertility is just one aspect of quality of life that may be impacted by cancer treatment, and the more high-quality data we bring to bear on cancer survivorship, the better we will be at not just treating cancer but also taking care of the whole patient for the many years they have ahead of them. This concludes this JCO Podcast. Thank you for listening.

This podcast describes the findings from a population-based retrospective decedent cohort study which suggest that palliative care involvement may be associated with a decreased need for high intensity of care during the final weeks of life in adolescents and young adults with cancer.   TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Impact of Palliative Care Involvement on End-of-Life Care Patterns Among Adolescents and Young Adults with Cancer: A Population-Based Cohort Study” by Kassam et al. My name is Erica Kaye, and I am Director of the Quality of Life and Palliative Care Research Division at St. Jude Children’s Research Hospital in Memphis, Tennessee, USA. My oncologic specialty is pediatric palliative oncology. In this paper, the authors aim to evaluate the prevalence and predictors of high-intensity end-of-life care in adolescents and young adults with cancer in Ontario, Canada, as well as assess the impact of palliative care involvement on intensity of care received at end of life. This topic is timely and important. Growing evidence demonstrates that adolescents and young adults with cancer, defined by the National Cancer Institute as patients diagnosed between the ages of 15 and 39, face a unique set of circumstances that may adversely impact their end-of-life experiences. Several single-institution studies in the U.S. have suggested that adolescents and young adults with advanced cancer disproportionately receive high intensity medical care in their final month of life compared to children or older adults, and these findings recently have been replicated in population-level studies in California and New York. These observations raise concerns about exposure of a vulnerable population to toxicity from high intensity care at a time when such interventions are less likely to offer meaningful benefit. However, these studies had several notable limitations: some involved only insured patients; others presented data only from inpatient end-of-life care; and none evaluated the impact of palliative care provision on the intensity of end-of-life care for adolescents and young adults with cancer. Moreover, findings from U.S.-centric data sets may not be generalizable to other countries. In this study, the authors assembled a retrospective decedent cohort of adolescents and young adults with cancer who died between 2000 and 2017 in Ontario, Canada using a provincial registry linked to population-based health-care data. Predicated on previously published validated metrics, they used a primary composite measure for high-intensity end-of-life care that included receipt of intravenous chemotherapy less than 14 days from death; more than one emergency department visit; and more than one hospitalization or intensive care unit admission less than 30 days from death. Secondary outcomes included measures of the most intensive end-of-life care, such as intensive care unit admission within 30 days of death, mechanical ventilation within 14 days of death, and death in the ICU, as well as palliative care physician involvement. Predictors of outcomes were determined using regression models. In a cohort of more than 7,000 adolescents and young adults with cancer across Ontario, authors found that approximately 44% experienced high-intensity end-of-life care – double the rate for adults and slightly higher than the rate for children in the region. This percentage is lower than that seen in single-site and population-level studies in the U.S., however lack of consistently defined high-intensity end-of-life indicators for adolescents and young adults with cancer make it challenging to compare findings across studies. Importantly, adolescents and young adults with hematologic malignancies were at highest risk for receipt of high-intensity care at the end of life in Ontario, affirming findings seen across pediatric and adult populations in different countries. Some hypothesize that unique pathologies specific to hematologic malignancies may increase the risk of experiencing higher intensity end-of-life care. For example, a patient with refractory leukemia often requires frequent blood transfusions to prolong life and optimize quality time; this can be challenging to coordinate in the outpatient setting and may necessitate inpatient hospitalizations at the end of life. In both the U.S. and Canada, continuation of transfusion support often precludes hospice enrollment, further preventing patients from receipt of subspecialty palliative care in the home. In this context, legislation to support concurrent provision of palliative and hospice care with cancer-directed therapy may have the potential to mitigate high-intensity end-of-life experiences for this vulnerable patient population. This study also found that palliative care physician involvement substantially reduced the odds of adolescents and young adults with cancer receiving high-intensity end-of-life care, including the most intensive experiences such as mechanical ventilation and dying in the intensive care unit. Palliative care physicians may lessen intensity of end-of-life care by promoting conversations about goals of care and advance care planning, coordinating complex medical care in the community, and providing real-time symptom management to decrease emergency visits or hospitalizations. However, further research is needed to explore these hypotheses. Ultimately, this study provides compelling evidence that palliative care involvement may lessen the risk of high-intensity end-of-life care in adolescents and adults with cancer. Unfortunately, universal access to subspecialty palliative care remains challenging, particularly in rural regions. Disparities in access to hospice and palliative care services for racialized communities remain deeply problematic as well. This study supports the need for institutional and regional programs and policies to provide equitable access to palliative care for adolescents and adults with cancer. Strengths of this study include its population-level design, large health services dataset, and use of relatively standardized indicators for defining high-intensity end-of-life care. Study limitations include its retrospective design, which inherently precludes causal inference. Additionally, involvement of a palliative care physician was used as a proxy for integration of subspecialty palliative care; however, subspecialty palliative care is an interdisciplinary field in which care may be provided by non-physicians, and the study did not account for this phenomenon.   Lastly, the study is predicated on certain assumptions about the negative ramifications of high-intensity end-of-life care. Notably, certain experiences categorized as high-intensity care, such as more than one hospitalization during the final month of life, may not be experienced as high-intensity or burdensome by patients or families. An adolescent patient may wish to be hospitalized on multiple occasions to optimize comfort at the end of life. Or a family may request hospitalization for respite, or to protect siblings from seeing suffering at end of life. Although technically high-intensity, these interventions also may represent goal-concordant comfort care, and further research is needed to determine best practices for optimizing care that aligns with the goals of adolescents and young adults at end of life. This concludes this JCO Podcast. Thank you for listening.

Minimal residual disease positivity is predictive of disease progression in patients with large B-cell lymphoma treated with anti-CD19 CAR T-cells.   TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article 'Monitoring of Circulating Tumor DNA Improves Early Relapse Detection After Axicabtagene Ciloleucel in Large B-Cell Lymphoma: Results of a Prospective Multi-Institutional Trial' by Frank et al. My name is Patrick Reagan, and I am an Assistant Professor of Medicine at the Wilmot Cancer Institute, University of Rochester in Rochester, NY. My oncologic specialties are lymphoma and cellular therapy. I would like to disclose consultancy for Kite Pharma. Frank and colleagues present data from a prospective, multicenter trial examining serial testing of circulating tumor DNA in 72 patients with large B-cell lymphoma who received treatment with the anti-CD19 CAR T-cell, axicabtagene ciloleucel, abbreviated as axi-cel. These patients had circulating tumor DNA monitored in plasma prior to lymphodepletion chemotherapy, as well as at multiple times following axi-cel infusion. Ninety-six percent of patients had adequate DNA to identify a clonotype to track over time at study enrollment, and 60 patients had an adequate sample for analysis at day 28 after axi-cel infusion. There are several key findings in this study. The first key finding is that circulating tumor DNA may serve as a surrogate for tumor burden. A lower level of circulating tumor DNA was associated with both improved disease and toxicity outcomes. Patients who had a lower baseline circulating tumor DNA had improved progression-free and overall survival, as well as less severe cytokine release syndrome and immune effector cell associated neurotoxicity syndrome.  A second key finding of this study is that circulating tumor DNA can serve as a marker for minimal residual disease in large B-cell lymphoma patients treated with CAR T-cells, and can be predictive of disease relapse. Seventy percent of patients who had durable response were negative for circulating tumor DNA one week following CAR T infusion. All patients with disease progression had at least one sample that was positive for minimal residual disease, and all but one were positive for minimal residual disease concurrently with radiographic progression. At day 28-post CAR T-cell treatment, negativity for minimal residual disease by circulating tumor DNA was strongly associated with improved progression-free and overall survival.   A third key finding in this study was that positivity for minimal residual disease was highly predictive in patients who have a partial response or stable disease at day 28-post CAR T-cell treatment. Deepening of response over time has been reported with various CAR T-cell treatments suggesting that there are limitations of PET CT to assess response, particularly at early time points. In the patients who had stable disease or partial response who were positive for minimal residual disease at day 28 following axi-cel, 15 of 17 patients had a progression-free survival event, while only two of ten who were negative for minimal residual disease had a progression-free survival event. This study has multiple implications for future clinical research, which may influence routine clinical care over time. High tumor burden defined by the sum of product diameters or metabolic tumor volume has been associated with both treatment failure and excess toxicity with axi-cel, as well as tisagenlecleucel. As a potential surrogate for tumor burden, baseline circulating tumor DNA could be useful in determining high-risk groups to target for clinical trial participation. Additionally, this could be a stratification factor for randomized studies involving CAR T-cells. Additional studies with axi-cel as well as tisagenlecleucel and lisocabtagene maraleucel, which are also commercially available for large B-cell lymphoma, are important to confirm this observation. Management of patients who initially achieve a partial response or have stable disease at the first disease assessment is a common clinical problem in patients with large B-cell lymphoma treated with CAR T-cells. A proportion of patients with large B-cell lymphoma who initially have partial response or stable disease will go on to develop a complete response over time. This has been reported in all of the commercially available anti-CD19 CAR T-cell products. In the ZUMA-1, JULIET and TRANSCEND trials, approximately one third to one half of patients who initially had partial response or stable disease went on to achieve a complete response. Patients who ultimately have progressive disease have poor outcomes with a median overall survival of 180 days. Those who have stable or progressive disease as best response have a medial overall survival of only approximately 50 days. Predicting which patients are at risk to relapse is important given the small window of time to intervene. It would also potentially spare low risk patients from additional therapy, which may be difficult to tolerate given the acute toxicity of CAR T-cell therapy, as well as the prolonged hematologic toxicity seen in some patients. Disease progression following anti-CD19 CAR T-cell therapy is a pressing clinical problem in patients with large B-cell lymphoma and there is a need for clinical trials. Clinical trials should be considered in all patients who relapse following CAR T cell therapy. Early detection of relapse can help to facilitate enrollment prior to the development of complications related to progressive disease that may preclude their enrollment. There are now multiple clinically active, targeted therapeutics in large B-cell lymphoma, and a trial of maintenance or consolidative therapy could be considered in this population. This could target only the highest risk patients by using positivity for minimal residual disease as assessed by circulating tumor DNA as a criterion for inclusion. Alternatively, this could focus more broadly on the patients with stable disease or partial response, but given these results, outcomes by circulating tumor DNA status would be important secondary endpoints. Either way, circulating tumor DNA would be critical to the study design and interpretation of results. This concludes this JCO Podcast. Thank you for listening. 

Venetoclax in combination with FLAG-IDA chemotherapy shows safety and promising efficacy in both untreated and relapsed/refractory AML in this phase 1b/2 study, providing a strong rationale for phase 3 trials incorporating this agent in patients fit for intensive therapy.   TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Venetoclax Combined with FLAG-IDA Induction and Consolidation in Newly Diagnosed and Relapsed/Refractory Acute Myeloid Leukemia” by DiNardo et al. My name is Richard Dillon, and I am a Clinical Senior Lecturer in Cancer Genetics at King’s College London and Consultant Hematologist at Guy’s Hospital, London, UK. My oncologic specialty is Adult Acute Myeloid Leukaemia. I'd like to note that my institution receives research funding support from Abbvie.   The recently published VIALE-A and VIALE-C trials demonstrated significant efficacy of venetoclax when added to low dose chemotherapy in patients with newly diagnosed AML who cannot receive intensive chemotherapy due to their age or comorbidities. Venetoclax has now become the standard of care for these patients, and there is growing interest in investigating how the potent anti-leukemic efficacy of this agent can be exploited in younger patients, who are fit to receive intensive treatment with curative intent. To date, only a small number of studies have addressed this important question.   In the front-line setting, a phase 1b study performed in Australia by Chua and colleagues tested the addition of 14 days of venetoclax to a regimen consisting of 7 days of infusional cytarabine and two doses of idarubicin for patients aged over 65 with previously untreated AML. This was well tolerated, and the overall response rate was 72%: 97% in patients with de-novo and 43% in patients with secondary AML.   Karol and colleagues from St. Jude’s Children’s Hospital performed a phase 1 study testing the combination of 28 days of venetoclax with varying doses of cytarabine and idarubicin in children with relapsed or refractory AML. At the recommended phase 2 dose, which was 600mg of venetoclax and eight doses of 1000mg per square meter cytarabine, with or without idarubicin, the overall response rate was 70%. Importantly, for children who received a lower dose of cytarabine (20 doses of 100mg per meter square), the response rate was markedly lower at 33%.   In the study referred to in this podcast, DiNardo and colleagues combined venetoclax with the FLAG-IDA regimen. FLAG-IDA is an intensive chemotherapy schedule incorporating high-dose cytarabine, typically used for patients with refractory or relapsed AML. And in this setting, overall response rates between 50 and 60% have been reported. FLAG-IDA has also been used in patients with newly diagnosed AML—for example, in the UK NCRI AML15 study, where the overall response rate was 86% and 5-year overall survival was 44%.   The current study comprised a phase 1b dose escalation in patients with relapsed or refractory disease, followed by a phase 2 dose expansion in both newly diagnosed and relapsed or refractory patient cohorts. In total, 68 patients were treated with the venetoclax FLAG-IDA combination. As expected, this combination was severely myelosuppressive, and during the dose-escalation phase, a number of alterations were made to the schedule to mitigate this toxicity, including reductions in the cytarabine dose to 1.5g per meter square and the length of venetoclax treatment to two weeks in induction and one week in consolidation. With these modifications, hematological toxicity at the recommended phase 2 dose was manageable. The time to count recovery was 31 days for previously untreated patients and 37 days for patients with relapsed or refractory disease and was not prolonged in patients who had undergone previous allogeneic stem cell transplantation. Haematological toxicity was more severe in the second cycle of treatment with 59% of patients experiencing delayed count recovery beyond day 45. Nevertheless, day 60 mortality was low at 4.4%.   The response rates observed in this study were impressive. At the recommended phase 2 dose, 97% of newly diagnosed and 70% of relapsed or refractory patients had achieved a composite complete remission, which included CR, CRi and CR with partial hematological recovery, CRh. CR or CRi was achieved in 72% and 48%, and MRD negativity by flow cytometry was achieved in 89% and 48% of patients with newly diagnosed and relapsed or refractory disease, respectively.   Although the number of patients was too small to reliably identify molecular and cytogenetic groups with a differential response, patients with relapsed or refractory AML with genotypes previously reported to be particularly sensitive to venetoclax containing regimens, which are NPM1, IDH1 and IDH2, appeared to have a particularly high rate of response with a composite CR rate of 100% and 12-month overall survival rate of 83%. In addition, the 7 patients with MLL rearrangements appeared to do particularly well, with a composite CR rate of 100% and 80% of patients testing negative for MLL fusion transcripts by PCR. One-year overall survival in this group was 80%, possibly highlighting MLL-rearranged leukemias as an additional group with particular sensitivity to BCL2 inhibition. This signal was not apparent in earlier trials using low doses of chemotherapy, perhaps because MLL rearrangements are much less frequent in older adults, or alternatively perhaps because this lesion requires higher doses of chemotherapy to synergise with BCL2 inhibition to overcome the apoptotic threshold.   On the other hand, there appeared to be some groups with less favorable responses. Patients with core-binding factor leukemias appeared to do less well than expected, with a median overall survival time of 7.6 months. Patients with these leukemias were excluded from the earlier phase 2 and 3 studies of venetoclax, so there is no prior clinical data regarding their sensitivity to BCL2 inhibition; however, this finding does concur with in vitro data suggesting a lack of sensitivity.   The outcomes for patients with TP53 mutations were disappointing with a median overall survival time of 9 months for newly diagnosed and 7 months for relapsed patients. Interestingly, even in the four TP53-mutated patients who tested MRD negative by flow cytometry, the TP53 mutation was still detectable by next-generation sequencing after treatment. The number of patients in these groups were small and will require confirmation in larger studies; however, alternative treatment strategies might be required for these patients.   Overall, these results appear extremely promising and suggest that venetoclax may have significant activity when used with intensive induction or salvage chemotherapy schedules in younger adults. This now needs to be confirmed in randomized trials comparing intensive chemotherapy with and without venetoclax in both the front-line and salvage settings. If these trials are positive, further comparative studies will be needed to define the best chemotherapy schedule to combine with venetoclax. While limited data indicate that standard doses of cytarabine are likely inadequate, the optimal dose of cytarabine, and the additional value of fludarabine and anthracyclines remains to be defined. Nevertheless, the study by DiNardo and colleagues represents a significant step forward in the deployment of venetoclax in young fit adults, with the hope that this will increase the rate of long-term cures from this aggressive and frequently fatal hematological malignancy.   This concludes this JCO Podcast. Thank you for listening.

This podcast comments on a large registry study evaluating the effect of ultra-high-resolution HLA typing on outcomes of unrelated donor transplantation.   TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article ‘Impact of Previously Unrecognized HLA Mismatches Using Ultra-High-Resolution Typing in Unrelated Donor Hematopoietic Cell Transplantation” by Mayor et al. My name is Navneet Majhail, and I am the Director of the Blood and Marrow Transplant Program and the Vice-Chair for the Department of Hematology and Medical Oncology at the Taussig Cancer Institute, Cleveland Clinic. My oncologic specialty is transplantation and cellular therapy.    For patients who are potential candidates for allogeneic hematopoietic cell transplantation, the first critical step is finding an HLA-matched donor. The HLA genes are located within one of the most gene rich regions of the human genome, are highly polymorphic, and encode proteins that critically modulate the body’s immune responses against a variety of stimuli. When selecting an unrelated bone marrow or peripheral blood stem cell donor, we typically try to identify donors who are matched at HLA genes where polymorphism is predominantly present, namely, class I genes HLA-A, -B, -C, and class II genes HLA-DRB1, -DQB1 and –DPB1. Guidelines recommend using a donor who is matched at least at HLA-A, -B, -C, and –DRB1, and preferentially at -DPB1 and -DQB1 as well.    Graft-versus-host disease or GVHD is an immune-mediated complication that continues to be a major threat to successful patient outcomes after hematopoietic cell transplantation. Better matching between the donor and the recipient lowers risk of GVHD, and guidelines recommend use of an HLA 8/8 matched unrelated donor, though in clinical practice we prefer an HLA 10/10 and even a 12/12 matched donor if one is available. In the past, HLA typing methods used ‘antigen-level’ serological testing. However, with advances in technology, the field has moved on to ‘allele-level’ or high-resolution typing which can discriminate among HLA genes that encode cell-surface proteins that ultimately constitute the antigen recognition domain, which is the functionally active portion of the HLA molecule that ultimately interacts with T-cell and NK-cell receptors. Research has shown that matching at allele-level is associated with lower risks of GVHD and better survival compared to historical serotyping-based methods, and DNA-based HLA-typing is the current standard of care.    Further advances in technology to next-generation sequencing or ultra-high-resolution typing can now allow characterization of the full HLA gene sequence. This has raised the question of the clinical significance of HLA polymorphisms in regions outside the antigen recognition domain. Prior studies in smaller cohorts of patients have raised the possibility that transplants using ultra-high-resolution matched donors may be associated with better survival and lower risks of acute GVHD. To definitively validate these findings, Mayor et al conducted a study in a cohort of >5,000 allogeneic transplant recipients from the Center for International Blood and Marrow Transplant Research. Patients had received a matched unrelated donor transplant for acute leukemia or MDS between 2008 and 2017. The manuscript that accompanies this podcast provides details of their study population, but overall their cohort was fairly representative of unrelated bone marrow and peripheral blood stem cell transplant recipients.     To summarize some key findings of their study, first, among donor-recipient pairs deemed HLA 10/10 match using high-resolution typing, 18% were found to not be a 10/10 match on ultra-high-resolution typing. Overall, only 12% of patients had a 12/12 ultra-high-resolution matched donor. Second, overall survival was comparable between patients receiving 12/12 ultra-high-resolution matched and mismatched transplants. Furthermore, there was no association of survival with the degree of ultra-high-resolution mis-match, that is, the number of loci where there was a mismatch. Similarly, when considering a subgroup of patients who were ultra-high-resolution matched at 10/10 loci, there was no difference in survival between patients who were 12/12 matched, that is, matched at DPB1, and those permissively or non-permissively mis-matched at DPB1. The authors did report an association of ultra-high-resolution matching with acute GVHD for their whole cohort, and associations with GVHD and transplant-related mortality in some subgroups, and I refer you to their JCO manuscript for details.      There are some caveats to consider in applying their findings to clinical practice, and a good study always leads to more questions. The probability of finding an adult HLA 8/8 high-resolution matched unrelated donor varies from 16% to 75% depending on recipients race and ethnicity – the chances of finding a 10/10 or 12/12 donor who is ultra-high-resolution matched is going to be significantly lower. How do we factor in the role of other known non-HLA unrelated donor selection factors such as donor age, donor sex, CMV status, ABO type, and graft source vis-à-vis ultra-high-resolution matching? Even in this highly selected cohort of patients who were actually able to get a transplant, nearly 90% did not have a 12/12 ultra-high-resolution matched donor – in this setting, how do mismatches at different loci compare with respect to outcomes? Do we change our transplant conditioning and GVHD prophylaxis regimens in ultra-high-resolution mis-matched unrelated donor transplants to reduce the risk of GVHD? Several studies have indicated comparable survival between matched unrelated donor and haploidentical related donor transplants – does the use of an ultra-high-resolution 10/10 or 12/12 HLA matched donor offer any outcome advantage compared to the haploidentical transplantation? Taken together and at this time, their findings are primarily applicable to patients who have the luxury of choosing from several young 10/10 HLA matched unrelated donors. Cost of HLA typing using next-generation sequencing is also a factor that needs to be considered.    Notwithstanding these ‘yet to be answered’ questions, there are advantages to ultra-high-resolution typing, and current technology does allow for rapid and unambiguous characterization of HLA genes with a rapid turnaround time. Many HLA labs are already implementing third-generation typing methods, and with increasing use and demand, it is expected to become cheaper and will no longer be cost-prohibitive.    Overall, with HLA-identical sibling, matched unrelated, haploidentical related, mis-matched unrelated, and umbilical cord blood, nearly all patients who need a transplant have a donor. It is heartening to see that our research has pivoted from “Is there a donor available?” to “What is the best donor?” for a given patient.     This concludes this JCO podcast. Thank you for listening. 

The PENELOPE-B phase III trial did not show a benefit to the addition of one year of the CDK4/6 inhibitor palbociclib to adjuvant endocrine therapy in patients with hormone receptor-positive/HER2-negative breast cancer and residual disease after neoadjuvant chemotherapy.   TRANSCRIPT This JCO podcast provides observations and commentary on the JCO article “Palbociclib for Residual High-Risk Invasive Hormone Receptor-positive, HER2 negative Early Breast Cancer – The PENELOPE-B Trial,” by Sybille Loibl and colleagues. My name is Erica Mayer, and I am a clinical investigator at the Dana-Farber Cancer Institute in Boston, MA who specializes in breast cancer. Since the initial approval of the CDK4/6 inhibitor palbociclib in 2015, this class of agents has become a standard part of management for most patients with hormone receptor positive HER2 negative advanced breast cancer. Use of one of the available CDK4/6 inhibitors - palbociclib, abemaciclib, or ribociclib - in combination with endocrine therapy, improves progression-free, and even overall survival, in the advanced disease setting, as shown in the respective trial series PALOMA, MONARCH, or MONALEESA. Although differentiated by their toxicity profiles, with palbociclib and ribociclib contributing more neutropenia and abemaciclib more diarrhea, across-the-board the benefit gained from use of these agents is remarkably preserved between trials, without apparent differential drug activity. Following the observation of benefit from use of CDK 4/6 inhibitors in the advanced setting, clinical trials evaluating the three available agents were subsequently launched to evaluate these agents in the adjuvant setting, after prior treatment with surgery, chemotherapy, and radiation if necessary. The first two trials to report in 2020, PALLAS and MONARCH-E, enrolled patients with early hormone receptor positive HER2- breast cancer, randomizing them to receive a CDK 4/6 inhibitor, palbociclib or abemaciclib respectively, for a planned 2-year duration, in addition to ongoing adjuvant endocrine therapy, versus ongoing adjuvant endocrine therapy alone. Notably, PALLAS enrolled patients with stage II and III breast cancer, whereas MONARCH-E targeted a high-risk group identified by tumor size, nodes, and Ki67 status. Initial reports from these trials were presented at an interim follow-up of about 20-24 months, a time when many were still receiving the combination therapy. The MONARCH-E analysis demonstrated a benefit from the addition of abemaciclib to endocrine therapy in prolonging invasive disease-free survival. This benefit was not observed with the addition of palbociclib in the PALLAS trial. The ongoing NATALEE trial, offering 3-years of reduced dose ribociclib in a similar setting, continues accrual. It is within this context that we place the PENELOPE-B trial. This trial enrolled the highest risk patients with early HR+/HER2- breast cancer: those with residual disease after preoperative chemotherapy and a high CPS-EG score, which is a calculation of anatomic stage and tumor biology meant to identify patients at highest risk of cancer recurrence. A total of 1250 patients were randomized to receive either one year of adjuvant palbociclib with ongoing adjuvant endocrine therapy, or placebo with endocrine therapy, and followed for a primary endpoint of invasive disease-free survival.  As expected, the study enrolled a very high-risk population, with many patients having at least T2 disease and 4 involved lymph nodes at time of surgery. At a median follow-up of 43 months, no difference in invasive disease-free survival was observed, with a 4-year iDFS of 73% in the intervention arm, versus 72.4% in the placebo arm. No clinicopathologic subgroup appeared to derive benefit from the research intervention. The toxicity experience was similar to that seen in the metastatic setting, with notable and expected hematologic toxicity, but no significant difference in overall non-hematologic adverse events. Overall, drug exposure was satisfactory, with about 17% of patients unable to complete the planned 1-year duration of therapy. The PENELOPE-B study makes its mark in the adjuvant CDK4/6 landscape in several important ways. First, PENELOPE-B has the greatest duration of follow-up, allowing analysis of mature data and outcomes during and following adjuvant CDK4/6 inhibition. Although it is tempting to interpret a slight visual divergence of the Kaplan Meyer curves during the palbociclib exposure, where there is an absolute difference in iDFS of 4.3% at 2 years, there is no statistical evidence that the 2-year iDFS estimates are different between the two arms, and therefore no evidence of time-dependent efficacy. Importantly, in regard to experiences within the other CDK4/6 inhibitor trials, which have reported at an earlier time point, longer-term follow-up of those trials will be necessary to determine stability and maturity of the observed results. Additionally, PENELOPE-B is the only placebo-controlled trial presented to date. For that reason, the toxicity data presented represents the purest description of the experience of receiving a CDK4/6 inhibitor in the adjuvant setting in a population with prior chemotherapy exposure. Finally, when discriminating among the CDK4/6 inhibitors study populations, it is important to remember that PENELOPE-B enrolled a population of greatest established risk, suggesting any apparent differential outcome among the trials is unlikely related to differing baseline risk of accrued patients. Overall, PENELOPE-B represents a significant contribution to the breast cancer field, and substantially adds depth and dimension to the exploration of CDK4/6 inhibitors in the adjuvant setting. At the time of publication, it is unclear if an approved role will emerge for a CDK4/6 inhibitor in adjuvant therapy for our early breast cancer patients. Many questions remain regarding patient/tumor selection, agent differentiation, duration of therapy, and potential biomarkers. Importantly, the correlative analyses planned for all of the CDK4/6 inhibitor trials and molecular exploration of patient samples will substantially improve our understanding of the impact of these drugs in the early setting, and our overall ability to treat this subset of breast cancer. While waiting for these data, we should continue our focus on providing the best possible care for our patients with hormone receptor-positive, HER2-negative breast cancer who are being treated with endocrine therapy. This concludes this JCO podcast. Thank you for listening.

Current clinical characteristics and demographics are not sufficient to capture aggressive disease in clinical trials of newly diagnosed DLBCL. Novel tools, such as measurement of tumor burden via ctDNA, are needed.   TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Short Diagnosis-to-Treatment Interval is Associated with Higher Circulating Tumor DNA Levels in Diffuse Large B-Cell Lymphoma” by Alig et al. My name is Matthew Maurer, and I am a statistician at the Mayo Clinic in Rochester, MN. My oncologic specialty is lymphoid malignancies. I have no relevant conflicts to disclose. The impact of any clinical research critically depends upon participating subjects being representative of the study population afflicted with the disease of interest and research efficiency is markedly enhanced when cohorts can be compared across studies. In newly diagnosed diffuse large B-cell lymphoma (DLBCL), there is a standard group of clinical variables that is typically captured and reported across studies. The International Prognostic Index, or IPI has been utilized as a prognostic model in aggressive lymphoma for nearly 30 years and remains relevant today. The IPI and its components, which consist of age, performance status, LDH, stage, and number of extranodal sites, provide the clinical characteristic backbone for trial eligibility and defining high risk disease in frontline DLBCL trials. Assessment of genomic features of the tumor using pathological techniques such as IHC and FISH can further identify high risk subsets of patients. However, despite these well-tested clinical tools to measure the aggressiveness of the disease, there remains significant heterogeneity in patient presentation and outcomes. Clinically, some patients will present with a real or perceived clinical urgency to initiate therapy as soon as possible. This clinical urgency often precludes these patients from enrolling on frontline trials. My colleagues from the University of Iowa / Mayo Clinic Lymphoma SPORE and I explored this phenomenon in our observational lymphoma cohort study by evaluating the time between a patient’s diagnostic biopsy and their initiation of chemotherapy.  We found that this simple measure of diagnosis to treatment interval, or DTI, was highly informative in the setting of newly diagnosed DLBCL.  Patients with a shorter DTI were more likely to be symptomatic, have advanced stage disease, poor performance status, and elevated LDH. Further, patients with a short DTI had significantly inferior outcomes, even after accounting for the standard clinical details of the IPI. These results were validated in a cohort of clinical trial patients from the French Lymphoma Study Association as well as subsequent studies. These data suggest that clinicians are managing patients with aggressive disease more urgently, and our current set of clinical variables is not sufficient to describe and compare patients across studies. Despite its simplicity and retrospective prognostic ability, DTI lacks specificity as a clinical characteristic for future studies. It can be easily influenced in an individual patient by numerous aspects unrelated to disease biology, such as physician preference or a patient’s available access to health care resources. In additional, the typical DTI can vary widely across health systems or institutions. In the paper accompanying this podcast, Alig and colleagues examine the relationship between DTI, conventional risk factors, circulating tumor DNA, and clinical outcomes. A strong association was observed between shorter DTI and increasing tumor burden as measured by baseline metabolic tumor volume and circulating tumor DNA. This is a key biologic confirmation that treatment urgency is directly related to disease biology. Importantly, the authors also showed that ctDNA was a highly informative variable in regards to prognosis in their dataset. ctDNA was an independent prognostic variable after adjusting for the IPI in Cox models for event-free and overall survival, and the prognostic ability of ctDNA was far superior to DTI in univariate models. The association between DTI and disease biology has direct implications for clinical trials in frontline DLBCL. Clinical trials that did not adequately enroll patients in need of urgent therapy were likely biased towards enrollment of patients with lower tumor burden.  In particular, single arm trials of novel therapies are particularly at risk, as these results are often evaluated in light of conventional clinical characteristics and compared to previous studies and/or clinical experience. This may also have contributed to the better than expected outcomes on the control arms in recent randomized trials of newly diagnosed DLBCL. Evaluation of tumor burden using ctDNA or metabolic tumor volume should allow us to better understand the impact of a study’s design on patient enrollment. The amount of tumor is a long-standing prognostic feature for newly diagnosed DLBCL. This has standardly been measured by broad clinical features such as stage, number of extranodal sites, and bulky disease. As the retrospective studies on DTI have shown, however, these features are not sufficient. Novel tumor burden measures like circulating tumor DNA are needed. ctDNA is not without its drawbacks in frontline DLBCL.  It is not clinically available for real-time assessment and significant work remains to be done to make it a routinely available and standardized biomarker, which includes independent validation of the results reported by Alig and colleagues. However, as we continue to develop and test new treatment strategies for DLBCL, we must also develop and test novel prognostic and predictive tools. Alig and colleagues have shown us that ctDNA has the potential to identify features of aggressive disease that our current tools do not. Capturing these features more precisely is vital for us to understand and interpret clinical trial results, as well as ensure future trial designs are enrolling the study’s intended patient population. As part of these efforts, clinical trials in newly diagnosed DLBCL should collect and store the necessary biospecimens to evaluate ctDNA in anticipation of a new generation of standard clinical characteristics. This concludes this JCO Podcast. Thank you for listening.

This podcast considers the impact of exclusion criteria on clinical trials, generalizability, and the complexity of modernizing eligibility while maintaining trial integrity.   TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Impact of Organ Function-Based Clinical Trial Eligibility Criteria in Diffuse Large B-cell Lymphoma (DLBCL) Patients. Who Gets Left Behind?” by Khurana et al. My name is Richard Little, and I am at the National Cancer Institute. My oncologic specialty is lymphoid and myeloid malignancies. I am a federal employee with no conflicts of interest to disclose.    The authors have contributed a timely and provocative analysis examining the lack of generalizability and disappointing results of repeatedly negative randomized phase 3 trials conducted over the past 15 years failing to improve on R-CHOP.  The authors have proposed that these failures may be in part explained by enrollment onto clinical trials patients who are not really representative of those with the disease, because eligibility criteria too often unnecessarily eliminate patients with laboratory values that reflect organ impairment not pertinent to the agents under study.  To test this inference, the authors leveraged a unique resource:  The Molecular Epidemiology Resource of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence, or SPORE. This SPORE is an NCI-funded research project initiated in 2002 and collects data in a uniform manner among consenting participants with newly diagnosed DLBCL who undergo treatment managed by their physician. This rich database enabled the evaluation of data in patients treated with R-CHOP or R-CHOP-like immunochemotherapy.   The investigators were able to categorize the SPORE participants in reference to the eligibility criteria of the important phase 3 studies recently conducted as either meeting eligibility of the phase 3 studies or not meeting eligibility due to out-of-range laboratory values.  Additionally, the SPORE data in some ways mimics clinical trial data in that events such as disease progression and death are captured, and these outcomes could be evaluated comparatively between patients categorized as clinical trial eligible and not eligible.  They indexed 7 trials, and for example, found that 12.9% of the SPORE participants did not meet eligibility for the PHOENIX study—that is the phase 3 trial of ibrutinib-R-CHOP vs placebo-R-CHOP showing no benefit of the addition of ibrutinib. Not surprisingly, those scored as ineligible had worse outcomes compared to those scored as eligible. For example, indexing eligibility for the PHOENIX trial, the overall survival hazard ratio for those scored not eligible versus eligible was 1.49 with a p-value of .002. The median survival of the SPORE cohort scored as ineligible for PHOENIX had a median overall survival of around 80 months, and the median survival for those sored as eligible had not yet been reached. Interestingly, treatment-related deaths were not found to be increased in the SPORE patients scored as ineligible compared to those scored as eligible,  but death due to progressive lymphoma was higher among those scored as ineligible.    So how does this relate to the inability to improve upon standard DLBCL therapy?    Khurana and colleagues' data highlight several features of clinical trials conduct related to trial outcomes.  The unnecessary exclusion of patients based on criteria not specific to the treatment can translate into eligible patients having a more favorable prognosis compared to individuals with the disease who are excluded from studies, but who nevertheless are treated with standard therapy used as a control in DLBCL clinical trials.  Populating randomized trials with the best prognosis patients can lead to reduced power to detect an outcome difference, even if one exists.  But what about the unnecessary exclusion of patients from clinical trials based on laboratory values that reflect organ dysfunction and poor outcomes as shown in the SPORE patients?  The authors document unequivocally that those patients deemed ineligible are at higher risk of death due to treatment failure: that is they die due to progressive lymphoma more than the SPORE patients scored as meeting clinical trial eligibility criteria. What we don’t know from the study as presented, is whether there were more dose delays and dose reductions among those scored as ineligible. This is fundamental toward an improved understanding of how to repair our clinical trials enterprise in DLBCL.  And what I mean by repair, is to broaden and expand clinical trials access to as many patients as possible and to have rigorous design and conduct of trials to detect true signals. There are two essential elements to address, and this data points the way but does not fully answer the questions.  To make trials generalizable, we must include as broadly as possible those patients with DLBCL.  However, if the SPORE outcomes are explained by an inability to administer therapy as planned in those scored as trial ineligible, then just broadening eligibility criteria could undermine the ability to detect a difference with new effective treatment by including too many patients unable to tolerate the therapy.  For example, some have suggested the negative results of the PHOENIX trial may be due to treatment intolerance among those aged 60 years and over. So it appears that trials increasing generalizability and reaching a positive trial endpoint for a novel treatment have a complex interaction, to say the least. It will be essential as diffuse large B-cell lymphoma therapeutic trials are developed to be mindful of differential prognosis and perhaps interrelated treatment tolerance of patients due to multiple factors, including degree of organ dysfunction.  The exclusion of patients with the disease understudy from clinical trials should be minimized.  Efforts to modernize clinical trial eligibility are being embraced by most stakeholders, and in my opinion is an essential social and medical responsibility for clinical trialists to meet.  The challenge is how to accomplish this important objective and appropriately design studies to enhance the ability to detect the desired study endpoint. To answer the question posed by the authors, we must endeavor to leave no one behind. We can accomplish this through statistical designs such as stratification of the randomization,  powered for the groups of interest -- as one such solution. Separate and specific trials for older or more frail patients is another solution.  And I dare say, we should focus on efforts to eliminate the CHOP backbone and develop better-tolerated therapy that those with organ dysfunction can benefit from. The VIPOR regimen presented by Melani and colleagues at the 2020 ASH meeting provides an example of the type of DLBCL research that could be of interest. The challenge of generalizability and its relevance to negative clinical trial results is becoming clearer if only to recognize the increasing complexity in meeting the needs of our patients.  But isn’t that what motivates us?   This concludes this JCO Podcast. Thank you for listening.

