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Journal of Clinical Oncology (JCO) Podcast

English, Sciences, 1 season, 527 episodes, 3 days, 56 minutes
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The Journal of Clinical Oncology features discussions of new and noteworthy results published in ASCO’s Journal of Clinical Oncology and how they impact clinical practice and research, hosted by Dr. Shannon Westin.
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Methylphenidate for Fatigue in Advanced Cancer

Dr. Shannon Westin and her guest, Dr. Patrick Stone, discuss the article, Methylphenidate Versus Placebo for Treating Fatigue in People with Advanced Cancer, a Randomized, Double-Blind, Multicenter Placebo-Controlled Trial, recently published in JCO. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we go in depth on manuscripts and research published in the Journal of Clinical Oncology. I am your host, Shannon Westin, Social Media Editor for JCO and a Gynecologic Oncologist by trade. I am thrilled today to present Methylphenidate Versus Placebo for Treating Fatigue in People with Advanced Cancer, a Randomized, Double-Blind, Multicenter Placebo-Controlled Trial. This manuscript is a dual publication in the Journal of Clinical Oncology and presentation at the European Association of Palliative Care Congress here on May 17, 2024.   And to review this incredible research with us will be Professor Patrick Stone, the Head of Department of Marie Curie Palliative Care Research Department, Division of Psychiatry at University College London. Welcome, Dr. Stone. Dr. Patrick Stone: Thank you very much. Thank you. Shannon Westin: Let's get right to it, we’ll level set. Can you speak a bit about the definition of cancer-related fatigue and how common it is in people with advanced cancer? Dr. Patrick Stone: Sure. I think fatigue is a difficult thing to nail down really and define it clearly, and there are lots of definitions out there. In many ways, the simplest definition is the EAPC, the European Association of Palliative Care's definition of just a subjective sensation of weakness, feeling tired, and exhaustion. The reality is that that symptom is very common in the general population. And so if you really want to get a handle on it, I think a good way to do it is to think about taking an operational definition and say, “Look, if fatigue is normally distributed approximately in the general population, then we should consider severe fatigue or pathological fatigue could be defined as fatigue that is worse than 95% of the general population. And if you think that definition, then prevalence of fatigue in patients with newly diagnosed breast or prostate cancer, for instance, is around 15%, so three times as common as the most severe fatigue in the general population. If you come to patients with newly diagnosed non-small cell lung cancer, it’s up to about 50%. And if you come to my area, which is palliative care and you go to a hospice and you ask people to complete a fatigue questionnaire, 78-80% of people complain of fatigue that is more severe than 95% of the general population. So that I think gives us a good handle on sort of the severity of this problem in cancer patients and how it progresses as disease progresses. Shannon Westin: I love this because I think we always struggle with exactly how to nail down the definition and exactly how to treat it. So I think that it’s a really nice transition to existing treatment options for this issue and exactly how they might work. Dr. Patrick Stone: The first thing to say is in medicine if you can find a cause then you give a treatment directed at the cause and obviously that applies to fatigue as well. So the first thing is to do a thorough assessment of your patient, and if you can find an easily remediable cause such as anemia, hypocalcemia, or hypomagnesemia, or maybe other things like depression, which might manifest as fatigue, then you should try and give a treatment directed at that cause. But, for many patients, there won't be a single clearly identifiable cause you can target. And then people use more broad spectrum approaches if you like. The most well-studied I think is exercise. And exercise, there have been lots of randomized controlled trials in different types of exercise and it’s a well attested treatment, which I think has good evidence of effectiveness, certainly in patients who are on treatment and in disease-free survivors. There is less evidence in advanced cancer because the trials are fewer. I would still say that there’s moderate quality evidence that exercise is effective in advanced cancer.  The other group of treatments, broadly speaking, would be psychological therapies, cognitive behavioral therapy and psychoeducational approaches, mindfulness based stress reduction, that sort of thing. And again, in earlier stage disease and in patients on treatment and in survivors, there’s more quality evidence that that sort of approach can help, if not alleviate fatigue, allow people to cope better with fatigue. But the evidence in advanced cancer is weaker than for exercise. So I think the evidence for the effectiveness of those psychological therapies is not so strong.  And then you come on to pharmacological therapies and there have been lots of trials of different agents. I won’t list them all because most of them are negative and don’t show any benefit. A few things which perhaps still show promise from previous trials, there have been, for instance, a few trials looking at ginseng as a herbal therapy. One very good quality trial showed benefit. Although another trial in advanced cancer didn’t replicate that finding, so that ginseng is out there. Steroids, widely used in advanced cancer for general relief of many symptoms like fatigue, lack of energy, low moods, appetite. But although widely used, surprisingly little hard evidence or effectiveness, specifically for fatigue, but one relatively recent, well conducted randomized control trial, provides us with some firm evidence, also, that dexamethasone can help in the short term in advanced cancer patients. It obviously wouldn’t be a recommended treatment longer term because of its side effects.   