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    Health & Fitness

    Journal of Clinical Oncology (JCO) Podcast

    The Journal of Clinical Oncology Podcast presents analyses and discussions centered on the latest findings published in ASCO’s flagship Journal of Clinical Oncology. Host Dr. Davide Soldato facilitates interviews and scholarly discourse on the most impactful published findings. The Journal of Clinical Oncology Podcast is the trusted resource that empowers you to integrate cutting-edge evidence into clinical practice.

    The year’s fellows interview authors and summarize the top Journal of Clinical Oncology articles in the series, JCO Article Insights.

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    Copyright: © Copyright by the American Society of Clinical Oncology

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    Latest Episodes:
    JCO After Hours: A Discussion With Antonio Di Meglio Feb 01, 2022
    Show notes

    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…

    Full show notes at the publisher

    JCO After Hours: A Discussion With Abby Rosenberg and Reshma Jagsi Jan 10, 2022
    Show notes

    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 w…

    Full show notes at the publisher

    JCO After Hours: A Discussion With Michael Gnant and Kathy Miller Dec 07, 2021
    Show notes

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


    JCO After Hours: A Discussion With Kirsten Beyer and Jennifer Griggs Nov 19, 2021
    Show notes

    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 neig…

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    Is Dose-Adjusted EPOCH-R the Optimal Treatment for Children with Primary Mediastinal B-Cell Lymphoma? Oct 20, 2021
    Show notes

    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.


    Steroid Dose and Taxanes Oct 10, 2021
    Show notes

    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.


    Commentary on GROINSS VII Sep 01, 2021
    Show notes

    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.


    Harnessing the Power of Registries to Understand the Impact of Treatment for Hodgkin Lymphoma on Fertility Aug 10, 2021
    Show notes

    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.


    Subspecialty Palliative Care Involvement May Lessen the Need for High-Intensity End-of-Life Care for Adolescents and Young Adults With Cancer Aug 01, 2021
    Show notes

    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.


    Can the Incorporation of Minimal Residual Disease Detection Enhance Post-CAR T Outcomes in Patients With Large B-Cell Lymphoma? Jul 10, 2021
    Show notes

    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.


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