This multi-institutional study highlights the heterogeneity of Phyllodes tumors of the breast and the importance of accurate pathology assessment and individualized surgical approaches.   LEE WILKE: This JCO podcast provides observations and commentary on the JCO article, Contemporary Multi-institutional Cohort of 550 Cases of Phyllodes Tumors from 2007 to 2017 Demonstrates a Need For More Individualized Margin Guidelines by Rosenberger, et al. My name Lee Wilke and I am a professor of surgery and the Hendrix chair in breast surgery research at the University of Wisconsin School of Medicine and Public Health in Madison, Wisconsin. My oncologist specialty is breast surgical oncology. I have no relationships to disclose related to these studies. As medical students we are asked to adopt an expanded vocabulary to describe a multitude of diseases. The word phyllodes is frequently one of those memorable medical school terms whose origin is Greek and describes a leaf-like growth. Phyllodes are rare tumors accounting for less than 1% of breast malignancies, with just over 2,000 patients diagnosed annually in the United States. Originally, the phyllodes tumor was described as cyst like and, therefore, the historic term cystosarcoma phyllodes was applied. Though these tumors are of connective tissue and fibroepithelial origin, they are infrequently cystic and not a true sarcoma. And therefore, the World Health Organization now classifies them as simply phyllodes tumors. They are importantly, for treatment approaches, sub-categorized into benign, borderline, and malignant based on detailed pathologic review of celularity, atypia, overgrowth, mitotic rate, and the borders of the tumor. Phyllodes tumors are listed in the National Institute of Health's genetic and rare diseases program. On the center's website, surgery is described as the primary treatment for these rare malignancies and 1 centimeter margins or greater are recommended for all subtypes of phyllodes tumors, with a note that these tumors are quote, "often treated with mastectomy", unquote. As specialists caring for patients with breast malignancies, we are rapidly learning that the one-size-fits-all approach is not appropriate, and the same is true for those individuals with phyllodes tumors. In the article that accompanies this podcast, to support a shift towards more individualized treatment, Dr. Laura Rosenberger from Duke University in North Carolina assembled a group of key collaborators from 11 US academic cancer centers to pool and evaluate their treatment approaches and outcomes for patients with phyllodes tumors. The investigators identified a total cohort of 550 patients with phyllodes tumors treated between 2007 and 2017. Consistent with systematic reviews of phyllodes tumor data sets, such as that by Lu et al in Annals of Surgical Oncology, with this JCO publication being the largest, the patients have a median age of 44. The malignant cohort is approximately 10%. And median tumor size is three centimeters, with a range to as high as 29 centimeters. Key facts found within this analysis are that 2% of patients underwent nodal evaluation, all with negative nodes. The addition of either a sentinel node or axillary surgery is not without risks to the patient. And unless the pre-surgical diagnosis raises the question of a simultaneous adenocarcinoma, patients undergoing surgery for a phyllodes tumor should not undergo nodal mapping or axillary surgery as these tumors are primarily local malignancies and do not metastasize via the lymphatic network. This is the first key takeaway from this paper, supporting the work of others that nodal surgery in phyllodes tumors is unnecessary. The second notable finding is the heterogeneity, even among academic medical centers, regarding the surgical approach. Approximately 38% of patients, or 209, proceeded to a second surgical intervention. 51 of these patients, or nearly 10% of the entire cohort, had negative margins at their first surgery. Of the group that underwent a second surgery, only six patients, or 3% of those proceeding to a second intervention, had residual disease. On the opposite end of the spectrum, of those patients with a positive surgical margin, which was 42% of the entire group, 74, or 32% of those with positive margins, did not proceed with a second surgery. These outcomes highlight that even among patients being treated at centers that one would assume would function similarly, patients could have everything from positive margins to additional surgery in the setting of negative margins. What is vital to note at this point, however, is that the recurrence rate for this cohort was only 3.3% or 18 patients-- 15 with a local recurrence and three with a distant recurrence. The recurrences were differentially associated with the phyllodes subtypes, with 1.3% in benign, 5.6% in borderline, and 6.9% in malignant phyllodes. In univariate logistic regression analysis, however, margin status and margin width did not predict for a recurrence and neither did type of surgery or patient age. Clearly, a one centimeter margin for a phyllodes tumor is not needed, just as we are likely finding is true for our adenocarcinomas of the breast. The authors don't go so far as to state that a positive margin is acceptable, but highlight the need for a national registry to evaluate an individualized surgical approach in this rare patient population. A final and third key point from this retrospective but important pooled patient analysis is the primary role the pathologist plays in determining the patient outcome. As I frequently comment to my cancer patients, the pathologist is the most important doctor you never meet. In Dr. Rosenberger's analysis, factors that were influential for local recurrence were all pathological variables-- grade, extent of atypia and overgrowth and tumor size. Currently, there are no College of American Pathologists guidelines for reporting phyllodes tumors. With this and other patient data sets highlighting the importance of these pathologic factors in patient outcomes, perhaps a standardization and education program for identifying each of these key findings within a phyllodes tumor should be developed. Without a good pathologist or team of pathologists, oncologic surgeons lack the tools they need to advise the patient on additional surgery and potentially adjuvant therapy. As the use of adjuvant therapy was small in this data set, conclusions could not be provided for or against radiation therapy. Thus, as with all rare tumors, a collaborative and team approach with development of a national registry is needed across community and academic institutions to standardize and evaluate the outcomes for these patients with the eventual goal of providing a more tailored treatment approach. This concludes this JCO podcast. Thank you for listening.  

In this study of cancer operations conducted during the COVID-19 pandemic, rates of pulmonary complications and SARS-COV-2 nosocomial infections were compared between patients operated on in COVID-19-free facilities and those operated on in non-segregated facilities. Because lower rates of pulmonary complications and nosocomial SARS-COV-2 infection were observed in COVID-free facilities, the authors propose a restructuring of surgical facilities and pathways for cancer patients during the COVID-19 pandemic. This JCO podcast provides observations and commentary on the JCO article “Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International Multicenter Comparative Cohort Study, “ by Bhangu et al.  My name is Ken Tanabe, and I serve as Chief of Surgical Oncology at Massachusetts General Hospital, Professor of Surgery at Harvard Medical School, and Deputy Clinical Director of the Massachusetts General Hospital Cancer Center in Boston, Massachusetts.  My oncologic specialty is surgical oncology.   The devastation and destruction brought about by the SARS-CoV-2 pandemic is difficult to fully comprehend.  At time of this podcast there are more than 28 million infections worldwide and nearly 200,000 deaths in the United States alone. Hospitals and healthcare networks have been uniformly challenged to provide care and safety for patients and providers. In response to this initial wave, elective operations were cancelled as a strategy to increase critical care resources, preserve Personal Protective Equipment – or PPE, and re-deploy surgical team members to support care for COVID-19 patients.  On a worldwide basis, this amounted to cancelation of a substantial number of operations.  And a significant fraction of these backlogged operations was for cancer. Once hospitals recognized they could handle the size and peak of the initial wave, they resumed elective cancer operations.  Some hospitals had the capacity to create COVID-19 free surgical units for these operations, as a strategy to reduce the risk of cross-infection of patients.  Subsets of cancer patients are known to be at higher risk from COVID-19 morbidity and mortality, including those with lung cancer.  However, creation of parallel pathways for COVID and non-COVID cancer patients diverts resources and is associated with significant costs.  The relative value of this maneuver is not known, but is of critical importance, particularly in light of catastrophic hospital finances created by the pandemic.   In the article that accompanies this podcast, the authors studied the impact of creation of COVID-19-free surgical facilities.  Specifically, they gathered data from 445 hospitals in which patients underwent operation either in a COVID-19-free surgical pathway, or alternatively underwent operation in a hospital that did not have separate, COVID-free surgical units. The study included over 9,000 patients that underwent cancer operations during the pandemic.  Hospitals in 54 countries are included, though the United Kingdom, Italy, Spain and United States accounted collectively for over 60% of the patients.  A surgical facility was defined COVID-19 free if it had a policy of segregation of COVID-19 patients in three specific areas of the hospital: the operating rooms, the ICUs, and the inpatient units.  Conversely, a surgical facility was not considered COVID-19 free if this segregation was absent in any of these three areas.   There are several key findings.  First and foremost, patients who underwent surgery within COVID-free units were younger and had fewer comorbidities compared to patients operated on in non-segregated surgical units. After adjustment for these differences, pulmonary complication rates were lower amongst patients operated on in COVID-free units compared to those operated on in non-segregated surgical units. The post-operative SARS-COV-2 infection rate was lower in COVID-free surgical units – 2.1% compared to the 3.6% observed in non-segregated units. The preoperative COVID testing rate was higher in the COVID-19-free surgical units.  Specifically, the testing rate was 39% in the COVID-19-free surgical units and only 23% in the non-segregated facilities.  However, in a sensitivity analysis for patients with a negative preoperative swab test, the benefit of COVID-19 free pathways remained apparent. The authors conclude it is likely that differences in SARS-CoV2 transmission rates are responsible for the lower pulmonary complication rates in those operated on in COVID-19-free surgical units.   The authors cite these observations as the basis for their recommendation for, quote, “major international redesign of surgical services -- based on local available resources -- to provide elective cancer surgery in COVID-19-free surgical pathways.”  End quote.  Of note, there are many hospitals and healthcare networks in the U.S., let alone worldwide, that don’t have the resources required to create COVID-19-free operating rooms, ICUs and in-patient wards amidst a devastating pandemic.  And thus, it’s imperative to understand if that is really the lesson learned here.   It is relevant to point out that COVID-19-free surgical units – whether they cause a lower rate of post-operative complications or are merely associated with these outcomes – are sought out by patients.  In my own surgical practice, once we resumed operations after the initial COVID-19 wave, some patients declined or further delayed vital cancer operations for fear of SARS-COV-2 at the hospital, despite my assurances of the strict infection control policies in place.    There are certainly limitations to this study.  The first is that selection bias was present: patients that underwent operation in COVID-19-free surgical facilities were significantly younger and healthier.  Although statisticians have developed strategies to adjust risk in scenarios like this, these approaches do not always completely remove bias.  The second limitation is that this study took place at a time during which relatively few patients were COVID-19 tested prior to operation.  Some of the observed effect in this study may be related to unknown SARS-COV-2 infection in asymptomatic patients.  Only 27% of patients underwent preoperative SARS-CoV-2 testing in this study.  Going forward, all patients are tested prior to surgical procedures.  The current study suggests an effect even when the analysis is limited to patients that were tested preoperatively, but a more robust analysis of post-operative transmission of infection in non-segregated facilities can be performed when all patients are tested preoperatively.    Another important limitation of the study is that the definition of COVID-19 free surgical pathway was arbitrary in the degree of completeness.  In the context of this retrospective, multi-institutional international study, the definition was relatively broad for purposes of inclusion, but simultaneously lacks some common sense, requiring only complete segregation of operating rooms, surgical ICUs, and inpatient wards to separate COVID-19 infected patients from those without infection.    To be designated as a COVID-19 free facility for purposes of this study, it was not required to have segregated facilities for preoperative check-in, separate recovery rooms, separate emergency rooms for patients presenting with post-operative complications, or even separate equipment and staff.  What is the impact of sharing with COVID-19 areas patient transporters, EKG and X-Ray machines, food service racks, language translators, or use of common elevators and corridors, or even common pneumatic tube cannisters in a pneumatic tube system that runs throughout the facility?  If the best performing hospitals that don’t have COVID-19 free pathways perform better than the worst performing hospitals that do have COVID-19 free pathways, what is it that these hospitals are doing that makes the difference?    In short, it seems more than just plausible that establishing infection control Standard Operating Procedures – or SOPs, staff training, and staff adherence to these SOPs are key to controlling spread of infection.  These are likely as important as segregation of just three parts of perioperative care.  In other words, this study demonstrates an association between having separate peri-operative facilities and a reduction in pulmonary complications.  But this type of study is unable to address whether a causal link exists.  Perhaps hospitals with the capability of achieving this segregation through duplicate facilities simply have more resources.  Perhaps they have more capable hospital administration and support that can more quickly implement the newest infection control policies.   Perhaps they have more PPE for hospital staff.  Given that many hospitals and health care networks do not have sufficient resources to create parallel, segregated COVID-19-free facilities for operations, drilling down on these important operational aspects for control of disease transmission is key.   The time period involved in the current report was one during which hospitals were struggling to cope with several challenges.  Of note, between May 14 and July 14 CDC data reveal that an average of 120 patients a day became infected with SARS-COV-2 inside U.S. hospitals.  During this time hospitals were managing gaps in testing – as were evident in the current report – and shortages of PPE required to protect staff and patients.  CDC data suggests hospitals have improved at controlling nosocomial SARS-COV-2 infections since then, with the risk dropping from 2% in mid-May to 1.2% as of mid-July.   These promising results are likely the result of better infection-control methods employed over time.  The impact of this downward trend was exemplified in a study from Brigham and Women’s Hospital that demonstrated only 1 case of nosocomial SARS-COV2 transmission over 12 weeks of the pandemic in which 9,149 patients were hospitalized and 8,656 days of COVID-19-related care were provided.  The infection-control strategies they implemented were thorough, improved over time, and did not involve a COVID-19-free surgical pathway.  The most recent changes implemented in the Brigham and Women's study included enhanced eye protection for employees, universal testing on admission, daily nursing screening for COVID-19 symptoms, and a hospital-wide shift to N95 masks for routine COVID-19 care.    The current study focused on cancer operations, but does control of SARS-COV-2 transmission inside hospital surgical units have as much impact on other kinds of operations? Yes, the observations are relevant more broadly.  Cancer patients are at greater risk for developing severe complications from COVID-19.  But a large segment of the adult population has at least one underlying risk factor for increased susceptibility to infection, as well as increased likelihood of severe complication or mortality.    Razzaghi et all have determined that the prevalence of any of five underlying, non-cancer conditions associated with increased risk for severe COVID-19–associated illness among U.S. adults is 47.2%.  Moreover, particular races have significant higher risk of infection and higher risk of severe complications.    Some health care systems have the resources to create separate surgical units to control nosocomial transmission.  But going forward, it appears that reducing in-hospital transmission of SARS-COV-2 to cancer surgery patients will rely primarily on rigorous implementation of aggressive and widely accepted infection control policies.   This concludes this JCO Podcast. Thank you for listening.

This podcast reviews the results of the whole genome sequencing study by Samur and colleagues that identified a genomic signature associated with superior survival in patients with newly diagnosed multiple myeloma. Disclosures: SAH has served on advisory boards or as a consultant for Adaptive Biotechnologies, Amgen, Celgene, Genentech, GSK, Oncopeptides, Sorrento; Takeda; has received research funding from Oncopeptides.     This JCO Podcast provides observations and commentary on the JCO article “Genome-Wide Somatic Alterations in Multiple Myeloma Reveals a Superior Outcome Group” by Samur et al. My name is Sarah Holstein, and I am an Associate Professor at the University of Nebraska Medical Center in Omaha, Nebraska in the United States. My oncologic specialty is plasma cell dyscrasias. I do not have any relationships to disclose related to these studies. The clinical heterogeneity of myeloma has long been appreciated as it is clear there is a broad range of disease behavior, with some patients having indolent disease and others having very aggressive disease. As a result, there has been significant interest in developing risk stratification systems that classify patients into different risk groups, thus providing some information about prognosis and potentially inform treatment decisions. Historically, staging systems were based on factors related to tumor burden. However, it is increasingly evident that the underlying disease biology is a key modulator of risk. Our ability to detect disturbances in the myeloma genome has changed dramatically over time. Metaphase karyotyping represents our lowest “power of magnification”. These studies led to the recognition that in general, hyperdiploidy involving odd-numbered chromosomes is associated with lower-risk disease while high-risk disease can involve translocations of chromosome 14, monosomy 13 and monosomy 17. Use of fluorescent in-situ hybridization (FISH) allowed for a higher power of magnification and identification of more subtle chromosomal abnormalities. Next, gene expression profiling studies utilizing small panels of genes, enabled classification of patients into different risk categories, although there was little concordance between the panels used in the various studies. The advent of deep whole genome sequencing technology has facilitated a much more “high-powered” view of the myeloma genome. In the article that accompanies this podcast, diagnostic bone marrow specimens were obtained from 183 patients enrolled in the IFM/DFCI 2009 study. This phase 3 study enrolled newly diagnosed transplant-eligible patients (up to age 65). All patients received three cycles of lenalidomide, bortezomib, dexamethasone (RVD) induction, underwent stem cell collection and then received consolidation with either 5 cycles of RVD or a single autologous stem cell transplant followed by 2 cycles of RVD. Of note, in the French portion of this study, all patients subsequently received one year of lenalidomide maintenance, while in the US portion, all patients received lenalidomide until progression. The French portion has already been published and showed a 14 month PFS benefit for the transplant arm compared to the non-transplant arm. Results from the US portion have not yet been released, but I would speculate that the PFS and OS for both arms will be superior to the French counterparts, given the existing data supporting the benefit of prolonged lenalidomide maintenance. Deep whole genome sequencing, with a median tumor depth of 75X, was used to interrogate the myeloma genome. Mutational signatures were based on identified single nucleotide variants, small insertions and deletions. The genomic scar score (GSS) was calculated based on allele-specific copy number alterations. A GSS of 5 or less was the cut-off for inclusion in the low GSS group. The goals of the study were to describe mutational loads and processes in order to establish genomically-defined subgroups, gain insight into patterns of evolution from clonal to subclonal mutations, and correlate these findings with clinical outcomes and more traditional risk factors. There were several key findings. First, mutational load varied amongst myeloma subgroups, with hyperdiploid myeloma having the lowest mutational load and t(14;16) having the highest mutational load. Second, analysis of mutational patterns led to identification of five separate mutational processes that contributed to eight mutational signatures. These five processes included: 1) an age-related process, 2) an AID/APOBEC process, 3) somatic hypermutation, 4) DNA repair, and 5) processes with unidentified etiology including the clock-like signature. Samur et al., found that these various processes contributed to different myeloma subgroups in different ways. For example, the age-related process was high in hyperdiploid myeloma, the APOBEC-related process was high in t(14;16) myeloma, the clock-like signature was high in t(4;14) myeloma and the DNA repair process was high in del(17p) and t(11;14) myeloma. Furthermore, analysis of these mutational patterns from a clonal vs subclonal perspective enabled insight into mutational development patterns of different subgroups of myeloma. Next, the GSS was correlated with mutational signature and clinical outcome data. The authors found that the frequency of a low GSS was higher in t(11;14) myeloma and lower in del17p, gain1q21, del1p and del13 subgroups. Patients in the low GSS group had a trend towards a longer median PFS and a statistically significant longer 4-year OS rate than other patients. In particular, patients with both low GSS and gain of chromosome 9 had a superior outcome compared to all other subgroups, with an OS probability of 100%. Patients with either low GSS and no gain(9) or with high GSS and gain(9) had intermediate outcome while those with high GSS and t(4;14), gain(1q) or no gain(9) had the worst OS. Although the numbers are quite small, an interesting finding was that for patients in the low-risk group (low GSS + gain(9)), there was a significantly superior PFS in favor of those patients in the transplant arm compared to the non-transplant arm. Overall, no statistically significant differences were found between the four subgroups and factors such as ISS stage, response, or achievement of MRD negativity.  The numbers in each subgroup were quite small though. Finally, the authors demonstrated that the low GSS could separate hyperdiploid myeloma into low-risk and high-risk subgroups. Overall, these studies are interesting because they provide insight into the mutational processes that drive different subgroups of myeloma and offer a potential method by which to differentiate low-risk hyperdiploid myeloma from high-risk hyperdiploid myeloma. The finding that there was a difference in PFS for patients who underwent transplant vs no transplant in the low-risk group (low GSS, gain(9)) is very intriguing. There has been much discussion centered around whether low-risk patients really “need” to go through a stem cell transplant since in general their outcomes are good. The present study, aside from highlighting the fact that our traditional methods of identifying low-risk disease are likely inadequate, raises the hypothesis that patients with low-risk disease may benefit even more from transplant than other risk groups. However, it is noted that this subgroup consisted of only 28 patients. In addition, it is not clear from the manuscript whether patients were in the US vs French portion of the study, thus differences in study design (i.e., lenalidomide maintenance duration) could impact PFS findings. Clearly, this type of whole genome sequencing analysis will need to be applied to additional prospective studies in order to validate the novel risk stratification system. For now, these results are not practice-changing. However, they provide a potential glimpse into the future, where whole genome sequencing analysis is performed as readily as FISH analysis, and where enrichment strategies using genomic markers are used to design clinical trials. Aside from studies evaluating the use of venetoclax in t(11;14)-positive myeloma and other studies focused on high-risk disease that encompass a variety of high-risk chromosomal abnormalities, the field of myeloma has not yet moved into an era of precision medicine. Whether whole genome sequencing can finally usher us into that era remains to be determined. While this plasma cell-centric analysis is certainly revealing, it is likely that in order to maximally target myeloma, the genomics analysis must be coupled with an equally in-depth understanding of the host’s immune system. This concludes this JCO Podcast. Thank you for listening.

This podcast describes a study addressing the use of dexrazoxane as a cardioprotectant in a cohort of more than 1,000 pediatric acute myeloid leukemia patients.   Transcript This JCO Podcast provides observations and commentary on the JCO article “Effect of Dexrazoxane on Left Ventricular Systolic Function and Treatment Outcomes in Patients with Acute Myeloid Leukemia: A Report From the Children’s Oncology Group” by Getz et al. My name is Elvira van Dalen, and I am an epidemiologist at the Princess Máxima Center for Pediatric Oncology in Utrecht, The Netherlands and a Coordinating Editor of Cochrane Childhood Cancer. My oncologic specialties are cardiotoxicity and systematic reviews and guidelines in the field of pediatric oncology. I have nothing to disclose. Anthracyclines are widely used in pediatric oncology. Unfortunately, one of their most serious adverse effects is cardiotoxicity, which can occur during or shortly after treatment, but also decades later. In the Dutch LATER Childhood Cancer study, we found a 10.5% cumulative incidence of symptomatic heart failure 40 years after cancer diagnosis in survivors treated with cardiotoxic chemotherapy. The Childhood Cancer Survivor Study and St Jude LIFE show similar results. Siblings report significantly less congestive heart failure than survivors. These are high risks, especially in this young patient population. Cardiotoxicity impairs quality of life and can lead to premature death. Prevention is thus very important. Extensive research has been devoted to the identification of possible cardioprotective interventions, like liposomal anthracyclines, increasing the anthracycline infusion duration and reducing the cumulative anthracycline dose. Concerning the cumulative anthracycline dose, it should be kept in mind that there is no safe dose. Another option is the use of cardioprotective agents like dexrazoxane. As shown in our Cochrane systematic review published in 2011 which is currently being updated, it prevents cardiac damage. But unfortunately, the majority of the evidence comes from studies addressing adult patients with breast cancer and these data cannot be extrapolated to children. In children as of yet only a few randomized trials have been performed, none including acute myeloid leukemia patients. In these pediatric studies, for clinical heart failure there were no significant differences between dexrazoxane and control groups, while results for asymptomatic cardiotoxicity varied with the outcome definition used. All studies were relatively short-term, and we don’t know how longer follow-up will influence these results. Thus far only a few small non-randomized studies including 50 children or less evaluated dexrazoxane in pediatric acute myeloid leukemia, all with limitations. The article by Getz and colleagues that accompanies this podcast adds important new information to the current knowledge of the use of dexrazoxane in pediatric acute myeloid leukemia patients and pediatric patients in general. It presents the results from the Children’s Oncology Group AAML1031 trial investigating the use of dexrazoxane during frontline treatment of pediatric acute myeloid leukemia. Between 2011 and 2016, patients younger than 30 years at diagnosis were enrolled. Almost 98% were younger than 21 years. The analyses included 1014 patients, of which 10% received dexrazoxane consistently at every anthracycline course and 90% were never exposed to dexrazoxane. Anthracycline treatment involved both daunorubicin and mitoxantrone. Low risk patients received a cumulative anthracycline dose of 444 mg/m2, while high risk patients received 294 mg/m2 assuming the daunorubicin equivalency conversion employed by the Children’s Oncology Group at the time of this protocol. Patients were followed for a median of 3.5 years, with an interquartile range of 2.5 to 4.7 years. Cardiac function was assessed using either echocardiography or multigated acquisition scans which were performed at regular intervals. Compliance with cardiac monitoring was more than 90% on-protocol, but less than 60% off-protocol. Left ventricular systolic dysfunction was primarily defined as a shortening fraction of less than 28% or an ejection fraction of less than 55%. In the report by Getz and colleagues that accompanies this podcast, 26.5% of patients consistently treated with dexrazoxane and 42.2% of patients that never received any dexrazoxane developed left ventricular systolic dysfunction. The hazard ratio was 0.55 with a 95% confidence interval of 0.36 to 0.86. There was a trend towards a worse grade of left ventricular systolic dysfunction without dexrazoxane. Some evidence pointed to recovery of systolic function, but as this was based on mean values instead of number of patients below the cut-off value it is possible that patients with good and bad values balanced each other out resulting in an adequate mean value. This can give the impression that there is no problem, while for some patients this might not be true. It is important to note that this was not a randomized trial, which would have provided the highest level of evidence to answer this type of question. Dexrazoxane was administered at the discretion of treating physicians. However, characteristics like sex, age, risk group, treatment arm, compliance with cardiac monitoring and follow-up were similar in both groups. Unfortunately, cumulative anthracycline dose was not reported for both groups, but it was stated that patients completed a median of 4 courses regardless of dexrazoxane exposure. An important question regarding any cardioprotective intervention is whether it can reduce cardiotoxicity without negative effects on anti-tumor efficacy and non-cardiac toxicities. At the moment, despite its clear cardioprotective effects, at least in adults, dexrazoxane is not routinely used in clinical practice. This might be explained by the suspicion of interference with anti-tumor efficacy and the occurrence of secondary malignancies. However, as shown in our Cochrane systematic review no significant differences between treatment groups were identified, which is in line with more recently published randomized trials. Studies often do not report data on anti-tumor efficacy and non-cardiac toxicities, but fortunately Getz and colleagues did. This is important as extrapolation of many of these data to other types of malignancies is difficult. Survival and relapse risk were comparable between groups. And even though this study did report on only a few non-cardiac toxicities, those that were reported were similar. Despite the relatively short follow-up period, four secondary malignancies occurred, three in the non-dexrazoxane group. This was not statistically significant different. None of the secondary malignancies was acute myeloid leukemia, but it might have been difficult to distinguish a secondary malignancy from a relapse. In summary, although this is not a randomized trial, this large study provides new knowledge on the use of dexrazoxane in pediatric acute myeloid leukemia patients with regard to cardiac function, anti-tumor efficacy and non-cardiac toxicities. Overall, dexrazoxane seems to be cardioprotective, at least within the relatively short follow-up period of maximal 4 years, without negative effects on anti-tumor efficacy and non-cardiac toxicities including secondary malignancies. Hopefully the authors will continue to follow these patients for long-term results. Even though this study does have limitations, it definitely adds to the knowledge of the use of dexrazoxane in children. It can help to inform the development of a much-needed evidence-based clinical practice guideline that is currently being developed by the International Late Effects of Childhood Cancer Guideline Harmonization Group. This concludes this JCO Podcast. Thank you for listening.

This podcast reviews the results of the observational study by Ladas and colleagues that found protective associations between dietary antioxidant intake and the occurrence of bacterial infections and mucositis.    TRANSCRIPT   This JCO podcast provides observations and commentary from the JCO article "The Protective Effects of Dietary Intake of Antioxidants and Treatment-Related Toxicity in Childhood Leukemia, A Report From the DALLT Cohort" by Ladas et al. My name is Wendy Demark-Wahnefried, and I am Webb Endowed Chair and Professor of Nutrition Sciences at the University of Alabama at Birmingham, as well as the Associate Director for Cancer Prevention and Control at the O'Neal Comprehensive Cancer Center at UAB in Birmingham, Alabama in the United States. I do not have any relationships to disclose regarding these studies, and my review is grounded by the fact that I am a nutrition scientist with particular expertise in cancer survivorship. The topic of nutrition and cancer generates a great deal of interest, especially once individuals are diagnosed with cancer. This is particularly germane with regard to antioxidants, since some scientists hypothesize that high levels of antioxidants may be beneficial for cancer control while others speculate that high levels may prevent apoptosis of cancer cells and actually impede the effectiveness of cancer therapy. However data are sparse, and there are very few studies of high quality, therefore the paper by Ladas and colleagues is both timely and important. The study enrolled 794 children ages 1 through 18 who were diagnosed with acute lymphoblastic leukemia. These children were enrolled from 10 institutions across the continental United States, Puerto Rico, and Canada. The children or their guardians completed age appropriate food frequency questionnaires that assessed dietary intake over the previous month and did so at two time points, soon after diagnosis and after the induction phase of treatment, or roughly a month after the first questionnaire. The nutrients that were studied were vitamins A, C, and E, as well as alpha, beta and total carotenoids-- these are the substances in plant foods that give the food its color-- and zinc. It should be noted that the antioxidant selenium was not studied. Nutrient intake was statistically analyzed in relation to bacterial infection and higher grade mucositis or inflammation of the digestive tract resulting in mouth sores or ulceration of the esophagus. Nutrient intake also was studied in relation to disease-free survival and minimal residual disease. Children were followed for up to 10 years. Of the 513 participants who completed the dietary surveys at both time points, 23% experienced a bacterial infection, and 16% experienced higher grade mucositis. Only 9% had higher levels of minimal residual disease, and 2% did not achieve complete remission. Results showed that children having diets with higher levels of antioxidants had a significantly lower risk of bacterial infection, with risk lowered by 10% to 27%, depending upon the antioxidant. Similarly, children having diets with higher levels of antioxidants had a significantly lower risk of higher grade mucositis, with risk lowered by 17% to 67%, again, depending upon the antioxidant. Importantly, evidence of protection was only observed for nutrients obtained through the diet and not nutritional supplements. In addition, no significant associations were observed between antioxidant intake, either through diet or supplements, and disease-free survival. This study has several strengths, in that it involved the participation of a diverse and ample sample of several children and their parents across several sites. Furthermore, data were collected at two time points. As always, there are limitations, and when relying on self-reported data there is always the risk of inaccurate reporting and misclassification. In addition, and thankfully, the number of children who had higher levels of minimal residual disease or who had not experienced complete remission was very small. And therefore, the study was likely under power to detect any associations between nutrient intake and these outcomes. Finally, because these results emanate from an observational study, cause and effect cannot be inferred. Thus the title of this manuscript, which begins with "The Protective Effects" in quotations, may be a bit of an overstatement. So what are the implications of this study? As noted previously, there are few data in this area, therefore more studies are needed to either confirm or refute these results. And such research is necessary in other cancer populations, such as among adults with other cancers who receive different therapies. Until such time, these data reinforce that a healthy diet may associate with lower risk of common treatment-related toxicities. It is noteworthy that investigators were only able to detect protective associations from antioxidants from dietary sources and not from supplements. These data reinforce both the American Institute of Cancer Research and the American Cancer Society guidelines that recommend that nutrients be obtained from foods rather than from supplements. As such, both clinicians and patients may have an interest in the dietary sources of antioxidants that were studied. Many people already know that citrus fruits are rich sources of vitamin C, but there are also other fruits and vegetables, such as strawberries, cantaloupe, and mangoes, as well as tomatoes, peppers and vegetables in the cabbage family, which also contain high levels of this nutrient. Foods that are high in vitamin E include plant oils, nuts, and seeds. Dark green and orange vegetables, and fruits, such as spinach, broccoli, sweet potatoes, apricots, and peaches are rich sources of carotenoids, which ultimately can be converted to vitamin A. Alternatively, preformed vitamin A in the diet can be obtained from animal products such as dairy products and eggs. Finally, foods rich in zinc include shellfish, poultry, legumes-- meaning dried beans, peas, and peanuts-- and red meat. In sum, these data reinforce current guidelines that encourage consumption of a well-balanced plant-based diet that has ample amounts of vegetables and fruit, at least 2 and 1/2 cups a day, as well as whole grains, nuts, seeds, and legumes. Such a diet may be beneficial in preventing common treatment-related toxicities, and larger studies may be able to discern potential associations with cancer-related outcomes such as disease-free survival. However, more study is required. This concludes this JCO podcast. Thank you for listening. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. For more original research, editorials, and review articles, please visit us online at jco.org. This production is copyrighted to the American Society of Clinical Oncology. Thank you for listening.

This podcast summarizes and provides commentary on the recent article by Yadav et al. in which the authors demonstrate that expansion of the current NCCN guidelines for genetic testing in breast cancer patients to include all women diagnosed at or below the age of 65 markedly improves the sensitivity for detecting pathogenic germline variants without requiring the testing of all breast cancer patients.   TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Evaluation of Germline Genetic Testing Criteria in a Hospital-Based Series of Women with Breast Cancer” by Yadav et al. My name is Erin Cobain, and I am a Clinical Lecturer at the University of Michigan Rogel Cancer Center in Ann Arbor, Michigan United States. My oncologic specialty is breast cancer. In this study, the authors sought to determine the sensitivity and specificity of current genetic testing criteria for the detection of pathogenic germline variants in women with breast cancer. Current national comprehensive cancer network (NCCN) guideline criteria, updated in January 2020, recommend that genetic testing be offered to all women diagnosed with breast cancer at age 45 or younger, those diagnosed with triple negative breast cancer at age 60 or younger as well as those with family history of breast, ovarian, prostate or pancreatic cancer that meet specific criteria. In addition, any patient with Ashkenazi Jewish ancestry is recommended to undergo testing. This most recent update to the guidelines also incorporates a recommendation to offer testing to individuals who have a greater than 5% risk of having a BRCA1 or BRCA2 mutation by prior probability models such as Tyrer-Cuzick or BRCAPro who would not otherwise meet criteria.  Prior to the publication of the present study by Yadav and colleagues, several recent articles including those by Beitsch et al. and Yang et al. indicate that many patients with pathogenic or likely pathogenic germline variants in genes associated with hereditary breast and ovarian cancer syndromes are missed by current testing criteria. The Beitsch et al. study analyzed results from a prospective registry whereby patients with previously or newly diagnosed breast cancer were consented and underwent genetic testing with an 80-gene panel test. Approximately 1,000 patients were enrolled and approximately half met NCCN guideline criteria for genetic testing. Among the patients who met NCCN guideline criteria, 9.4% had a pathogenic or likely pathogenic variant identified. For those patients not meeting NCCN guideline criteria for testing, 7.9% had a pathogenic or likely pathogenic variant. This led the authors to conclude that nearly half of breast cancer patients with pathogenic germline variants would be missed by NCCN criteria. Similarly, Yang and colleagues examined a cohort of patients with personal or family history of breast or gynecologic cancer from a Medicare database undergoing genetic testing. Data from over 4,000 patients tested indicated that the rate of identifying a likely pathogenic or pathogenic germline variant was nearly identical in the cohorts that met NCCN guideline criteria for testing versus those that did not, with the rate of pathogenic germline variants being approximately 10% in both groups. Indeed, the results from these studies lead the American Society of Breast Surgeons to issue a recommendation in October 2019 that all patients with personal history of breast cancer undergo genetic testing. While this recommendation would undoubtedly identify more patients with genetic susceptibility to breast cancer and other malignancies, the implications of this recommendation must be considered. Large scale testing would more readily identify patients with moderate penetrance genes that are without established cancer risk reduction guidelines. More testing also leads to increased identification of variants of uncertain significance, presenting challenges both for patients and their providers attempting to best counsel individuals with an ambiguous result. Finally, inequities in access to testing and genetic counseling resources as well as increased healthcare costs that result from broad testing are of major concern. If cost of testing is not covered by insurance, paying out of pocket may not be feasible for many patients.  In the present study, Yadav and colleagues attempted to address some of these apprehensions regarding the adoption of widespread genetic testing in breast cancer patients. The investigators enrolled patients with personal history of breast cancer over a 16 year period of time into a registry and evaluated for pathogenic germline variants in 9 cancer predisposition genes, including ATM, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, and TP53. These genes were selected because there are clear management recommendations in the NCCN guidelines when they are identified.  The authors found that among almost 4,000 women tested, those meeting current NCCN guideline criteria for testing (comprising 48% of the cohort) were more likely to harbor a pathogenic germline variant than those women who did not meet criteria. The rate of detection of pathogenic germline variants was 9% and 3.5% in these groups respectively. Despite the updated NCCN guideline criteria identifying patients with pathogenic germline variants more readily, there are undoubtedly still patients missed by these criteria. The authors conducted subsequent analysis to include all women diagnosed with breast cancer at age 65 or younger, which achieved 90% specificity for the 9 cancer predisposition genes selected and greater than 98% specificity for identification of pathogenic germline variants in BRCA1 and BRCA2. Given this, the authors concluded that expanding the NCCN genetic testing criteria to include all women diagnosed with breast cancer at or before the age of 65 will markedly improve the sensitivity of genetic testing and avoid the need to evaluate all patients with personal history of breast cancer. The major limitations of this study were that cost-effectiveness of this approach was not analyzed, and the majority of the patients included in the registry were White, limiting the applicability of these findings to a diverse patient population. Despite these limitations, this study offers a promising and considered approach to genetic testing in patients with personal history of breast cancer. While validation of this approach in additional study cohorts would be of great value, this data strongly suggests that testing all patients at or below age 65 at the time of breast cancer diagnosis achieves a balance between the two current testing paradigms, identifying the vast majority of patients at risk, and avoiding unnecessary testing of many. This concludes this JCO Podcast. Thank you for listening.

The combination of pembrolizumab and lenvatinib is a promising second line option for metastatic or recurrent MSS endometrial cancer, although there can be considerable toxicity and choosing appropriate patients is key.   TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Lenvatinib and Pembrolizumab in Patients With Advanced Endometrial Cancer” by Makker et al. My name is Meghan Shea, and I am an Instructor of Medicine at Harvard Medical School at Beth Israel Deaconess Medical Center in Boston, Massachusetts. My oncologic specialty is gynecologic oncology. Patients with advanced endometrial carcinoma have limited options after receiving the carboplatin and paclitaxel doublet for recurrent or metastatic disease. The study that accompanies this podcast evaluates the combination pembrolizumab and lenvatinib, providing a much needed second-line option for this patient population. The approval of single-agent pembrolizumab for tumors with microsatellite instability (from here on referred to as MSI high) does not have immediate relevance for the majority of patients with advanced endometrial carcinoma who have microsatellite stable disease (from here on referred to as MSS). Makker et al. now report the results of an ongoing phase 1b/2 study of pembrolizumab, an anti-PD1 antibody, and lenvatinib, an oral tyrosine kinase inhibitor that targets the VEGF-receptor, in patients with metastatic endometrial carcinoma. Eligibility criteria included patients with an ECOG 0 to 1 who had confirmed metastatic disease with less than or equal to 2 prior lines of systemic therapy. Notably the majority were not heavily pre-treated; 52.8% of patients in the study had only one prior line of systemic treatment. Patients received lenvatinib 20 mg once daily orally continuously and pembrolizumab 200 mg intravenously every 3 weeks – with a maximum duration of 2 years for pembrolizumab. All patients had imaging at baseline and then every 6 weeks for first 24 weeks and then every 9 weeks thereafter. The primary end point was objective response rate at 24 weeks. Forty-one of the 108 patients, 38%, had a response at 24 weeks with a median follow up of 18.7 months.  As expected, the MSI high tumors had a higher response rate of 63.6%, although this was a minority of the study population, only 11 patients. Most importantly, the patients with MSS tumors had a response rate of 37.2% with a median duration of response of 21.2 months. The histology did not appear to impact the response rate – the majority of patients had endometrioid (50.9%), although the study population also contained a reasonable proportion of serous and clear cell (38%) compared to the expected frequency in the general population of advanced uterine cancers. The PD-L1 status positive or negative did not correlate with response. One might question, before accepting a complicated regimen with both oral and IV chemotherapy as a new second-line standard option, whether anyone has studied the activity of either single agent lenvatinib or single agent pembolizumab in a similar population, especially for those with MSS disease. With the caveats of cross study comparisons, it appears that neither single agent is as active as the current combination. For instance, Vergote et al reported results of a phase 2 study of lenvatinib monotherapy for advanced endometrial cancer, where the response rate was only 14.3% with median progression free survival of 5.4 months. Likewise, Ott et al studied single agent pembrolizumab in endometrial cancer with 18 of 19 patients having MSS cancer, resulting in only a 13% response rate and progression free survival of 1.8 months.              So you may be wondering, what’s the catch? The issue is the potential toxicity of this doublet regimen, with 66.9% or 83 of 108 patients, having a grade 3 or 4 treatment-related adverse event. Overall 17.7% of the patients discontinued one or both drugs. Notably, pembrolizumab was never dose reduced - only dose held or discontinued. Most strikingly, 62.9%, roughly two thirds of patients, required a dose reduction of lenvatinib. Only 11 patients (that is 8.9%) stayed on full dose 20 mg of lenvatinib for greater than 6 months. The average dose for lenvatinib was 14.4 mg daily. The toxicity profile of lenvatinib may be related to the fact that it is a multi-targeted tyrosine kinase inhibitor that targets not only vascular endothelial growth factor receptors, but also fibroblast growth factor receptors, platelet-derived growth factor receptor alpha, RET and KIT. There were 51 deaths during this study; the majority occurred during follow up due to progression of disease. However, there were 16 deaths while on study, 4 considered treatment emergent adverse events and 2 judged to be treatment related.  The four deemed treatment emergent were due to gastrointestinal perforation, intestinal obstruction, general health deterioration and metabolic encephalopathy. The two deemed treatment related were from septic shock and intracranial hemorrhage. The National Comprehensive Cancer Network (NCCN) guidelines have added the combination of pembrolizumab and lenvatinib to their list of second line therapeutic options, and it also has been approved by the Food and Drug Administration (FDA). This recognizes the fact that this combination has the highest response rate of the available drugs listed, and thus should be a strong consideration for second line therapy for patients with MSS endometrial carcinoma. However, ensuring that this treatment is appropriate for a given patient is of the utmost importance.  First the patient must be a candidate for immunotherapy – ideally not on chronic prednisone and/or have an active autoimmune disease. In contrast to prescribing single agent anti-PD-1 or anti-PD-L1, a performance status of 0 to 1 is important with this combination. The most appropriate patient should have controlled blood pressure prior to initiating drug, be able to monitor their blood pressures, take their oral chemotherapy as prescribed, and readily report any new symptoms. I avoid prescribing this drug combination if the patient has a bleeding disorder, recent clotting, uncontrolled hypertension, or is at high risk of a fistula or bowel obstruction. Lenvatinib is a renally-cleared drug, and thus patients with a reduced glomerular filtration rate (GFR) require renal dosing. This is especially relevant for patients with recurrent uterine cancer, whose kidney function is dynamic, especially in the setting of hydronephrosis. In my practice, I consider starting patients with normal renal function at 14 mg lenvatinib daily, given that the vast majority of patients on study were eventually dose-reduced. Furthermore, I might start the lenvatinib dosing even lower for patients with dynamic renal function and for those who have a baseline GFR lower than 30. Overall this study provides a promising second line option for metastatic or recurrent MSS endometrial cancer, with responders having a durable response.  Patient selection and dose adjustments are key considerations to avoiding and managing toxicity. This concludes this JCO Podcast. Thank you for listening.