And then we really come on to the crux of this study which is probably the most widely studied single agent beyond that, is methylphenidate, which is a psychostimulant agent, raises central dopamine catecholamine levels in the brain. And there’s probably a thousand or so randomized control trials sort of being conducted looking at that prior to prize of this study that we’re talking about. Shannon Westin: I would love to hear a summary of the data that were pre-existing in this study. So how well does methylphenidate seem to work, or what were the conflicting results that were seen prior? Dr. Patrick Stone: I think the rationale for this study was that it was the perfect background to justify another randomized controlled trial, which there have been– Well, I can’t remember exactly how many there were in existence before my trial started, but when I last looked, there were 10 studies, 10 randomized controlled trials in cancer patients. Most of those trials have been neutral. They've shown no benefit over placebo, so most of the individual trials are negative. But meta-analyses always tend to show a positive result. So when you count the trials together, it gets you over the finishing line and you can see a positive benefit. But individually, the trials were quite heterogeneous, they’re quite different. There were only four trials prior to the publication of this one that were done specifically in advanced cancer patients. One of them was published only a couple of years ago while my study was going on. And of those four trials, three of those have also been neutral, not showing a benefit over placebo. One study involving 28 patients and using a PRN as required dosing schedule showed some benefit. But the other studies with a total of about 330 odd patients have been neutral.   Shannon Westin: I think that brings us to a great transition, just to talk a little bit about the design and objectives of your current study. Dr. Patrick Stone: Well, what we wanted to do was take the best bits, if you like, of the previous studies, and try to give ourselves the best chance of finding a clinically meaningful improvement in fatigue in patients with advanced cancer. And I was focusing on advanced cancer, principally because I'm a specialist in palliative medicine. That's the group of patients I'm most working with, whereas a lot of the studies have involved mixed groups of cancer patients or patient's disease-free or on treatment. But we looked at patients who were under the care of palliative care services, with incurable cancer, with a prognosis estimated to be less than a year or around a year.  We wanted to try to get the dose of the medication up to a good level because some of the other studies which have shown benefit have got up to quite high levels of methylphenidate, approximating to about 40 to 60 milligrams of methylphenidate a day or equivalent. And we wanted to give the drug in an individually titrated dose because that would reflect the way it is used in clinical practice. You would adjust the dose like you might with morphine for pain relief. You would expect to adjust the dose of this medication up to get a therapeutic benefit. So we had this titration period where we adjusted the dose of the drug every week. We reviewed whether patients were feeling better, worse, or the same. We asked about side effects. And on the basis of the response to those questions, we either went up with the drug or kept the dose the same, or, if necessary, would come down. The primary endpoint was designed to be fatigue after six weeks of dose titration, plus or minus a window of two weeks, accepting the fact that we might miss a few patients at the six-week mark, for whatever reason. So we had a little window around that. That's what we were looking to do.  Shannon Westin: And why did you choose the six-week time point? Dr. Patrick Stone: Well, there was no obvious time point to choose. One of the biggest positive studies previously was by Lower and colleagues back in 2009, and they had found their maximum benefit at around four weeks, or it took rather four weeks to reach the maximum benefit. So we wanted to give the patients in our trial every chance of demonstrating the benefit, and they'd also escalated the doses in their study up to above 40 milligrams or equivalent. And so we wanted to go up as high as we could, and we didn't feel that if we were adjusting the dose every week, that we could get up to a sufficiently high dose in any shorter time span. So six weeks sort of fitted, allowing us to titrate the dose up to a maximum of 60 milligrams a day, which is where we wanted to get up to. Shannon Westin: And what about a little bit more detail on the population you included, and maybe give us a sense of how well you think that represents your general population affected by fatigue in the setting of advanced cancer? Dr. Patrick Stone: We recruited patients from hospices, so that's inpatient palliative care units in the UK, but also from hospital palliative care services, from oncology outpatient services as well, oncology patients who are under the care of palliative care services, and we also recruited from some community palliative care services. So we had quite a good spread of settings, and all of our patients had advanced incurable cancer under the care of palliative care services. But I would say, I think by the nature of doing this randomized controlled trial, inevitably we ended up with quite a selected population, just because of the inclusion and the exclusion criteria that we had to apply. And the regulators were quite clear about who we shouldn't be putting on the drugs. And I think by the time you've excluded all the potential adverse consequences of using methylphenidate, we probably