This podcast will discuss the findings from a phase II trial of gemcitabine, cisplatin and PARP inhibitor therapy in germline BRCA/PALB2 mutant pancreatic cancer and discuss an optimal treatment strategy in this setting.   TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “A Randomized, Multi-Center, Phase II Trial of Gemcitabine, Cisplatin with or without Veliparib in Patients with Pancreas Adenocarcinoma and a Germline BRCA/ PALB2 Mutation” by O'Reilly et al. My name is Daniel Renouf, and I am a medical oncologist at the BC Cancer Vancouver Centre in Vancouver, Canada. My oncologic specialty is pancreatic cancer. In this podcast, we will be discussing an important and evolving area that is changing our standard treatment strategies for pancreatic cancer. Progress has been slow for pancreatic adenocarcinoma, which is now the third leading cause of cancer-related death in North America and is projected to become the second leading cause of cancer-related death within the next decade. Modest gains in our treatments have been achieved with new chemotherapy combinations, including FOLFIRINOX and gemcitabine and nano-albumen bound-paclitaxel, yet still the majority of patients diagnosed with advanced disease will live for less than one year. There is a critical need for improved treatment options as well as clinically relevant predictive markers to guide our therapeutic decision making. The first clinically important predictive marker in pancreatic cancer is germline BRCA/PALB2 mutation status, which is present in 5-9% of pancreatic adenocarcinomas. Multiple translational studies and case series have demonstrated distinct molecular features of these tumors, as well as unique clinical characteristics. Germline BRCA/PALB2 mutant pancreatic adenocarcinomas have been noted to be sensitive to platinum agents and be associated with a better prognosis. Despite this data, and a general acceptance within the community that platinum agents are the preferred therapies in this setting, there is minimal prospective trial data specifically assessing the activity of platinum combinations in germline BRCA/PALB2 mutant pancreatic adenocarcinoma. At a plenary session at ASCO 2019 and its subsequent publication, the POLO trial assessed the role of maintenance therapy with a poly-ADP ribose polymerase (PARP) inhibitor (olaparib), compared to placebo, in patients with metastatic pancreatic adenocarcinoma and germline mutations in BRCA/PALB2 who had responded or had stable disease after initial therapy with FOLFIRINOX. This was a positive trial, demonstrating that maintenance olaparib significantly improved progression-free survival compared to placebo. There was no difference noted in overall survival, but this data was not yet mature. The role of combining a PARP inhibitor with platinum-based chemotherapy as upfront treatment in this patient population is yet to be defined.  A previous Phase I trial of gemcitabine, cisplatin and the PARP inhibitor veliparib determined a recommended phase II dose for velipirib in this combination and demonstrated promising efficacy in germline BRCA-mutant pancreatic adenocarcinoma. In the article that accompanies this podcast, Dr. O’Reilly and colleagues report on the results of a phase II prospective trial comparing gemcitabine and cisplatin versus gemcitabine, cisplatin and veliparib in patients with advanced pancreatic adenocarcinoma with germline aberrations in BRCA/PALB2. In the trial, patients with locally advanced or metastatic pancreatic cancer who had not received chemotherapy in the advanced setting, had a good performance status, and who harbored germline aberrations in BRCA/PALB2 were randomized. A total of 50 patients were enrolled, and the results demonstrated good efficacy in both arms, with a response rate of 74.1% in the veliparib arm and 65.2% in the control arm. Median progression-free survival was 10.1 months and 9.7 in the veliparib and non-veliparib arms respectively, and median overall survival was 15.5 and 16.4 months. Of note, for the entire cohort, 2-year overall survival was notably high at 30.6%, and 3-year overall survival was 17.8%. Grade 3-4 toxicities, including neutropenia, thrombocytopenia, and anemia were greater in the veliparib arm. The authors concluded that gemcitabine and cisplatin demonstrated significant activity in BRCA/PALB2 germline mutant pancreatic adenocarcinoma, and the addition of concurrent veliparib did not improve efficacy. Given this promising data, it was concluded that gemcitabine and cisplatin should be considered a standard treatment for BRCA/PALB2 germline mutant pancreatic adenocarcinoma. This is an important trial, as it is one of the first to specifically assess platinum chemotherapy prospectively in this patient population and has important implications for treatment strategies for pancreatic cancer, the first of which is that testing for germline BRCA/PALB2 mutations should now be considered standard of care for all newly diagnosed pancreatic adenocarcinomas. Not only does this have important treatment implications for the patient; it also has strong relevance to the patients’ family members, as it was found to also harbor a germline BRCA/PALB2 mutation. Screening and potential prevention strategies could be considered for other cancers, such as breast and ovarian. Secondly, if a patient is found to have a germline BRCA/PALB2 mutation, the data from this trial in combination with the body of literature in this setting would suggest that first line therapy with a platinum agent should be considered. In this setting, one could consider either FOLFIRINOX or gemcitabine and cisplatin. The efficacy of gemcitabine and nano albumen bound-paclitaxel in this patient population is not clearly defined, but in the context of data from other disease sites also demonstrating increased sensitivity to platinum in this patient population, and given many patients with advanced pancreatic adenocarcinoma are often not well enough to received multiple lines of therapy, a first line platinum combination should be strongly considered. Thirdly, this trial demonstrates that there is no additional benefit from adding a PARP inhibitor to chemotherapy in this setting, but there is added toxicity, and thus this strategy should not be considered at this time. Finally, given that toxicity from platinum-based chemotherapy is cumulative, the question of an optimal maintenance strategy remains. The POLO trial demonstrated that there is activity and a progression-free survival benefit when using olaparib as a maintenance post upfront platinum-based chemotherapy when compared to placebo, and therefore this represents one potential strategy. One criticism of the POLO trial is that many centers do not stop treatment and instead continue therapy without the platinum after an initial response. In patients responding to initial treatment with FOLFIRINOX, maintenance FOLFIRI is often considered. Data from a second line trial of FOLFIRI with or without veliparib presented as a poster discussion at ASCO 2019 by Dr. Chiorean and colleagues noted that BRCA/PALB2 mutant tumors also appear to have increased sensitivity to FOLFIRI. At this time, the optimal maintenance strategy after upfront platinum therapy is yet to be fully defined, and further research in this setting is needed. In addition, to what extent these strategies should be applied to patients with pancreatic adenocarcinomas that are germline BRCA/PALB2 wildtype but have other homologous recombination deficiency defects requires further investigation. In summary, this is an exciting time in pancreatic adenocarcinoma as we now have a clinically important biomarker to guide treatment strategies. This important trial by Dr. O’Reilly and colleagues further solidifies the importance of BRCA/PALB2 germline testing in pancreatic adenocarcinoma and that first line platinum-based chemotherapy should be considered in these patients. This concludes this JCO Podcast. Thank you for listening.

Towards improved characterization of immune-related adverse events in the setting of pre-existing autoimmune disease. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Immune Checkpoint Inhibitor Therapy in Patients with Preexisting Inflammatory Bowel Disease”, by Abu-Sbeih et al. My name is Katy Tsai, and I am Assistant Professor of Medicine in the Division of Hematology/Oncology at the University of California, San Francisco. My oncologic specialty is the treatment of advanced melanoma and non-melanoma skin cancers.   Immune checkpoint inhibitors, referred to as ICIs in this podcast, have transformed the landscape of treatment options in oncology. While ICIs were first approved for the treatment of advanced melanoma in 2011, since that time, ICIs have shown activity in a variety of other histologies. Anti-PD-1 or anti-PD-L1, with or without anti-CTLA-4, are now approved for the treatment of lung cancer, head and neck squamous cell carcinoma, renal cell carcinoma, and many others. While ICIs can result in durable responses, their continued use can be limited by the development of immune-related adverse eventsimmune-related adverse events. Because these events are believed to be autoimmune in nature, there are intuitive safety concerns about ICI use in patients with known autoimmune disease. Can patients with pre-existing autoimmune disease be safely treated with ICI? Are these patients more likely to experience immune-related adverse events related to their autoimmune disease? Is this risk increased if their autoimmune disease is severe, with a history of required immunosuppression? These are all important questions faced by healthcare providers, questions which are not well studied due to the exclusion of patients with known autoimmune disease from pivotal ICI clinical trials.   To address these questions, Abu-Sbeih and colleagues chose to focus on ICI use in patients with pre-existing inflammatory bowel disease. This is a clinically relevant population of interest, given the relatively high incidence of immune-related diarrhea and colitis with ICI use; these immune-related adverse events occur in almost half of patients receiving combination anti-CTLA-4 and anti-PD-1 or PD-L1, about one-third of patients receiving anti-CTLA-4, and less frequently in patients receiving anti-PD-1 or PD-L1 alone. Abu-Sbeih and colleagues conducted a retrospective, multicenter study in which 102 patients – half with Crohn’s disease, half with ulcerative colitis – received ICI between 2010 and 2019. 17 patients received anti-CTLA-4, and 85 received anti-PD-1 or anti-PD-L1. This is a notable cohort of patients, as previous meta-analyses have reported on the safety of ICI use in much smaller numbers of patients with inflammatory bowel disease, and with less detailed clinical characterization of their inflammatory bowel disease. Univariate and multivariate logistic regression were used to assess the risk of gastrointestinal, or GI, adverse events, and was compared to a control population of 11,377 ICI-treated patients without inflammatory bowel disease, from the same participating institutions.   An important observation made by the authors was that the rate of GI immune-related adverse events in the inflammatory bowel disease cohort was significantly higher at 41%, compared to 11% in the non-inflammatory bowel disease cohort. Univariate analysis identified anti-CTLA-4 (given as monotherapy or in combination) as a risk factor for GI immune-related adverse events compared to anti-PD-1/L1 therapy but showed only a tendency toward significance in multivariate analysis, as did inflammatory bowel disease involving the colon. Although none of the collected clinical variables reached significance in multivariate analysis, the authors’ analysis of outcomes in the inflammatory bowel disease cohort is illuminating. Of the 41 inflammatory bowel disease patients who developed diarrhea, 51% had peak grade 3 or 4 diarrhea, 76% received glucocorticoids, and 29% required additional immunosuppression with infliximab or vedolizumab. 4% developed colonic perforation, with half of those patients requiring surgical intervention. Also of note, patients who were identified as having active inflammatory bowel disease within 3 months of ICI start had higher grade diarrhea compared to patients with inactive inflammatory bowel disease. Endoscopy data were also available for 48 inflammatory bowel disease patients. Interestingly, of the 41 patients who were noted to have normal or mild inflammatory findings, 18 (43%) developed any GI immune-related adverse events, 5 (12%) of which were grades 3-4. In the 7 patients with moderate/severe inflammatory findings, 5 (71%) had GI immune-related adverse events of any grade, 2 (29%) of which were grades 3-4.   Despite the higher rate of GI immune-related adverse events and associated complications in the inflammatory bowel disease cohort compared to the non-inflammatory bowel disease cohort, there were no fatalities. Additionally, 48% of patients in the inflammatory bowel disease cohort were identified as having complete response, partial response, or stable disease to ICI therapy, a clinical benefit rate similar to those reported in ICI clinical trials. It seems, then, that the benefits of ICI therapy in this population may well outweigh the risks, particularly for patients with inflammatory bowel disease who may have no viable alternative therapy available for their malignancy.   Overall, despite the inherent limitations of retrospective analysis, this work represents the largest study to date investigating the risk of GI immune-related adverse events in patients with cancer and comorbid inflammatory bowel disease who were treated with ICIs. It provides evidence for increased incidence and severity of GI immune-related adverse events, and complications thereof, in a well-annotated cohort of patients with inflammatory bowel disease. As these patients continued to receive clinical benefit from their ICI therapy, these findings can help better inform pre-ICI treatment counseling in patients with preexisting inflammatory bowel disease, and better prepare them for expected risks of treatment. At the same time, this work also raises a number of questions for further investigation. Is anti-CTLA-4 truly safe to use in this population, or was this limited by the small number of patients receiving anti-CTLA-4 in this study? Should ICI therapy be delayed to allow for optimal treatment of active inflammatory bowel disease, to decrease the risk of severe GI immune-related adverse events? What additional guidance can be given to providers regarding when to initiate additional immunosuppressive therapy, and should this be driven by endoscopic findings? These questions and more can and should be investigated in future larger-scale prospective studies. For the time being, based on the data presented, I would certainly be more cautious about giving a more aggressive immunotherapy regimen – that is, combination anti-CTLA-4 and anti-PD-1/L-1 – in a patient with highly symptomatic inflammatory bowel disease. Also, while numbers in this study were small, it seems that endoscopic evaluation prior to ICI start could be helpful in risk stratifying for severe GI IRAE. While inflammatory findings on endoscopy may not necessarily be an absolute contraindication to use of ICI, it seems these results would certainly be helpful in shared decision-making with the patient regarding their risk of developing GI IRAE and weighing other potential treatment options. Finally, and most importantly, this data demonstrates that some patients with inflammatory bowel disease who receive ICI for their malignancy can derive clinical benefit with manageable toxicities, suggesting that the mere presence of comorbid inflammatory bowel disease should not be a blanket exclusion criterion for ICI clinical trials.   This concludes this JCO Podcast. Thank you for listening.

This podcast describes a study examining aerobic capacity in a cohort of over 1200 adult survivors of childhood cancer and related impairments of cardiac, pulmonary and neuromuscular body systems, to understand how aerobic capacity influences all-cause mortality. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article 'Exercise Intolerance, Mortality, and Organ System Impairment in Adult Survivors of Childhood Cancer' by Ness et al. My name is Kristin Campbell, and I am a licenced physical therapist and associate professor in the Faculty of Medicine at the University of British Columbia in Vancouver, Canada. My oncologic specialty is in rehabilitation, primarily related to breast cancer. Exercise intolerance is a global measure of functional capacity that reflects the complex integration of body systems. It is well established in the general population that exercise intolerance is predictive of future cardiovascular health and mortality. Whether this relationship also existed for adult survivors of childhood cancer was examined by Ness and colleagues in the article that accompanies this podcast. . In the largest study to date of its kind, this manuscript reports on a comprehensive and methodologically rigorous examination of exercise intolerance measured by a gold standard maximal cardiopulmonary exercise test in over 1200 adult survivors of childhood cancer who are part of the St. Jude’s Lifetime Cohort Study. The first main finding is the low levels of exercise capacity in this sample of childhood cancer survivors despite a relatively young mean age of 35 years. The observed maximal aerobic capacity, or VO2peak, ranged on average between 25-27 ml/kg/min, which fall into the “poor” or “very poor” categories of age and sex matched normative values. Compared to 285 community controls who were friends or family members of the cohort patients, the observed maximal aerobic capacity values for childhood cancer survivors were on average 22% lower. In fact, these values are actually more consistent with values seen in healthy adults in their seventies or eighties. Furthermore, the low value of maximal aerobic capacity may also be an underestimate. Thirteen percent of individuals in the St. Jude’s cohort who agreed to participate in the study were not cleared to undertake the maximal cardiopulmonary exercise test due to recent diagnosis of cardiac or pulmonary disease, or lab values and symptoms indicating cardiac or pulmonary issues. This suggests that the prevalence of exercise intolerance may be even greater in a real-world clinical setting than that observed in this cohort. To examine the association between exercise intolerance and mortality, the authors defined exercise intolerance as a maximal aerobic capacity of A unique feature of this study is that the authors also undertook comprehensive measures of host, treatment, and lifestyle factors to better understand how these factors influence exercise intolerance. These additional measures included cardiac imaging at rest, autonomic response, measured by blood pressure response to the maximal graded exercise test, standard pulmonary function testing, quadriceps strength testing, and peripheral sensorimotor function using the modified total neuropathy scale. This data provides a rare look into the acute and chronic responses to exercise of the cardiovascular, pulmonary, autonomic and neuromuscular systems in those exposed or not exposed to cardiotoxic agents and will appeal to those an interest in exercise physiology. Odds of exercise intolerance were highest with reporting Of note, the type of treatment received impacted the presentation of exercise intolerance. Lower exercise tolerance was observed in individuals who received >350 mg/m2 of anthracyclines, >30 Gy of chest radiation, >20 Gy of cranial radiation and receipt of carboplatin. As a result, the authors suggest that even asymptomatic childhood cancer survivors who have received these treatments be screened by medical providers for any required medical management prior to recommending or implementing an exercise program.  Furthermore, while ejection fraction of 1.5 SD above age- and sex-predicted increased the odds of exercise intolerance with an odds ratio of 1.71 in those exposed to cardiotoxic agents and an odds ratio of 1.29 in those not exposed to cardiotoxic agents. The authors suggest that the use of echocardiology derived strain be expanded from current published guidelines from the American Society of Clinical Oncology on Prevention and Monitoring of Cardiac Dysfunction to identify early cardiac dysfunction in childhood cancer survivors with exercise intolerance and normal ejection fraction. The study does have some key limitations. It is cross-sectional in design, making it difficult to assign temporal relationships between impairments in body systems and exercise tolerance. For example, is it the treatment that causes impairments in body systems that then limit exercise tolerance, or does situational inactivity due to side-effects of cancer treatment drive exercise intolerance and this in turn negatively impacts the exercise response of body systems? Furthermore, while there was a high participation rate and participants did not differ from non-participants by age, race or sex, not all eligible survivors enrolled. This may over or underestimate the prevalence of exercise intolerance or impact on mortality. In considering the implications of these findings to clinical oncology, the authors acknowledge that adult survivors of childhood cancer face unique challenges in engaging in physical activity. In light of the high prevalence of exercise intolerance in childhood cancer survivors and the association to all cause mortality, the authors suggest that survivors may require referral to trained exercise specialists to learn how to accommodate specific impairments and deficits in order to reap the benefits of engaging in exercise. In the United States, the appropriate exercise specialists could include physical therapists, occupational specialists, certified exercise physiologists or physical medicine and rehabilitation specialists. Oncology providers are encouraged to include these individuals on their care teams and establish a connection to available programming in their healthcare facility or community to provide adult survivors of childhood cancer with greater access to appropriate exercise programming aimed at improving exercise tolerance. This concludes this JCO podcast. Thank you for listening.

This podcast describes the results of the BLOOM study, evaluating the efficacy of osimertinib in EGFR-mutated lung cancer with leptomeningeal disease after failure of prior EGFR TKI therapy. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Osimertinib In Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer and Leptomeningeal Metastases: The BLOOM Study” by Yang et al. My name is Jürgen Wolf and I am the medical director of the Center for Integrated Oncology at the University Hospital of Cologne in Germany. I am a medical oncologist with expertise in personalized lung cancer care.   About 10% of patients with advanced EGFR-mutated lung cancer suffer from leptomeningeal disease. While this disease manifestation in non-small-cell lung cancer is generally associated with a particularly poor prognosis, with survival times of only a few months, the question arises whether treatment with specific tyrosine kinase inhibitors might enable a better disease control. Most studies evaluating the efficacy of 1st and 2nd generation EGFR-TKIs in leptomeningeal disease were retrospective and difficult to interpret, given the heterogeneity of the disease as well as of the preceding treatment procedures. Small prospective studies with patient numbers below 20 tested standard dose erlotinib or afatinib as well as high-dose pulsatile EGFR TKI treatment and reported disappointing results with survival times of around 4 months only.   The 3rd generation EGFR TKI osimertinib initially was approved for T790M positive failure of 1st and 2nd generation EGFR TKIs and is now commonly regarded as 1st line standard treatment for EGFR-mutated lung cancer based on a superior progression-free survival, overall survival and toxicity profile. In studies with primates and healthy volunteers, osimertinib has been shown to exert a higher blood-brain barrier permeability and a higher brain exposure compared with other TKIs. In the AURA clinical development program for osimertinib, 22 patients with T790M-positive relapse after EGFR TKI treatment and leptomeningeal disease were retrospectively identified, and an impressive median overall survival of 18.8 months was reported. A small prospective Japanese trial evaluated osimertinib in 13 patients with T790M-positive leptomeningeal disease which, however, could be confirmed only in 5 patients. Responses were seen in some patients, and the median progression free survival for all patients was reported with 7.2 months.   The BLOOM study part B, which is discussed in this podcast, is a multicenter phase I study evaluating osimertinib in EGFR-mutated lung cancer patients with leptomeningeal metastases and failure of previous EGFR TKI treatment. Study objectives were the assessment of clinical parameters like response, overall survival neurological status, and safety but also pharmacokinetics in blood and cerebrospinal fluid. Main inclusion criteria included confirmed diagnosis of EGFR Exon 19 deletion or L858R mutation and confirmation of leptomeningeal disease by positive cytology of cerebrospinal fluid and at least one leptomeningeal site assessable by MRI. There were two sequential cohorts, one unselected for the T790M mutation and with stable non-CNS disease at enrollment, and one for T790M positive patients without the requirement for stable non-CNS disease. Osimertinib dose was 160 mg once daily, which is twice the approved dose. Besides investigator-based response assessment, according to RECIST, leptomeningeal disease was also assessed by a neuroradiological blinded central review according to the RANO-LM working group criteria, which integrates clinical examination, cerebrospinal fluid cytology and neuraxis MRI.   41 patients from South Korea and Taiwan were included, 20 in the unselected and 21 in the T790M-positive cohort. About 70% of the patients had co-existing brain mets and about 50% prior radiotherapy. For 4 patients, no response data from the independent review were available.   The confirmed overall response rate for leptomeningeal disease was impressive at 62% as assessed by blinded independent review and nearly identical between both cohorts.  By comparison, the overall response rate was only 27% by investigator assessment, which, in turn, revealed a higher stable disease rate. Prior brain radiotherapy had no influence on efficacy. Median duration of response was comparable between blinded independent review and investigator, with 15.2 and 18.9 months, respectively. In about one third of the evaluable patients confirmed CSF clearance could be observed. PK analysis indicated that plasma concentration of osimertinib and its active metabolites reached steady state by day 15; the ratio for osimertinib exposure in cerebrospinal fluid vs. plasma was around 16%.   Surprisingly, only half of the patients had an abnormal neurological baseline assessment, most of them with mild symptoms. Symptom stabilization occurred in 54% during treatment; only 5% showed regression of neurological functions.   Overall, median progression-free survival, as assessed by the investigators, was 8.6 months and median overall survival 11 months. Progression-free survival and overall survival differed markedly between both cohorts. For instance, overall survival was 16.6 months in the unselected and 8.1 months in the selected group. Possibly, the requirement for stable non-CNS disease in the unselected group was partly responsible for the better survival outcome in this subset . However, this has to be interpreted cautiously in view of small patient numbers and large confidence intervals.   Osimertinib 160mg was well tolerated in the majority of patients with the known osimertinib side-effect profile. However, 24% of the patients suffered from adverse events grade 3 or more—possibly related to osimertinib, according to the investigators’ assessment. Dose reduction had to be performed in 12% and discontinuation of treatment in 22% of the patients due to adverse events. 17% of the patients had fatal events that did not appear to be causally related to osimertinib.   What can we learn from this study? This is the largest prospective study so far in this setting and osimertinib clearly shows clinical efficacy. The study methodology was sound, with response assessment by blinded independent review and based on RECIST criteria as well as on the RANO criteria established in particular for leptomeningeal disease. The overall response rate of leptomeningeal disease of around 60% and the duration of response of around 15 months is clinically relevant in particular, as it is correlated with improvement or at least neurological stabilization in most patients. Although the toxicity of the treatment is substantially higher than reported in osimertinib trials so far, it is manageable, and the risk/benefit ratio appears to be favorable.   What are the limitations of the study? Patient numbers are small, and the patients are heterogeneous with respect to several important factors such as pretreatment whole-brain radiotherapy, occurrence of simultaneous CNS metastases and neurological symptoms. Thus, absolute values for efficacy have to be interpreted cautiously, and comparison with already published trials remains difficult. Also, unfortunately in view of the toxicity, the question remains open whether the 160mg dose, which is not approved, is actually necessary. Finally, since osimertinib increasingly becomes the first-line treatment standard in EGFR-mutated lung cancer, the number of patients with failure of 1st- or 2nd-generation EGFR TKI treatment will decrease.   Despite these limitations, the trial provides the most convincing data so far in this special patient population and, in my opinion, defines  an important new option to consider for patients with EGFR-mutated lung cancer and leptomeningeal disease after failure of previous EGFR TKI treatment.   This concludes this JCO Podcast. Thank you for listening.

This podcast reviews the results of KEYNOTE 164 investigating the use of pembrolizumab for mismatch repair deficient metastatic colorectal cancer, the place of this agent in the current clinical paradigm, and future directions to identify which patients are most likely to benefit from this treatment strategy. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article 'A Phase II, Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164' by Le et al. My name is Dustin Deming, and I am an associate professor at the University of Wisconsin Carbone Cancer Center in Madison, Wisconsin. My oncologic specialty is gastrointestinal oncology. Microsatellite instability high status or mismatch repair deficiency is found in approximately 15% of early stage colorectal cancers, but only 3-4% of metastatic colorectal cancer. The mechanisms by which these cancers acquire their DNA repair aberrations can vary, including germline mutations, somatic mutations and promoter methylation, which is often observed in the setting of the hypermethylation phenotype associated with BRAF mutations. This distinct colorectal cancer subtype is of particular interest for immunotherapy strategies as the lack of adequate mismatch repair can lead to 1000s of mutations and also fusions leading to the potential for expression of more neoantigens.   This world-wide phase 2, open-label study enrolled 124 patients with microsatellite instability high or metastatic mismatch repair deficient colorectal cancer following 2 or more lines of standard therapy in cohort A and following 1 or more lines of therapy in cohort B. Patients received pembrolizumab 200 mg every 3 weeks, up to 2 years, until progression, unacceptable toxicity, or withdrawal. The primary endpoint was objective response rate by Response Evaluation Criteria in Solid Tumors version 1.1 by independent central review and secondary endpoints included duration of response progression-free survival, overall survival, safety and tolerability.   At the time of this report the median follow-up for cohort A was 31.3 months and 24.2 months for cohort B. The objective response rate was 33% for both cohorts. This includes 7 patients who achieved a complete response. The median PFS was 2.3 months for cohort A and 4.1 months for cohort B. For those patients that developed an objective response the duration of response was quite prolonged with the median duration of response not reached in either cohort. The median overall survival was 31.4 months for cohort A and not reached in cohort B. This treatment was well-tolerated in this population with the most common toxicities being fatigue, pancreatitis, and increased alanine aminotransferase or lipase.   Overall pembrolizumab is an exciting addition to the treatment strategy for patients with metastatic mismatch repair deficient cancers. Based on these results, in part, this agent is now FDA approved for patients with previously treated microsatellite instability high or mismatch repair deficient metastatic colon cancers after fluoropyrimidine, oxaliplatin, and irinotecan, and for patients also for non-colorectal solid tumors following at least one prior therapy, regardless of tumor type or origin. This was the first FDA approval of a tumor histology agnostic anticancer therapy.   Long-term follow-up from this, and similar cohorts, is required to further define the duration of response for these patients, as there is hope that some of these patients could even be cured. Unfortunately, it is only a minority of patients that seem to benefit from this approach as demonstrated by the short median progression free survival in both cohorts. A better understanding of which patients are likely to benefit from immunotherapy approaches are clearly needed.    The presence of Lynch syndrome was not captured in this study to evaluate for differential response in this setting. The BRAF mutation status was collected and across both cohorts 14 patients had BRAF mutant cancers. The response rate for these patients was 43%. A similar benefit was also observed in KRAS or NRAS mutant and wild-type cancers. This study was limited in its ability to further assess those factors that could influence pembrolizumab response given the relatively small sample size and limited biospecimen collection.   Further clinical trials are investigating the use of anti-PD1 therapies for these patients in the first-line and adjuvant settings, in combination with chemotherapy and with other immune checkpoint agents, such as CTLA4 and LAG3, among others. This includes Checkmate 142, which is a phase II study that is examining nivolumab and ipilimumab in a cohort of 46 patients with microsatellite instability high or mismatch repair deficient colorectal cancer in the first-line setting. Preliminary results were presented at the 2018 European Society of Medical Oncology meeting demonstrating a 60% objective response rate and a 12 month progression free survival of 77%. These early results are promising, but further investigation is needed.   As we look forward to which factors could be leading to a lack of clinical benefit from these agents it is important to consider those factors that are intrinsic to the cancer cells, tumor microenvironment, and patient specific factors. Tumor cell intrinsic factors include important cell attributes for the immune response such as the tumor mutation burden, MHC class I expression, including beta-2-microglobulin expression, the mutation profile, including alterations in WNT signaling shown to be important for immunotherapy resistance in metastatic melanoma, and tumor heterogeneity. There is also a growing understanding of factors that are important within the tumor microenvironment for tumors to be permissive to immune cell infiltration. These factors include differences in the immune and fibroblast cell subtypes present and also the presence of certain matrix proteins. This includes a matrix proteoglycan called versican that my laboratory and others have demonstrated has immunosuppressive properties, but can be cleaved by ADAMTS proteases to an immunostimulatory fragment. Additionally, patient specific factors need to be considered such as the microbiome, immunosuppression and adverse event management.   In summary, the results of KEYNOTE 164 are a significant advance for patients with microsatellite instability-high and mismatch repair deficient cancers. Long-term follow-up from this study and further studies into the most efficacious clinical setting to use these agents will continue to advance the clinical use of immunotherapy options for these patients.   This concludes this JCO Podcast. Thank you for listening.

This podcast evaluates results from a phase II clinical trial of pembrolizumab for relapsed Mycosis Fungoides and Sezary Syndrome in the context of the current systemic treatment landscape for this disease. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article "Pembrolizumab in Relapsed and Refractory Mycosis Fungoides and Sezary Syndrome: A Multicenter Phase II Study" by Khodadoust et al. My name is Jennifer Amengual, and I am an Assistant Professor of Medicine at the Columbia University Irving Medical Center in New York, New York, USA. My oncologic specialty is lymphoma. Mycosis fungoides, otherwise known as MF, and Sezary Syndrome, its leukemic variant, are rare subtypes of cutaneous T-cell lymphoma. Although most patients with MF have indolent disease, those with advanced stage MF often experience resistance to systemic therapy with a persistent and progressive disease course, which has a negative impact on overall well-being and survival. Patients may have intense pruritus, which can then put them at increased risk for staphylococcus infection, sepsis and in turn can trigger disease flare. Advanced-stage MF is a chronic disease that is not considered curable; therefore, it is necessary to consider management strategies that provide symptom relief and can be maintained over a long period of time. Most patients cycle through a multitude of therapies, often including skin-directed and, later, systemic therapies. Many of the acceptable therapies are derived from retrospective studies or single-arm trials; therefore, it is not possible to objectively compare outcomes and toxicity. In order to put the outcomes of pembrolizumab in context of other acceptable treatment modalities, I will discuss some of these treatments now. Systemic retinoids, such as bexarotene, are taken orally and can induce an overall response of 45-55%. The drug is well tolerated but can lead to hypertriglyceridemia and hypothyroidism, requiring monthly monitoring and frequent treatment with lipid-lowering agents and thyroid hormone replacement. Low-dose methotrexate, administered either orally or by intravenous infusion weekly, can lead to response rates between 30 and 50%. Common side-effects include mucositis, cytopenias and gastrointestinal upset. Pralatrexate is a novel antifolate drug that when studied using half the dose of that which is approved for PTCL , induced a 45% response rate for patients with MF. The treatment is also well tolerated, with the most common side-effects being mucositis and thrombocytopenia. There are 2 histone deacetylase inhibitors approved for use in MF and Sezary Syndrome. Both romidepsin and vorinostat have overlapping toxicity profiles, including gastrointestinal disturbances, fatigue, anorexia, and cytopenias. Romidepsin is also associated with ECG abnormalities. In patients with cutaneous T cell lymphoma, romidepsin has demonstrated a response rate of 34% and is associated with a median duration of response of 15 months. Vorinostat, an oral drug, has demonstrated a response rate of 30%. Recently, 2 biologics have been in used for patients with MF. Brentuximab vedotin is an antibody drug conjugate which targets the surface marker CD30 and brings monomethyl auristatin E into the cell. It is associated with a response rate of 70% in MF. Responses are significantly better in those with greater than 5% of CD30 expression. The most common side-effect is peripheral neuropathy. Mogamulizumab is a humanized antibody directed against the chemokine receptor CCR4.  This agent was studied in a randomized trial compared to vorinostat, where it led to a PFS of 7.7 months and response rate of 28%. The most common adverse events were attributed to infusion reactions, rash, diarrhea, and fatigue. There was also an increased risk of graft-versus-host disease in patients who subsequently went on to allogenic transplant, which needs to be considered when using this treatment strategy. As you can see, there are many different approaches to the treatment of advanced-stage MF and Sezary Syndrome, and the drugs I have discussed do not encompass an exhaustive list. Immune checkpoint antibodies against Programmed cell death protein 1 otherwise known as PD-1 interfere with inhibitory signaling pathways expressed on exhausted T-cells and wake up these cells allowing them to perform anti-tumor activities. The investigators rationalize the use of PD-1 inhibitors in MF and Sezary syndrome given PD-1 dysfunction and altered expression on MF cells and  the skin microenvironment. The Cancer Immunotherapy Trials Network performed a multicenter phase II single-arm study of pembrolizumab in 24 patients across 8 centers with relapsed or refractory MF or Sezary Syndrome. Of the 24 patients enrolled, 9 had MF and 15 had Sezary syndrome. Most had advanced disease represented by tumor stage disease, erythrodermic presentation, or were stage IIIB or higher. Patients received a median of 4 prior lines of systemic therapy. In addition, 4 patients had evidence of histologic large cell transformation. These represent some of the most challenging clinical situations. Pembrolizumab was administered every 3 weeks for 24 months or until withdrawal of consent, adverse reactions or investigator’s decision. The therapy was well tolerated, with no grade 4 or 5 immune-related adverse events. There were, however, 11 immune-related adverse events observed among 9 patients. This led to discontinuation of treatment in 4 patients, all due to grade 3 events including pneumonitis, duodenitis, hepatitis, and a corneal ulcer. Interestingly, over half of the patients with Sezary Syndrome experienced a flare of their symptoms early in their treatment course. This manifested as increased erythema, pruritus, and peripheral edema. Patients were managed with topical steroids and close observation. Only 1 patient had a prolonged reaction requiring systemic therapy, and no patients were discontinued from therapy due to flare of their disease. Patients with MF did not experience any skin toxicity. The authors investigated the relationship of this reaction to response and found that 3 of 8 Sezary patients who experienced a skin flare went on to achieve a response, whereas only 1 of the 7 Sezary patients who did not have a flare achieved a response. Using mass cytometry profiling of PBMCs, the authors observed a sevenfold increase in PD-1 expression on circulating Sezary cells in patients who experienced a flare. Although these observations were made across a small number of patients, it will be worthwhile to pay attention to this in future studies to determine if this is a true predictor for flare reaction or response. Pembrolizumab demonstrated significant clinical responses in 9 of 24 patients, leading to an overall response rate of 38%. This falls right into the range with other acceptable treatment options. Patients were heavily pretreated, yet the number of prior lines of therapy did not impact the response to pembrolizumab, possibly owing to non-overlapping mechanism of action. In addition, responses were seen in both MF and Sezary patients and those with erythrodermic and tumor stage presentations. There was a trend toward better outcomes in the MF patients. Responses were durable, and the median duration was not reached within a follow-up period of 58 weeks. The 1-year PFS was 65%, and OS was 95%. Two responding patients relapsed 8 to 12 weeks after discontinuation of treatment. The authors discuss that this may indicate the need for continuous treatment in this patient population, which is contrary to the general treatment strategy used for checkpoint inhibitors in other malignancies. Although this study only enrolled 24 patients, pembrolizumab appears to have similar outcomes as other drugs used in advanced-stage MF and Sezary Syndrome, with an acceptable toxicity profile. It produces a long duration of response, making it an attractive addition for patients suffering from this disease. Pembrolizumab does not have overlapping mechanism of action with most of the drugs used today and can therefore be easily integrated into the sequence of treatment for patients with MF and Sezary Syndrome. Finally, it is possible that pembrolizumab’s effects will enhance those seen with other agents. We should look forward to confirmatory clinical trials of pembrolizumab for the management of patients with MF or Sezary Syndrome. This concludes this JCO Podcast. Thank you for listening.