have ended up with a group of patients who were relatively fit compared to the general run-of-the-mill palliative care population, I would say. So I think that that is a limitation with regards to the generalizability of our result. Shannon Westin: How did you measure fatigue in this study? What was the mechanism for that objective? Dr. Patrick Stone: It's a subjective rating scale. We use a very well-established and well-validated measurement instrument. It's the Functional Assessment of Chronic Illness Therapy FACIT-F which is the fatigue subscale of their anemia subscale, which is a 13-item questionnaire, very well validated and widely used in lots of previous studies. Higher scores represent better quality of life and, therefore, lower levels of fatigue. So that's the scale that we used. Shannon Westin: Got it. So let's get to it. How well did methylphenidate work to impact fatigue compared to placebo? And were there any groups that seemed to have a bigger impact? Dr. Patrick Stone: Well, the bottom line, of course, is that at six weeks, plus or minus two weeks, there was no statistically significant benefit for methylphenidate over placebo. There was a two-point improvement in fatigue scores, but it wasn't statistically significant. And two points on the FACIT-F did not reach our predetermined five-point difference that we regarded as representing a minimally clinically important difference. We looked at lots of secondary fatigue endpoints. We measured fatigue every week over the whole course of the study. And actually, at weeks 2, 3, 4, 5, and 6, there was indeed a statistically, nominally statistically significant difference in fatigue scores. But I really would not want anybody to read anything over much into that finding because it was not a pre-stated hypothesis of our study. It wasn’t a pre-stated endpoint, it was a secondary outcome. And moreover, even if this was regarded as a statistically significant finding, and as I say, it was only nominally statistically significant finding, the magnitude of the change was still not sufficiently large that I think it would want to influence your clinical decision making. With other groups just to say, we did look specifically at whether patients with the most severe fatigue would experience benefit over and above other patients, because in a previous study, that looked at modafinil, an agent that promotes vigilance, although the overall finding was neutral in a subgroup of patients with the most severe fatigue, modafinil seemed to work. So we thought we better check in this study whether patients with the most severe fatigue had a differential benefit. But we found no such effect. We found no difference in patients who were on or off treatment or indeed among the patients who scored highest with the depression subscale on the hospital anxiety and depression scale. None of these subgroups showed any benefit over placebo. Shannon Westin: How did patients tolerate methylphenidate? Was it tolerable? Dr. Patrick Stone: That was the thing I think that I was most relieved about. I am a cautious and anxious investigator, and the last thing I wanted to do was to put palliative care patients at risk by giving them a drug which might cause some harm. So I was very relieved when we analyzed the results to confirm that methylphenidate was very well tolerated. There was no real pattern of evidence for any increase in adverse effects over placebo. In fact, when we looked at just people who self-reported severe adverse effects, we found a higher rate in the placebo group than in the methylphenidate group in fact. And in terms of serious adverse events, there were 25 serious adverse events in both groups, so there was, again, no pattern that suggested methylphenidate was causing harm. So, yes, it was well tolerated, but did not result in a clinically important improvement in fatigue. Shannon Westin: Were you surprised by the results?  Dr. Patrick Stone: I honestly went into this with an open mind. I didn't come in with a real fixed agenda that I want to prove that this thing works. In fact, although methylphenidate was being used by some of my colleagues around the country and I know it’s used by some colleagues internationally, personally I was not using it because I didn't feel the evidence was strong enough to justify using it. So I was waiting for the results of my own trial before making my decision. And I don’t plan now to be using it on the basis of the results of the study. Shannon Westin: Sounds pretty definitive. It's always frustrating, and I know our patients, when we tell them to exercise when they're exhausted, they’re like, “Are you kidding me?” Right? So it would be wonderful if there is like the perfect pill that we can give them. It's certainly disappointing. What do you think we should be exploring next for the resolution of fatigue in this patient population?  Dr. Patrick Stone: Well, I think one thing. Going back to your very first question to me about defining fatigue, I think one problem is we don’t really have a mechanistic understanding of what we’re talking about here necessarily with cancer related fatigue. And it’s a bit of an umbrella term, I suspect, for a lot of different things, and may have a common endpoint in terms of the symptom. But maybe if we could better define, if you like, for want of a better word, the phenotype of fatigue, it may be that we could actually target a treatment in certain subgroups of patients that may be of more benefit. So maybe some greater basic science pinpointing what is causing fatigue, so that we can design the treatments, rather than just try repurposing existing drugs on the off chance that they work. And the other thing is okay, maybe we can't pinpoint a particular cause, we think it’s multi factorial. If we think it’s multifactorial, then perhaps we ought to be using a multimodal treatment approach and maybe it’s actually exercise, psychological therapies, and diet, plus or minus a drug, and that’s the approach if we can’t pinpoint a specific cause. Shannon Westin: I love the idea of incorporating the  translational work to really try to understand the etiology better and then use something more targeted. It's that version of precision medicine but for palliative care as well. I really like that.   Well, this has been awesome. Thank you so much, Dr. Stone. I think that your insight is so much appreciated, and thank you for putting together this definitive work to help us treat our patients better every day. I really appreciate the time you took.  Dr. Patrick Stone: Thank you very much. Shannon Westin: You're so welcome.  And thank you to our listeners. This has been methylphenidate versus placebo for treating fatigue in people with advanced cancer, randomized, double-blind, multicenter, placebo-controlled clinical trial. And again, this is a dual publication in the JCO as well as a presentation at the European Association of Palliative Care Congress on 5/17/24. And we are so thrilled that you could join JCO After Hours and we hope you will check out our other offerings wherever you get your podcasts. Have an awesome day.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
5/17/202420 minutes, 16 seconds
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Introducing JCO Oncology Advances with Dr. Jonathan Friedberg and Dr. Pamela Kunz

JCO Editor in Chief, Dr. Jonathan Friedberg interviews Dr. Pamela Kunz, Editor in Chief of the new premier open access journal, JCO Oncology Advances. Dr. Friedberg and Dr. Kunz discuss what is to come from the journal and the benefits of an open access journal.  TRANSCRIPT Dr. Jonathan Friedberg: Hello and welcome to another episode of JCO After Hours. I'm your guest host, Jonathan Friedberg, Editor in Chief of JCO, and today we have a very special episode with Pamela Kunz, Associate Professor of Medicine in the Division of Oncology at Yale School of Medicine and Yale Cancer Center. As the new editor in chief of JCO Oncology Advances, she is with us today to share a new opportunity for authors to submit to ASCO’s new online open access journal.   Pam, welcome. Dr. Pamela Kunz: Thank you. Dr. Jonathan Friedberg: I guess my first question to you is, why did you take this role of editor in chief? People have asked me the same question, and I'm still, I think, trying to figure out the answer. So how did you decide to do this? Dr. Pamela Kunz: That's a great question, and I might ask you the same thing. I think as I've gone on in my career, I really like saying I think about what I say yes and no to, and like saying yes to things that I think can make a difference and have real impact. And as a clinical trialist and someone who really hopes to advance the field scientifically, I think it was really exciting to think about helping to craft the future of the science of oncology and to also do it in a way, as we will later talk about open access, but do it in a way that really thinks about a broad audience, because open access really requires us to think about meeting the needs of our audience, as the articles will likely have broader reach. Dr. Jonathan Friedberg: So, I mean, I can say I'm very excited about this journal. We do have a number of outstanding papers that we're not able to accept at JCO and knowing that there'll be a good home for these papers is heartwarming for me.   Can you tell me a little bit about your vision and goals for this journal? You're really starting with a blank palette. It must be exciting to try to craft what this is going to be about.  Dr. Pamela Kunz: It is really exciting. It's a little scary, I'll be honest, to have a blank slate, but I'm appreciative of you and the other editors in chief and staff for helping to provide some guidance. I think that in the beginning, as you were speaking to, there's an opportunity for us to really keep some great science in the JCO family. And so at least early on, we're hoping to really attract and think about publishing some earlier phase trials that may not quite meet the bar of getting published in JCO. So, phase I, phase II trials, even secondary analyses that yield important data from some of the larger phase III trials. This will be an evolution, I think, also. I think that what we may look like this year may look a little bit different in future years, but at least initially, we'll be focusing on some of the earlier phase clinical trials. I'm now framing this around beyond the clinical trial of secondary analyses quality of life, PROs. One thing that's exciting, a new article type will be plain language summaries. So really interpreting the clinical trial for patients and the lay public, I think that's an initial way that we're going to be thinking about it. Dr. Jonathan Friedberg: And who do you see as the audience for this journal? Dr. Pamela Kunz: Well, the opportunity that we have with open access is that we really have a much broader audience than we will have had historically with some of the non-open access journals. And I think that means that we have an obligation to be thinking about who that audience is. So, it's a great question. I think our audience will certainly be some of our typical readers, really, the oncology scientific community, but it will likely also be other physicians, primary care physicians, community oncologists, global oncology, and even patients, patient advocacy groups. So, I think that we have to be, as we're crafting and thinking about new article types, those article types, and the content that we create really has to meet the needs of the audience. Dr. Jonathan Friedberg: And to that end, I know we've discussed, you had some discussions with your group about brief reports as another article type that is somewhat differentiating for the journal. Dr. Pamela Kunz: Yes, exactly. And I think this also speaks to really trying to attract science that may be earlier in its development. And maybe an author, a team has an idea or a smaller scientific report that they'd like to publish. It may not quite meet the bar for JCO, but maybe we think that this is something that's exciting, that will lead to future studies, and that's exactly what we're hoping to attract.  