This podcast discusses the results and implications of a recent study on gender bias in speaker introductions at an international oncology conference. This JCO Podcast provides observations and commentary on the JCO article "Evaluating Unconscious Bias: Speaker Introductions at an International Oncology Conference" by Duma et al. My name is Dr. Tatiana Prowell. I am an Associate Professor of Oncology at Johns Hopkins Kimmel Cancer Center and Breast Cancer Scientific Liaison at the U.S. Food and Drug Administration in Silver Spring, Maryland. My oncologic specialty is breast cancer. In the article that accompanies this podcast, Duma and colleagues report the results of a retrospective observational study of speaker introductions at two consecutive years of ASCO Annual Meetings. The investigators hypothesized that female speakers in oral sessions would be introduced with a professional form of address less frequently than male speakers. For the purposes of the study, they defined a professional address as use of a title such as Professor or Doctor, followed by the speaker’s full name or last name, or the speaker’s full name followed by doctoral degree. A team of four male and four female reviewers analyzed 781 video recordings of oral sessions from the 2017 and 2018 ASCO Annual Meetings and recorded the gender of the introducer and speaker and how the speaker was introduced. They found that female speakers received a professional form of address 62% of the time whereas male speakers were introduced professionally 81% of the time, a difference that was statistically significant. Duma and her colleagues also assessed whether the gender of the introducer was associated with a difference in the likelihood of receiving a professional introduction. They found that male moderators introduced female speakers professionally a little more than half the time, whereas they introduced men professionally in 80% of cases.  Interestingly, when serving as introducers, women were more likely than men to include a professional form of address, which they did about three-quarters of the time, regardless of whether they were introducing men or women.  Perhaps the most striking result of the study was that one in six female speakers was introduced by her first name only, a surprising degree of informality for a high-profile conference like the ASCO Annual Meeting, which draws more than 40,000 attendees per year. By comparison, male speakers were introduced by first name alone in just 3% of presentations. In a multivariate analysis that included gender, degree, academic rank and geographic location of the speaker’s institution, male speakers were 2.5 times more likely to receive a professional introduction compared to female speakers.    This study adds to a growing body of literature in medicine investigating the prevalence of gender bias in speaker introductions. For example, previous studies of speaker introductions over a 3 year period of Mayo Clinic Internal Medicine Grand Rounds and at an American Society of Colon and Rectal Surgeons Annual Meeting reported similar findings. In both cases, female speakers were less likely than men to be introduced using a professional form of address, and women introducers more consistently referred to speakers by a professional title, regardless of whether the speaker they were introducing happened to be a man or a woman.   This study raises two key questions: why do we see this, and how can we fix it? A speaker introduction, especially at an international conference, is by definition a formal ritual, and yet one so familiar to us that we may have lost sight of its purpose. It would be easy enough for speakers to introduce themselves. Every speaker has an opening slide that shows his or her name and institutional affiliation. So why choose someone, and often someone well-known within the field, whose role is to introduce the speakers at all?  What leads us to say, “Dr. Carol Greider is Bloomberg Distinguished Professor, Director of Molecular Biology and Genetics at Johns Hopkins University, and a recipient of the 2009 Nobel Prize in Medicine”? I believe we do this for two reasons. First, formal introductions provide a moment, however brief, to demonstrate our collective respect for the speaker and his or her scientific contributions. Second, the information in the introduction signals to any who are not familiar with the speaker that the person is credible, knowledgeable, and worthy of our attention. Although more than 50% of medical school matriculants and about 40% of medical school faculty are women, they remain underrepresented at higher academic ranks and in leadership roles. Only about one-quarter of full professors are women, and fewer than 1 in 5 department chairs are women. Women are also less likely than men to be the first or senior author of manuscripts and thus less likely to be standing at the podium. As a result, the names and work of women in medicine may well be less familiar to the audience. Female introducers may therefore be more likely to assign value to use of a professional form of address. If this were true, one might expect to see women more consistently use a professional form of address when introducing speakers, and this is in fact what Duma and her colleagues observed.    The more troubling question is why men approached the introduction of male and female speakers so differently and why male speakers were 2.5 times more likely to be introduced with a professional title than women. I believe that most moderators, if presented with data from their own sessions, would be surprised to learn that they introduce men and women differently. This is called unconscious bias, and we are all susceptible to it. While the root causes of unconscious gender bias are numerous, one of these is surely the dearth of women occupying senior positions in medicine. As a community, we have tremendous power to remedy this source of unconscious bias. But while we can all re-commit ourselves to mentoring and sponsoring women in order to create more visible examples of female leaders in medicine, these efforts will not change the face of medicine, nor eliminate our unconscious gender bias, overnight. And yet, this is a change that needs to be made now. A male colleague of mine described introducing a woman at the podium by her first name as the verbal equivalent of rubbing the shoulder of a female professional acquaintance, then extending a handshake to a male professional acquaintance, that is to say, an inappropriate degree of familiarity with the woman. However, even in circumstances where the introducer and speaker are well-known to one another, formal settings call for formality. I call my physician husband “honey” at home, but if I were moderating an ASCO Annual Meeting session in which he was a panelist and said “Honey, why don’t you take that question?” it would of course be ridiculous.  Using respectful forms of address in formal settings like conference sessions is ultimately a mark of professionalism and, in 2019, non-negotiable.    The good news is that, unlike many problems in medicine, this one has a couple of solutions that we can implement immediately. We can provide a simple standardized script at the podium that ensures all speakers receive an equitable introduction. All conferences should implement this now, and in fact, motivated by Duma and her colleagues’ work, session chairs will receive such a script for introductions at the 2020 ASCO Annual Meeting. Perhaps more importantly, though, we can appreciate the formal introduction as a ritual that has been conserved through generations of scientists for a reason. Regardless of our gender, all of us as physicians remember that feeling when were July interns and the attending said of us on rounds something like, “Dr. Smith will be back to explain the plan to you in more detail.” In that moment, when we were called Doctor before an audience of our patients and our peers, we felt respected, capable, confident, and proud. Let’s commit to ensuring that all of our colleagues have that feeling every time they take the podium.    This concludes this JCO Podcast. Thank you for  

Treatment-free survival is a novel endpoint in immunotherapy. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Treatment-Free Survival: A Novel Outcome Measure of the Effects of Immune Checkpoint Inhibition—A Pooled Analysis of Patients With Advanced Melanoma” by Regan et al. My name is Adil Daud, and I am Professor of Medicine and Dermatology and Director of the Melanoma Program at the University of California, San Francisco. My oncologic specialty is medical oncology. Cancer therapy has achieved great success in the last 40-50 years. Where treatment with chemotherapy required inpatient hospitalization and gut-wrenching toxicity, therapy today can often be achieved with lower grade side effects and limited time in the hospital or outpatient infusion center. While these changes have brought enormous benefit to patients, many patients feel that the tug of ongoing therapy for metastatic or advanced cancer and long for a time where therapy is not continuing, and the word “cure” is not completely out of mind. Allied to these concerns is the rise and expansion of immunotherapy for cancer. The growth and spread of neoplasm often triggers the immune system, which mobilizes in response. While cancers can use a variety of adaptive mechanisms to evade the immune system, blocking these evasive mechanisms can produce lasting responses and, in some cases, durable tumor-free intervals. Cytokine therapy as exemplified by IL-2 offered this benefit since its approval in the 1990’s for renal cell cancer and for melanoma for approximately 10-20% of patients treated. The CTLA4 antibody, ipilimumab has had a similar long-term disease control rate with a better toxicity profile. However, it is the anti-PD-1 monoclonal antibodies, used by themselves or with ipilimumab that have made treatment-free survival a tangible and achievable goal for many patients with cancer especially those with cutaneous melanoma. Measuring the effect of treatment is traditionally done with measures of disease control. These include tumor shrinkage as measured by an agreed upon method such as RECIST or irRECIST or by lengthening of time-either lifespan or time without progressive disease (progression-free survival). However, it is possible that a similar lifespan could be achieved in one of 2 different ways-either continuous treatment with a drug or a shorter-term treatment that stops within a few months and then the patient has no further treatment. Comparing these treatments that are profoundly different for a patient but similar in terms of standard time or disease control measures demands new measures that can help describe the benefit of one or the other treatment. In the JCO article that accompanies this podcast, Regan et al, in an analysis of 1077 patients across 2 different randomized trials, attempt to provide such a measure. They define treatment-free survival as interval between time to ICI cessation to the time to subsequent therapy or death.  With this measure, the shorter the therapy and the more delayed the need for subsequent therapy (or death) the longer this interval is. Combination immunotherapy is notoriously toxic and while treatment duration can be short, the side effect duration can be prolonged. Could TFS be contaminated with toxicity ? to answer this question, Regan et al introduce another endpoint, TFS with and without toxicity and partition this with persistent and late onset grade ≥3 toxicity. These endpoints are illustrated in Figure 1. Below the familiar Kaplan-Meier overall survival curve is a slice showing survival after subsequent therapy initiation (so factoring in progression). Below this is the TFS without toxicity. Below this slice is the TFS with toxicity and below this is the time on IO therapy. With this division, the familiar KM curve gives a lot more information and illustrates the difference between nivo-ipi combination therapy and nivolumab monotherapy. While the overall survival is not statistically different between these 2 treatments (as shown in previous publications) the TFS lets us see what is going on with patients. In Figure 4 we can see that in the combination nivo-ipi arm the TFS (mean) is 11.1 months vs 4.6 months for nivo alone and 8.7 months for ipi alone. These numbers indicate that TFS alone does not convey the full picture as ipi beats nivo in this measure due to the short duration of ipi treatment while extensive previous data including from keynote 006 show us that pd-1 therapy exceeds ctla4 therapy in virtually every other measure of health. If we look at TFS subtracting toxicity, again ipi nivo beats nivo handily with 10 months vs 4 months but again ipi with 8.5 months slots in the middle. Figures 5A, 5 B and 5C show us the TFS partitioned by grade ≥3 treatment-related adverse events, grade ≥2 TRAEs or by the use of  immune suppressants. To summarize this interesting manuscript, overall survival can be subdivided into TFS and time on therapy and time following subsequent therapy. The TFS can be further subdivided into TFS with or without toxicity (≥2 or ≥3 TRAE or use of immune suppressants). These additional  measures give some granularity to the survival and let us see what exactly survival constitutes, time off treatment and toxicity or time on treatment and with side effects. These measures have several limitations: one of the important ones is introducing differences between treatment arms which by primary outcome measures have no difference by standard PFS or OS and by favoring short duration high toxicity treatments (such as ipi) over low toxicity, low intensity chronic treatments (such as nivo). These are value judgements which matter to many patients but need to be understood as such. In oncology, we need to make these value judgements explicit and make the tradeoffs clear. Ultimately though, the importance of TFS and similar outcome measures may be that they encourage this conversation and help our field open up to what matters. This concludes this JCO Podcast. Thank you for listening.

TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Progression of Disease Within 24 Months (POD24) in Follicular Lymphoma Is Associated With Reduced Intratumoral Immune-Infiltration” by Dr. Tobin and colleagues. My name is Dr. Carla Casulo, and I am Associate Professor of Medicine, Hematology and Oncology at the Wilmot Cancer Institute of the University of Rochester in Rochester, NY, USA. My oncologic specialty is Lymphoma.   Follicular lymphoma is the most frequently occurring indolent non-Hodgkin lymphoma and has a long natural history, with median overall survival nearing two decades. Patients with follicular lymphoma may experience a variable clinical course, with periods of long remission punctuated by episodes of recurrent lymphoma requiring re-treatment. Among all patients, up to one third will have early disease recurrence, defined as occurring within 24 months of diagnosis. Please note that progression of disease within 24 months will be referred to as POD24 for the remainder of this podcast. These patients have inferior survival, ranging from 25-50% at 5 years. Consequently, POD24 has become a robust and well accepted indicator of identifying high-risk patients.   The implications of POD24 were first identified through our analysis of the National Lymphocare Study, which sought to test the hypothesis that time to disease progression had an impact on subsequent patient outcomes. 588 patients treated with RCHOP were included. Patients with POD24 were defined as early progressors, and those without relapse or death within 24 months were defined as the reference group. Patients with POD24 had OS of 50% at 5 years compared to 90% in the reference group. These findings have subsequently been independently validated by numerous investigators worldwide, corroborating the adverse prognostic impact of an early disease related event in follicular lymphoma. The largest of these validation studies pooled individual patient data from 5,453 patients on 13 Clinical Trials using the Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) Investigation.     In the FLASH analysis, we identified that male gender, poor performance status, high follicular lymphoma international Prognostic index (FLIPI) score, and elevated baseline beta 2 microglobulin B2M as predictors of early death and progression. Moreover, it confirmed POD24 as an early clinical endpoint of poor survival in follicular lymphoma that should be utilized to identify patients for prospective clinical trials.   The current status of biomarkers in follicular lymphoma has emerged from a wealth of clinical and laboratory-based factors to classify risk, towards a biologic based, molecular approach merging clinical factors with our current understanding of the follicular lymphoma genomic landscape.     There are numerous well-established and emerging clinical prognostic indices used at the time of diagnosis in follicular lymphoma that can help discriminate general outcome. These include the FLIPI and FLIPI -2. To an extent, these prognostic markers can identify subsets of patients with an expected POD24 with a sensitivity between 60-78%, and a specificity between 56-58%. However, in an attempt to use a precision approach, investigators from the German Low-Grade Lymphoma Study Group harmonized clinical and pathologic data to create a clinico-genetic risk model aimed at more accurate risk prognostication in patients receiving front line chemoimmunotherapy. They performed deep DNA sequencing from formalin fixed pre-treatment biopsies to analyze the mutational status of genes in 151 patients with follicular lymphoma tumor samples. The resulting prognostic tool, called the m7-FLIPI, distilled down 74 genes into 7 genes with non-silent mutations occurring at a variant allele frequency of 10% or greater, and combined these with high risk FLIPI status and ECOG performance status. These included genes that increased risk of progression, including EP300, FOX01, CREBBP, CARD11, and those that decreased risk of progression, including EZH2, ARID1A, and MEF2B. The cumulative risk score was calculated by combining relative weights of these genes in a multivariate analysis predicting failure-free survival. This m7-FLIPI score was tested to identify POD24 but only captured about 50% of patients as high risk. A later model included only 3 genes, including EP300, FOX01 and EZH2, performance status and FLIPI score. Defined as the POD24-PI, this was more sensitive at identifying POD24 patients but did not outperform other metrics due to lower specificity.   Biologic classification of POD24 patients remains an ongoing international research priority to seek actionable targets that might change the natural history of follicular lymphoma and improve survival of patients more likely to have morbidity and death from their disease. Several years ago, in the pre-rituximab era, the Leukemia and Lymphoma Molecular profiling project identified the importance of the follicular lymphoma tumor microenvironment in predicting favorable or poor outcome. The follicular lymphoma tumor microenvironment is composed of tumor infiltrating T cells, regulatory T cells, and lymphoma-associated macrophages. The immune survival score or ISS established that differential expression of gene expression signatures from intratumoral immune cells in the tumor microenvironment affected survival, and particular increased expression of macrophages was associated with poor prognosis.   The impact of the follicular lymphoma immune microenvironment on survival is changing in the current era of chemotherapy combined with antiCD20 immunotherapy, and particularly by available drugs that reverse tumoral immunosuppression by blocking programmed cell death. Studies from solid tumor literature demonstrate that low levels of tumor infiltration immune cells are associated with inferior survival. In follicular lymphoma, then, precise characterization of high or low immune infiltrating cells in the tumor microenvironment may have a critical effect on understanding the mechanisms of POD24. This particular relationship is what Tobin and colleagues investigated in the current study.   In this analysis, targeted gene sequencing using NanoString technology from paraffin-embedded tissue and multi-spectral immunofluorescence on a tissue microarray was applied to two groups: a discovery cohort of 132 patients from Princess Alexandria Hospital with early- and advanced-stage follicular lymphoma who received either chemotherapy or observation and two independent validation cohorts of 198 patients with advanced-stage disease treated with RCHOP and RCVP from the German Low grade lymphoma Study Group and the British Columbia Cancer Agency. They also performed T cell repertoire analysis, flow cytometry, immunofluorescence, and next-generation sequencing.   Here, they defined POD24 as primary refractory disease following treatment, transformation to a more aggressive histology, and relapse within 24 months of diagnosis, which is a more liberal definition from what was initially described in the national lymphocare study but does encompass patients at highest risk of lymphoma-related death.   Gene expression profiling revealed distinct clustering of follicular lymphoma samples based on high or low expression of immune infiltrating cells. Low expression of four immune markers, including PDL-2, TNFalpha, CD4, and CD68 were all associated with poor outcome, but the most specific marker with the highest specificity and sensitivity was PD-L2. They then dichotomized PD-L2 expression into “immune infiltration high” and “immune infiltration low” in subsequent analyses. PD-L2 is an immune checkpoint present broadly on both tumor cells and the tumor microenvironment. To localize its distribution, they performed flow cytometry in fresh FL samples and quantified PD-L2 expression by PCR. They identified that PD-L2 gene expression was distributed in both CD20+ tumor cells as well as non CD20+ cells in the tumor microenvironment. However, the proportion of PD-L2 was lower in the CD20+ cells. Overall, there was lower expression of all immune cells in the immune infiltration low phenotype compare to the immune infiltration high phenotype.   They tested the relevance of immune infiltration and POD24. Consistent with numerous other studies, POD24 events occurred in about 24% of patients. Patients with POD24 events in the Princess Alexandria discovery set were more enriched for the immune infiltration low phenotype. These findings were also validated in the British Columbia cancer agency and German lymphoma study group populations. Nearly 50% of patients with low PD-L2 had POD24 events, compared to 16% in those with high PD-L2, concluding that low PD-L2 identifies a subset of patients enriched for POD24. When evaluating the mutational profiles of those with immune infiltration high versus immune infiltration low based on the m7-FLIPI genes, mutations were detected equally among both populations, suggesting that this mutational profiling is not influenced by the immune infiltration phenotype.   The data presented by Tobin and colleagues makes an important contribution to our understanding of the biological and immune-based mechanism influencing early disease-related events in follicular lymphoma. They demonstrate that reduced immune infiltration is associated with greater chance of POD24. While the sensitivity of this was high, similar to other prognostic markers, it still did not capture the entire subset of future POD24 cases, underscoring the significant heterogeneity within this high-risk patient population. However, there remains opportunity to include PD-L2 as a surrogate for poor risk disease. If further applied to immunohistochemistry or other widespread diagnostic methods, it has the potential for more widespread application. Further validation is still required, particularly to patients treated with novel agents or other immunotherapies. However, the assessment of immune infiltration as described by these findings appears to be an encouraging step in determining risk of POD24. This concludes this JCO Podcast. Thank you for listening.

This podcast summarizes the findings of the Lunenburg Lymphoma Biomarker Consortium systematic evaluation of MYC rearrangements in DLBCL, and discusses the prognostic impact of MYC, BCL2 and BCL6 rearrangements, and implications for FISH testing in newly diagnosed DLBCL.   TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Prognostic Significance of MYC Rearrangement and Translocation Partner in Diffuse Large B-Cell Lymphoma - A Study by the Lunenburg Lymphoma Biomarker Consortium” by Rosenwald et al. My name is Jeremy Abramson, and I am an attending physician at the Massachusetts General Hospital and an Associate Professor of Medicine at Harvard Medical School. My oncologic specialty is lymphoma. MYC rearrangements occur in approximately 10% of diffuse large B-cell lymphomas and have been associated with a worse prognosis.  When the MYC translocation occurs in concert with translocations of BCL2, BCL6, or both, initial series have suggested particularly poor outcomes with few patients achieving long term survival with conventional therapies.  This entity has been classified in the current WHO classification as high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 and is more conventionally known as double (or triple) hit lymphoma.  Though initial series painted a grim prognosis for these patients, more recent larger series have suggested that approximately 40% of double hit lymphoma patients may be cured, and that outcomes may be improved with more intensive regimens such as dose-adjusted EPOCH-R.  Most of these published series to date, however, continue to be limited by significant selection bias whereby cases with the most aggressive clinical or histopathologic features are likelier to be tested for MYC translocations, thus potentially excluding more prognostically favorable patients.  The small size of series to date has also made it difficult to assess more granular questions in MYC translocated diffuse large B cell lymphoma, hereafter referred to as DLBCL, such as the prognostic impact of MYC translocations when occurring without other translocations, the impact of translocation partner with MYC (Ig or non-Ig gene locus) in double hit lymphoma, and the significance of MYC/BCL6 double hit lymphomas which are far less common than MYC and BCL2.  Another practical question is who should we be testing for MYC translocations in the first place? Do we need to test every new case of DLBCL?  Or should we routinely test only an enriched population, such as those with MYC protein expression by immunohistochemistry, or GCB-like DLBCLs, which include the majority of double hit lymphomas? In the article that accompanies this podcast, the Lunenberg Lymphoma Biomarker Consortium  presents the single largest and most systematic analysis to date of MYC translocations in DLBCL, and sheds significant light on many of the most outstanding questions in this population. The Consortium studied over 2000 cases of DLBCL with available tissue and clinical data, drawn from large prospective cooperative group studies as well as population-based registries in Canada, the United Kingdom and the United States. The median age of the cohort was 66 years, and the median follow up was mature at greater than 6 years. All patients were treated with R-CHOP or R-CHOP-like therapy.  MYC rearrangements were found in 11% of patients. One third of these occurred as a sole rearrangement, 39% in concert with a BCL2 rearrangement, 15% with a BCL6 rearrangement, and 12% with both (i.e. triple hit lymphoma). Patients with MYC rearrangements had higher risk features by the IPI score than the entire DLBCL population, and patients with double/triple hit lymphoma had higher clinical risk factors than patients with MYC rearrangements alone. Patients with double or triple hit lymphoma had a significantly inferior outcome in terms of both progression free and overall survival compared to the overall DLBCL cohort, while no negative prognostic impact was conferred by a MYC translocation alone. Notably, the prognostic impact was only observed in the first 2 years from diagnosis.  They also compared the 31 MYC/BCL6 double hit patients with 82 MYC/BCL2 double hits, and found similar outcomes in the groups, validating that MYC/BCL6 double hit lymphomas should be considered high risk along with their BCL2 translocated counterparts. Prognosis for triple hit lymphoma was no worse than double hit lymphoma.  Perhaps most striking, however, was how well double and triple hit lymphoma patients did when compared to previously published retrospective studies. In this comprehensive evaluation by the Consortium, approximately 60% of double and triple hit lymphoma patients remained progression free beyond 5 years, and two thirds remained alive.  These remarkable data suggest that the majority of double and triple hit lymphomas identified by broad screening of the DLBCL population may be cured with chemoimmunotherapy and should offer encouragement to patients and providers alike.  Importantly the Consortium's analysis includes only patients with DLBCL morphology, so excluded double/triple hit patients with Burkitt or Burkitt-like histology who may have an inferior outcome compared to the double hit lymphoma patients in this analysis. MYC and BCL2 protein expression (so called dual expressor lymphomas) was also analyzed in 1414 cases with available tissue. MYC (≥40%) and BCL2 (≥50%) co-expression was associated with an inferior outcome compared to he general DLBCL population, though better than double/triple hit lymphomas, and notably the majority of dual expressor patients remained free from progression and alive at greater than 2 years of follow up after treatment with R-CHOP-like therapy. On evaluation by cell of origin, patients with GCB-like DLBCL had a slightly more favorable outcome compared to non-GCB, as defined by immunohistochemistry.  GCB-like DLBLC more commonly had MYC rearrangements, and exclusively contained the MYC/BCL2 subset of double hit lymphoma, while MYC/BCL6 cases occurred within both cell of origin subgroups. These robust data from this large systematic analysis address several pressing questions regarding MYC-rearranged DLBCL.  First, they tell us that a MYC rearrangement in the absence of a rearrangement of BCL2 and/or BCL6 does not predict an adverse outcome in DLBCL and may be treated as a routine DLBCL with R-CHOP-like therapy. Second, we learn that MYC translocation partner in the setting of a double/triple hit lymphoma matters, with the negative prognosis driven by MYC/Ig translocations rather than MYC rearranged with a non-Ig partner which does not appear to confer negative prognostic influence. Third, while MYC/BCL6 double hit lymphomas are uncommon, they appear to predict similarly inferior outcomes as MYC/BCL2 double hit lymphomas and triple hit lymphomas.  And fourth, very importantly, the outcome of double/triple hit DLBCL, though inferior to the entire DLBCL population, appears much better than previously estimated with approximately two thirds of patients achieving long term progression free and overall survival when treated with standard chemoimmunotherapy.  It warrants emphasis that this applies to cases morphologically classified as DLBCL, not necessarily to cases with Burkitt-like or blastoid features which were not included in the LLBC study and likely have a less favorable outcome.  For this reason, it is essential that pathologists signing out cases as aggressive B-cell lymphoma with translocations of MYC and BCL2 and/or BCL6 also indicate the morphologic subtype as DLBCL versus a higher grade appearance as this information will be essential for clinicians in applying the LLBC findings to prognostication in the clinic. Finally, this study provides us critically needed guidance in determining which cases warrant evaluation with fluorescence in situ hybridization (FISH) to detect MYC, BCL2 and BCL6 rearrangements. Presently, practice patterns are mixed with some centers testing all cases for MYC, while others test only enriched populations such as GCB-like DLBCL or double expressor DLBCL, and still other centers not routinely evaluating MYC at all in DLBCL.  The Consortium data validate that MYC translocations in DLBCL affect a sufficient proportion of the population and confer sufficient prognostic importance as to warrant testing.  They also show us that conventional immunohistochemistry for either cell of origin or MYC/BCL2 double expression status are not sufficient to direct FISH testing. Testing only GCB-like DLBCL would indeed identify all cases of MYC/BCL2 double hit lymphomas but would fail to identify a significant proportion of MYC/BCL6 double hit cases.  Performing FISH only on cases meeting current immunohistochemical thresholds for MYC and BCL2 double expressor lymphomas would fail to identify more than one quarter of cytogenetically defined double hit lymphomas, which would also be unacceptable. These data therefore support testing all newly diagnosed cases of DLBCL and high-grade B-cell lymphoma with FISH for MYC.  A positive FISH assay for MYC should prompt reflexive testing for both BCL2 and BCL6, which would then differentiate cases of single hit cases with MYC translocations alone from the higher risk double and triple hit lymphoma patients. The fact that the prognostic impact of double and triple hit lymphoma is seen only within the first 2 years from diagnosis underscores the need to optimize upfront therapy in these diseases. The data from the Lunenburg Lymphoma Biomarker Consortium suggest that R-CHOP-like therapy remains an acceptable standard of care in double expressor lymphomas, DLBCL cases with isolated MYC rearrangements, and perhaps even double/triple hit lymphomas with DLBCL morphology, though these cases have increasingly been treated with more intensive regimens such as dose-adjusted EPOCH-R or Burkitt-like regimens based on prior series.  In the absence of data clearly supporting one approach versus the other, I would consider either intensive approaches or standard R-CHOP as reasonable considerations in cases of double hit lymphoma with DLBCL morphology and should be individualized to the patient. Ultimately, we would like to overcome biological liabilities with biologically directed therapies, and the US Intergroup is now conducting a randomized clinical trial evaluating chemoimmunotherapy with or without the BCL2 inhibitor venetoclax specifically in double hit and double expressor lymphomas, with the chemoimmunotherapy backbone being dose adjusted EPOCH-R for double hits, and R-CHOP for double expressors. Participation in this important study is encouraged. This concludes this JCO Podcast. Thank you for listening.

This podcast discusses the work of Sheetz and colleagues describing the impact of centralization of high-risk cancer surgery within health care systems and networks in the United States. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Centralization of High-Risk Cancer Surgery Within Existing Hospital Systems” by Sheetz et al. My name is Stephen Edge, and I am Vice President of Healthcare Outcomes and Policy and Professor of Surgery and Oncology at the Roswell Park Comprehensive Cancer Center and the University at Buffalo in Buffalo, NY. My oncologic specialty is surgical oncology. Recent years have seen substantial consolidation of hospitals and practices into networked care systems. The benefits of health networks may include efficiencies of scale, better ability to thrive in the shifting health care economy, and enhanced quality. In the article that accompanies this podcast, Dr. Sheetz and colleagues at the University of Michigan studied the impact of health care networks on the outcome of high-risk cancer surgeries for pancreas, esophagus, lung, colon and rectal cancer. They examined the distribution of these surgeries in health care networks, and the relationship between outcomes and the degree of centralization of surgeries to a high-volume network hospital. There is a well-established relationship between hospital case volume and operative mortality for complex cancer surgery, most pronounced for pancreas and esophagus cancer. Some countries now mandate regionalization of these procedures to high volume centers. Most, but not all, studies show that regionalization improves outcomes for these procedures. Organized regionalization of cancer surgery in the United States has been limited though market forces have led to some consolidation of high-risk surgeries. This has been encouraged through recommendations of the Leapfrog Group that for the last 25 years has set minimum hospital volume standards for high risk surgeries. Sheetz and colleagues used the Medicare Provider Analysis and Review (MedPAR) files that include all beneficiaries of Medicare Part A to identify persons age 65 and older undergoing pancreatectomy, esophagectomy, lung resection, colectomy and proctectomy for the years 2005 – 2014. They used American Hospital Association data to identify hospital characteristics such as size, teaching status and which hospitals are in the same health system if any. They combined these data with information from the National Inpatient Sample to derive estimates of the total number of cases of each type beyond Medicare beneficiaries. They defined a “high volume hospital” and “high volume system” as one that met the Leapfrog Group volume criteria; and centralization of surgery as the proportion of surgeries of each type performed at the highest volume hospital in a given health network. Outcomes assessed were 30-day mortality after surgery, major complications, and hospital readmission. The procedures most centralized in networks were pancreatectomy and esophagectomy with a mean of 71% and 51%, respectively. However, for pancreas surgery 74% and for esophagus surgery 84% of systems did not meet or have a hospital that met the Leapfrog Group volume recommendations for pancreatectomy. Complications were about 20% lower for pancreas and esophagus surgery at health systems with the highest surgery centralization. The impact on complications of lung and colorectal surgery was less. More important was the reduction in risk-adjusted 30-day mortality. For pancreas and esophagus surgery the mortality at the most centralized systems mortality was 60% and 53% lower, respectively, then the least centralized systems. The absolute rates dropped from 8.9% to 3.7% for pancreas and 10.3% to 4.8% for esophagus surgery. The reduction for lung resection was less and there was no significant mortality difference for colorectal surgery. Importantly, the team observed the same level of reduction associated with system surgery centralization for low volume and high-volume systems, and those with and without a high-volume hospital. Certainly, this study is not without its limitations. Because the MedPAR files include primarily fee-for-service Medicare, they had to estimate the total number of cases. They did not have specific information on the health systems or the distance of patients from a high-volume center. They did not know the systems’ governance relationships or the degree of coordination between system hospitals, services and providers. However, the study reinforces the well-established volume-outcome relationships in the context of hospitals with common governance. While individual surgeons may be excellent at low volume hospitals the finding of a greater relative impact on mortality than complications suggest that it not just the surgeon, but that high-volume hospitals with their larger teams and resources are less likely to “fail to rescue” a patient with a major complication. This was realized within these health systems. Networks with a common governance and shared financial and reputation risk should be motivated to assure best outcomes and limit inefficiency. Networks have central program oversight and should pay more heed to factors that impact quality and have the ability to foster providing the right care at the right place. They also should be more attuned to the needs of their customers and their unique geographic and economic situations and can meet the needs of people in dense metropolitan areas and the vast expanses of rural America. However, referral to the network flagship cannot be a one-way street. Health systems should establish programs that address these cancers across the continuum of the disease. Evidence shows that some of those who might benefit from these high-risk surgeries never see a team to help determine this. Conversely, many or people with pancreas, esophageal and lung cancer present with disease not amenable to surgery. It makes sense for a health system to assure that all patients with these cancers get a full, multidisciplinary evaluation and that those who cannot have resection receive appropriate referral or return to providers close to home who can provide the necessary care, clinical trials, and supportive services. When the volume/outcome associations were first described, organized medicine was slow to address the issue and instead tried to fathom what factors led to better outcome with volume. In the absence of policy and professional leadership, market forces slowly changed practices so that now many or most of the very high-risk procedures are done at high volume centers. But this has taken 30 – 40 years and likely impacted many lives. Conversely, surgeons and policy makers have led the charge to regionalize other high-risk services such as trauma care, cardiac surgery, and pediatric surgery. The findings of Sheetz et al. support renewal of efforts in policy and practice to assure cancer patients receive the best options. Sheetz and colleagues are to be congratulated for their insightful work. Despite its inherent limitations, they have shed light on a key area needing attention of health systems, professional societies and policy makers. This concludes this JCO Podcast. Thank you for listening.

Dr. Osama Rahma, an Assistant Professor of Medicine at Harvard Medical School, Dana-Farber Cancer Institute, discusses the role of MSI in gastric cancer. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Individual Patient Data Meta-Analysis of the Value of Microsatellite Instability as a Biomarker in Gastric Cancer” by Pietrantonio et al. My name is Osama Rahma, and I am an Assistant Professor of Medicine at Harvard Medical School, Dana-Farber Cancer Institute in Boston, Massachusetts. My oncologic specialty is Gastrointestinal Cancer and Cancer Immunotherapy. Despite the advances in surgical approach and perioperative multimodalities in gastric cancer, the recurrence rate remains over 50%. While many patients benefit from perioperative chemotherapy many others don’t derive such benefits and experience toxic side effects. Accordingly, there is an unmet need to identify prognostic markers to guide  chemotherapy decisions in the neoadjuvant and adjuvant settings. Microsatellite instability has been well established as a prognostic marker in colon cancer that correlates with better overall survival and potential lack of benefit from adjuvant chemotherapy in stage II disease. The question is whether microsatellite instable gastric tumors have similar behavior? To answer this question, subgroups analyses of patients with MSI high tumors were performed in both the MAGIC and the CLASSIC trials which established perioperative ECF chemotherapy in non-Asian population and adjuvant capecitabine and oxaliplatin in Asia, respectively as the standard of care in resectable gastric cancer. Although MSI tumors were found to be less likely to benefit from chemotherapy, the low incidence of MSI tumors in both trials of 8-10% made it very challenging to draw  meaningful conclusions.   In the article that accompanies this podcast, Pietrantonio et al performed individual patient level data meta-analysis testing the prognostic significance of microsatellite instability in both the MAGIC and CLASSIC trials. In addition, the analysis included the ARTIST study, which tested adding radiation to adjuvant capecitabine and cisplatin in Asia and the ITACA-S study which tested adjuvant FOLFIRI, docetaxel and cisplatin vs 5-fluorouracil and folinic acid in Europe in radically resected gastric cancer. The meta-analysis included 1556 patients, 63% Asian and 37% Europeans. Patients were stratified using microsatellite instability status and based on whether they received multimodality therapy in all 4 trials or surgery only in the MAGIC and CLASSIC trials. 7.8% of patients had MSI high tumors and  70.8 % received multimodality treatment. Consistent with prior reports of individual trials, patients with MSI high tumors had better outcomes compared to MSI low or MSS tumors. Specifically, the 5-year disease free survival rate was 71.8% vs 52.3% and 5-year overall survival was 77.5% vs 59.3%. MSI remained a significant independent prognostic factor for improved disease-free survival and overall survival in a multivariate analysis in addition to Asian ethnicity, low TNM staging, and receiving multimodality therapy. In addition, MSI was noted to be more prevalent in the Asian population and was a better prognostic factor in Asians compared to Europeans.   Importantly, MSI high tumors did not benefit from perioperative chemotherapy with 5-year disease free and overall survival of 70% and 75%, respectively for those who received chemotherapy compared to 77% and 83% for MSI high patients who did not receive chemotherapy. In contrast patients with MSI low or MSS experienced benefit from perioperative chemotherapy compared to surgery alone. Finally, MSI status did not affect post-recurrence survival. However, this was limited by the small number of MSI high patients who experience disease recurrence.   This study has several limitations including its retrospective nature, the relatively small number of patients with MSI high tumors of 121, and the heterogenicity of administered treatment in the 4 trials including different regimens of neoadjuvant and adjuvant chemotherapy with or without radiation. In addition, D1 surgery was performed in Europe while D2 surgery was performed in Asia. In summary, I think this study supports the adoption of microsatellite testing as a routine biomarker in patients with operable gastric cancer. The result of microsatellite testing should be discussed in a multidisciplinary fashion since perioperative chemotherapy may result in more harm than benefit in MSI high tumors. This study among others highlights the unique behavior of microsatellite instable tumors which is driven by their unique immune profile including increased T-cell infiltration and activation due to higher mutational load and neoantigens compared to microsatellite stable tumors. PD-1 inhibitors are effective in more than 50% of MSI tumors in the advanced setting and in 15-25% of gastric tumors with positive PD-L1 expression.  Accordingly, future clinical trials should stratify gastric cancer patients based on their microsatellite status and PD-L1 expression while incorporating immunotherapy in the early disease setting.   This concludes this JCO Podcast. Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article, "Treatment of Childhood Nasopharyngeal Carcinoma with Induction Chemotherapy and Concomitant Chemoradiotherapy: Results of the Children’s Oncology Group ARAR0331 Study" by Rodriguez-Galindo et al. My name is Suzanne Wolden, and I am the Director of Pediatric Radiation Oncology at Memorial Sloan Kettering in New York City, USA.  My oncologic specialty is Pediatric Radiation Oncology. This important manuscript summarizes the results of Children’s Oncology Group protocol ARAR0331 for childhood nasopharyngeal carcinoma.  The study enrolled 111 patients, of whom 75% were male and 47% were African American, with a median age of 15.  Eligible patients had AJCC stage IIb-IVC disease and received three cycles of induction chemotherapy with 5-fluorouracil and cisplatin followed by concurrent cisplatin and radiotherapy.  Three patients had progressive disease during induction chemotherapy, eight were removed from the study due to physician or parent preference, and another three were not evaluable.  This left 97 patients evaluable for response and concurrent chemoradiotherapy.  Responses and radiotherapy treatment plans were not centrally reviewed but were left to the judgement of the treating institution.  All patients received 45 Gy to comprehensive head and neck fields encompassing the nasopharynx and bilateral level I-V lymph nodes.  A boost to the nasopharynx and residual gross nodal disease was prescribed based on response.  The full dose of 70.2 Gy indicated for stable disease was given to 18.6% of patients while 77.3% received the protocol specified dose for complete or partial response of 61.2 Gy or lower.  Another 4.1% of patients received intermediate non-protocol doses of 63.9-66.6 Gy.  The trial was amended to reduce the cycles of concurrent cisplatin during radiotherapy to two from three after unacceptable rates of renal and gastrointestinal toxicities were reported.    This trial was limited to patients age 18 years and younger and consisted primarily of American patients.  It is notable that the demographics of nasopharynx cancer in these young patients differ significantly from adults with this diagnosis.  Most patients are teens since nasopharynx cancer is vanishingly rare in younger children.  The majority were male, and nearly half were African-American.  Nasopharynx cancer is quite rare in teens of Asian descent, in stark contrast to the adult population.  In international series, it has been noted that teens in countries around the Mediterranean also have a relatively high incidence of this rare cancer.  The study illustrates that pediatric patients are much more likely than adults to have advanced disease and WHO type III, Epstein Barr virus-associated histology. Despite a lack of central review, the response rate appears to be quite high to induction therapy as one might expect with WHO type III carcinoma.  It is surprising that any patients had progressive disease, and I suspect that the rate of partial and complete response may have been even higher than what is inferred from the radiation boost doses given.  Nonetheless, the strategy of induction therapy was highly successful in allowing a large majority of patients to receive reduced doses of radiation.  It is important to note that all patients received 45 Gy to initial comprehensive fields rather than the 50 Gy typically used for adults and that smaller, more forgiving fractions of 1.8 Gy were used in comparison to the standard 2 Gy for adult head and neck cancer.  While some patients received a standard adult boost dose of 70.2 Gy, 81.4% received a lower boost dose.  In most cases, this was the protocol specified 61.2 Gy, a 13% dose reduction.  Even with these significantly lower doses, local control was exceptionally high, with only 5.5% of patients experiencing local failure with or without a distant relapse. The successful reduction in radiotherapy doses in this study is incredibly important and by far the most newsworthy aspect of this paper.  Even full or nearly grown teens experience dramatically more severe late effects of radiotherapy compared to older adults.  The severity of soft tissue fibrosis 10 or more years after full doses of radiation to the head and neck is so great that many patients require feeding tubes and tracheostomies.  The rate of second malignancy is also much higher in young patients.  The rate of distant relapse of 10.5% was low, considering that patients with metastatic disease at diagnosis were enrolled.  It is possible that with more advanced staging scans such as FDG-PET, metastatic lesions can be more easily detected and defined.  In that case, they can be targeted with radiotherapy to decrease the risk of relapse.  This approach has been shown to be effective in achieving cure in adults.  It is unlikely that an increase in chemotherapy beyond what was used in this protocol would be tolerated or worth the added toxicity.  Indeed, it is unclear whether the 3rd cycle of concurrent cisplatin was beneficial since there was only a trend for improved EFS and the cumulative toxicity is significant.  One must be mindful that increases in systemic therapy have been shown to decrease tolerance for head and neck radiotherapy.  This can be counterproductive to outcome if there are delays, breaks or failure to complete the course of radiation. This trial was so successful in its ability to decrease radiation exposure in young patients, that we should be inspired to go further.  My thoughts regarding the next trial would be to use PET scans for staging and response assessment and to push the radiotherapy doses lower.  This approach is currently being investigated for adult HPV associated head and neck cancer with doses as low as 30 Gy.  Perhaps in pediatric (or even EBV positive adult) nasopharynx cancer, 30-36 Gy would be enough for the comprehensive initial fields with boost doses in the range of 50-60 Gy for those who respond favorably to induction chemotherapy.  Dose reductions of this magnitude would make major differences in the acute and especially the late toxicities.  In addition, modern radiation technologies such as proton therapy allow improved avoidance of normal tissue exposure for these young, curable patients. In summary, this article provides evidence that response-based radiation dose reduction is possible for pediatric nasopharynx cancer.  Even with numerous limitations, the outstanding results of this trial inspire us to continue moving forward in the direction of reducing radiation exposure for these young patients.  Long-term follow up is also urged to quantify the expected benefits of these therapeutic changes. This concludes this JCO Podcast.  Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article “Maintaining Outstanding Outcomes Using Response and Biology-Based Therapy for Intermediate-Risk Neuroblastoma: A Report From the Children's Oncology Group Study ANBL0531” by Twist et al. My name is Javed Khan, and I am Deputy Chief and Senior Investigator at the Genetics Branch and an Attending for the Pediatric Oncology Branch of the National Cancer Institutes of the NIH in Bethesda, Maryland. My oncologic specialty is Pediatric Hematology Oncology. Childhood cancer is a life-threatening disease where survival rates have increased exponentially to over 75% over the past three decades. However, this has come at a considerable cost with significant incidence of late effects including hearing loss, scoliosis, hypothyroidism, growth and development delay, infertility, psychological, emotional, cognitive and neurological sequelae, and secondary malignancies. Most of these late effects have been attributed therapy including chemotherapy, surgery and radiation. In the manuscript that accompanies this podcast, Twist et al report on the results of the Children’s Oncology Group study ANBL0531, whose primary aim was to reduce therapy for subsets of children aged =95% for the entire cohort. Neuroblastoma is an extracranial pediatric malignancy of neural crest origin that has often been described as an enigmatic cancer due to its significant clinical, molecular and biological heterogeneity. For example, some patients with widely metastatic disease are cured with minimal or no therapy whereas others have relentless progression to death despite intensive therapies.  There has been considerable progress in dissecting out the causes of this heterogeneity and developing prognostic biomarkers to stratify the risk based on several clinical, histological and molecular markers. At the time this clinical study was performed, and the manuscript written, the authors stratified patients using several clinical and biologic parameters including age, the International Neuroblastoma Staging System, MYCN amplification status, the International Neuroblastoma Pathology Classification of histopathology, and tumor DNA index. An additional marker utilized in this study was loss of heterozygosity determination of the tumors at chromosome bands 1p36 and 11q23. This stratification strategy has led to the identification of low and high-risk groups where therapy is more clearly defined and patients with low risk have excellent outcome for most patients with surgery alone and watchful waiting. For high-risk disease, significant strides have been made using a combination of surgery, aggressive chemotherapy, radiation followed by Chimeric Antibody 14.18 anti GD2 therapy, GM-CSF, IL-2 and Isotretinoin, however the five-year survival remains guarded at 40-50%. In the intermediate-risk group, the subject of this study, although the 5-year survival rates of 90-95% have been achieved, this group is significantly heterozygous raising the possibility of reducing therapy for subsets of patients within this group. This was the motivation for this study. Thus, the goal of this clinical protocol, ANBL0531, was to refine the minimal therapy needed to achieve excellent outcomes for patients with intermediate-risk neuroblastoma, with the aim to maintain an overall 3-year OS rate of > 95% for the entire cohort. Patients were stratified into Groups 2, 3, or 4, who were assigned to receive a minimum of 2, 4, or 8 cycles of chemotherapy, respectively. Chemotherapy was identical to that used on a previous study A3961. Reduction of therapy was planned to be achieved for patients with biologically favorable tumors (Groups 2 and 3) by using the achievement of Partial Response (PR) to chemotherapy +/- surgery to be the endpoint of therapy, rather than the achievement of Very Good Partial Response (VGPR) as was previously used on A3961. If the treatment endpoint was not achieved after completion of the scheduled chemotherapy courses, additional cycles of therapy could be administered, and patients re-evaluated following every 2 cycles to determine if the treatment endpoint has been achieved. VGPR, a more stringent response criteria, was used for Group 4 patients which includes those with age1). These patients also received Isotretinoin (13-cis-retinoic acid, Accutane) for maintenance therapy, as they would have previously received this treatment on high-risk protocols. Thus, these patients would receive a significant reduction in therapy compared to prior studies.  These patients were closely monitored by interim stopping rules. Rescue therapy for this study for patients with an inadequate response to initial therapy and for patients with progressive, non-metastatic disease utilized standard cyclophosphamide and topotecan. Reduction of therapy was also planned and achieved on their study by reducing potential surgical morbidity for patients with stage 4S disease, who would no longer be required to undergo resection of their primary tumor. In the manuscript, the authors report that 404 evaluable patients were enrolled between 2007 and 2011, They found that compared to legacy COG studies, subsets of patients with locoregional disease, infants with stage 4 or 4S tumors, and toddlers with stage 3 or 4 disease had a reduction in treatment. The 3-year event-free survival (EFS) and OS were 83.2±1.9% and 94.9±1.1%, respectively. Infants with stage 4 favorable biology tumors (n=61) had superior 3-year EFS compared to patients with >= unfavorable biological feature (n=47; 86.9±4.4% versus 66.8±7.0%; p=0.02), with a trend towards OS advantage (95.0±2.8% and; 86.9±5.1% respectively p=0.08. For patients with localized disease OS was 100%. They conclude that comparable/excellent survival was achieved with this biology- and response-based algorithm, with reduction of therapy for subsets of intermediate-risk neuroblastoma patients. However, more effective treatment strategies are still needed for infants with unfavorable biology stage 4 disease. For the 32 infants with hyperdiploid, favorable histology (FH) stage 4 tumors with LOH at 1p36 or 11q23, or missing LOH data, intensification of treatment on ANBL0531 compared to A396110 did not reduce the risk of relapse previously reported for infants with tumors that harbor these genetic anomalies. Three-year EFS for this cohort was 68.6% (95% CI: 52.2-85.1%) versus 86.9% (95% CI: 78.3-95.4%) for stage 4 infants with favorable biology (p=0.04). Overall survival was not significantly different, indicating that many of the infants with 1p36/11q23 aberrations were successfully salvaged. Of the 20 patients who received CPM/TOPO due to an inadequate response to initial therapy, 9 achieved ≥VGPR. However, 6 of the 20 patients developed PD or relapsed, and 1 died, indicating that more effective treatment is needed for patients who do not meet the defined treatment endpoint after 8 cycles of chemotherapy. Take home messages: This is an important study with clinical implications for intermediate-risk neuroblastoma where the authors show that it is possible to reduce therapy based on a clinical Partial Response (PR) endpoint compared to Very Good Partial Response (VGPR). This most likely reflects the biology of the disease such that tumors that are responding to therapy will continue to involute. However, more effective therapy is needed for those patients who develop progressive disease (PD) or relapse or do not meet the defined treatment endpoint after 8 cycles of chemotherapy as these patients continue to have poor outcome. This will await the result of current biological and genomic studies and the development of novel therapies targeting ALK or RAS, or epigenetic targeting of MYC or MYCN activated tumors, or immunotherapeutic approaches such as adoptive cell therapies consisting of chimeric antigen receptor (CAR T cell) or, NK cells, or the use of immunocytokines such as hu14.18-IL2 or antibody drug conjugates. All these holds promise for future sub-stratification and new therapies for children with intermediate and high-risk neuroblastoma. This concludes this JCO Podcast. Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article “Dose-Adjusted EPOCH-R Compared to R-CHOP as Frontline Therapy for Diffuse Large B Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial CALGB 50303 (Alliance)” by Bartlett et al. My name is Patrick Stiff, and I am Division Director of Hematology-Oncology at Loyola University Stritch School of Medicine in Maywood, Illinois. My oncologic specialty is hematologic malignancies and stem cell transplantation.     CHOP has remained the chemotherapy backbone of choice for the treatment of diffuse aggressive non-Hodgkin lymphoma since the 4 arm randomized SWOG study was performed 25 years ago1. Since then, only the addition of rituximab has improved patients' outcome2.   Investigators have tried to improve outcomes by employing other strategies like increasing drug intensity, shortening the interval between cycles, adding newer agents, changing the method of administration, and adding transplantation, but none clearly demonstrated a survival advantage. Among these strategies is an infusional one designed to increase apoptosis and inhibit BCL6 and p-glycoprotein in resistant cells.  While SWOG tested infusional CHOP in 2001 and found no difference in outcomes, compared to bolus CHOP3, the NCI group has explored a modified CHOP infusional regimen known as EPOCH consisting of etoposide, vincristine, and doxorubicin given simultaneously as a continuous 4 day infusion with a bolus dose of cyclophosphamide at the end of the 4 days along with daily oral prednisone Combined with aggressive dose escalations based on nadir myelosuppression, they tested this regimen with rituximab, EPOCH-R, reporting an impressive 5 year PFS of 79% in an unselected study of 72 patients from 3 centers4.  Based on this, 18 CALGB institutions treated 69 patients with dose adjusted EPOCH-R, demonstrating a similar 62 month TTP of 81%, with an impressive 100% TTP for the germinal center B cell subgroup as defined by the Hans algorithm, all seemingly superior to R-CHOP5.  Equally impressive was a Phase II study in mediastinal B cell NHL with a 5-yr EFS of 93% administered without consolidative radiotherapy, added frequently to R-CHOP6.  Therefore, a head-to-head comparison was the natural next step.   The trial that accompanies this podcast was designed to compare the PFS and OS at 3 years between patients treated with 6 cycles of dose adjusted EPOCH-R to the standard R-CHOP.  The trial opened in 2005 and enrolled 524 patients with either DLBCL, primary mediastinal BCL or intravascular large cell NHL over an 8+ year period to its close in 2013.  Seventy-four % had stage III/IV disease and 12% high IPI disease.   Eighty-eight percent of the R-CHOP and 82% of the dose adjusted EPOCH-R cycles were administered with 75% of the dose adjusted EPOCH-R patients receiving initial dose escalations per protocol. At a median follow-up of 5.2 years the 5 year PFS and OS were 66 and 85% for the R-CHOP treated patients no different from the 68 and 77.5% for the dose adjusted EPOCH-R  patients.  Prognostic factors for PFS were age > 60, IPI, and double expressers (15.6% of the 270 with complete data) for MYC, BCL-2 and BCl-6.  There were a number of post hoc subgroup analyses performed. Of these, the PFS for the combined High and High intermediate IPI group was higher for the dose adjusted EPOCH-R group (p = 0.041) but no difference in OS was noted.  In none of the other subgroups was a benefit seen for dose adjusted EPOCH-R including CNS relapses, mediastinal B cell NHL, double expressors or those with MYC positivity although percentages of these subgroups were small.  There were however significantly increased grade III-IV myelotoxic and non-myelotoxic complications for the infusional regimen. Should we take these results as the final word on the lack of a benefit of dose adjusted EPOCH-R in the treatment of DLBCL?  In other words is this a case of "déjà vu all over again"?.  This trial recruited slowly, 524 patients over more than 8 years, with 2 (20% of the phase II study5) were excluded.  Second there was the requirement for submission of fresh/frozen material including a second biopsy if needed thereby likely eliminating mostly patients with rapidly progressing disease.  Together possibly with some investigator bias, given the promising Phase II data, there was a decrease in High IPI enrollment of only 12% versus the 20% in the Phase II study, which extended to other high risk patients including double expressors, C-Myc positive, and mediastinal B cell disease. Combined these led to the 3 year PFS for R-CHOP of 72%, 17% better than the planned outcome. However, considering the trial exclusions, and ultimately a PFS similar to that of other recent R-CHOP experiences7,8 one could argue that the 3-yr 55% PFS endpoint for this trial was far too conservative.  While the R-CHOP PFS was 17% better than planned, the dose adjusted EPOCH-R 5-yr PFS was 7% worse than the Phase II results, which is difficult to explain considering the earlier studies, in which the more favorable patients did better5. A lower administered dose intensity compared to prior studies4,5 was not apparent with the incidence of grade III/IV febrile neutropenia and neurotoxicity similar to the Phase II trial.  However 82%  vs 91% of those in the Phase II study completed all dose adjusted EPOCH-R cycles with the decrease mostly due to on treatment deaths and AEs, suggesting that when used in a more 'real world setting' this regimen is more toxic than initially seen.  Might those who completed therapy also have had dose reductions or delays that could also have impacted PFS?  Finally, this report does not include PFS based on cell of origin(COO), which for patients with  germinal center B cell of origin in the Phase II study was 100%.  Perhaps the germinal B cell percentage was lower than in the Phase II studies as well. So what can be concluded about these negative results?  The authors conclude that there was a "potential patient selection bias", at least partially explainable by trial design, and that this "may preclude generalizibility….to specific subgroups".  I would conclude that given the outcome and toxicity data, for the low and low intermediate IPI patient, R-CHOP remains the treatment of choice.  The post hoc PFS improvement for the high risk subgroup might argue for dose adjusted EPOCH-R, but the lack of an OS advantage in this subgroup needs to be acknowledged. However, other compelling phase II studies in high risk subsets, e.g double hit, underrepresented in this trial, still makes the efficacy of dose adjusted EPOCH-R in certain circumstances an open question.  This concludes this JCO Podcast. Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article “Erlotinib Versus Gemcitabine Plus Cisplatin as Neoadjuvant Treatment for Stage IIIA-N2 EGFR-Mutant NSCLC (EMERGING-CTONG 1103): A Randomized Phase II Study” by Zhong et al. My name is Tony Mok, and I am a Professor of Clinical Oncology at the Chinese University of Hong Kong in the Prince of Wales Hospital in Hong Kong. My oncologic specialty is Medical Oncology.   With the advent of molecular targeted therapy, patients harboring driver oncogenes may now survive longer and better than before, and EGFR mutation is the prime example of such achievement. However, evidence for “cure” of patients with metastatic EGFR mutation positive lung cancer remains scanty. In contrast, It may be more reasonable to first attempt cure of patients with earlier stage disease using molecular targeted therapy. CTONG 1103, published in this issue of Journal of Clinical Oncology, is the first randomized study comparing neoadjuvant erlotinib with chemotherapy for patients with stage IIIA EGFR mutation positive lung cancer.   CTONG 1103, the report that accompanies this podcast, is not an easy study to conduct. Between December 2011 and December 2017, investigators from 17 centers across China managed to screen 386 patients with stage IIIA non-small cell lung cancer (NSCLC) and identified only 72 (which is about 19%) eligible EGFR mutation positive patients. They were randomized to receive either erlotinib 150mg daily for 42 days or two cycles of chemotherapy using gemcitabine and cisplatin as neo-adjuvant therapy. After neoadjuvant therapy, 73% of the erlotinib arm, and 63% of the chemotherapy arm, received curative surgery, including two patients in erlotinib arm who received pneumonectomy. The primary endpoint of this study is tumor response rate, which is 54.1% for erlotinib and 34.3% for chemotherapy. However, the odds ratio of 2.26 for tumor response rate was not statistically significant. Two other important and impactful endpoints include major pathological response and progression free survival (PFS). Major pathological response is defined as less than 10% residual viable tumor cell and it occurred only in 10.7% of patients who received erlotinib and none with the chemotherapy. But on the other hand, PFS was significantly better with erlotinib arm, reporting median of 21.5 month comparing with 11.4 months with chemotherapy arm.   In reference to the primary endpoint of tumor response rate, we should conclude that CTONG 1103 is a negative study. Zhong et al has reasonably estimated the sample size based on a presumptive response rate of 70% in the erlotinib arm and 36% in the chemotherapy arm.  The reported response rate at 54.1% with erlotinib in this study has significantly fallen short of the expected rate of 70%, which was actually the widely accepted response rate in patients with stage IV disease. The authors selected to offer 42 days of neo-adjuvant erlotinib in order to match the two cycles of neo-adjuvant chemotherapy. While there is no biologic reason to explain the low response rate in earlier stage disease, the shorter duration of treatment may contribute to the relatively lower response rate. The other important outcome is the major pathological response of 10.7% with neo-adjuvant erlotinib, which is supposed to be a surrogate for overall survival. Hellman et al were among the first groups to suggest the predictive power of major pathological response for neo-adjuvant chemotherapy for patients with early stage lung cancer. The lower than expected major pathological response may be considered a surrogate indicator for overall survival but it is more important to wait for the mature survival outcomes.   A negative study can still be impactful. This study has established the feasibility of neo-adjuvant EGFR TKI for patients with potentially resectable EGFR mutation positive lung cancer. The first single arm phase II study on pre-operative gefitinib published in 2009 in the Journal of Clinical Oncology enrolled 36 patients but only 6 harbored the activating EGFR mutations. Tumor response was observed in 4 patients and all were positive for the mutations. Another single arm study published in 2018 in the journal The Oncologist enrolled 19 patients with EGFR mutation positive stage IIIA NSCLC and treated with neoadjuvant erlotinib for 56 days. Tumor response rate was 42.1% and resection rate was 68.4%. Only 5 of the 14 patients (35.7%) with surgical resection had documented pathologic downstaging from N2 to N0/N1 disease. The median PFS and OS was 11.2 and 51.6 months respectively. CTONG 1103 is the first and only randomized comparative study that confirmed the feasibility and efficacy of neo-adjuvant EGFR TKI. Tumor response rate is higher than chemotherapy by 20% although not statistically significant, but toxicity profile is better, which is an established fact from multiple phase III studies on advanced stage disease. The resection rates were similar between the two arms but it was unclear how many of the enrolled patients had unresectable disease prior to neo-adjuvant therapy. Key objectives of neo-adjuvant therapy are to down-stage tumor/nodal disease and to improve resectability. This randomized study may potentially document if erlotinib is more capable of converting unresectable stage IIIA disease to being resectable, however, this data is not currently available.   The authors of the current study have also reported improvement in progression free survival, but we cannot conclude that the improvement is solely due to the neo-adjuvant therapy. As per study protocol, patients from neo-adjuvant EGFR TKI arm did receive 12 months of erlotinib as adjuvant therapy while the chemotherapy arm received only 2 more cycles of similar treatment. Considering the duration of therapy, the adjuvant erlotinib may in fact  contribute more to prolongation of progression free survival than the neo-adjuvant therapy. In 2017 in the journal Lancet Oncology, the same group of investigators have reported a randomized phase III study comparing adjuvant gefitinib with chemotherapy and the median disease free survival was 28.7 months and 18.0 months, respectively. All patients enrolled in this study had resectable lung cancer with over 60% of patients having N2 disease, and the authors had concluded on the potential survival advantage of adjuvant EGFR TKI. Thus, the improvement in progression free survival should be explained by both neo-adjuvant and adjuvant erlotinib.   In summary, CTONG 1103 is a negative study but it has significant impact on management of stage IIIA EGFR mutation positive lung cancer. With high screening failure rate at 80%, it took the authors 6 years to enroll 72 patients. This study will remain the only randomized study on this patient group for a long time as similar  large scale phase III trials of this strategy will be unlikely. Clinicians are obligated to share and explain CTONG 1103 to patient with stage IIIA EGFR mutation positive lung cancer. For patients with resectable disease at presentation, the benefit of neo-adjuvant EGFR TKI may be debatable. But for patients with un-resectable stage IIIA disease, neo-adjuvant EGFR TKI may potentially downstage the disease status and facilitate resection.     This concludes this JCO podcast. Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article 'Late Relapses in Patients With Diffuse Large B-Cell Lymphoma Treated With Immunochemotherapy' by Yang et My name is Ann LaCasce, and I am an Associate Professor of Medicine at the Dana-Farber Cancer Institute in Boston, USA.  My oncologic specialty is lymphoma. This podcast discusses the recent paper evaluating the risk of late relapse in patients with diffuse large B-cell lymphoma who are event free 24 months after diagnosis. The goal of upfront chemoimmunotherapy in patients with diffuse large B-cell lymphoma (DLBCL) is the permanent eradication of disease. In the era of rituximab, few studies with sufficient follow-up have examined the risk of late recurrence.  An analysis of patients with DLBCL from the University of Iowa/Mayo and validated in a separate cohort from the French Study Group of Adult Lymphoma demonstrated that patients who were alive and disease free at 24 months from diagnosis had overall survival rates equivalent to the age and sex matched general population.  Despite this finding suggesting cure, late relapses are not uncommon.   In this manuscript, patients enrolled in the Molecular Epidemiology Resource of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence with newly diagnosed diffuse large B-cell lymphoma or DLBCL with concurrent indolent lymphoma were identified.  847 of the 1324 patients treated with chemoimmunotherapy with or without radiotherapy between 2002 and 2015 were event free at 24 months.  These patients were subsequently analyzed for late relapse.  The majority of patients (87%) had DLBCL without evidence of co-existing indolent lymphoma. With a median follow-up of 62.9 months, 78 patients developed recurrent disease, and the cumulative incidence of late relapse was approximately 7% at 3 years, 9% at 5 years and 10 % at 8 years after achieving EFS24.  Of the patients who developed recurrent lymphoma, 55 had DLBCL alone at baseline and 23 had DLBCL with concurrent indolent lymphoma. Among the patients with DLBCL alone.  36 developed recurrent DLBCL and 13 ad indolent lymphoma (12 with follicular lymphoma and 1 with marginal zone lymphoma).  6 patients did not have pathologic confirmation of disease subtype at the time of recurrence. For the 59% of patients with cell of origin data determined using the Hans algorithm, rates of relapse in patients with DLBCL alone did not differ between those with germinal center derived (GCB) versus non-GCB subtypes.  Individuals with GCB DLBCL were more likely to relapse with indolent lymphoma. Of the 23 patients with concurrent indolent lymphoma at baseline, 9 relapsed with DLBCL and the remaining 11 relapsed with indolent lymphoma 10 of whom had the same subtype at initial presentation (7 with follicular lymphoma, 1 marginal zone lymphoma, 1 chronic lymphocytic leukemia, one unspecified).  One patient who had current DLBCL and FL relapsed with MCL and the subtype was unknown in 3.  Patients with concurrent indolent lymphoma at initial diagnosis were more likely to experience late relapse which was driven by indolent recurrence.  In multivariable analysis, concurrent indolent lymphoma and GCB subtype were independent predictors of relapse.  In patients with DLBCL alone, GCB subtype was associated with indolent relapse but not DLBCL relapse.  Advanced stage and higher IPI score were associated with higher risk of recurrent DLBCL but not indolent relapse.  In terms of outcome, median survival after recurrence was approximately 39 months after EFS24, 30 months for those with DLBCL and the median was not reached in patients with indolent lymphoma.   This study emphasizes the importance of long- term follow-up of our patients with DLBCL.  Hematologists/oncologists typically see patients frequently after the completion of initial therapy but over time, visits become less frequent or not at all for some patients who remain in remission beyond the 5 year mark. Multiple studies have examined surveillance strategies in this setting. The likelihood of identifying recurrent disease in an asymptomatic patient with a normal physical exam is extremely low. In addition, there is no clear evidence that surveillance imaging or early detection of an asymptomatic recurrence impacts on overall survival. This is particularly true for patients who relapse with indolent disease, some of whom may be followed expectantly.   Others may be candidates for low-dose palliative radiation or reduced intensity therapies.  The National Comprehensive Cancer Network Guidelines , which are widely used by physicians as well as payors to determine insurance coverage, recommends symptom guided imaging in patients with a history of early stage DLBCL and CT scans no more often than 6 months for up to 2 years after the completion of therapy in patients with advanced stage disease. Imaging is associated with false positives, radiation exposure and is expensive for our health care system. In addition, anxiety associated with scans is common and may have negative impact on patients.   None-the-less, given that recurrences do occur, educating survivors and their physicians, including primary care providers, to be vigilant for the development of persistent symptoms without clear explanation, as well as B symptoms and lymphadenopathy is important. Setting expectations with patients is also essential, as is caution in using the term cure.  Although the vast majority of patients who remain in remission beyond 2 years after the completion of initial therapy are likely to remain disease free, a small minority will go on to develop recurrent aggressive or indolent lymphoma.  In patients with GCB subtype of DLBCL, discussion of the risk of the subsequent development of an indolent lymphoma may be warranted. Future studies examining changes in cell free DNA during and after therapy, as well as the development of other novel biomarkers may eventually allow us to be more accurate in our prognostication for patients.  In addition, understanding the biology of late recurrence to ascertain whether the recurrence represents the original clone or is distinct may ultimately be important for therapeutic approaches and outcome.   This concludes this JCO Podcast. Thank you for listening.    

This JCO Podcast provides observations and commentary on the JCO article “Resumption of Immune Checkpoint Inhibitor Therapy After Immune-Mediated Colitis” by Abu-Sbeih et al. My name is David Oh, and I am an Assistant Professor at the University of California, San Francisco. My oncologic specialty is genitourinary medical oncology and cancer immunotherapy.                                   While immune checkpoint inhibitors, or ICIs, can lead to durable responses even when other standard therapies have failed, their therapeutic window is often limited by immune-related adverse events or IRAEs which are thought to be autoimmune in nature. Immune-mediated diarrhea and colitis are a frequent IRAE with ICIs, affecting up to a third of patients receiving anti-CTLA-4, approaching half of patients receiving anti-CTLA-4 in combination with anti-PD-1 or anti-PD-L1, and less frequently patients receiving anti-PD-1 or anti-PD-L1 alone. Since there is often overlap between IRAEs and response or survival with ICIs, and IRAEs such as colitis can require interruption of treatment and immunosuppression in patients who may have failed other treatment options, many providers are faced with an important question: is it safe to resume ICIs after patients have initial diarrhea and colitis, and what are the risk factors for another episode of diarrhea and colitis? To address this question, which has not been well studied, Abu-Sbeih and colleagues in this issue of JCO performed a retrospective multicenter analysis of patients who had initial immune-mediated diarrhea and colitis requiring ICI interruption, and then subsequently resumed ICI from 2010 to 2018. From a starting population of 550 patients with initial diarrhea and colitis with ICI, they identified 167 patients who subsequently resumed ICI for a re-treatment rate of 30%. This represents a notable cohort with this degree of clinical annotation. For their initial therapy leading to diarrhea and colitis, about half of these patients had initially received anti-PD-1 or PD-L1 therapy, and a quarter each had initially received either anti-CTLA-4 therapy or combination. The majority of these patients had melanoma, with a smaller proportion of non-small cell lung and genitourinary cancer patients. At the time of re-treatment, 80% of these patients received an anti-PD-1 or anti-PD-L1 alone, while the others were re-treated with anti-CTLA-4 alone.   An important observation by the authors was that upon re-treatment of the 167 patients, 57 patients, or about a third, experienced recurrent diarrhea and colitis requiring permanent discontinuation of therapy. The grade of diarrhea and colitis most frequently seen was less severe, graded as less than or equal to Grade 2. As expected, 81% of these patients with recurrent diarrhea and colitis received steroids, while 12% of patients required further immunosuppression with either infliximab or vedolizumab which blocks the integrin alpha-4-beta-7.   Univariate and multivariate analyses were used to identify risk factors for recurrent diarrhea and colitis upon ICI resumption. Univariate analysis identified more severe initial diarrhea and colitis as a risk factor for having recurrent diarrhea and colitis on ICI re-challenge. Initial severity was determined either by longer duration of initial symptoms or requirement for initial immunosuppression. Multivariate analysis confirmed initial severity as a risk factor, and also found that a lower risk of recurrent diarrhea and colitis was associated with initial anti-CTLA-4 use, as well as with choice of anti-PD-1 or anti-PD-L1 therapy at the time of re-challenge regardless of their initial therapy. Importantly, even though resumption of anti-CTLA-4 was associated with a higher risk of recurrent diarrhea and colitis, the severity of recurrence, as determined by frequency of immunosuppression and grading of diarrhea and colitis, were actually similar to when anti-PD-1 or anti-PD-L1 were resumed.   Overall, then, despite the limitations of retrospective analysis, this work provides evidence from a substantial patient cohort across tumor and treatment types that recurrent diarrhea and colitis with ICI retreatment following initial interruption for diarrhea and colitis may occur in less than half of patients and is generally less severe. Furthermore, the risk of recurrent diarrhea and colitis is less likely in patients who had less severe episodes of initial diarrhea and colitis, who previously received initial anti-CTLA-4, or who are re-challenged with anti-PD-1 or anti-PD-L1 therapy. Although the choice of anti-PD-1 or anti-PD-L1 for re-treatment reduces the risk of recurrent diarrhea and colitis, the actual severity of recurrent episodes is similar to re-treatment with anti-CTLA-4 therapy. As a practical matter this can provide guidance to providers about whether to consider ICI resumption, and which agents to consider, based in part of characteristics of their initial treatment and IRAE. This will be particularly important for patients who experienced clinical benefit from their initial ICI therapy, or have limited other treatment options. At the same time, this work also prompts a number of questions for further investigation. Why does prior anti-CTLA-4 therapy leading to initial diarrhea and colitis yield a lower risk of recurrent episodes? Is there an association between recurrent diarrhea and colitis after ICI re-challenge and ongoing response to therapy? Finally, do different ICI-responsive cancer types exhibit higher or lower risk for recurrent diarrhea and colitis? These and other questions can be addressed by future studies involving larger and well-annotated patient cohorts at multiple centers.                                                                                              This concludes this JCO Podcast. Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article “PET Score Has Greater Prognostic Significance Than Pre-Treatment Risk Stratification in Early-Stage Hodgkin Lymphoma in the UK NCRI RAPID Study” by Barrington et al. My name is Brue Cheson, and I am at Georgetown University Hospital, Lombardi Comprehensive Cancer Center. My Hematologic-oncologic specialty is Lymphoma.   Hodgkin lymphoma is clearly one of the most dramatic success stories in modern oncology. More than 90% of patients with limited disease and about 85% with advanced disease are cured using conventional chemotherapy regimens.  As a consequence, current clinical trials are focusing on augmenting or modifying treatment for those at higher risk and decreasing the intensity or duration of therapy for those at a lower risk of treatment failure.   One important question has been: how best to distinguish those disparate groups?  Over the years, various prognostic scoring systems have been devised.  The International Prognostic Scoring System (IPSS) differentiated patients into 6 groups using 7 clinical and laboratory factors.  However, only 7% of patients are in both the most and least favorable groups.  The German Hodgkin study Group (GHSG) and the EORTC each published criteria slightly different from each other for treatment selection.  Nevertheless, it is not clear that any of these schemas remains relevant in the context of current Hodgkin regimens.  More importantly, they do not reliably dictate how to treat patients, nor do they offer therapeutic targets.   FDG-PET scanning has revolutionized our management of patients with lymphoma.  In 2005 we first demonstrated that integration of PET into standard response assessment improved the ability to distinguish between residual tumor and fibrosis in patients with diffuse large B-cell lymphoma, leading to a revision of standardized response criteria. More recent studies have confirmed this observation in Hodgkin lymphoma and other histologies. Patients with advanced Hodgkin lymphoma can be distinguished into high and low risk groups based on PET scan results after 2 cycles of standard ABVD chemotherapy, regardless of their pretreatment IPSS score.  In a number of studies, reacting to the positive interim scan by intensifying therapy achieved outcomes markedly improved over expected.   In the paper that accompanies this podcast, Sally Barrington and her colleagues performed a secondary analysis of the RAPID trial to evaluate the role of pre-treatment risk factors and PET results in predicting outcome of patients with early stage Hodgkin lymphoma.  This study accrued 602 patients who were treated with standard ABVD and underwent PET scanning after the third cycle.  Those with a negative scan (a Deauville score of 1-2) were randomized to no further treatment vs involved field radiotherapy.  Despite a failure to demonstrate non-inferiority of progression-free survival in this cohort, the overall survival was the same, thus sparing 90% of patients unnecessary radiotherapy.  Those with a positive scan (defined as a Deauville score of 3-5), the primary focus of the current manuscript, received an additional cycle of ABVD plus radiotherapy.  Only the 21 patients with a Deauville score of 5, defined as an SUV at least 3 times greater than that of the liver, had an inferior time to progression or greater risk of Hodgkin-related death.  Importantly, this finding was independent of pretreatment prognostic factors using either the GHSG or EORTC scores.  Whether this observation can be extrapolated to patients with features not eligible for the RAPID study, such as those with bulky mediastinal disease or B-symptoms, is presently unknown.  Nonetheless, these data support the role of metabolic imaging over standard clinical and laboratory risk factors.   But we are clearly doing this all wrong.  Why do we treat all patients the same and then wait until the disease has demonstrated resistance before we alter therapy?  Several recent papers support the notion that anticipatory, biologically-based, risk-adapted approaches may be feasible. Pre-treatment total metabolic tumor volume (defined as the sum total of all metabolically active lesions) can predict outcome in Hodgkin lymphoma as well as follicular, diffuse large B-cell and primary mediastinal large B-cell lymphoma.  High heterogeneity of intratumoral FDG uptake distribution on PET-CT may be a marker of chemoresistance in solid tumors as well as various lymphoma histologies.  Unfortunately, those tests do not provide a target against which to direct a specific agent.  In contrast, a number of investigators have demonstrated a correlation between bcl-2, p53, FOXP3, CD68, STAT1, pattern of PD-1 expression, mutational patterns derived from next generation sequencing, and other factors in pre-treatment Hodgkin node biopsies and outcome.  Thus, if we are able to predict outcome prior to treatment, why do we expose patients to drugs to which we know they will not benefit? The goal of treatment should be anticipatory, risk-adapted strategies whereby patients with a high likelihood of benefit may receive standard of care, unless there is another clinical question being addressed.  On the other hand, those unlikely to benefit as determined prior to therapy should be spared the waste of time and toxicity and treated with novel regimens directed at specific targets.  Both groups should be monitored during treatment for the emergence of mutations, with treatment altered accordingly.  Yes, we may be a long way from having the appropriate tools for such an approach.  But, to quote the geneticist, molecular engineer and chemist George M. Church, “The best way to predict the future is to change it”.  Anticipatory, risk-adapted strategies could do just that.   This concludes this JCO Podcast. Thank you for listening.