Dr. Jonathan Friedberg: And I guess folding into maybe some of the input from your new editor team and editorial board, what features do you look for when reviewing novel research for publishing? How do you decide what gets in and what doesn't? Dr. Pamela Kunz: Well, we are newly open, so this is something that we are also really, as a team, thinking about in real time. And I think that we certainly want JCO Oncology Advances to be the premier open access journal. So, we really still want the bar to be high in terms of high-quality science. As we have crafted and are still building our editorial team and editorial board, we are developing diverse expertise. So, we want content expertise. We have expertise in biostatistics. That's really critically important. So, we still want the biostats to be strong, and we want to ensure that, I think, that the conclusions are still really valid. So, I think really having a bar that's high for the science is still going to be critically important.   I think another thing that we may be looking at, again, given that we're looking at earlier phase clinical trials, is really the potential for impact, because, you know this, but JCO will really be publishing the large majority of the randomized clinical trials, and we may be thinking about publishing some of the earlier trials. So potential for impact will be important as well.  Dr. Jonathan Friedberg: Yeah, and I guess that gets into the next question, and I'll give an editorial opinion, I can't resist, I guess, as an editor, on what authors should think about as far as submitting. I really like the way you framed impact, and impact of a manuscript might go beyond changing practice in clinic tomorrow, but an important negative study which changes the way the trials are done in the future, or a preliminary study that leads to important phase II and phase III trials are very impactful for the field. And I guess one of the things I always advise authors is to help the reader and the editor understand what the next step is for their work. That can go in the discussion, it can go in the cover letter, but because of these results, the field should do X, Y, and Z. I think that's a really important thread that the reader should be able to see. I trust you might agree with that. But do you have any other insights for authors as they're preparing manuscripts for this journal that you'd like to share?  Dr. Pamela Kunz: That's a great idea, and you just gave me an idea to really maybe formally include that. I think one thing along those lines that we've been thinking about as it relates to our audience is to formally have, even in our manuscripts that aren't formally a lay language or plain language summary, to really have a short section that translates it. And I think translating the science is critically important as we're thinking about bringing in other community members, whether it's patients, patient advocates, primary care physicians, or those who may not be experts in oncology, but are really hoping to learn about the science of oncology. So that's an element that we're thinking of introducing to the manuscripts. Dr. Jonathan Friedberg: Yeah, I think knowing your audience is critically important. And that said, I think that oncology practitioners are interested in broad topics as long as you can distill it down, it's not only clinical trials.  Dr. Pamela Kunz: That's right.  Dr. Jonathan Friedberg: You've mentioned a couple of times this term, open access, and this has been a real, I think, revolution during a transformational time in publishing. Maybe just for the people who are a little bit less familiar, define that, and what's the potential benefit of an open access Journal? Dr. Pamela Kunz: open access publishing is a way; I think there are both advantages and disadvantages. It's certainly been a trend in oncology publishing. And in fact, I think some of the research that the JCO staff did found that over the last five years, about 30% of manuscripts are now being published via open access. Open access means, practically speaking, that the authors take on an article processing fee. So, there is a charge to the authors. However, the downstream benefit of that, there are benefits to authors, there are benefits broadly to the scientific community, and benefits to society. They sort of fall in those three categories.   The benefits to the authors are that there is certainly a chance of higher citations to the scientific community. There's an opportunity for broader scientific dissemination of the science. And then for society, we talked about the audience really shifts when there is open access. There's no paywall for patients or patient advocacy groups or non-oncology providers to get access to the content. I think it is a real paradigm shift, and I think it's both an opportunity, but also as an editor in chief and as the publishing community, we have an obligation to also think very intentionally about where there may be some potential for disparity. So, for example, if there is an article processing fee, we need to be sure that that's not a barrier. And if it is a barrier, is it disproportionately affecting certain populations, like low middle income countries or under or unfunded researchers? So, I hope that we can really be deliberate and thoughtful about that, as we are tracking this. Dr. Jonathan Friedberg: I guess just some of the nuts and bolts. I know that you've put a lot of thought into trying to keep the fees as low as possible. And can you just maybe talk about how you've benchmarked them and maybe groups that get discounts? Dr. Pamela Kunz: Yes. So, we are really trying to target a little bit around the median or below. So, we will be very competitive in terms of our peer journals, and in addition, there will be discounts that are really based on World Health Organization standards for low-middle income countries. And we certainly, on a case-by-case basis, can discuss with authors if there are hardships that we need to be aware of. So, I think we really don't want that to be a huge barrier. And I think, and I'd love your thoughts on this, too. I think that with this paradigm shift in publishing, I think there's an obligation for our institutions to really think about how they're going to support authors at their own institutions for this. Dr. Jonathan Friedberg: Yeah, I agree, and I know that the ranges that you've discussed are certainly in line with many other oncology journals. And to that end, given the number of papers that are being published in this space, I think it speaks to resources being appropriately directed toward that.  Dr. Pamela Kunz: Can I ask you a question? Dr. Jonathan Friedberg: Sure.  Dr. Pamela Kunz: So, because I think this was one of your ideas of really getting this journal started, why was it the right time for JCO to have an open access journal? Dr. Jonathan Friedberg: So, I've been at the job now close to three years, and we take a look at where papers that don't quite meet the bar for JCO go. It's a very interesting analysis, but although JCO has four other journals in the family, each of those journals are fairly specialized with a narrow scope that includes some of what JCO publishes. But I would say in total, only about 15% of the articles that we reject might be appropriate for one of those four journals. So that leaves 85% of the papers finding a home elsewhere outside of the JCO family. So, I think certainly we felt that there were a lot of great papers that we'd like to find a place for in the JCO family. And that was one source.  I think the other is an appreciation that I'm still learning about this transformative time in medical publishing. And the old model of people subscribing to a magazine that they get once a month, and what publishing is, is really being turned on its head. People consume content based on a tweet or a link. There's a lot of graphics and video that goes into presenting this content. Funders as well as sponsors of research are really insisting that papers be made available to the broad public immediately, kind of questioning the copyright model and the need for subscription journals. So, I think really getting involved in this space and having a robust open access journal in the ASCO family is a critical direction to go. And based on all of the research that we've done; we really feel it is a great time.  Dr. Pamela Kunz: Great.  Dr. Jonathan Friedberg: One last question for you, as we're kind of leaving the audience with something. So, in addition to those benefits, based on your very early experience working with the ASCO staff and knowing about ways that ASCO and the JCO journals can promote manuscripts, our websites and search functions, what's the hook that people should choose this journal over another oncology open access journal? Dr. Pamela Kunz: Great question. I mean, I think there are a number. Certainly, the JCO brand is strong and really top in the field. And I think that that in and of itself should be a draw for authors. I think that also our link with a professional society, with ASCO, is critically important. And I think that many oncology professionals see ASCO as their professional home. And I think having a journal and a journal family that's really linked with that professional society is important. And you and I have talked about really doing more to really enhance that link with ASCO. And I think that we will be doing that some at the annual meeting this year with promoting JCO Oncology Advances.  And I think that also, given that oncology really has become this global community, and ASCO has certainly become a global community, and the spirit and philosophy of open access, I think that really aligns nicely, and I think that it'll help us reach a broader community by having open access. And I think that that's a real advantage for authors. Dr. Jonathan Friedberg: Yeah, I totally agree. And I think that as we continue to survey the landscape and come up with new content and areas of new focus like artificial intelligence and machine learning, which has been a big new trend, I think you're going to be able to have access to these cutting-edge manuscripts that will impact the field for sure moving forward. Any last comments for our listeners?  Dr. Pamela Kunz: Just to please submit your work. We're open for business, and I'm excited. So, thanks, Dr. Friedberg and to the team. I'm excited for the opportunity and we look forward to our first publications, hopefully, will be out this summer.  Dr. Jonathan Friedberg: Well, thank you so much for taking the time and thank you to our listeners. To learn more about JCO Oncology Advances, how to submit, the scope of the journal, just go to ascopubs.org. There's a whole detailed section there. We look forward to seeing your manuscripts. Thank you so much. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      
5/9/202416 minutes, 36 seconds
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JCO Article Insights: Atezolizumab Plus Bevacizumab, Chemotherapy in EGFR, ALK NSCLC