This podcast provides observations and commentary on the JCO article "Randomized, Double-Blind, Phase II Study of Regorafenib in Patients with Metastatic Osteosarcoma" by Davis et al. My name is Brian Van Tine, and I am an Associate Professor of Medicine in the Division of Oncology at Washington University School of Medicine. My oncologic specialty is sarcoma. Osteosarcoma (OS) is the most common type of primary malignant bone cancer, frequently occurring in children and adolescents. It can also be found in older adults around the age of 70, but unfortunately, though rare, can be found in patients of any age. Thus, Osteosarcoma is a disease that not only do pediatric oncologists need to know about, but also adult oncologists. Osteosarcoma occurs primarily at the metaphysis of the bone, in regions of rapid bone growth, in bone-forming cells called osteoblasts. Various risk factors for the development of osteosarcoma include underlying bone pathologies, such as Paget’s Disease, prior radiation treatment, and genetic predisposition due to mutations, such as Li-Fraumeni Syndrome, caused by mutations to TP53, or in retinoblastoma mutation patients. Currently, in the curative setting, OS is treated with chemotherapy with cisplatin, doxorubicin, and high-dose methotrexate (HD-MTX), followed by surgical resection of the tumor.  Patients who relapse with metastatic disease have limited options, regiments such as ifosfamide with etoposide and gemcitabine with docetaxel are used with an expected 4-month PFS of only 12%, but the standard of care for osteosarcoma has not changed in 30 years. This is where the Sarcoma Alliance for Research and Collaboration, or SARC for short, comes in.  SARC is a non-profit organization dedicated to the development and support of research for the prevention, treatment and cure of sarcoma.  It is a collaborative group comprised of leading sarcoma physicians dedicated to performing clinical trials in rare diseases.  It is their 24th trial and is the subject of the JCO article that accompanies this podcast, where Dr. Lara Davis and colleagues report their findings of a Randomized, Double-Blind, Phase II Study of Regorafenib in Patients with Metastatic Osteosarcoma. This trial took place across 12 US centers between 2014 and 2018 and enrolled 42 patients between the ages of 18 and 76. Once again, the age distribution highlights that osteosarcoma is not just a pediatric disease, and that there is a dedication to rare disease researchers to accrue to rare disease clinical trials at SARC.   In this trial, patients were randomized one to one to either Regorafenib or placebo on a 28-day cycle and responses were assessed using RECIST version 1.1 every 8 weeks.  At the time of progression on placebo, patients were allowed to crossover to Regorafenib. Following the release of the European REGOBONE trial, a study of similar design that showed a significant benefit of regorafenib in osteosarcoma patients, an independent Data Safety and Monitoring Committee (DSMC) was convened by SARC due to concerns regarding continuing to enroll on a placebo-controlled study. The committee recommended closing the study after enrollment of 42 or the 48 planned patients.    Here is what they found.  At the time of analysis, they found a progression free survival of 3.6 months for Regorafenib and 1.7 months for placebo with a hazard ratio of = 0.42; a 95% confidence interval of 0.21-0.85, and a p=0.017.  Given the crossover design, there was no overall survival seen with a p-value of 0.62.   In addition, no new safety concerns with regorafenib treatment were identified during SARC024 and adverse events were generally manageable with dose reductions.  Notably, the median dose at the end of blind treatment was 120 mg. Taken together, this makes this the second trial to clearly show benefit for the use of single agent Regorafenib for the treatment of Osteosarcoma Highlighting the issues with using RECIST to evaluate tumors that make bone in their matrix, only 3 patients on Regorafenib achieved a partial response.  Whether this is a cytostatic response to Regorafenib or part of the bone biology of osteosarcoma will need to be determined in future work.  There are a number of meaningful observations that come from this trial.  First, and most obviously, Regorafenib is active for the treatment of osteosarcoma and it is oral.  While at this time, it is not listed in the NCCN guidelines, this publication makes the second randomized trial supporting its use.  I would hope the guidelines change to reflect these publications soon. Next, there was a very important paper published in JCO in 2016 by senior author Katy Janeway. It was a summary of seven negative phase II trials from the Children’s Oncology Group (COG) that established the natural history of unresectable osteosarcoma to have an event free survival (EFS) of 12% at 4 months.  They concluded that, “This evaluation provides a baseline for disease progression in a population of children and young adults with recurrent/refractory osteosarcoma that can be used as comparison for the design of future phase II trials in osteosarcoma.” In the current trial and the REGOBONE trial, the placebo arms of this trial and the REGOBONE study demonstrate similar rapid progression: 10% in 16-week PFS in SARC024 and 0% in 12-week PFS in REGOBONE. These become the 8th and 9th trials with a placebo arm that supports the data of the 2016 JCO publication that stated that the progression free survival of placebo for the treatment of osteosarcoma is well established. To be fair to the authors and to be clear, SARC24 was started two years before the Janeway publication, but are supportive of stopping placebo controls in phase II trials of osteosarcoma in future trial designs. Once again, the authors are to be congratulated on their findings, which I find practice changing.  Their dedication to rare cancer research is benefitting patients that agree to participate in clinical trials.  Working together they have identified an active agent for the treatment of osteosarcoma.  It will be interesting to see what the next steps are for the SARC team, as they have proposed combination studies based on Regorafenib in their discussion.  Finally, rare disease research and clinical trials in sarcoma are desperately needed to improve the outcomes of our patients.  Thank you to JCO for highlighting the work from Lara Davis and colleges and the Sarcoma Alliance for Research and Collaboration.  This national organization has sites across the country where sarcoma patients can enroll on clinical trials.  A list of adult and pediatric sarcoma referral centers and the clinical trials that are available in sarctrials.org.  This concludes this JCO podcast. Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article “Therapy-Related Cardiac Risk in Childhood Cancer Survivors: An Analysis of the Childhood Cancer Survivor Study” by Bates et al. My name is Joseph Carver, and I am the Chief of Staff at the Abramson Cancer Center of the University of Pennsylvania in Philadelphia, Pennsylvania. My specialty is cardio-oncology. It is universally accepted that therapeutic radiotherapy and/or anthracycline-based chemotherapy have a significant impact on the heart resulting in cardiac morbidity and mortality. High risk groups are now defined on the basis of a doxorubicin-equivalent anthracycline dose of ≥250 mg/m2 and/or total radiation dose of ≥30 Gy when the heart is in the treatment field.   It is universally accepted that therapeutic radiotherapy and/or anthracycline-based chemotherapy have a significant impact on the heart resulting in cardiac morbidity and mortality. High risk groups are now defined on the basis of a doxorubicin-equivalent anthracycline dose of ≥250 mg/m2 and/or total radiation dose of ≥30 Gy when the heart is in the treatment field.  Total dose delivered does not reflect specific cardiac exposure.  This has led to report the mean heart dose that is the percent cardiac volume within the radiation fields.  For most treated patients, discovery of anthracycline cumulative dosing is easily abstracted and straightforward. For modern therapeutic radiation, however, historical mean heart dose or other cardiac dosimetric parameters have not been traditionally reported and may be more difficult to obtain. This has led to a lack of consensus about the cardiovascular risk when the total dose is   In the article that accompanies this podcast, Bates et al1 enhance our understanding of the association between cardiac volume exposure to different radiation therapy doses and rates of serious cardiac conditions among long term survivors of pediatric cancer and reaffirms the association of cumulative anthracycline dose and subsequent risk for cardiomyopathy.   With data from the Childhood Cancer Survivorship Study, they determined the rates of self-reported grade 3-5 cardiac conditions as defined by Common Terminology Criteria for Adverse Events  v4.03 in 24,214 >5-year survivors who were treated for a variety of cancers at a median age of 7 years.  Evaluation occurred at a median follow-up of 20.3 years with a median attained age of 27.5 years.  Late cardiac risk was compared to 5,046 untreated siblings.  For each survivor, radiation fields were reconstructed on age-specific phantoms to calculate estimated mean heart dose and the percent of heart volume receiving at least 5 Gy (low dose) and 20 Gy (higher dose).  Doxorubicin-equivalent doses were similarly abstracted.   Toxicity parameters were any cardiac disease, coronary artery disease and heart failure.  They found a cumulative incidence of cardiac disease, 30 years from diagnosis of 4.8% (95% CI 4.3-5.2). There was a dose relationship between mean heart dose and all parameters.  Both low-moderate doses (5-19.9 Gy) to a large volume of the heart (>50%) and higher doses (≥20Gy) to small cardiac volumes (0.1-29.9%) were associated with an increased risk of cardiac disease. Heart failure drove the risk of high doses to small volumes while CAD drove the risk of low doses to large volumes.   Similarly, they reconfirm the relationship between cumulative anthracycline dosing and any cardiac disease with an increased risk for those treated at a younger age (≤ 13 years of age).  An increased relative risk for any cardiac disease was also present with any anthracycline exposure (0.1-   This study shows that low-moderate dose RT to a large volume of the heart and higher-dose RT to a small volume of the heart increase the risk of late cardiac disease. It also reconfirms the association of cumulative anthracycline dosing and cardiac risk, especially in patients who were treated at   What are the take-home points of this study? In spite of modern techniques to deliver therapeutic radiation and avoid the heart, a “safe” cardiac dose has not been well-defined.  Two large retrospective, phantom-based studies have shown an increased risk of coronary heart disease of 7.4% per 1 Gy MHD in breast cancer and lymphoma patients. These studies have not only alerted radiation oncologists to the potential risk of even “low” radiation doses to the heart but have also driven them to push RT planning algorithms to optimize one parameter, mean heart dose. The problem with this single metric is that two treatment plans with vastly different dose maps can have the same mean heart dose: 1) low dose spread out to a large volume such as in an intensity modulated radiotherapy plan; or 2) high dose to a small volume (that may include the left anterior coronary artery) with almost no dose to the rest of the heart such as in breast tangents or a proton therapy plan. Even with current image-driven treatment planning algorithms that prioritize a low mean heart dose, it is still possible to deliver higher doses of radiation to cardiac substructures.  The results from this paper have major implications for treatment planning and delivery, informing us to be wary of low dose generic mean heart dose metrics and makes a case for universal adaptation of the quantification of structure-specific dose exposure and attention to the “low-dose cloud” in the rest of the heart.   For survivorship and surveillance, there are implications for guideline development evolving one step beyond binary “high risk/low risk” stratification to understand that any exposure to anthracyclines and/or therapeutic radiation is part of a continuum of risk: low risk is not no risk. This continuum informs health care providers to a proactive management approach for the late survivor population that includes aggressive management of cardiac risk factors present at initial evaluation and those that emerge over the decades of survivorship.     It is equally as important to reiterate that the late cardiac toxicity due to therapeutic radiation and anthracyclines pales in comparison to the risk associated with untreated traditional cardiac risk factors: (obesity, cigarette smoking, sedentary life style, diabetes, hypertension and the metabolic syndrome) and when they are present in this population, they magnify the 4.8% cardiac event risk defined by Bates.     This study also provides additional rationale for the field of cardio-oncology- for greater collaboration between medical and radiation oncologists and cardiologists at every step of the cancer treatment continuum.   I congratulate Bates and colleagues for this potentially paradigm changing contribution and am optimistic that further enhancements in radiotherapy planning and delivery will reduce late cardiac toxicity and improve survival.   This concludes this JCO Podcast. Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article Durable Tumor Regression and Overall Survival in Patients with Advanced Merkel Cell Carcinoma Receiving Pembrolizumab as First-Line Therapy by Paul Nghiem, MD, PhD et al. My name is Reed Drews, and I am a member of the Cutaneous Oncology Program at Beth Israel Deaconess Medical Center in Boston, MA. My oncologic specialty is non-melanoma skin cancers.   Merkel cell carcinoma is a rare, aggressive neuroendocrine skin malignancy with high propensity for local recurrence and regional lymph node and systemic metastases. Its incidence rises exponentially with aging and is 10-fold higher in chronically immunosuppressed patients. When Merkel cell carcinoma is advanced and/or unresectable, historical 5-year overall survival rates are low, from 14 to 27%. Cytotoxic chemotherapies, like platinum plus etoposide used in other high-grade neuroendocrine malignancies, have not yielded durable response rates.   The cutaneous cell (or cells) of origin in Merkel cell carcinoma remains controversial. Nevertheless, scientists have identified 2 pathogenetic pathways leading to Merkel cell carcinoma. In 80% of cases, clonal integration of a polyomavirus leads to Merkel cell polyoma virus-positive Merkel cell carcinoma. In the other 20% of cases, ultraviolet light-induced DNA damage leads to polyoma virus-negative Merkel cell carcinoma. Polyoma virus-negative Merkel cell tumors display predominant cytosine to thymine transitions, a signature of DNA damage from UV light, and they have a 100-fold greater mutational burden than virus-positive Merkel cell cancers. For both subtypes, loss of immune surveillance, as with aging or chronic immunosuppression, contributes to Merkel cell carcinoma development, with diminished non-self-antigen recognition of UV-induced neo-antigens in virus-negative tumors and viral oncoproteins in Merkel cell polyoma virus-positive tumors.   Given these factors, investigators have recently studied whether immune checkpoint inhibitors might hold promise for managing advanced Merkel cell carcinoma. To date, 3 antibody inhibitors of the programmed cell death-1 pathway (abbreviated PD-1), including anti-PD-ligand-1 avelumab, anti-PD-1 nivolumab and anti-PD-1 pembrolizumab, have been tested in patients with chemotherapy-refractory and/or treatment naïve Merkel cell carcinoma. The 62% objective response rate from avelumab in treatment-naïve Merkel cell carcinoma was nearly twice that observed in chemotherapy-refractory disease. In 2017 avelumab became the first immune checkpoint inhibitor approved by the FDA for advanced Merkel cell carcinoma. Nivolumab yielded similar results, as did pembrolizumab according to a 2016 report from Nghiem and colleagues of a multicenter, phase 2, non-controlled study with 26 patients.   As reported in this JCO publication, Nghiem and colleagues have now increased their cohort to 50 patients through the multicenter expanded phase 2, Cancer Immunotherapy Trials Network-09/Keynote-017 trial. They administered pembrolizumab 2 mg/kg intravenously every 3 weeks for up to 2 years. Median follow-up time was 14.9 months, with a range from 0.4 to 36.4 months. This represents the longest follow-up to date of any anti-PD-1 pathway inhibitor for first-line treatment of advanced Merkel cell carcinoma. The 50-patient cohort included 43 patients with (stage IV) distant metastatic disease and 7 with stage IIIB recurrent locoregional disease not amenable to definitive surgery or radiation therapy. All patients had normal organ and bone marrow function and an Eastern Cooperative Oncology Group performance status of 0 to 1. Key exclusion criteria were previous systemic therapy for unresectable Merkel cell carcinoma, immunodeficiency or systemic immunosuppressive therapy, active autoimmune disease, concurrent second cancer, and active central nervous system metastases.   The median age of enrolled patients was 70.5 years, with 80% age 65 or older. 64% of patients had Merkel cell polyoma virus-positive tumors. For previous management of their primary Merkel cell carcinoma, 42 patients had had surgery, and 35 patients had had radiation treatment. While no patient had previously received systemic therapy for advanced Merkel cell carcinoma, 3 patients had received adjuvant chemotherapy greater than 6 months prior to study enrollment.   Patients received a median of 10.5 doses of pembrolizumab – range 1 to 35 doses—and the median treatment duration was 6.6 months – range 1 day to 23.6 months. Radiographic responses were assessed centrally per Response Evaluation Criteria in Solid Tumors, version 1.1. Responses were generally rapid and durable with 2.8 months as the median time to response – range 1.5 to 9.7 months. The objective response rate to pembrolizumab was 56%, with complete and partial responses of 24% and 32%, respectively; 10% had stable disease; and 32% had progressive disease.   At time of data analysis, 20 of 28 responses were on-going, and the median durability of response had not been reached. The Kaplan-Mier estimation of response durability at 24 months was 79.1%. Median progression free survival was 16.8 months, and the Kaplan-Mier estimation of progression free survival at 24 months was 48.3%. Median overall survival had not yet been reached. The Kaplan-Mier estimation of overall survival rate at 24 months was 68.7%.   Tumor viral status, as determined by small T-antigen specific antibodies in serum or large T-antigen expression in tumor biopsies by immunohistochemistry, did not correlate with any study outcomes, such as progression free survival or overall survival. However, a trend towards improvement of these outcomes appeared in patients with PD-L1-positive tumors, as defined by cell-surface PD-L1 expression on at least 1% of tumor or immune cells.   The safety profile of pembrolizumab in advanced Merkel cell carcinoma was similar to that in other studies of anti-PD-1 pathway inhibitors: 28% of patients had grade 3 or greater treatment-related adverse events, causing 14% of patients to discontinue treatment. A 73-year old male patient with widely metastatic Merkel cell carcinoma and pre-existing atrial fibrillation died after developing pericardial and pleural effusions 1 day after one infusion of pembrolizumab. Other adverse events were generally manageable and typical of complications of anti-PD-1 pathway inhibitors, including adrenal insufficiency, colitis, hyperthyroidism, hypothyroidism, infusion-related reaction, myocarditis, pancreatitis, pneumonitis, maculopapular rash and thyroiditis.   With such impressive rates of durable tumor regression and overall survival, on December 19, 2018, the FDA granted accelerated approval to pembrolizumab for treating patients with recurrent locally advanced or metastatic Merkel cell carcinoma. Today’s standard of care for advanced Merkel cell carcinoma is an anti-PD-1 pathway inhibitor, and the NCCN Clinical Practice Guidelines in Oncology in 2018 recommended avelumab, nivolumab and pembrolizumab as preferred first-line therapy for advanced Merkel cell carcinoma, ahead of cytotoxic chemotherapy.   Future studies must determine what role anti-PD-1 pathway inhibitors will play in the neo-adjuvant and adjuvant settings when managing early stage Merkel cell carcinoma with high-risk features. Prior to immune check point inhibitors, neo-adjuvant and adjuvant chemotherapy were considered case-by-case, absent strong evidence for benefit.  However, now with impressive results from anti-PD-1 pathway inhibitors in advanced Merkel cell carcinoma, adjuvant nivolumab and avelumab are being evaluated in 2 randomized phase II trials. Nivolumab is also undergoing study in the neoadjuvant setting, and researchers presented promising preliminary results of a phase I/II study at the 2018 American Society of Clinical Oncology Annual Meeting. We look to Nghiem, his colleagues and other investigators to keep us informed regarding future advances, including insights into mechanisms of resistance to the immune checkpoint inhibitors.   This concludes this JCO Podcast. Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article Gonadal Functioning and Perceptions of Infertility Risk among Adult Survivors of Childhood Cancer: A Report from the St. Jude Lifetime Cohort Study by Lehmann et al. My name is Leslie Schover, and I am retired from the faculty of MD Anderson Cancer Center and currently Founder of Will2Love.com a digital health company in Houston, Texas. My oncologic specialty is cancer-related problems with reproductive health, i.e. sexual function and fertility.   Damaged fertility is unfortunately quite common in survivors of childhood cancer. A variety of chemotherapy drugs, as well as surgery affecting parts of the reproductive system or radiation therapy focused on the pelvis or brain, can damage spermatogenesis, reduce ovarian reserve, or interfere with uterine function. In general, males are more at risk than females for cancer-related infertility. Some survivors do not undergo puberty without hormonal support. For others, fertility may recover over time. However, many young women who have menstrual cycles in their teens or twenties are at risk for premature ovarian failure, leaving a narrowed window of time to become pregnant. Men do not know whether they have normal sperm counts, motility, or form unless they have had a recent semen analysis. People diagnosed with cancer before puberty may never have been counseled about fertility. Even survivors treated as teens or young adults typically do not know their fertility status unless they have consulted an expert in reproductive endocrinology or andrology. Surveys of young survivors suggest that the majority want to have children, particularly those who are childless.   A number of studies have documented markers of infertility or reduced rates of offspring in survivors of cancer, but little has been known about their perceptions of their fertility status. In the paper that accompanies this podcast, Lehmann and colleagues present novel data about the risk perceptions for infertility compared to indicators of actual gonadal function in over a thousand long-term survivors of childhood cancer participating in the St. Jude Lifetime Cohort. None of the participants already had children or a previous pregnancy. The mean age of the sample was 29, with a mean follow-up of 22 years since cancer diagnosis. 85% were white and 32% had at least a 4-year college degree. 52% were married or in a relationship. Only 10% of men and 16% of women had been tested for infertility outside of the study.   Gonadal function was measured by a semen analysis in 56% of men and by a panel of hormones in the others. In women under age 40, status as fertile vs. sub-fertile was assigned by chart review based on menstruation, diagnosed premature ovarian failure, or hormonal assays. Perception of risk for infertility was based on one question with a Likert scale of 5 response options, comparing one’s own fertility to that of peers who had not had cancer. Answers were dichotomized into two categories: perceived at risk for fertility or perceived normal fertility.   62% did perceive themselves as at risk for infertility. Those who perceived their fertility as damaged had characteristics that would indicate potentially more knowledge about cancer and fertility, including being older, white, in a relationship, having a college education, a history of gonadotoxic treatment, having tried unsuccessfully to conceive, or having sexual dysfunction.   In actuality, 24% of women and 56% of men had evidence of impaired gonadal function. However, actual medical status had no significant relationship to perceptions of risk. The most common discordance was that the survivor believed him or herself to have damaged fertility when medical tests appeared normal. This included 20% of men and 44% of women. Inaccurate perceptions were more common in respondents who were white, had more education, had more gonadotoxic cancer therapy, were very concerned about their fertility, and had sexual dysfunction. In contrast only 16% of men and 5% of women overestimated their fertility potential.   In terms of clinical implications, it is common for young survivors to overestimate their risk of infertility. Such beliefs can diminish quality of life. A young person who feels like “damaged goods” may be distressed about the future and perhaps reluctant to date or to enter into a committed relationship. For women, risky drinking was another factor associated with overestimating fertility risk. Risky drinking, and the notion that pregnancy is impossible, may contribute to findings in other studies of excess rates of unintended pregnancies and failure to use consistent contraception in young adult female survivors. Those unaware of their damaged fertility maybe in for distress and disappointment if they try for a pregnancy. Clearly a greater effort should be made to inform young survivors about risks to fertility and to refer them for testing at intervals of fertility status.   It appears that women are much more likely than men to perceive themselves as potentially infertile, despite the fact that men are more likely to be infertile. However, the measures of gonadal function used in women were not sensitive enough to predict the likelihood of diminished ovarian reserve in the future. Many young survivors of cancer can conceive in their teens or twenties, yet have a steeper than normal drop-off in ovarian reserve with aging, so that their menopause occurs far before the average age of 51. In fact, women’s fears in this study that they will have trouble getting pregnant in the future may be more accurate than they appear. Age at first pregnancy has steadily increased in our society, with women postponing childbearing until they have completed educational goals or established a working life. More cancer survivors are likely to run out of time before they are ready to have a child. One solution may be commercial egg banking before age 25-30, if fertility preservation was not accomplished before starting cancer treatment. Egg banking is expensive, however, and does not guarantee a future pregnancy.   This survey adds to our knowledge of the informational needs of survivors of cancer in childhood or teen years. Both medical and counseling support should be more readily available. Survivors with lower health literacy would be particularly good targets for such services.   This concludes this JCO Podcast. Thank you for listening.

This JCO podcast provides observations and commentaries on the JCO article entitled "Indeterminate Pulmonary Nodules at diagnosis in Rhabdomyosarcoma: Are they clinically significant?"  A report from the European Pediatric Soft Tissue Sarcoma Study Group by Bas Vaarwerk, MD et al. My name is Alberto Pappo and I am the head of the division of solid tumors at St Jude Children’s Research Hospital in Memphis, TN. My oncology specialty is pediatric oncology.  In this report, Bas Vaarwerk, and investigators from the European Pediatric Soft Tissue Sarcoma Study Group evaluated the significance of indeterminate pulmonary nodules at diagnosis in children with rhabdomyosarcoma defined as the presence of less than 5 pulmonary nodules measuring less than 5mm or 1 pulmonary nodule that measured between 5 and 9 millimeters. This analysis included 316 patients who were enrolled on the EpSSG RMS 2005 study for non-metastatic rhabdomyosarcoma from September 2005 through December 2013 and for whom chest computed tomography scans were obtained at diagnosis and were available for review. Treatment in the EpSSG RMS 2005 study was stratified according to risk group, pathology, post-surgical stage, site, nodal involvement, size and age. All patients received multi agent chemotherapy with ifosfamide (except for low risk patients), vincristine and actinomycin D (IVA chemotherapy). High risk patients were randomized to IVA or IVA with doxorubicin and after 9 courses if in complete remission, were eligible for a second randomization between end of therapy and additional maintenance therapy with 6 courses of vinorelbine and cyclophosphamide Local control was determined by risk group, tumor site, age and response to therapy and radiotherapy was given at week 13 in doses ranging from 36 to 51.4Gy. All chest computed tomography scans were reviewed by the local radiologist at the treating center. Data was obtained and recorded using case report forms.  All computed tomography scans were performed with minimum slice thickness of 3 to 5 mm.  The median age at diagnosis for the 316 eligible patients was 5.4 years and the median follow up time for the cohort was 75 months.  There were 249 (78%) patients who did not have a pulmonary nodule and 67 (21%) who had at least one indeterminate pulmonary nodule. Patient and treatment characteristics were similar between the 2 groups; 80% of the patients presented with Group III  unresectable disease, 54% had high risk disease, and 71% had favorable histology tumors such as embryonal histology tumors.  Twenty four percent of patients received maintenance chemotherapy and 77% were treated with local radiotherapy A total of 100 nodules were identified in the 67 patients. Nodules ranged in size from 1 to 8 mm.  69% of the patients presented with one pulmonary nodule, 92% of the patients had nodules that measured less than 5 mm 85% of the nodules were unilateral. The 5-year event-free survival for patients with indeterminate pulmonary nodules was 77% and for those without nodules 73.2%. These differences were not statistically significant with a p value of 0.68. The 5-year overall survival rates were 82% for patients with indeterminate pulmonary nodules and 80.8% for those without nodules. The differences between these 2 groups were not statistically significant with a p value of 0.76.   There were no significant differences in outcomes based on the number or size of the nodules.  Similarly, there were no differences in clinical outcome based on histology, fusion status, age and type of chemotherapy received. Lung metastases developed in 3% of patients with indeterminate pulmonary nodules and in 1.6% of patients without nodules a value that was not statistically significant. The authors conclude that the presence of indeterminate pulmonary nodules in newly diagnosed children with rhabdomyosarcoma as defined in this report does not adversely affect the outcome of these patients and these children can be adequately treated with non-metastatic risk-based clinical protocols. This report highlights the challenges of assigning risk and therapy based on the presence of a limited number of small pulmonary nodules in children with newly diagnosed rhabdomyosarcoma when they are detected using newer imaging modalities such as thin cut computed tomography of the chest. The authors have successfully demonstrated in this retrospective study that newly diagnosed patients with rhabdomyosarcoma who present with indeterminate oligometastatic disease to the lung which in this study was defined as the presence of 4 or fewer pulmonary nodules measuring less than 5 mm or one nodule that measures 5 to 9 mm, have similar outcomes to patients who present without pulmonary nodules. More importantly, these patients can be treated with less intense trials that may include the use whole lung irradiation which is known to significantly increase the risk of breast cancer in childhood cancer survivors. The authors have implemented a standardized definition for indeterminate oligometastatic lung disease which is highly reproducible and easily implemented.  Their results are thought provoking and deserve further validation in a well- designed prospective clinical trial. Because of the lack of pathologic correlation with imaging findings in this report, it is not possible to determine which patients truly had oligometastatic disease to the lung. It is conceivable that some of the 67 patients with indeterminate nodules did not have actual metastatic rhabdomyosarcoma in the lung, or alternatively these results may also indicate that current risk-based therapies for localized disease are effective at eradicating small oligometastatic disease. It is important to point out however, that in this report, about one fourth of the patient population was assessed using reconstruction widths of ≤ 1.25 mm, which might have identified a larger number of small nodules of uncertain significance. In addition, 69% of the patients with indeterminate nodules had only one nodule, 92% had nodules that measured less than 5 mm and 85% had unilateral disease.  All of these factors have been associated with a significantly lower likelihood of identifying biopsy proven metastatic disease in pediatric patients with sarcomas. These findings raise questions as to whether thin cuts In summary, this report opens new areas for clinical research that could lead to a uniform strategy for defining metastatic pulmonary disease in pediatric rhabdomyosarcoma and a more precise method for  risk-stratifying disease in this patient population.   This concludes this JCO Podcast. Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article “Tamoxifen pharmacogenetics and metabolism: Results from the prospective CYPTAM study” by Sanchez-Spitman et al. My name is Vered Stearns, and I am a Professor of Oncology and Co-Director of the Breast and Ovarian Cancer Program at the Kimmel Cancer Center at Johns Hopkins in Baltimore, Maryland. My oncologic specialty is medical oncology. In the paper that accompanies this podcast, the authors report results of a prospective clinical study designated CYPTAM, which was designed to correlate endoxifen serum concentrations and outcomes of women prescribed adjuvant tamoxifen. The investigators enrolled 667 women with breast cancer who were initiating tamoxifen or who have been on tamoxifen for fewer than 12 months. The investigators obtained blood samples for CYP2D6 genotyping using the Amplichip CYP450 Test, and measured steady state concentrations of endoxifen with a high-performance liquid chromatography-tandem mass spectrometry. Co-primary endpoints included association of recurrence-free survival with endoxifen concentrations and with CYP2D6 genotypes. The patients were censored at the time of tamoxifen-discontinuation in case of a transition to an aromatase inhibitor. Several additional endpoints included disease-free survival, complete relapse-free survival, complete disease-free survival and overall survival. The statistical analysis plan was designed as a gate-keeper analysis for the co-primary objectives. Only if an association was found with a p-value below 0.05, were the remaining objectives considered.   The authors were not able to demonstrate an association between endoxifen concentrations and recurrence-free survival on tamoxifen. They also were not able to demonstrate an association either when exploring endoxifen concentrations in quartiles or when considering other thresholds. Likewise, there was no association between CYP2D6 genotypes and recurrence-free survival.   Almost two decades ago, researchers recognized that the absence or inhibition of the CYP2D6 enzyme is associated with very low concentrations of endoxifen, a potent and abundant anti-estrogen metabolite of tamoxifen. Whether low concentrations of endoxifen predict an inferior survival outcome has not been definitively determined. Multiple retrospective and small prospective studies evaluated CYP2D6 genotypes and survival outcomes and have provided mixed evidence. Clinicians have, therefore, wondered whether CYP2D6 genotype testing or endoxifen monitoring will assist in treatment recommendations. The CYPTAM investigators attempted to prospectively correlate endoxifen serum concentrations and outcomes for women taking tamoxifen.   The CYPTAM study is associated with several limitations, and, therefore, it does not provide a definitive answer to the controversy. For example, women were enrolled in the study either before starting tamoxifen or up to 12 months after initiation of the drug. This strategy could have led to incomplete baseline data and to the exclusion of individuals with early recurrences. In addition, about two-thirds of study participants transitioned to aromatase inhibitors following a short course of tamoxifen. The sequential administration of tamoxifen and aromatase inhibitors is superior to tamoxifen alone. Some of the patients who transitioned to aromatase inhibitors could have suffered a recurrence had they have stayed on tamoxifen alone. Furthermore, the authors did not have information regarding concomitant CYP2D6 inhibitor use. CYP2D6 inhibitors are commonly co-administered with tamoxifen and can contribute to misclassification of the CYP2D6 phenotype.    The challenge moving forward is that single agent adjuvant tamoxifen is rarely used. Most postmenopausal women with hormone receptor-positive breast cancer are recommended an  aromatase inhibitor instead of, or in sequence with, tamoxifen. Premenopausal women with high risk hormone receptor-positive tumors are recommended ovarian suppression with tamoxifen or an aromatase inhibitor. Women prescribed tamoxifen alone are usually at extremely low risk of recurrence, and a prospective study in this group of women will require a large number of participants to demonstrate differences between phenotypes. Given current practice, it may not be feasible to fully determine the role of endoxifen concentrations and CYP2D6 genotypes as predictors of tamoxifen efficacy.   Retrospective analyses that used samples obtained through large prospective studies, such as the Arimidex, Tamoxifen, Alone or in Combination and the Breast International Group 1-98, failed to demonstrate an association between CYP2D6 phenotypes and survival outcomes. Taken together, the data at present are insufficient to recommend CYP2D6 testing or analysis of metabolic profile in women for whom tamoxifen is considered. Indeed, clinical guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network do not recommend CYP2D6 genotyping. Moving forward, prospective studies of altered metabolism due to single nucleotide polymorphism, or administration of inhibitors, should be considered in clinical trials of standard and novel agents as these can lead to differences in drug efficacy and toxicity.   This concludes this JCO Podcast. Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article “Impact of Surveillance Imaging Modality on Survival After Recurrence in Patients with Favorable Histology Wilms Tumor: A Report from the Children's Oncology Group” by Mullen et al. My name is Dr. Meredith Irwin, and I am an oncologist and Professor at the Hospital for Sick Children and University of Toronto in Toronto, Canada.  My oncologic specialty is pediatric solid tumors. Wilms tumor is the most common pediatric kidney tumor. With current therapies, the 5-year overall survival for newly diagnosed patients is 90%. For the 15% who relapse, most commonly in the lung or abdomen, the cure rates still often exceed 50%. The likelihood for cure is based on a number of risk factors, including histology, stage and previous therapies. Thus, similar to many pediatric cancer patients, those with Wilms undergo surveillance imaging during and following completion of upfront therapy in order to potentially discover recurrences sooner with the hope that early identification of lower disease burden will translate to higher salvage rates. However, to date, several small studies have failed to demonstrate that early detection of recurrence by surveillance imaging is associated with better prognosis for pediatric cancers including medulloblastoma, lymphoma and neuroblastoma. Moreover, with increasing awareness of the potential risks from imaging-associated ionizing radiation exposures and associated financial costs, there is significant interest in generating evidence to determine optimal surveillance strategies and limit cumulative exposures. To address these issues for Wilms tumor, the study by Mullen et al was designed to determine whether, compared to relapses detected by surveillance with chest x-ray and ultrasound, those detected with cross-sectional CT imaging were associated with improved survival rates. To do this, four authors retrospectively reviewed flowsheets and imaging reports for patients who recurred on the 5th National Wilms Tumor Study (NWTS-5) between 1995 and 2002 to determine whether their relapses were identified by signs/symptoms or scheduled surveillance imaging.  If by imaging, they recorded the modality- CT, ultrasound and/or chest x-ray. The study cohort included the 281 patients who recurred following initial diagnosis of favorable histology unilateral Wilms. All patients underwent imaging at specified time intervals, but the modalities varied. The 5-year overall survival for this cohort post-relapse was 67%, which is similar to other studies. 48% of recurrences were detected with routine surveillance by chest x-ray or ultrasound, 25% by surveillance with CT, and 25% presented with symptoms between scheduled imaging, most commonly pain or abdominal mass. Certain characteristics differed among these groups. The CT-detected patients were more likely to be stage 4, and in the symptoms group, more relapses were extrapulmonary and occurred post-treatment.  The authors asked whether the specific method of detection of relapse impacted prognosis. Although recurrences detected by symptoms were associated with an inferior 5-year survival of 55%, versus 76% for the imaging-detected group, there were no differences in survival for patients based on the imaging modality used for detection at any point during or following therapy. There was also no significant advantage to CT over u/s or x-ray for abdominal and chest relapses, respectively. Although a higher number of foci detected at recurrence and larger relapse size correlated with inferior outcomes, analyses failed to find a significant advantage for CT use in the subgroups of lung-only relapses or advanced-stage patients. The authors also examined financial burden and radiation exposures. To determine the economic impact, the authors predicted costs based on US Medicaid/Medicare reimbursement rates.  For patients with stage III disease, more than 200 imaging studies (with estimated costs between $20,000 and $45,000) were required to identify one relapse. For stage IV, between 158 and 190 studies costing more than $15,000 were needed. Estimated radiation exposures from these surveillance protocols varied between 9.4 and 83 mSv, depending on the total number of CTs. Although it is difficult to quantify how cumulative radiation doses may impact future cancer risks, expert groups have estimated that there is a 1 in 1,000 increased risk of future cancer deaths for every 10mSv exposure at age 10, and these risks are higher for patients exposed at younger ages. Other potential negative consequences of surveillance imaging not examined by these authors include the associated psychological stress for families, which is termed “scanxiety,” and possible adverse neurological effects of anesthetic agents for young children.   The significance of this report is that it is the first study to compare the utility and cost of different imaging methods for the identification of Wilms tumor recurrences. In comparison to x-rays or ultrasounds, there was no advantage to using CT, which is costlier and resulted in higher radiation exposures. It is possible that an advantage to CT was not identified in part because only the best prognosis patients, those with favourable histology, were included. The authors excluded those with bilateral disease, who often have germline predisposition syndromes, and patients with anaplastic histology, which has a higher relapse rate Ideally, a prospective RCT design would be performed to determine whether cross-sectional imaging would be superior to ultrasounds/x-ray combinations. However, given the overall excellent survival for Wilms tumor, the number of patients required to detect a significant survival advantage would likely be very large. In addition, given the cost and potential late effects of radiation exposures, engagement from oncologists, radiologists and families might be challenging.  In conclusion, the findings in this manuscript support the recommendations by Mullen and colleagues that surveillance post completion of therapy for favorable histology unilateral Wilms does not need to include CT scans and can instead be based on symptoms and ultrasound and/or x-rays. These authors did not specify whether duration of surveillance could be limited; however, a recent publication in Lancet Oncology by Brok and colleagues supported consideration of a cut-off of two years. Their SIOP study reported that the detection of one relapse 2-5 years post-therapy required 500 scans. Importantly, it remains possible that for rare patient subsets with anaplastic histologies or other biomarkers of unfavorable disease, which may include 1q LOH, surveillance protocols might need to be adjusted. This may be similar to strategies for other tumors, such as neuroblastoma, where, in comparison to patients with high-risk disease, those with low or intermediate-risk disease with survival rates of more than 80-90% are increasingly undergoing surveillance regimens without frequent CT scans, which, in part, is determined based on clinical and biological risk factors. These approaches to risk stratification of imaging are increasingly being used. Thus, clinicians may begin to modify surveillance based on the risk of recurrence for a particular subgroup of patients, similar to precision medicine approaches for treatment. However, it will be important to perform studies similar to the accompanying manuscript to generate evidence to inform and support precision surveillance imaging recommendations that are specific to different tumor types. This concludes this JCO podcast. Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article, "Impact of Baseline Steroids on Efficacy of PD-(L)1 Blockade in Patients With NSCLC" by Arbour et al. My name is Deepa Rangachari, and I am an Assistant Professor of Medicine at the Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, Massachusetts, USA. My oncologic specialty is thoracic cancers.   For decades, the management of advanced non-small-cell lung cancer has relied on use of cytotoxic chemotherapies with a median overall survival not exceeding one year.  As this longstanding therapeutic approach has been limited by modest efficacy, finite durability, and significant treatment-associated toxicity,  evolving better tailored, more effective, and less toxic care strategies has long been an unmet need. Beginning in the mid-2000s with the identification of actionable oncogenic driver mutations in the epidermal growth factor receptor, the landscape for personalized care in advanced non-small-cell lung cancer has been permanently transformed. Today, the evidence-based standard of care for upfront therapeutic stratification in all patients with advanced stage disease relies on mandatory genomic and immunologic profiling, with emphasis on identifying subsets of patients who will experience better outcomes and  less toxicity through the use of disease-specific therapies.   It is in this landscape that the use of immune checkpoint inhibitors has flourished for patients with lung cancer. Since 2015, 3 different immune checkpoint inhibitors—Nivolumab, Pembrolizumab, and Atezolizumab—have all gained approval from regulatory agencies for management of patients with advanced stage non-small-cell lung cancer on the basis of phase III studies showing improved overall survival with more durable responses, less toxicity, and better quality of life with checkpoint inhibitors when compared with chemotherapy.[1-5]  This benefit has been seen in both previously treated patients regardless of tumor programmed death ligand 1 (hereafter referred to simply as “PD-L1”) status and in upfront management of patients with high tumor PD-L1, defined by a tumor proportion score >/= 50%. Combined chemoimmunotherapy for patients with non-squamous disease regardless of tumor PD-L1 status is also now a vetted approach.[6]   With widespread use of immune checkpoint inhibitors now the standard of care for many patients with this disease, important pragmatic concerns regarding concurrent use of checkpoint inhibitors and corticosteroids have emerged. Specifically, as many patients will present with refractory anorexia, nausea, fatigue, pain, brain metastases, and/or dyspnea for which corticosteroids are often used as helpful adjuncts to cancer-directed therapy for symptomatic palliation, what if any are the consequences of concurrent use? How do we balance these symptomatic issues against the need for delivering effective cancer therapy?   Due to concerns for the immunomodulatory effects of corticosteroids on T-cell activity and function, nearly all clinical trials leading to approval of these agents have excluded patients requiring the equivalent of Prednisone 10-20mg daily or more prior to initiation of checkpoint inhibitor therapy. In contrast, there is now an emerging body of evidence suggesting the safety of subsequent corticosteroid use, once checkpoint inhibitors have been started, for management of immune-related adverse events , without jeopardizing any previously achieved therapeutic benefit.[7, 8]   But what about those patients being newly initiated on checkpoint inhibitors who have been previously maintained on palliative corticosteroids?   In the article that accompanies this podcast, Arbour and colleagues present important insights into this question.  This is a retrospective analysis of 640 patients with advanced non-small-cell lung cancer with immunotherapy-naïve disease treated with checkpoint inhibitors at the Memorial Sloan Kettering and Goustave Roussy Cancer Centers from 2011-2017. Data regarding steroid dose, mode of administration, and indications for use were collected along with efficacy of checkpoint inhibitors as assessed by an independent team of radiologists using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. At the time of checkpoint inhibitor initiation, 90/640 (14%) of patients were receiving the equivalent of Prednisone 10mg/day or more; an additional 17 patients (or 3% of the total study population) were receiving   The most common indications for steroid use reflect those seen in routine clinical practice: dyspnea/respiratory symptoms (33%), fatigue (21%), and brain metastases (19%).  Clinicopathologic characteristics between the steroid and no steroid groups were generally well balanced.  As might be expected, however, there were more patients with poor performance status and history of brain metastases in the steroid group.   Amongst the Sloan Kettering cohort, steroid use of >/= 10mg/day was associated with statistically significant reductions in objective response rates (6% vs. 19%), median progression free survival (1.9 vs. 2.6 months), and median overall survival (5.4 vs. 12.1 months) in the steroid vs. no steroid groups, respectively. Similar findings were seen in the Gustave Roussy cohort.  Pooled data from both cohorts confirmed the same detrimental impact of baseline steroid use >/= 10mg/day.  On multivariable analysis, the findings of inferior response rates and worse progression free and overall survival in those receiving Prednisone >/= 10mg/day were upheld. Further, a similar decrement in checkpoint inhibitor efficacy was observed in patients receiving >/= 20mg/day of Prednisone as compared to those receiving lower doses of 10-19 mg/day.   Patients receiving and then discontinuing steroids 1-30 days prior to initiation of immune checkpoint inhibitors had intermediate progression free and overall survival as compared to those receiving steroids on the same day and those not receiving any steroids within 30 days of starting a checkpoint inhibitor.   The authors do additionally note that 6 patients achieved a partial response to checkpoint inhibitor therapy, despite steroid use at treatment initiation and with durable responses for most of these patients lasting >15 months.   Notable strengths of this investigation are the analysis of real world clinical scenarios where steroid use is often a pragmatic reality and the availability of highly relevant details regarding steroid dose, indication, duration, and initiation/discontinuation relative to checkpoint inhibitor therapy. Outcomes with immune checkpoint inhibitors seen in patients receiving   Limitations of the study include its retrospective nature and overall low incidence of steroid use.  With the advent of combined chemoimmunotherapy regimens, finite duration steroid use concurrently with each cycle of treatment for prevention of chemotherapy-related nausea and rash has become standard.   However, as patients in this study were treated with immune checkpoint inhibitor monotherapy, the impact of these finite, repeating courses of steroids is not explored here. Further, though multivariable analysis confirmed the independent association between steroid use and inferior outcomes with checkpoint inhibitors, a mechanistic explanation for this has not yet been elucidated. Lastly, immunologic profiling results (i.e. tumor PD-L1 status and tumor mutation burden) were not reported.   In my own practice and consistent with the observations made by Arbour and colleagues in this analysis,  I try to minimize or avoid the use of daily palliative steroids for patients in whom immune checkpoint inhibitor therapy is shortly anticipated.  Whenever possible, steroid-sparing alternatives should be considered and used. However, in those patients who require steroids and without reasonable alternatives (i.e. those with brain metastases and intracranial edema), medically necessary steroid therapy should not be deferred or discontinued until it is clinically safe to do so.    Arbour and colleagues should be congratulated on their important contribution to this highly relevant clinical issue.      This concludes this JCO Podcast.  Thank you for listening.         References: Reck, M., et al., Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med, 2016. 375(19): p. 1823-1833. Borghaei, H., et al., Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med, 2015. 373(17): p. 1627-39. Rittmeyer, A., et al., Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet, 2016. Brahmer, J., et al., Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med, 2015. 373(2): p. 123-35. Herbst, R.S., et al., Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet, 2016. 387(10027): p. 1540-50. Gandhi, L., et al., Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med, 2018. 378(22): p. 2078-2092. Horvat, T.Z., et al., Immune-Related Adverse Events, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol, 2015. 33(28): p. 3193-8. Schadendorf, D., et al., Efficacy and Safety Outcomes in Patients With Advanced Melanoma Who Discontinued Treatment With Nivolumab and Ipilimumab Because of Adverse Events: A Pooled Analysis of Randomized Phase II and III Trials. J Clin Oncol, 2017. 35(34): p. 3807-3814.