In this JCO Article Insights episode, Rohit Singh provides summary on two articles published in the April 10th issue of the Journal of Clinical Oncology. The first article, "Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non–Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04)" describes a randomized, open-label, multicenter, phase III study evaluating the efficacy of atezolizumab plus bevacizumab, paclitaxel, and carboplatin (ABCP ) in EGFR- or ALK-mutated NSCLC that progressed before TKI therapy. The second is the accompanying Oncology Grand Rounds. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Rohit Singh: Hello and welcome to JCO Article Insights. I'm your host, Dr. Rohit Singh. Today I will provide a summary of a Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non–Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04), by Dr. Park and colleagues from Seoul, Korea. The purpose of this study was to evaluate the efficacy and safety of the ABCP regimen based on IMpower150 in patients with EGFR or ALK mutated non-small cell lung cancer who had progressed on prior targeted treatment.   I will also discuss an Oncology Grand Round case titled "Management of Treatment Resistance in Patients with Advanced EGFR Lung Cancer: Personalization, Parsimony, and Partnership", by Dr. Vallillo and colleagues from Lahey Hospital Medical Center and Tufts University School of Medicine, Boston, Massachusetts. Oncology Grand Round cases help us to give a clinical context to the clinical trial.   While TKIs are the established standard of care for non-small cell lung cancer harboring driver mutations, most patients will develop resistance to these treatments. Immune checkpoint inhibitors, with or without chemo, have shown clinical benefits of immune checkpoint monotherapy in patients with EGFR-mutated non-small cell lung cancer. Consequently, platinum-based chemo is the standard of care for patients with EGFR TKI failure. This was a phase III, multicenter, open-label, randomized trial conducted at 16 hospitals across the Republic of Korea. Patients diagnosed with stage four non-small cell lung cancer with sensitizing EGFR mutation or ALK translocation were included in the study. Patients were randomly assigned to the ABCP arm or chemo-only arm in a 2:1 ratio. Eligible patients were stratified on the mutation type (EGFR mutation vs. ALK translocation) and the presence of brain metastasis. No crossover to atezolizumab was permitted.  The recruitment with T790M mutation was capped at 30%. Patients who responded continued to receive maintenance with atezolizumab until disease progression or unacceptable toxicities occurred. If a patient was identified to have an acquired T790M mutation after the failure of a first or second-generation EGFR TKI, the patient had to be treated with a third-generation EGFR TKI before enrollment. The primary endpoint was investigator-assessed objective response rate according to research criteria. The secondary endpoints included overall survival and progression-free survival at one and two years, and the duration of response, along with a safety analysis. Investigators also did an exploratory biomarker analysis based on PD-L1 expression and its correlation with the response. They also analyzed the distribution of tumor-infiltrating lymphocytes, and a cut-off of 20% inflamed score was used to compare the two arms. Overall, 228 patients were enrolled, 154 in the ABCP arm and 74 in the chemo-only arm. Most patients were female at 56.1% and never smokers at 62.7%. Brain metastasis was present in 42.7% of patients. Most patients had previously received EGFR TKI therapy, however, only 8% and 30% received third-generation TKI as first-line therapy in the ABCP arm and  chemo-only arm, respectively. The majority of the patients were EGFR at  90%.  The median duration of follow-up for the study population was 26 months. The objective response rate in the ABCP arm was significantly higher at 69.5% compared to 42% in the chemotherapy alone arm. The median PFS was significantly longer in the ABCP arm at 8.48 months versus 5.6 months, and the duration of response was similar at around seven months in both arms. The median overall survival was also similar at around 20 months in both arms, with a hazard ratio of 1.01. In the subgroup of patients with brain metastasis at the time of study enrollment, PFS was significantly longer in the ABCP arm at 8.4 months compared to 4.4 months in the chemotherapy-only arm. In contrast, no difference in PFS was observed in the subgroup without brain metastasis. Regarding EGFR mutation status, there was no difference in PFS or OS between the two arms in the EGFR deletion 19 subgroup. However, a favorable PFS was observed in the EGFR L858R subgroup. For those with acquired EGFR T790M mutation, there was no difference in PFS between groups, whereas a favorable PFS was observed in the subgroup without EGFR T790M mutation.  In the exploratory biomarker analysis, interestingly, the impact on PFS was correlated with PD-L1 expression. The study found that the higher the PD-L1 expression, the better the PFS. In patients with PD-L1 expression of more than 50%, the hazard ratio was 0.24 for PFS. This is an interesting observation. As in previous studies, we have seen that PD-L1 expression does not have a strong association with response to checkpoint inhibitors in patients with driver mutations. Based on the distribution density of tails in the tumor bed, the inflamed score was calculated using artificial intelligence. For patients with 20% of the imflamed score, the ABCP arm has significantly prolonged PFS at 12.9 months compared to 4.8 months. The median number of ABCP treatment cycles was 4, with 12 for atezolizumab and 8 for bevacizumab as maintenance therapy, pemetrexed maintenance was administered for a median of 10 cycles. The incidence of grade 3 or higher side effects was 35.1% in the ABCP arm compared to 15% in the chemotherapy-only arm. Peripheral neuropathy, alopecia, and myalgias were the most prevalent side effects. Interesting notably, 54% of patients in the ABCP arm required treatment interruption or dose modification, and there were three reported deaths in the ABCP arm, two due to pneumonia and one due to cerebral embolic infarction. Around 10 patients or 13.5% of patients in the chemotherapy-only arm required dose interruption or modification.   