Read the related article "First-Line Trastuzumab Plus an Aromatase Inhibitor, With or Without Pertuzumab, in Human Epidermal Growth Factor Receptor 2–Positive and Hormone Receptor–Positive Metastatic or Locally Advanced Breast Cancer (PERTAIN): A Randomized, Open-Label Phase II Trial" by Rimawi et al on JCO.org.   Transcript: This JCO Podcast provides observations and commentary on the JCO article ‘First-Line Trastuzumab Plus an Aromatase Inhibitor, With or Without Pertuzumab, in HER2-Positive and Hormone Receptor-Positive Metastatic or Locally Advanced Breast Cancer (PERTAIN): A Randomized, Open-Label Phase II Trial’ by Rimawi et al.  My name is Sara Tolaney and I am Assistant Professor of Medicine at Harvard Medical School and Senior Physician at Dana-Farber Cancer Institute in Boston, Massachusetts.  My oncologic specialty is breast cancer. Since the seminal report of the benefits of adding trastuzumab to chemotherapy, we have seen an improvement in survival for patients with metastatic HER2-positive disease from approximately two years to now almost 5 years.  This dramatic improvement in outcomes can be attributed to the use of continued anti-HER2 therapy beyond progression as well as the introduction of new HER2-directed therapies.  The largest improvement in survival has come from the addition of pertuzumab to a taxane and trastuzumab as seen within the CLEOPATRA study.  This resulted in an impressive almost 16-month improvement in overall survival and established this regimen as a first line standard in the metastatic setting. While chemotherapy and dual anti-HER2 therapy is the current first line treatment approach, we are now left with the question about how best to optimize therapies available to us, and whether or not there are other first line approaches we could consider in order to lessen toxicity.  One potential alternative approach for patients with hormone-receptor positive, HER2-positive disease could be to consider the use of hormonal therapy.  There has been some concern that hormone-receptor positive tumors that are also HER2-positive may be relatively resistant to hormonal therapy.  One reason for this may be that activation of HER2 can result in direct phosphorylation and activation of the estrogen receptor.  This potential HER2 and ER bidirectional cross-talk has provided justification for combinatorial therapy targeting both of these pathways concurrently.  There have been at least three trials that have examined the addition of single agent HER2-targeted therapy to hormonal therapy.  The TAnDEM trial randomized a little over 200 patients with hormone-receptor positive, HER2-positive breast cancer to either anastrozole alone or in combination with trastuzumab as first line therapy and found a 2.4-month improvement in progression free survival, but no difference in overall survival.  The dual EGFR/HER2 tyrosine kinase inhibitor, lapatinib, has also been investigated in combination with hormonal therapy.  A phase 3 study in the first line metastatic setting found that adding lapatinib to letrozole improved progression free survival from 3.0 to 8.2 months, and another trial that looked at adding lapatinib to fulvestrant found an improvement in progression free survival from 3.3 to 5.9 months.  These three studies suggest that single agent HER2-targeted therapy adds modestly to endocrine therapy, and there has therefore been interest to see if dual HER2 targeted therapy added to hormonal therapy would result in a more significant improvement in outcomes. Since data from CLEOPATRA had suggested that the addition of pertuzumab and trastuzumab to chemotherapy led to significant improvements in disease-free and overall-survival, In the article that accompanies this podcast, Rimawi and colleagues were interested in exploring if adding pertuzumab to trastuzumab and hormonal therapy could offer additional benefits.  The PERTAIN study was a multicenter phase 2 trial that  enrolled 258 patients with locally-advanced or metastatic hormone-receptor positive, HER2-positive breast cancer who had not previously received systemic therapy in the advanced disease setting, outside of endocrine therapy, and randomized them to receive trastuzumab plus an aromatase inhibitor or trastuzumab plus pertuzumab and an aromatase inhibitor.  Patients were allowed to receive induction chemotherapy with a taxane for 18-24 weeks in combination with trastuzumab (with or without pertuzumab) at the treating investigator’s discretion; this was decided prior to randomization and patients were stratified by whether or not they had received induction chemotherapy.  The trial demonstrated an improvement in progression free survival from 15.8 months to 18.89 months with the addition of pertuzumab to an aromatase inhibitor and trastuzumab, meeting its primary endpoint.  This improvement in progression free survival was not associated with a significant improvement in objective response rate (63.3 vs 55.7%).  It is important to note that 57% of patients in the trial received induction chemotherapy, and subgroup analyses demonstrated that amongst those who did not receive chemotherapy, the addition of pertuzumab improved progression free survival from 12.45 months to 21.72 months.  In contrast, amongst those who received induction chemotherapy, the median progression free survival was similar for those who received pertuzumab compared to those who did not, 16.89 and 16.85 months respectively.  This group of patients who received induction chemotherapy had more visceral disease and a shorter medial time since initial breast cancer diagnosis.  Grade 3 and 4 adverse events were more common in those patients receiving all three agents (50.4% vs 38.7%) and the most common toxicities were diarrhea, alopecia and nausea. The PERTAIN trial represents the first randomized trial to investigate the addition of pertuzumab to trastuzumab with an aromatase inhibitor and suggests that endocrine therapy with dual anti-HER2 therapy may be a reasonable treatment approach for some patients with hormone-receptor positive, HER2-positive metastatic breast cancer.  There is also data looking at a different dual anti-HER2 therapy approach with endocrine therapy from the phase 3 ALTERNATIVE trial.  This study looked at the benefits of adding lapatinib to an aromatase inhibitor and trastuzumab and demonstrated a 5-month improvement in progression free survival, but no improvement in overall survival.  These studies suggest that upfront endocrine therapy with dual anti-HER2 therapy may offer a novel treatment option for patients that is likely less toxic and associated with a better quality of life than chemotherapy-based treatment.  One must weigh the pluses and minuses of each treatment approach when choosing the appropriate first line therapy for patients.  Endocrine therapy with dual anti-HER2 therapy has not yet been shown to be associated with a survival benefit, and is associated with lower objective response rates than that seen in the CLEOPATRA study, so it may not be the best approach in a patient with significant visceral disease at presentation, but may be an optimal approach in patients with limited tumor burden, or those who are not optimal candidates for chemotherapy.  Work is also ongoing in the PATINA trial to see if adding cdk 4/6 inhibition to endocrine therapy and dual anti-HER2 therapy, after induction chemotherapy, will have even further benefit. This concludes this JCO Podcast.  Thank you for listening.

Read the related article "Addition of Vincristine and Irinotecan to Vincristine, Dactinomycin, and Cyclophosphamide Does Not Improve Outcome for Intermediate-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group" on JCO.org This JCO podcast provides observations and commentary on the JCO article “addition of vincristine, irinotecan to vincristine, dactinomycin and cyclophosphamide does not improve outcome for intermediate risk rhabdomyosarcoma a report from the Children’s Oncology Group by Hawkins, et al.” My name is Alberto Pappo and I am a pediatric oncologist and Head of the Division of Solid Tumors at St Jude Children’s Research Hospital in Memphis, Tennessee. Investigators of the Children’s Oncology Group (COG) developed a prospective randomized study to improve the outcome of patients with intermediate risk rhabdomyosarcoma by comparing the addition of the doublet vincristine and irinotecan (which will be called the irinotecan arm) to standard vincristine actinomycin D and cyclophosphamide (which will be called the VAC arm) to VAC chemotherapy only. Intermediate risk disease comprises the largest subgroup of patients with rhabdomyosarcoma and comprises patients with embryonal histology who present with tumors that are non-metastatic and unresected and arise in unfavorable sites as well as patients who present with non-metastatic alveolar histology tumors. The authors nicely review prior failed strategies that were aimed at increasing the outcome of this group of patients including dose intensification of active agents as well as the  addition of novel agents such as ifosfamide, etoposide and topotecan. 1-3 Irinotecan is a prodrug that is converted to its active metabolite SN38 and inhibits topoisomerase I. In a front-line trial for patients with metastatic rhabdomyosarcoma demonstrated a high level of activity with a 70% early response rate and an 8% disease progression rate.4 Based strong preclinical and clinical data, this agent was incorporated into an upfront randomized trial for rhabdomyosarcoma testing the benefit of adding vincristine and irinotecan to standard VAC in intermediate risk rhabdomyosarcoma. Eligibility criteria included patients with embryonal rhabdomyosarcoma who had stage II and III clinical Group 3 disease and any alveolar rhabdomyosarcoma without evidence of distant metastases.  During the first 12 weeks the two treatments were identical in duration of schedule with the exception of the substitution of irinotecan for dactinomycin and cyclophosphamide at week 4 and for cyclophosphamide at week 7 and 10 in the irinotecan arm.  During the next 30 weeks irinotecan replaced actinomycin D and cyclophosphamide at weeks 16, 19, 25, 31 and 37 in irinotecan arm.  Patients were evaluated for response at week 15, 30 and at the end of therapy.  Radiation therapy unlike the prior COG D9803 trial  started early at week 4 instead of 12 and the dose was determined by the clinical group and histology with doses ranging to 36 Gy for those with clinical group I and II to 50.4Gy for those with Group III disease. The study was designed with an 80% power to detect an overall increase in the long term event-free survival from 65% with VAC chemotherapy to 76% with the doublet VAC VI with a sample size of 486 patients.   Between December 2006 and December 2012 there were 481 patients enrolled on the study of whom 33 were ineligible.  Of the remaining 448 eligible patients 222 were randomized to VAC and 226 were randomized to the irinotecan arm.  The patient’s characteristics were similar between both arms and to other COG trials. There was a slight predominance of males, 61% of patients were between 1 and 10 years of age and 71% were Caucasian.  Embryonal rhabdomyosarcoma was the predominant histology seen in 53% of the patients and 86% had clinical Group III disease. The most common primary site was parameningeal followed by bladder prostate, extremity and retroperitoneum.    With a median followup for surviving patients of 4.8 years the estimated 4 year event-free survival was 63% for the VAC arm and 59% for the irinotecan arm.  The estimated 4 year overall survival rates was 73% for the VAC arm and 72% for the irinotecan arm. There were no differences in radiographic response among clinical Group III patients as assessed by institutional report by week 15 and no evidence of differences in outcome by treatment arm in the histologic subgroup analysis.  When compared to the previous trial D9083 which had slightly different eligibility criteria, there were no differences in event and overall survival for patients with alveolar rhabdomyosarcoma. However, patients with embryonal tumors had an inferior 4 year event-free survival in this trial when compared to patients in D9803 although the 4 year overall survival rates were similar.  The vast majority of treatment failures were due to tumor progression or recurrence. The 4 year local failure rate was 22.4%, the 4 year regional lymph node failure rate was 5.7% and the 4 year distant failure rate was 18%.  Hematologic toxicity and febrile neutropenia were more commonly observed in the VAC arm whereas diarrhea and mucositis were more prevalent in the irinotecan arm. Hepatopathy was more common in the VAC arm and patients in the irinotecan arms who developed grade 3 4 diarrhea were more likely to carry the UGT1A1  7/7 genotype.  The authors conclude that the addition of vincristine and irinotecan to a VAC backbone failed to improve the outcome of patients with intermediate risk rhabdomyosarcoma. However, the lower cumulative doses of cyclophosphamide in the irinotecan arm which could potentially reduce the risk of infertility in selected patients and the lower rates of hematologic toxicity in this regimen have provided a rationale for the COG to use a VAC irinotecan backbone in their current up front randomized trial for intermediate risk rhabdomyosarcoma.   This trial highlights the lack of significant advances in the therapy of pediatric rhabdomyosarcoma despite the fact that irinotecan showed significant preclinical and clinical activity in metastatic patients with this disease.5,6 Similarly, in a previous study, the addition of another camptothecin, topotecan failed to improve the outcome of intermediate risk patients despite promising clinical activity in newly diagnosed metastatic patients 7suggesting that identification of novel agents based on their activity in  phase II window studies for high risk rhabdomyosarcoma is not an optimal method for selecting active compounds that could be incorporated into front-line studies for intermediate risk disease. As suggested by the authors of the paper just discussed, other novel mechanisms of drug testing such as randomized phase II studies in recurrent disease might offer alternative more effective strategies for identifying agents to be tested in intermediate risk patients. In contrast to this results, the European Pediatric Soft Tissue Sarcoma Study Group has recently reported at the ASCO 2018 meeting improved outcomes for a similar population of patients when maintenance therapy with low dose cyclophosphamide and vinorelbine is added to a backbone of vincristine, ifosfamide and actinomycin D (VAI). 8  In this trial, patients with non metastatic incompletely resected embryonal rhabdomyosarcoma arising in unfavorable sites and localized alveolar rhabdomyosarcoma without nodal metastases who achieved a complete remission after 9 cycles (27 weeks) of VAI with or without doxorubicin were randomized to stop treatment or receive maintenance chemotherapy with six 28 days cycle of vinorelbine and cyclophosphamide.  The study was initially designed with an 80% power to detect an increase in the 3 year EFS from 55% to 65% with a hazard ratio of 0.67 but was then amended to allow detection of a relativity reduction rate in the relapse rate of 50%.  This trial accrued 670 patients of whom 371 were eligible and 186 were assigned to the standard arm and 185 to the maintenance arm.  The clinical features were well balanced between the two groups. With median follow up of 5 years in surviving pts, the 3 year event-free survival and overall survival in the maintenance arm and the standard arm were  78.4% vs 72.3% (p value 0.061) and 87.3% vs. 77.4 (p value = 0.011).  The investigators concluded that the addition of maintenance therapy is a novel strategy that improves the outcome of this group of patients with rhabdomyosarcoma and establishes the new standard of care for patients in Europe.  The results of this trial however, need to be interpreted with caution and cannot be generalized. The follow-up of patients is relatively short and only those who achieved a complete radiographic response after chemotherapy were eligible to be randomized, no information was provided regarding outcomes of patients who were randomized to receive doxorubicin, there are only 9 cycles of chemotherapy given prior to randomization to maintenance therapy whereas the COG studies give 14 cycles of therapy and finally, there are slight differences in the eligibility criteria when compared to the previous COG  trials.    In conclusion, the addition of an irinotecan backbone to standard VAC chemotherapy does not improve the outcome of patients with intermediate risk rhabdomyosarcoma. However, the irinotecan containing regimen offers potential advantages such as outpatient administration of chemotherapy, reduced hematologic toxicity and cumulative cyclophosphamide exposure and has therefore become the standard backbone for patients with intermediate risk rhabdomyosarcoma in the United States.  This concludes this JCO podcast.  Thank you for listening.    

Intensifying therapy in children with pediatric B-ALL and IKZF1 deletions leads to improved survival. Read the related article "Intensifying Treatment of Childhood B-Lymphoblastic Leukemia With IKZF1 Deletion Reduces Relapse and Improves Overall Survival: Results of Malaysia-Singapore ALL 2010 Study" on JCO.org

Discussion of a recent study that evaluated prospectively psychosocial well being measures in breast cancer patients before and after receipt of CPM. Read the related article "Prospective Study of Psychosocial Outcomes of Having Contralateral Prophylactic Mastectomy Among Women With Nonhereditary Breast Cancer" on JCO.org

This podcast discusses the important risks and potential benefits of PD-1 immune checkpoint blockade in patients with thymic epithelial neoplasms. Read the related article "Pembrolizumab for Patients With Refractory or Relapsed Thymic Epithelial Tumor: An Open-Label Phase II Trial" on JCO.org

GRAALL-2005 study shows no overall benefit for cyclophosphamide intensification in older adults with ALL, despite a general improvement in outcomes for the younger adults. Read the associated article by Huguet et al on JCO.org.

Highlighting the importance of BCMA-CAR T therapy for patients with relapsed refractory multiple myeloma and discusses future avenues of clinical investigation. Read the related article "T Cells Genetically Modified to Express an Anti–B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma" on JCO.org

This podcast includes commentary upon a large case control series that examined the incidence of cardiac injury in association with radiation dose to distinct segments of the left ventricle and coronary arteries. Read the associated article by Taylor et al on JCO.org.

This is an evaluation of PCI in stage III Non-Small-Cell Lung Cancer.  While the incidence of symptomatic brain metastases is reduced, neurological toxicity is increased and no effect on survival is demonstrated. This trial reconfirms that routine administration of PCI is not a current standard of care. Read the associated article by De Ruysscher et al on JCO.org. This JCO Podcast provides observations and commentary on the JCO article 'Prophylactic Cranial Irradiation (PCI) Versus Observation in Radically Treated Stage III Non-Small-Cell Lung Cancer (NSCLC): A Randomized Phase III NVALT-11/ DLCRG-02 Study' by De Ruysscher et al. My name is Everett Vokes, and I am the Chairman and Professor of Medicine at the University of Chicago in Chicago, United States of America. My oncologic specialty is head and neck and lung cancer. De Ruysscher et al present a randomized trial evaluating the role of prophylactic cranial irradiation, referred to as PCI in this podcast, in patients with stage III non-small-cell lung cancer treated with curative intent. In doing so they have addressed an important issue. Brain metastases are a frequent site of treatment failure and can occur in isolation from additional system disease. It has been postulated that PCI could prolong survival and disease-free survival. In localized small-cell lung cancer, PCI has already been shown to decrease the incidence of brain metastases by about 50% with an impact on long-term survival. However, it is well established that PCI can lead to neurocognitive decline associated with reduced quality of life. Specifically, the authors initially staged patients with a contrast enhanced brain CT or MRI and randomized patients to observation or PCI after concurrent or sequential chemoradiotherapy with or without surgery. Patients were randomized 1:1; PCI was designated to start at a maximum of 6 weeks after the last chemoradiotherapy and could be given as 36 Gy in 18 fractions, 30 Gy in 12 fractions or 30 Gy in 10 fractions. Patients were then monitored for disease progression including symptomatic brain metastases within 24 months from the time of randomization as primary endpoint. Quality of life measurements were performed as well. Key symptoms were defined as signs of increased intracranial pressure, headache, nausea and vomiting, cognitive or affective disturbances, seizures and focal neurological symptoms. MRI or CT was triggered by such symptoms. The initial goal was to randomize 300 patients. However, accrual was slow and was decreased to 175 randomized patients overall. Between 2009 and 2012, 195 patients were registered, 175 were randomized, 87 to PCI and 88 to observation. The proportion of patients developing symptomatic brain metastases two years after therapy was 7% in the PCI group and 27% in the control group. This compares to a historical average of approximately 30%. PCI thus did decrease the cumulative incidences of symptomatic brain metastases. However; neurological adverse events were also increased. In particular, grade I-II memory impairment and cognitive disturbance were significantly increased in the PCI arm. Non-neurologically events such as alopecia, fatigue and headache were also significantly more frequent in the PCI group. When evaluating patient reported adverse events, headache was reported to occur significantly more frequently in the PCI arm. Of interest, neurological side effects tended to increase over time after PCI whereas non-neurological adverse events were highest during PCI and decreased over time. Overall survival at median follow-up of 51 months was not improved, with a hazard ratio of 0.9. PCI did significantly increase time to develop brain metastases, and the median progression-free survival was slightly longer at 12.3 versus 11.5 months in the PCI group, but again this was not statistically significant.. Overall, this study does demonstrate that PCI can significantly reduce the incidence of symptomatic brain metastases in patients with stage III non-small cell lung cancer. However, this comes at the cost of increased neurological adverse events even though most of these were mild in nature. Furthermore, an impact on overall survival was not demonstrated. It could be argued that this study was somewhat small and that a larger study could have shown a more pronounced effect, especially on progression-free survival, which did show a trend favoring PCI. On the other hand, symptomatic brain metastases nowadays can be treated at the time of recurrence with SBRT and other modern radiotherapy techniques. In addition, the recent durvalumab trial (PACIFIC) demonstrating that consolidation durvalumab can increase progression-free survival also demonstrated a reduction in brain metastases in durvalumab treated patients, suggesting that improved systemic therapy may emerge as a better approach to tackling the clinical problem of brain metastases in stage III NSCLC. So is PCI a recommended standard of care for patients with stage III NSCLC? While I congratulate the authors on conducting this ambitious and randomized trial addressing an important key question, my answer is no. Treatment with durvalumab is an evolving new standard and neurological side effects of PCI are not to be ignored. Treating patients with cranial radiation at the time of actual progression seems like the better approach in the meantime. This concludes this JCO Podcast. Thank you for listening.

The public perception of medical marijuana has outpaced medical knowledge. Oncologists encounter an increasing number of patient questions and interest regarding its use. This study highlights the beliefs, attitudes and knowledge of medical oncologists regarding the therapeutic use of marijuana. View the related article Medical Oncologists’ Beliefs, Practices, and Knowledge Regarding Marijuana Used Therapeutically: A Nationally Representative Survey Study by Braun et al on JCO.org.   This JCO Podcast provides observations and commentary on the JCO article ‘'Medical Oncologists' Beliefs, Practices and Knowledge Regarding Marijuana Used Therapeutically: A Nationally-Representative Survey Study' by Braun  and colleagues. My name is Kimberson Tanco, and I am an Assistant Professor at the University of Texas MD Anderson Cancer Center in Houston, Texas. I am a Palliative Medicine physician. Medical marijuana is one of the fastest growing medical issues nationwide, so much so it is now legal under certain conditions in more than half of the country, with additional limited indications in certain “non-legal” states for pediatric refractory epileptic conditions.1  Most of the current trials are directed towards non-cancer conditions. In contrast, in the article that accompanies this podcast, Braun and colleagues highlight a variety of key issues that face oncology practitioners regarding cannabis and its potential uses and toxicities. As healthcare professionals, it is inevitable that we will be asked by our patients and/or their caregivers about the use of medical marijuana, either in a legalized or a non-legalized state. This study does a good job of recording clinician beliefs and practices from different regions of the nation. It also points out a very important fact that the interest and curiosities about the use of medical marijuana far outpaces our knowledge base as demonstrated in their results. It was very interesting to know that up to 80% of oncologists conducted discussions and 46% recommended medical marijuana for clinical use  as compared to only 30% feeling sufficiently knowledgeable enough to make informed recommendations. This is quite a change from 2010, when they cited that only 20% of family practitioner respondents in Colorado would recommend medical marijuana and The authors highlighted key points from the study including the need for expedited clinical trials exploring potential medicinal effect of marijuana in oncology, the need for educational programs about medical marijuana and policies to incentivize the training of clinicians on this issue. In the next few minutes, I would like to discuss these points. Their first point about the need for clinical trials is certainly a key step into understanding the pharmacology and effects of cannabis, which would help improve educational programs and open up federal, state and institutional policies. However, there are a variety of challenges faced in conducting medical marijuana research.2 In spite of changes in state policy and increasing prevalence of cannabis use, cannabis is still not legalized by the federal government and remains a Schedule I substance. Furthermore, an investigator must navigate through the National Institute on Drug Abuse or NIDA, Food and Drug Administration, Drug Enforcement Administration, state departments, state boards, institutional review boards, and funding sources among others. Additionally, supply of cannabis for research purposes is only available through NIDA and is sourced from the University of Mississippi, which has been the sole cultivator since 1968. An important point is that federal supplies of cannabis may also have been harvested earlier and stored in freezer, and may have lower potencies than those sold in state-regulated markets. Hence, investigator results may have to be taken with caution as they relate to appropriate dosing of cannabis products, particularly when they will be taken from state dispensaries. Additionally, there are drug delivery challenges in inhalation, vaporization or ingestion as well as what the author perfectly described as “entourage effects” in where the effect may be different after administering the whole plant vs. isolated cannabinoids. On the other hand, as a benefit of conducting more standardized trials, we can also compare through head-to-head trials the benefits and toxicities against currently available oral cannabinoids such as dronabinol and nabilone. The study also demonstrated that oncologists believed that medical marijuana can be beneficial for certain symptoms like anorexia, nausea, and anxiety. Standardized trials would allow us to discover and outline indications, dosages, mode of delivery and more for these symptoms that plague cancer patients. The second key point is about improving educational programs and is reflected by the results of the study showing only 30% of oncologists feel that they have sufficient knowledge regarding cannabis. In my personal experience, I have been noticing increasing sessions about medical marijuana in various national conferences. Although this is good to see, educational access needs to spread faster and broader. Key concepts including pharmacology, potential uses, adverse effects, and drug interactions should be continued into local, institutional and even into medical school level. While there was no consensus by respondents regarding the comparative effectiveness of marijuana as a treatment for pain, majority supported using it as an adjunct to standard pain management strategies, which is an especially relevant issue in the setting of an opioid crisis. Cannabinoids may have inhibitory activity in certain cytochrome enzymes and glycopeptides. For example, it has potential inhibitory activity on CYP2D6 and CYP3A enzymes while inducing CYP2E1. These activities may affect levels of certain opioids such as fentanyl, methadone and other drugs like anesthetic agents.3 It may also have potential inhibitory activity to P-glycoprotein which may increase drug levels of certain agents like paclitaxel and etoposide. Further research is needed to be able to better understand these interactions. A key finding this study demonstrated is the perception of oncologists that medical marijuana has a lower risk than opioids for addiction, overdose and death. With the ongoing opioid epidemic, similar to any national movements or epidemics, there is a natural trend to react and use other substances over opioids, which is still the gold standard for cancer pain treatment. Recent studies have shown decreases in opioid prescribing rates in states that legalized marijuana use.4,5 One wonders if the national and media scrutiny of the dangers of opioid use coupled with the increased excitement over the potential uses of marijuana downplay any of its potential adverse effects. It is also reasonable to consider whether we are opening a can of worms by substituting one addictive substance with another, or whether we are addressing the addiction issue by simply replacing the substance involved. These are important arguments that we do not have time for in this podcast and would be better discussed in another forum. The third key point is development of policies. Statewide, we have seen increasing legislation to legalize cannabis not only for medical use but also for recreational purposes. Unfortunately, even in legalized states, several institutions do not have policies and guidelines that deal with this issue.6 Clinicians are left to make medical decisions regarding patients using cannabis by themselves or try to deflect the topic altogether. The debate of medical marijuana is only starting. Clinical trials are needed to better understand its pharmacology to arm oncologists and other clinicians to better care for their patients. As the public perception of cannabis has blossomed over recent years and state-regulated dispensaries have provided medical marijuana to patients, the medical field has an opportunity to learn from what can already be observed and advance this into more standardized and scientific testing. This concludes this JCO Podcast. Thank you for listening.

This commentary summarizes findings from a study of racial disparities in medical financial hardship, identifies gaps in the current evidence base, and discusses health policy considerations for to reducing the risk of financial hardship. Read the related article "Financial Impact of Breast Cancer in Black Versus White Women" on JCO.org

This podcast discusses a phase II trial evaluating the combination of everolimus and fulvestrant compared to fulvestrant alone in pretreated hormone receptor-positive metastatic breast cancer in terms of context within the current hormone treatment environment and toxicity management. Read the related article Randomized Phase II Trial of Fulvestrant Plus Everolimus or Placebo in Postmenopausal Women With Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer Resistant to Aromatase Inhibitor Therapy: Results of PrE0102" on JCO.org

This  podcast discusses a CCSS study of very late infection-related mortality in asplenic adult survivors childhood cancer, with risk increasing precipitously after age 40.  Read the related article "Late Infection-Related Mortality in Asplenic Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study" on JCO.org

This podcast describes the extended follow-up of the large International phase II CheckMate 205 study of single-agent nivolumab for patients with relapsed/refractory classical Hodgkin lymphoma after failure from autologous stem cell transplant. Read the related article on JCO.org.

This podcast provides comment on the accompanying JCO article “ENGAGE: Evaluation of a streamlined oncologist-led BRCA mutation testing and counseling model for patients with ovarian cancer” by Nicoletta Colombo, et al and evaluates the need for new delivery models for genetic testing for oncology patients. Related Article: Evaluation of a Streamlined Oncologist-Led BRCA Mutation Testing and Counseling Model for Patients With Ovarian Cancer

This commentary examines whether patient-reported outcomes were substantially different in men given chemohormonal therapy versus hormone therapy in the CHAARTED randomized controlled trial. Related Article: Quality of Life During Treatment With Chemohormonal Therapy: Analysis of E3805 Chemohormonal Androgen Ablation Randomized Trial in Prostate Cancer

This podcast reflects upon a recent retrospective study of breast cancer patients with local regional recurrence, and whether imaging is needed for all such patients. Read the related article on JCO.org.

This podcast discusses whether the primary outcomes and study design for the reported trial were properly pre-specified and pre-registered prior to accruing participants. Related Article: Improving Breast Cancer Surgical Treatment Decision Making: The iCanDecide Randomized Clinical Trial

This podcast reviews the aims, methodology, and results of a population-level study that investigates the value of specialized pediatric palliative care services for children with cancer at the end of life, as well as discussing practical ways in which individuals and institutions can immediately apply study findings towards improvement of clinical care, education, and research initiatives. Related Article: Predictors of Specialized Pediatric Palliative Care Involvement and Impact on Patterns of End-of-Life Care in Children With Cancer

This podcast reviews the current evidence for using radiofrequency ablation or stereotactic body radiotherapy as primary treatment for nonsurgical management of early stage hepatocellular carcinoma.    Related Article: Radiofrequency Ablation Versus Stereotactic Body Radiotherapy for Localized Hepatocellular Carcinoma in Nonsurgically Managed Patients: Analysis of the National Cancer Database

This podcast addresses the clinical implications of the high cost of the 21-gene assay in women with ER-positive, node-negative breast cancer. Related Article: Population-Based Study to Determine the Health System Costs of Using the 21-Gene Assay

Though opioid abuse is clearly an issue for cancer patients post-surgery, many other potential factors were not accounted for and should be included in a more in-depth study that goes beyond database analysis. Related Arcticle: New Persistent Opioid Use Among Patients With Cancer After Curative-Intent Surgery

The paper examines the cost-effectiveness of schedules of bone-modifying agents in patients with breast cancer and skeletal metastases and supports the 3-month administration of the generic zoledronic acid in terms of cost and efficacy. Read the accompanying article on JCO.org.

In this randomized trial, momelotinib was non-inferior to ruxolitinib for spleen response but was less effective in controlling symptoms. Related Article: SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor–Naïve Patients With Myelofibrosis

A Danish population based study of adults with acute myeloid leukemia is described, and the potential significance of educational level as a predictor of receipt of allogeneic transplant and overall survival is explored. Read the associated article on JCO.org. 

With a large database analysis, the authors found an increase in hospice use among older patients with AML at the end of life, but this increase was largely driven by late enrollment. Read the associated article by Wang et al on JCO.org.

T-cell therapies targeting viral diseases have evolved from a patient-specific therapy, targeting a single virus, and requiring multiple months of specialized manufacturing, to readily-available cell banks capable of targeting multiple viruses for many individuals. Read the associated article by Tzannou et al on JCO.org.

This podcast examines the growing evidence to support the link between risk factors for cardiovascular disease and cancer. Related Article: Guideline-Based Statin Eligibility, Cancer Events, and Noncardiovascular Mortality in the Framingham Heart Study

Normalization of PET-CT is a strong predictor   for progression free survival (PFS) and overall survival (OS) in multiple myeloma (MM) Related Article: Prospective Evaluation of Magnetic Resonance Imaging and [18F]Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography at Diagnosis and Before Maintenance Therapy in Symptomatic Patients With Multiple Myeloma Included in the IFM/DFCI 2009 Trial: Results of the IMAJEM Study

Randomization to different methotrexate and steroid treatment strategies was not related to neuropsychological outcome in children treated for B-ALL, but age and insurance status were significant predictors. Read the associated article "Neurocognitive Functioning of Children Treated for High-Risk B-Acute Lymphoblastic Leukemia (HRALL) Randomized to Capizzi (CMTX) Versus High- Dose Methotrexate (HDMTX): A Report From the Children’s Oncology Group (COG)" on JCO.org.

This podcast summarizes the study finding and discuss the clinical and policy implication of an article to appear in JCO that examined the impact of low-income subsidy on the utilization, adherence, and costs of oral immunomodulatory drugs among elderly myeloma patients. Read the article Subsidies for Oral Chemotherapy and Use of Immunomodulatory Drugs Among Medicare Beneficiaries with Myeloma by Olszewski et al.

In a unique approach to subsequent malignancy research, Teepen and colleagues report on subsequent solid cancer risk associated with chemotherapy exposure among survivors of childhood cancer, and emphasize the need for greater future collaborative survivorship research efforts. Related Article: Long-Term Risk of Subsequent Malignant Neoplasms After Treatment of Childhood Cancer in the DCOG LATER Study Cohort: Role of Chemotherapy

The SWORD study is one of the first randomized controlled trials targeting fear of cancer recurrence (FCR) and results support the efficacy of cognitive behavior therapy for the treatment of FCR, a prevalent and distressing concern among a significant proportion of cancer survivors. Related Article: Efficacy of Blended Cognitive Behavior Therapy for High Fear of Recurrence in Breast, Prostate and Colorectal Cancer Survivors; The SWORD- study, A Randomized Controlled Trial by van de Wal et al.

This podcast discusses the role of consolidation stem cell transplantation in patients with double-hit lymphoma who achieve a complete response to front-line therapy and also focuses on the benefit of intensive versus standard therapy for this disease. Related Article: Outcomes of Patients With Double-Hit Lymphoma Who Achieve First Complete Remission

This podcast summarizes and discusses the findings from a study by Guy and colleagues about the economic impact of chronic conditions in cancer survivors in the United States. Related Article: Economic Burden of Chronic Conditions Among Survivors of Cancer in the United States

This randomized controlled trial shows that Treatment Summary Survivorship Plans increase physician recommendation of needed care among breast cancer survivors but may not significantly impact patient adherence. Related Article: Randomized Controlled Trial of Survivorship Care Plans Among Low-Income, Predominantly Latina Breast Cancer Survivors

This podcast discusses the association between smoking and risk of death from pancreatic cancer.

Patients who had autologous reconstruction had higher satisfaction with breasts and well-being than patients who had implant-based reconstruction, but both groups experienced substantial physical morbidity.

This podcast describes the results and implications of the article published by Landier et al, describing the relationship between 6-MP ingestion habits and outcomes, as well as adherence, among children with acute lymphoblastic leukemia.

By Amanda Psyrri  The findings of KEYNOTE-055 are summarized and compared to other immunotherapy studies in recurrent/metastatic head and neck squamous cell carcinoma. Related Article:  Pembrolizumab for Platinum- and Cetuximab-Refractory Head and Neck Cancer: Results From a Single-Arm, Phase II Study

Podcast re: 'Three-year Follow-up of an Alectinib Phase 1/2 Study in ALK-Positive Non-Small-Cell Lung Cancer: AF-001JP' by Tamura et al.

This podcast discusses the JCO article, "Late Relapse of classical Hodgkin Lymphoma: An Analysis of the German Hodgkin Study Group HD7-HD12 Trials" by Paul Jan Bröckelmann, et al. which demonstrates that late relapses are seen in a small fraction of early stage good risk Hodgkin lymphoma patients, which increase in incidence up to 20 years and do not appear to plateau, and examines the implications of these findings with respect to therapy and disease biology.

By Kenneth Bradstock This podcast describes a clinical trial of clofarabine in consolidation therapy for adults with acute myeloid leukemia. Related article: Randomized Phase II Study of Clofarabine-Based Consolidation for Younger Adults With Acute Myeloid Leukemia in First Remission

Dr. Wiestner highlights characteristics of ibrutinib resistant CLL as reported by Woyach and colleagues and discusses how these data refine the management of CLL in the area of targeted therapy and can stratify patients for future clinical trials.

Summary and discussion of JCO paper by Yurgelun at al. using a 25-gene panel to demonstrate a nearly 10% germline mutation rate in colorectal cancer patients independent of high-risk factors.

By Stacie B. Dusetzina Considering the role of network coverage on access to accredited cancer institutions and potential out-of-pocket costs for patients. Related Article: Access to Accredited Cancer Hospitals Within Federal Exchange Plans Under the Affordable Care Act  

By Linda E. Carlson This podcast discusses the target study in the context of other research on mindfulness-based interventions for cancer patients and survivors, providing a critique and suggestions for clinical interpretation and future research. Related Article: Mindfulness-Based Cognitive Therapy in Advanced Prostate Cancer: A Randomized Controlled Trial

By Christopher R. Flowers Modeling studies like the one presented by Qiushi Chen and colleagues can project where needs and opportunities exist to address the pricing structure of medications and the selection of management strategies in CLL. Related Article: Economic Burden of Chronic Lymphocytic Leukemia in the Era of Oral Targeted Therapies in the United States

This podcast provides commentary on a large dataset describing the expected frequency, severity and kinetics of immune-related adverse events associated with nivolumab monotherapy and the expected use of corticosteroid supportive therapy together with observations relating to the associations between immune adverse events, corticosteroid use and efficacy.

By Deepa Rangachari This podcast focuses on the use of trastuzumab in adjuvant therapy for early stage, Her2-positive breast cancer and ongoing efforts to identify predictive and prognostic biomarkers for the assessment of treatment-related cardiac toxicity. Related Article: Role of Troponins I and T and N-Terminal Prohormone of Brain Natriuretic Peptide in Monitoring Cardiac Safety of Patients With Early-Stage Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer Receiving Trastuzumab: A Herceptin Adjuvant Study Cardiac Marker Substudy

If you are an oncologist and think that it isn’t part of your job to listen to your patients talk about depression, I urge you to re-consider.  As Sullivan and colleagues show, depression can be lethal.    

This podcast highlights the innovative methodology employed in this study to determine risk factors for chemotherapy induced peripheral neuropathy, as well as implications of the findings to clinical practice and future investigation of immune mechanisms of this toxicity.

This podcast will assist readers in understanding the clinical implications of the paper by Yanik and colleagues.  The paper describes the occurrence of Kaposi’s sarcoma and lymphoma in the era of effective anti-HIV therapy where patients appear to be doing well from the standpoint of HIV clinical assessment, but continue to develop cancers associated with AIDS.

Implicit bias affects oncologists and their patients -  a few steps can help

This podcast is a discussion of a clinical trial by Lesokhin et al which evaluated nivolumab monotherapy in patients with relapsed or refractory hematologic malignancies.

This podcast discusses the prevalence of and risk factors associated with a phenotype of accelerated aging among ALL survivors. Measurement and implications of frailty/pre-frailty are discussed.

This podcast comments on two independent pediatric studies on both sides of the Atlantic showing the relevance of 1q gain in poor prognosis Wilms tumors which raises the perspectives for therapeutic modifications.

While ten-year overall survival has increased for German patients with heritable retinoblastoma, treatment modalities including radiation and/or chemotherapy can impact overall survival.

The Children's Oncology Group study led by Larsen et al. showed that children and young adult patients with high-risk B cell acute lymphoblastic leukemia benefit from receiving high-dose methotrexate during interim maintenance 1 and that those aged 1 to 9 years benefit from receiving dexamethasone for 14 days during induction.

This podcast discusses the study by McMeekin and colleagues regarding their analysis of the prognostic and predictive implications of mismatch repair deficiency status among a tissue sample registry cohort of 1,024 endometrioid-type endometrial adenocarcinomas.

A central histopathological analysis of tumor material sampled within the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) Trial shows that lymph node involvement is the only independent predictor of survival following chemotherapy plus resection

Restrictions on nutrition, social contacts, and pets are not effective anti-infective measures in children with acute myeloid leukemia.

This podcast will review results from screening ultrasound and tomosynthesis in women with dense breasts and will discuss current and future use of MRI screening which may include average risk women.

In this podcast, Dr. Andrew Ko discusses the SIRFLOX trial evaluating whether the addition of radioembolization to systemic chemotherapy confers any benefit in patients with liver-dominant metastatic colorectal cancer, and whether the results should compel us to rethink our use of this technology for this disease indication.

Impact of site of metastasis on overall survival in castration refractory prostate, and its implications on patient care and clinical trial design.

This podcast This JCO Podcast provides observations and commentary on the JCO article, "A European collaborative study of natural history, outcomes and validation of prognostic and response criteria in IgM related AL amyloidosis."

This podcast puts into context the findings from Hart and colleagues, highlighting the clinical care and research implications.  

In this podcast, the article by Meropol et al. describing a randomized trial of a web-based educational tool versus a standard text-based resource is analyzed and placed in context of other challenges that limit the enrollment of adult cancer patients in contemporary clinical trials.

A study by Ramsey and colleagues suggests that extreme financial distress as manifested by personal bankruptcy might be associated with worse mortality in cancer patients. Long-term solutions have to focus on policy shifts involving how we set prices for drugs and how we design health insurance, but for more immediate solutions interventions have to focus on the oncologist and patient.

The Ki-67 proliferation index improves the prognostic value of the MIPI score.

Ethnicity’s impact on diagnosis and survival of T-cell lymphoma

An update on clinical trials that have included children with hepatocellular carcinoma

This podcast reviews the International Bladder Cancer Group’s recommendations regarding definitions and endpoints for the development of non-muscle-invasive bladder cancer clinical trials.

Discussion of a phase I trial of the checkpoint inhibitor atezolizumab in metastatic renal carcinoma.

This podcast reviews the accompanying article to provide the audience an understanding of the data and rationale to support updating the INRC primary site response criteria.

This podcast provides commentary on the importance of symptom assessment in Polycythemia Vera, and how this may impact therapeutic decision-making.

This podcast describes the evolving role of Gallium-68 somatostatin-receptor PET imaging in the evaluation of patients with well-differentiated neuroendocrine tumors, and compares the diagnostic sensitivity of this imaging modality to conventional scans.

Summarize the paper by Asselin et al and review the risks of therapy-related cardiomyopathy and evidence supporting dexrazoxane use in pediatric oncology.

Recent findings represent an important and exciting step in applying the rapid advance of sequencing technologies to generate molecularly-driven approaches towards the detection of gynecologic malignancies.  More work is needed to better define and validate where such an approach might add most meaningfully in the search for effective methods of ovarian and endometrial cancer detection and diagnosis.

The randomized placebo controlled trial of progesterone receptor blockade showed no difference in survival, finally answering the question about hormonal therapy in this disease and raising new questions about how to move forward quickly.

This podcast discusses the study by Hennink and colleagues regarding their randomized controlled trial of a 3-year versus 6-year interval for screening colonoscopies in individuals with a family history of colorectal cancer.

This podcast reviews the current knowledge of staging and prognosis of mycosis fungoides and Sezary syndrome and evaluates the CLIC study, which aims to develop a prognostic index that can be used with patients who are diagnosed with advanced disease.

This podcast summarizes new evidence about the role of travel distance, oncologist density, and insurance in receipt of guideline-based chemotherapy for patients with stage III colon cancer.

This podcast will discuss the association of obesity and risk of developing colorectal cancer in Lynch syndrome patients based on a manuscript by Mohammad Movahedi and colleagues. In this manuscript, they report an association between obesity and increased risk of colorectal cancer as well as the potential benefit of aspirin to reduce the risk of colorectal cancer in obese Lynch syndrome patients.

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This podcast will examine data on utilization, toxicity and survival outcomes with the use of intraperitoneal chemotherapy for initial treatment of ovarian cancer at six NCCN institutions.

Analogous to prior analyses with ABVD, in a large series of Hodgkin lymphoma patients treated with BEACOPP, Haverkamp and colleagues from the German Hodgkin Study Group report that early discontinuation of bleomycin or vincristine due to toxicity has no impact on cure rates or survival.

This podcast explores the complicated relationship between potency, toxicity, and duration of therapy, and how each impacts the overall efficacy of therapy.

This study involved working together across oceans, regulatory bodies in various countries, different cultures in 4 cooperative groups, different standard chemotherapy administration guidelines, and putting aside personal biases and styles to work together and come up with a document acceptable to all, in order to conduct an international trial in a rare disease for the benefit of children with osteosarcoma.

The two recent papers by Kitagawa, et al and Rose, et al, give us treatment options and tools that help maximize not only the benefits of survival with treatment but minimization of non-beneficial treatment toxicity through identification of patients with advanced and recurrent cervical cancer that are most and least likely to benefit.

This podcast places the results of SWOG S0809, a phase II intergroup trial of adjuvant capecitabine/gemcitabine followed by radiotherapy and concurrent capecitabine in extrahepatic cholangiocarcinoma and gallbladder carcinoma, in context with prior conflicting data and discusses implications for development of a definitive phase III trial.

This is a well-annotated study demonstrating that men treated with androgen deprivation therapy for prostate cancer have impaired cognitive performance within six months of starting therapy and that a specific genetic polymorphism may lend toward greater susceptibility to cognitive impairment.

This is a requested commentary regarding a concurrently-published manuscript which evaluated the utility of omega-2 fatty acids for the treatment of aromatase inhibitor-associated arthralgias.

A meta-analysis of 7 randomized trials comparing EGFR kinase inhibitors to chemotherapy for advanced EGFR-mutant lung cancer has shown that some populations gain greater benefit from targeted therapy – namely never-smokers, woman, and tumor harboring exon 19 deletions.

This podcast discusses a novel immunotherapy approach using an allogeneic whole tumor cell vaccine to prime, and a recombinant antigen-encoded bacterial vector to boost, immune responses against pancreatic cancer and explains why this approach may be beneficial in the treatment of advanced pancreatic cancer.

In summary, healthcare providers caring for breast cancer patients hopefully recognize the need for consideration of genetic testing in appropriate individuals, and communicate that need to the patient. A discussion about why genetic testing is not appropriate may be as beneficial as one about why it is, and oncology providers should consider briefly discussing genetics with all patients, even if the subject is provider-initiated.

Review and comments on BFM experience of ALL hematopoietic transplantation.

This podcasts provides perspective on a recent report evaluating disease volume and surgical complexity on post-operative tumor residuum and survival in ovarian cancer patients.

In this podcast, Dr. Claire Snyder discusses how patient-reported outcomes provide a critical perspective to evaluating health conditions and their treatment, and describes several tools available to facilitate the measurement and application of PROs. 

An analysis of the PROFILE studies and opportunities for treatment of ALK-rearranged non-small cell lung cancer

The development and practical utility of a model developed in the Mayo benign breast disease cohort to predict invasive breast cancer risk after benign breast disease is described.

This JCO Podcast provides observations and commentary on the JCO article, "Large retroperitoneal lymphadenopathy as a predictor of venous thromboembolism in patients with disseminated germ cell tumors treated with chemotherapy" by Amirrtha Srikanthan, et al.

This is an oral commentary on patients with endometrial or rectal cancer, and their risk of developing second malignancies with or without radiation.

In a randomized RTOG study of chemotherapy concurrent with accelerated vs standard fractionated radiotherapy for head and neck cancer, it was found that patients treated in institutions who accrued a large number of patients had better outcomes compared with those treated at low-volume institutions, highlighting the importance of referring patients with advanced cancer to high-volume centers.

This four-arm randomized controlled trial of cognitive behavioral therapy for insomnia in cancer patients confirmed its effectiveness but did not demonstrate benefit from the addition of a daytime wakefulness-promoting agent.

This podcast reviews the available data from clinical trials using cyclooxygenase-2 inhibition with chemotherapy in non-small cell lung cancer and provides a perspective on patient selection and future directions.

This podcast is a review of the submitted article by Dr. Wentzensen and colleagues regarding multiple cervical biopsies at the time of colposcopy and the implications for the management of cervical dysplasia.

A secondary analysis of a multicenter randomized trial suggests that the R-ACVBP regimen may improve outcomes in younger patients with the non-germinal center B-cell subtype of diffuse large B-cell lymphoma.

Modifying therapy based upon positive DTCs in breast cancer.

NCIC SC.20 demonstrates that a second course of radiation for painful osseous metastases significantly improves patients quality of life and function.

Long-term follow up from the landmark, NCI-sponsored adjuvant trastuzumab trials confirms the clinical benefits and clinical safety of this important therapy.

This podcast provides a commentary on the association of braf mutation and thyroid cancer showing an increase risk of recurrence in patients with thyroid cancer that harbor this mutation.

In this podcast, the results of the S0008 adjuvant intergroup trial are discussed and placed in the context of current advances in melanoma treatment.

This is a prospective study of proton radiotherapy for rhabdomyosarcoma showing equivalent efficacy with photon treatment.

Tailoring treatment in intermediate-risk pediatric Hodgkin lymphoma is feasible using an early response-based assessment for the omission of radiotherapy.

Given the high rate of unplanned hospitalizations in older cancer patients, multidisciplinary care is needed for outcomes improvement.

Minimal residual disease monitoring has been very helpful in early response evaluation and risk stratification of children with acute lymphoblastic leukemia (ALL). This podcast discusses the pros and cons of extended MRD monitoring throughout the duration of therapy for childhood ALL.

This podcast describes the report of a cohort of Chinese patients with known prior hepatitis B exposure, receiving rituximab as part of their therapy for lymphoma. The podcast includes a summary of the trial and discussion of the finding that while reactivation of hepatitis B is common in this population, if treatment with antivirals is started soon after the detection of a positive viral load, then pathology related to hepatitis B can be avoided.

In this paper, the authors demonstrate that only a very small percentage of patients from 2 large, prospective cohorts developed recurrent diffuse large B-cell lymphoma detected solely on post remission imaging. In addition, the overall survival of these patients was not different from that of patients who presented with symptoms or findings on physical exam. I will review the data and discuss its possible implications for the clinical care of patients in remission at the completion of front-line chemotherapy.

A phase I/II study of the antibody-drug conjugate glembatumumab vedotin (CDX-011 or CR011-vcMMAE) in patients with locally advanced or metastatic breast cancer, reveals an acceptable safety profile and promising clinical activity in GPNMB expressing breast cancer.

Conventional GVHD prophylaxis with calcineurin inhibitors has a high incidence of chronic GVHD. Kanakri et al show that post-transplant administration of High dose cyclophosphamide is an effective way of reducing chronic GVHD. Limitations of this approach and alternative approaches are briefly discussed.

Many new oncology drugs are expensive. Drug prices may not reflect the whole cost of new agents, as increases or decreases in adverse effects compared to previously available therapies may influence cost comparisons. This podcast summarizes a meta-analysis of the economic consequences of adverse effects in 41 registration trials that led to approval of new oncology drugs between 2000 and 2011.

This podcast discusses a phase 2 trial of cabozantinib in men with advanced bone-metastatic prostate cancer, using a novel method to assess bone scan response.

This podcast discusses the results and practical implications of a population-based study that found an increased fracture risk after cystectomy for bladder cancer.

This podcast discusses the current state of knowledge regarding allogeneic transplantation as a treatment modality for advanced systemic mastocytosis.

This study assessed diabetes mellitus risk in long-term Hodgkin lymphoma survivors, and found that a mean pancreatic tail dose of 36 Gy or higher was associated with a significantly increased risk of diabetes mellitus. This finding has important implications in the follow up of long-term Hodgkin lymphoma survivors, and also suggests that in newly diagnosed patients with upper abdominal involvement, the pancreas should be included as in organ-in-risk in the radiotherapy planning.

This podcast reviews the publication of the RESORT manuscript, and puts these results into context with the recently published Ardeshna trial of rituximab vs. observation in follicular lymphoma, concluding that there is no longer a role for rituximab maintenance in low tumor burden follicular lymphoma.

This podcast will use the study reported by Bejar and colleagues to review the role of screening for TET2, DNMT3A, and particularly TP53, mutations in deciding whether to recommend allogeneic hematopoietic cell transplant for patients with myelodysplastic syndromes.

This JCO Podcast provides observations and commentary on the JCO article, "Oncology Fellows' Career Plans, Expectations and Well-Being: Do Oncology Fellows Know What They are Getting In To?" by Tait D. Shanafelt, et al.

This study reports surprisingly good outcomes for children with Ph-like ALL treated on the St. Jude Total Fifteen clinical trial.

Corticosteroids are recommended as part of the WHO analgesic ladder but there is limited evidence for their efficacy for the treatment of pain in cancer patients.

The availability of reconstructive surgeons restricts the use of immediate breast reconstruction, creating unintended inequities even in a system with universal health care coverage.

This podcast describes the rising epidemic of HPV-associated oropharynx cancer, its unique demographic profile and natural history, and comments on new findings from Carole Fakhry et al. regarding patterns of disease recurrence seen in patients enrolled on RTOG 0129 and 0522.

This podcast discusses the report of cardiac monitoring data from the HERA trial, places the findings in context with data from other trials, and considers how the report relates to clinical practice.

This is a review of breast needle biopsy for the diagnosis of breast cancer and how surgeons and geography affect utilization and the resultant impact on quality of care.

FISH genetics, LDH and beta 2-microglobulin can identify a group of newly diagnosed myeloma patients with a two-year survival of only 52% in spite of bortezomib-based therapy.

The current study, reporting on the upfront use of lenalidomide and rituximab in CLL, suggests high response rates and excellent tolerability in younger as well as older patients, albeit with a modest median progression-free survival.

This podcast summarizes the findings of a recent longitudinal functional MRI study examining the effects of breast cancer chemotherapy on multitasking-related brain activation and its relationship to cognitive complaints, and discusses implications and future directions.

This podcast discusses the measures to optimize central-nervous-system-directed therapy in children with acute lymphoblastic leukemia.

This trial supports the use of neoadjuvant capecitabine monotherapy as a potentially more convenient radiosensitizer that does not sacrifice surgical and pathologic outcomes in rectal cancer. However, further study is needed.

This podcast reviews the current role of PET and radiotherapy in PMBL.

This podcast concerns the potential complimentary role played by PET and CT in the assessment of response in patients with Hodgkin lymphoma.

Among more than 2,000 patients with an invasive cancer, more than 5% had a mutation in PTEN and almost half of these patients had a second malignancy. This observation has implications for patients with breast, endometrial and thyroid cancer, and those with known PTEN mutations.

This partner study suggests that spouses of people with HPV-positive oropharyngeal cancer do not have elevated oral HPV prevalence and the partners’ risk for oropharyngeal cancer remains low.

This JCO podcast provides observations and commentary on the JCO article, "Provision and discussion of survivorship care plans with cancer survivors: Results of a nationally representative survey of oncologists and primary care physicians" by Danielle Blanch-Hartigan, et al.

The study provides evidence that several patients with high-risk ALL who show a favorable MRD response to chemotherapy can achieve a cure without stem cell transplantation.

This podcast summarizes and provides clinical conclusions of a large international study on ovarian cancer incidence and outcomes in women with BRCA1 and BRCA2 mutations.

In this podcast, I will discuss first-line usage of anti-EGFR therapies in metastatic colorectal cancer in the context of the PEAK trial findings with a focus on the emerging data surrounding RAS oncogene mutations in treatment selection.

This JCO podcast provides commentary on the accompanying JCO article "Underestimation of risk of a BRCA1 or BRCA2 mutation in women with high grade serious ovarian cancer by BRCAPRO: A multi-institution study" by Molly S Daniels, et al, and evaluates the need for BRCAPRO in patients with ovarian cancer and the benefit of identifying germline BRCA and other mutations in this population.

This podcast discusses the results of an analysis of the risk of severe gastrointestinal toxicity associated with the administration of bevacizumab to women with advanced ovarian cancer.

Observations from the AURELIA trial evaluating bevacizumab combined with chemotherapy in platinum resistant recurrent ovarian cancer patients and results from Patient-Reported Outcomes.

This JCO podcast provides observations and commentary on the JCO article, Survival, Durable Tumor Remission, and Long-Term Safety in Patients with Advanced Melanoma Receiving Nivolumab,” by Suzanne Topalian, et al.

Coincident with increased reconstruction with mastectomy are higher rates of mastectomy for early stage cancer and contralateral prophylaxis, suggesting the need for assessment of decision support tools and understanding of the patient perspective.

Early commencement of adjuvant chemotherapy is unlikely to be relevant for the majority of patients but unnecessary delay may be unwise for patients in whom the effect of adjuvant chemotherapy is expected to be significant.

This podcast describes the recent experience of single agent rituximab as management for newly diagnosed and relapsed nodular lymphocyte predominant Hodgkin lymphoma. The podcast includes a summary of the trial and discussion of the implications of the findings that rituximab has activity in both the upfront and relapsed setting.

The mature results of a randomized comparison of S-1 versus observation in Japanese patients who have undergone a D2 resection for gastric cancer continue to show a significant survival benefit supporting the use of post-operative chemotherapy.

Children treated for medulloblastoma using reduced dose craniospinal radiation with local tumor bed boost have improved neurocognitive outcomes compared with conventional therapy, pointing to an opportunity for prevention of severe late effects by treatment modification.

The meta-analysis by Houssami and colleagues notes no recurrence benefit of breast MRI, and adds to a growing body of data demonstrating that the use of breast MRI in the non-high risk preoperative setting provides little benefit when used routinely.

Reflections on a new report describing the successful therapy of lymphomas using adoptively transferred T cells targeting EBV latent membrane proteins.

This podcast provides observations and commentary on the study by Payne and colleagues entitled ‘Phase II Pilot Study of Intravenous High Dose Interferon with or without Maintenance Treatment in Melanoma at High Risk of Recurrence.'

An increased-dosage radioimmunotherapy for upfront treatment of follicular lymphoma achieves excellent results, raising questions on the best choice of treatment in this disease.

This podcast describes the recent experience of high dose cytarabine induction in patients with acute myeloid leukemia (AML), as reported in the EORTCGIMEMA AML-12 trial. The podcast includes a summary of the trial and discussion of the implications of the finding that high dose cytarabine induction improves outcomes in younger patients with AML.

MRI done prior to surgery can be useful in determining the long-term outcomes after surgical resection in patients with rectal cancer.

The study by Kapoor et al supports reporting outcome of clinical trials using more stringent uniform response criteria.

This podcast reviews outcomes for elderly patients with HODGKIN lymphoma at diagnosis and at the time of relapse.

Sentinel node biopsy should be performed for melanomas greater than or equal to 0.75mm in thickness but not for melanomas less than 0.75mm in thickness.

This podcast discusses Neben and colleagues' paper on FISH findings and smoldering myeloma.

This JCO Podcast comments on the JCO article, "Interim Cosmetic and Toxicity Results From Rapid: A Randomized Trial Of Accelerated Partial Breast Irradiation Using 3D Conformal External Beam Radiation Therapy" by Ivo A. Olivotto, et al.

Before we can use MRD as a guide of post-remission therapy in AML, we have to standardize our methods for MRD quantification and agree on the definition of MRD-positive versus MRD-negative patients.

ACRIN 6668/RTOG 0235 demonstrates that a post chemoradiotherapy PET scan for locoregionally advanced non-small cell lung cancer can be used as an early indicator for long-term outcome.

Added to the complexity of the widening variety of vaccines that are in current clinical trial for human cancers, and the increasing sophistication of our tools for assessment of the immune response underlying these vaccine interventions, this podcast discusses the elements of trial design and reporting in relation to the trial EORTC 18961.

Lenalidomide is a promising agent for the treatment of mantle cell lymphoma.

The results of CALGB 50202 reported by Rubenstein and colleagues demonstrate the feasibility, safety and efficacy of the MT-R induction and EA consolidation regimens in newly diagnosed PCNSL patients.

This podcast reviews the biology and treatment of relapse of acute myeloid leukemia following hematopoietic transplantation.

The ability of an advance care planning discussion to affect end-of-life decisions is tested in a randomized, controlled trial of patients with advanced cancer.

The AVAPERL trial reveals a significant improvement in progression-free survival with the combination of pemetrexed/bevacizumab compared with bevacizumab alone as maintenance therapy for advanced non- small-cell lung cancer, but the clinically relevant endpoint remains overall survival.

This JCO Podcast provides observations and commentary on the JCO article “Osteonecrosis of the Jaw and Oral Health-Related Quality of Life After Adjuvant Zoledronic Acid: An Adjuvant Zoledronic Acid to Reduce Recurrence Trial Subprotocol (BIG01/04)" by Emma Rathbone et al.

Minimal residual disease predicts outcomes in myeloma.

This podcast provides an overview and commentary on Amant et al.'s study of breast cancer diagnosed during pregnancy.

This podcast provides observations and commentary on the JCO article,"Results of an international randomized phase 3 trial of the mTOR inhibitor, ridaforolimus, versus placebo to control metastatic sarcomas in patients following benefit from prior chemotherapy" by authors George Demetri, et al.

Loss of PTEN expression did not predict resistance to trastuzumab in early stage HER2 positive breast cancer in the large US cooperative group phase III trial N9831.

This podcast describes the current and future use of molecular testing, including micro RNA expression, in the management of AML.

This podcast focuses on emerging concerns about adult outcomes in survivors of acute lymphoblastic leukemia treated in childhood and adolescence in the context of the report by Zeller and colleagues documenting neuroanatomical and neuropsychological impairment in a large sample of adults treated successfully for ALL without cranial radiation therapy and healthy controls.

This Podcast reviews the results of the analysis conducted by Metzger-Filho et al. regarding the benefit of trastuzumab for patients with invasive lobular breast cancer treated on the Herceptin Adjuvant Trial (HERA) and provides perspective regarding the clinical significance of these findings.

This podcast summarizes findings regarding cigarette smoking and disease-free survival in a Phase III adjuvant colon cancer trial.

The paper reviewed comes to the conclusion that rituximab maintenance prolongs PFS in patients transplanted for follicular lymphoma , without causing relevant toxicity.

Response after early chemotherapy cycles might identify patients who could safely forgo consolidation with radiotherapy.

This podcast reflects on the outcome of minimal intensity conditioning in over 1000 recipients of sibling and unrelated donor transplant.

This podcast provides commentary and observations on the long term results summary of RTOG 91-11 in which concurrent chemoradiation was shown to provide superior outcome over induction chemotherapy or radiation alone to achieve larynx preservation and locoregional tumor control.

This podcast reviews findings on the prevalence of off-label cancer therapy use and the estimated costs associated with it.

If transplantation is selected as the treatment approach, the net effect is likely to be similar with allogeneic or autologous transplantation with the higher early mortality rate in the allogeneic patients offset by a higher relapse rate in the autologous patients.

The fluoroquinolone class of antibiotics is a major target for antimicrobial stewardship programs, and the conservation of their effectiveness is important.

This podcast provides perspective on findings in a large population-based evaluation of overall survival and cancer-specific survival in patients with CLL who develop a second primary cancer.

One third of gastric cancers harbor genetic or epigenetic alterations in the CDH1 gene, and those with structural changes have a poorer prognosis; gastric tumor profiling for oncogenic amplifications and mutations may identify targets for personalized therapeutics.

This podcast considers the evolution, utility, and acceptability of the terms 'cancer survivor' and 'cancer survivorship' and comments on a recent article in JCO that addresses the extent to which such labels matter to survivors and others affected by this disease.

This podcast discusses approaches to risk assessment of contralateral breast cancer and factors which predict the risk.

Amongst several different liver directed therapy approaches, chemoembolization (called TACE) and radiofrequency ablation (called RFA) are most commonly used worldwide. However, the efficacy of TACE and RFA remains limited.

A discussion of a phase 2 trial of a MEK inhibitor in patients with V600 BRAF mutations and consideration of other relevant results with targeted therapies in this population.

This podcast discusses therapeutic options for MDS patients including azacytidine and allogeneic stem cell transplantation.

This video support tool describing CPR lets patients make much better informed decisions about the use of CPR. Physicians often feel that CPR will not be of help to patients but nevertheless feel obligated to offer it or not withhold it. This video support tool describing CPR might enable patients to make much better informed decisions about the use of CPR. Letting patients view this 6 minute video convinced the great majority of them that CPR would not be unlikely to help them, which is very consistent with the medical facts. Nearly all of them felt very comfortable with watching the video. Maybe we should have this in a looptool available in every oncologist’s office.

Radioimmunotherapy alone or in sequential combination with chemotherapy is effective initial treatment for follicular lymphoma, though comparable (and not superior) to other management options for this population.

Whole-brain radiation therapy of metastases to the brain is not innocuous - it is associated with decrements in health-related quality of life. It is still unknown if the potential benefits outweigh the impact of the side effects.

This is a commentary on the role of MET in cancer using Choueri et al as an example of rationale therapeutics and translational research.

A discussion of treatment approaches for newly diagnosed aggressive AIDS-related lymphomas

Seven year follow up of B-31 demonstrates a striking and reassuring lack of longer-term cardiac events.

More adjuvant chemotherapy is not always better for early breast cancer patients - Discussion and consequence for clinical practice.

The podcast reviews the evolution of staging and treatment of Hodgkin lymphoma, reducing the toxicities and torture while maintaining a high level of cure.

In this podcast, Attar and colleagues explore whether patients aged 60-75 who enter remission with bortezomib added to standard anthracycline plus cytarabine chemotherapy during induction can be safely treated with intermediate dose cytarabine along with dose escalating bortezomib during consolidation. This regimen was tolerated at the highest dose of bortezomib tested, 1.3 mg/m2, and further randomized studies of this regimen will be planned.

This podcast will review a JCO article showing that the use of breast brachytherapy as a method of delivering partial breast radiation after breast conserving surgery was associated with higher rates of complications than the conventional approach of whole breast radiation.

This Podcast provides observations and commentary about referral practices of oncologists to specialized palliative care.

This podcast characterizes the clinical utility of the screening tests recommended by the Children’s Oncology Group in the care of long-term survivors.

Publication of a large collaborative group trial appears to definitively demonstrate the safety of sentinel lymph node biopsy as replacement for inguinal-femoral lymphadenectomy, or does it?

In this podcast, results of a randomized phase III clinical trial evaluating the use of Rituximab maintenance therapy following autologous stem cell transplantation in patients with relapsed diffuse large B cell lymphoma are summarized. The results demonstrate that Rituximab maintenance therapy does not result in improved event free or overall survival in this patient population.

Melissa Cousino and colleagues found that few parents understand the scientific purpose of phase I pediatric clinical trials.

The prognostic importance of ALK-protein expression was established over a decade ago. More recent studies emphasize that age is also an important driving force and in patients <40 years, the distinction between ALK-positive and ALK-negative ALCL is less clear.

Although gemtuzumab ozogamicin has been withdrawn from the marketplace, three randomized trials prompt review of that decision.

This podcast summarizes and places in clinical context two studies describing straightforward immunohistochemical methods to risk-stratify diffuse large B-cell lymphoma.

Cognitive impairment occurs in a subset of breast cancer survivors after chemotherapy but the incidence remains unknown.

This podcast discusses the manuscript by Tejpar et al in which patients whose colorectal tumors harbor a specific KRAS mutation, G13D, appear to have benefit in two clinical trials with regard to tumor response and progression-free survival with cetuximab treatment.

Although historically toxicity was often thought to be a biomarker of efficacy, often it appears to be a marker of dose intensity and individual susceptibility as is the case in this retrospective study of taxane induced peripheral neuropathy and breast cancer outcome.

In this podcast, Dr. Hudis reviews the use of a novel nomogram to predict the benefits of postoperative adjuvant radiation therapy for older women with early stage breast cancer. This discussion highlights the information from prospective randomized trials, their limitations, and the potential for a nomogram to guide clinicians facing patients who might not have qualified for the earlier studies.

As oncologists treat an increasing number of older patients with colon cancer, and as treatment options improve for older patients, oncologists should work with geriatricians to make the best treatment decisions.

This podcast will provide a critical evaluation of the combination of bortezomib, thalidomide, and dexamethasone in relapsed multiple myeloma

This Podcast reviews and comments on the use of the National Comprehensive Cancer Network (NCCN) Breast Cancer Outcome Database to demonstrate the actual rollout of the use of gene expression profile (GEP) testing for women with hormone receptor positive, node negative breast cancer and the accompanying changes in breast cancer chemotherapy utilization

This Podcast reviews the design and results of the present study by Kennecke et al. and provides perspective regarding the clinical significance of these findings.

This podcast reviews the rationale behind evaluation of metformin as a potential anti-cancer agent in breast cancer and describes the findings of a recent window of opportunity trial looking at the impact of metformin upon proliferative indices in women with early breast cancer.

This podcast reviews the results of the FACT trial in the context of other ongoing and proposed studies of endocrine therapy combinations.

This podcast describes a phase 2 trial brentuximab vedotin in patients with Hodgkin lymphoma that has recurred after autologous hematopoietic stem cell transplantation. The podcast discusses the rationale for the trial, response to therapy, and associated toxicities. Future application of brentuximab vedotin to CD30+ malignancies is considered as well.

In this study, the implications of long term follow up of the German Rectal Study on clinical practice and future trial design will be discussed.

Carboplatin-Gemcitabine-Bevacizumab represents an additional regimen to consider for management of recurrent platinum sensitive epithelial ovarian cancer, although it raises several questions regarding the role of bevacizumab in this disease setting.

This podcast discusses adjuvant therapy in elderly NSCLC patients.

The podcast highlights recent JCO articles that underscore the need for improved assessment and management of cancer and treatment-related symptoms.

The CHER-LOB trial is one of several that has demonstrated that adding lapatinib to trastuzumab and chemotherapy improves on the rates of complete pathological response among women receiving neoadjuvant therapy for HER2 positive breast cancer. Because the relationship between pCR and long-term outcomes remains ambiguous, this regimen is not recommended for ordinary use. However, these findings are a powerful support to the hypothesis that dual-modality anti-HER2 therapy is a potent combination.

A reflection on the problems clinicians face when making a decision on how best to advise patients regarding management of early clear cell carcinoma of the ovary.

This podcast provides observations and commentary on the JCO article "High risk of symptomatic cardiac events in childhood cancer survivors.

This podcast reviews a negative phase III clinical trial of cetuximab combined with chemotherapy in first-line metastatic colorectal cancer and focuses on the interaction of targeted therapy combined with chemotherapy.

This podcast partitions patients with early melanoma into those with very favorable features and compares them to those with a higher risk for dying of metastatic melanoma.

Incorporating the information form Dr Marconi's systematic review on the question "Does sedation at the end of life hasten death", I will provide useful guidance regarding how to discuss this issues with patients and their families.

This podcast describes the results from a subgroup of 732 women in the NSABP B-24 trial for the treatment of DCIS, where ER status was available, and describes how this can be used as a predictive test for response to adjuvant tamoxifen.

In this podcast, I will review a JCO article showing that the publication of CALGB C9343 trial results had little influence in practice patterns in the United States. I will discuss possible study-specific reasons for the lack in change of practice and explore the author’s implication that practitioners are more apt to adopt trials that add technologies and/or treatments compared to those that withhold therapies.

This podcast will discuss the current role of characterizing KRAS and BRAF in the management of colorectal cancer as well as a manuscript by Popovici and colleagues entitled "Identification of a poor prognosis BRAF-mutant-like population of colon cancer patients". In this manuscript, a molecular signature that characterizes a subgroup of colorectal cancers that behave like BRAF mutant tumors but do not have true BRAF mutations. The research moves beyond analysis of a single gene to characterize a tumor’s phenotype.

Patients with epidermal growth factor receptor (EGFR) gene mutations should receive EGFR tyrosine kinase inhibitors as 1st line therapy because they produce higher response rates, long progression free survival, reduced toxicity, improved symptom control and convenience of oral administration compared to chemotherapy doublets.

This JCO Podcast provides observations and commentary on the JCO article, "Randomized Phase III study comparing Paclitaxel Cisplatin Gemcitabine and Gemcitabine Cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC 30987 Intergroup Study" by Joaquim Bellmunt et al. It provides my perspective that considers both statistical metrics and clinical outcomes in decision making for difficult to treat diseases.

The management of patients with early stage Hodgkin lymphoma with unfavorable characteristics remains a topic for study.

This podcast reports on a phase I/II trial investigating novel anti-CD22, moxetumomab pasudotox, in the treatment of patients with refractory hairy cell leukemia, which demonstrated responses in the majority of patients at all dose levels.

When dose dense treatment was first described we were greatly enthusiastic for all women with breast cancer. As the experience has matured we now realize that the benefit is confined to women with ER negative cancers. We think it is time to question our use of CSFs and dose dense treatment in ER+ women based on 2 large trials and a conclusive meta-analysis.

This podcast summarizes and discusses the outcome results of the GOG Lap2 trial which shows safety and clinical benefits of laparoscopy as compared to laparotomy for surgical staging and treatment of uterine cancer.

This is a commentary on a report from the EBMT demonstrating a higher relapse rate after allogeneic transplantation in AML patients with FLT3 ITD mutations.

Long-term follow-up of efficacy and toxicity outcomes from the IES study of adjuvant aromatase inhibitor therapy in postmenopausal estrogen receptor positive breast cancer

This podcast discusses the findings from the manuscript by Munster et al. regarding the use of ovarian suppression for fertility preservation in young women receiving adjuvant chemotherapy in the context of the current literature and future directions.

The study by Marin et al is another milestone in our understanding how to manage CML patients on tyrosine kinase inhibitors.

This podcast will summarize the results of Efstathious et al and discuss possible mechanisms of resistance to castration based therapies in prostate cancer.

Targeting the Angiopoietin-Tie2 axis is a promising alternative antiangiogenic strategy for the treatment of ovarian cancer that exhibits non-overlapping toxicities with inhibitors of the VEGF signaling pathway.

This podcast reviews data from a recent publication on the use of "early" interim PET scanning in diffuse large B-cell lymphoma and comments on the clinical utility of this imaging technique in the current management of patients with this disease.

Biopsy of presumed metastatic breast cancer sites confirms the diagnosis in most women and alters therapy in 14% of women in a prospective study of 121 patients but its impact on outcome could not be reliably assessed.

This podcast provides a commentary on the article by Wu et al that addresses disparities in systemic therapy for breast cancer.

This Podcast reviews the background of the MA.17 trial, the results of the present manuscript and provides perspective on the current findings.

This podcast summarizes the findings of this JCO article and provides commentary on its applicability to practice.

This podcast will critically review randomized phase III trial data examining the relative role of taxane monotherapy versus combination therapy as first-line treatment for HER2-negative metastatic breast cancer.

This podcast discusses findings and implications of a recent survey study on attitudes and knowledge about cancer pain among medical oncologists

This podcast will explore the feasibility of a nonoperative "wait and see" approach based on strict selection criteria in patients with locally advanced rectal cancer who achieve a complete clinical response after chemoradiation.

This podcast reviews the evidence that women testing negative for known familial BRCA1/2 mutations should adhere to current population breast cancer screening guidelines.

This Podcast provides observation and commentary on the JCO article "Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer".

Podcast to review the article "Occult Metastases in Length Nodes Predict Survival In Resectable Non-Small Cell Lung Cancer: Report of the ACOSOG Z40040 Trial" by Rusch et al.

The ATAC investigators collected comorbidity data on more than 9000 women and this article illustrates that it provides key information.

Rapid, dramatic shifts are ongoing in the population-level epidemiology of oropharynx cancer in the United States.

EGFR mutation is a predictive biomarker for maintenance erlotinib but its clinical application is limited. This podcast will explain why.

This podcast summarizes the incidence and long-term outcome of osteonecrosis in a large prospective study of children treated for acute lymphhoblastic leukemia with the dexamethasone-based Dutch Childhood Oncology Group-ALL 9 Protocol.

This podcast evaluates the context and reviews results of a randomized phase III trial comparing R-CHOP given at conventional 21 day intervals with R-CHOP given at 14 day intervals in patients with newly diagnosed follicular lymphoma.

This podcast reviews the randomized double-blind placebo-controlled trial reported by Boekhout et al. that evaluates venlafaxine and clonidine for the treatment of hot flashes in women with breast cancer.

This podcast reviews the retrospective study by Arun et al. and discusses the lack of consensus regarding the relative chemosensitivity of breast cancers in mutation carriers and non-carriers as well as the optimal neoadjuvant chemotherapy for mutation carriers.

Androgen deprivation therapy may not be associated with an increase in cardiovascular mortality in all men but only those with a prior cardiac event due to known coronary artery disease.

Stage II colon cancer with high risk factors is often treated with adjuvant therapy, however new data raise questions about the usefulness of this practice.

Commentary on a successful study in which genotype-guided tamoxifen dosing increased endoxifen concentrations in women with reduced CYP2D6 metabolism.

Estrogen plus progestin and estrogen alone have different effects on mammographic density and breast cancer.

This is a commentary on a recent study comparing two risk calculators for use in the setting of prostate cancer screening.

This podcast describes the analysis of the IPASS study population by EGFR mutation and EGFR FISH biomarker status, and also discusses the results and controversial analysis of overall survival from this trial.

The use of arsenic trioxide as a single agent can produce long lasting remissions and a significant cure rate in patients with acute promyelocytic leukemia.

In this podcast, results of randomized phase III clinical trial evaluating the effects of a patient specific idiotype tumor vaccine in patients with follicular lymphoma are summarized. The results demonstrate that idiotype vaccination may improve disease free survival in patients with follicular lymphoma who achieve a remission following chemotherapy.

The addition of oxaliplatin to fluorouracil-based neoadjvuant chemoradiation for locally advanced rectal cancer significantly increases toxicity but does not improve the pathologic complete response rate.

The term targeted therapy is often used in cancer drug development. This podcast will discuss the study of a mEK inhibitor where the investigators actually looked at the impact on the target as well as whether the drug worked or did not work.

Commentary on a new small molecule inhibitor of angiogenesis in combination with chemotherapy for metastatic breast cancer.

This SEER based study demonstrated that the advanced radiation therapy technique of three-dimensional conformal radiation therapy improved survival compared to the previously used method.

This podcast will discuss the basic background of myelodysplastic syndromes and the clinical implications of TP53 mutations predicting outcomes in del(5q) MDS.

This podcast describes the long term outcomes of patients treated with chemotherapy first, followed by either cystectomy or radiation therapy. It provides important information to practicing physicians who treat this disease in helping make decisions about the utility and effectiveness, as well as safety, of using chemotherapy for muscle invasive bladder cancer.

In this week's podcast, Dr. Jaine discusses the recent manuscript by Paik and colleagues evaluating BRAF mutations in patients with advanced lung cancer. The potential impact of BRAF mutations and outcomes with current therapies for lung cancer are discussed.

In this podcast, Dr. Neal J. Meropol provides his perspective on two large randomized studies of vatalanib in patients with metastatic colorectal cancer.

By Mary Daly. Stage at diagnosis of breast cancer among women with BRCA1/2 mutations was available for women enrolled in a multi-modality screening protocol including breast MRI, and for women who were screened with routine mammography. There was a significant increase in early stage at diagnosis for women in the MRI protocol compared to those in the mammography alone group.

By David Ryan. This JCO Podcast provides observations and commentary on the JCO article, "Clinical Significance of Circulating Tumor Cells Including Cancer Stem-like Cells in Peripheral Blood for Recurrence and Prognosis in Colorectal Cancer Patients with Dukes stage B and C" by authors Hisae Iinuma, et al.

By Reed Drews. This JCO Podcast provides observations and commentary on the JCO article, "Safety and Efficacy of TG101348, a Selective JAK2 Inhibitor, in Myelofibrosis" by authors Animesh Pardanani, et al.

By Lisa Carey. The randomized Phase III trial, Ribbon-1, was designed to examine whether the benefit of bevacizumab added to chemotherapy in metastatic breast cancer was specific to the taxanes or if the benefit could accrue regardless of the chemotherapy backbone. PFS was improved with the addition of bevacizumab to several cytotoxics, including capecitabine, taxanes, and anthracyclines. OS was not improved. This podcast reviews the salient design, results, and implications of this trial and puts it in context of other bevacizumab trials and controversies.

By David Avigan. This podcast describes a phase III randomized study comparing the efficacy and toxicity of Denosumab with Zolendronic Acid for the prevention of skeletal complications in patients with malignancy.