In conclusion, patients with EGFR-mutated or translocated non-small cell lung cancer who had failed prior TKI ABCP regimen showed a statistically significant prolongation of PFS and response rate compared to chemo alone. Patients in the subgroup with EGFR L858R, without acquired T790M mutation, and presence of brain met showed more benefit. There was no difference in overall survival, though we need more mature data. Adverse events were higher in the ABCP arm. Interestingly, in the exploratory analysis, a high PD-L1 and an inflamed score of more than 20% showed PFS benefits. Though we need to take into consideration that this trial was done and all the patients were grouped from a single country considering Asian ethnicity. And most importantly, the majority of patients were treated with first- and second-generation TKIs, whereas third-generation TKIs are the standard of care in the United States.  Coming to the Oncology Grand Round, in this case, we will discuss the management of treatment resistance in patients with advanced EGFR-mutated lung cancer. A patient with a 20-pack-a-year history of tobacco use presents with weight loss and hip pain, found to have a lung mass, skeletal mets, and brain mets, and was diagnosed with lung adenocarcinoma. The patient goes with palliative radiotherapy for the brain mets. Comprehensive tumor Merkel profiling demonstrated an EGFR mutation exon 19 and alteration P53. The patient was started on third-generation EGFR TKI osimertinib. However, after 17 months, the patient has symptomatic disease progression. Usual approach, if feasible, re-biopsy at the time of progression to evaluate for possible new mutations which can guide treatment options. As mentioned earlier, in the trial, acquired resistance to the TKI is inevitable and heterogeneous. There were various mechanisms which have been proposed regarding resistance, including a second-site EGFR alteration, upregulation of bypass pathway, histological transformation to small cell histology, or suboptimal drug penetration.  There are various approaches after disease progression on EGFR TKI. Combining EGFR-directed therapies to address resistance is an option. Prime results from the MARIPOSA-2 study showed amivantamab plus chemotherapy with or without lazertinib in EGFR-mutated non-small cell lung cancer after disease progression showed a better objective response rate at 64% compared to 36% in the chemo-alone arm. It also showed improved PFS with a median of 6.3 compared to 4.2 in the chemo-alone arm. Combining immune checkpoint inhibitors, EGFR-mutated non-small cell lung, I say has been disappointing in advance of EGFR-mutated non-small cell lung, and combination therapy studies are needed to improve outcomes. Studies, as I discussed ATTLAS, have shown that combining a VEGF inhibitor with ICIs and chemotherapy can lead to a better objective response rate and PFS. However, further clinical trials are needed to figure out the better subgroup of patients who can benefit from this combination.   Should the TKI be continued beyond progression in EGFR-mutated advanced non-small cell lung cancer? Continuing the primary EGFR TKI treatment beyond progression may be considered for patients with indolent or asymptomatic progression or localized progression. We can consider radiation, surgery, or ablation. This approach will potentially delay the need to change systemic therapy in patients. However, for patients with multifocal disease progression requiring chain systemic therapy it may be more beneficial to switch to next-line systemic therapy options like platinum doublet with or without immunotherapy and VEGF inhibitors. In the case presented, the decision was made to continue osimertinib along with platinum doublet, deferring the addition of immunotherapy and VEGF inhibitor. This choice was based on factors like the patient's history of brain metastases and intracranial control. There is also a high risk of toxicity, especially pneumonitis, with immune checkpoint inhibitors after using targeted therapy, the patient showed clinical and radiographic improvement while on this treatment regimen.  The decision to continue or change therapy at cancer progression is based on factors like drug tolerability, patient preferences, and specific subgroups with different outcomes, such as those with brain metastasis or specific EGFR mutation subtypes. Choosing between combination therapy strategies that concept progression involves personalized decision-making to optimize treatment outcomes. Ultimately, the approach to management should be tailored to individual patient needs, preferences, and eligibility for different treatment modalities.  This is Rohit Singh. Thank you for listening to JCO Article Insights. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You will find all the ASCO shows at asco.org/podcasts. Thank you. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions ofASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.        
4/29/202411 minutes, 29 seconds
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Commonly Held Beliefs About Cancer Survivorship

Dr. Shannon Westin and her guests, Dr. Emily S. Tonorezos and Dr. Michael Halpern, discuss their article, "Myths and Presumptions About Cancer Survivorship" recently published in the JCO. TRANSCRIPT The guests on this podcast episode have no disclosures to declare.   Shannon Westin:Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we go in depth on manuscripts published in the Journal of Clinical Oncology. I am your host, Social Media Editor of the JCO, Shannon Westin, and also a GYN Oncologist by trade. I'm thrilled to bring a topic that is very close to my heart. We're going to be talking about a Comments and Controversies article published in the JCO on November 16, 2023, entitled "Myths and Presumptions about Cancer Survivorship." I know you all will find this topic as enthralling as I have, and the authors do not have any conflicts of interest.  I'm joined by two of the authors on this important work. The first is Dr. Michael Halpern, he’s the Medical Officer in the Health Assessment Research Branch of the Health Care Delivery Research Program. Welcome, Dr. Halpern. Dr. Michael Halpern: Thank you for having us on. Shannon Westin: We're also accompanied by Dr. Emily Tonorezos, the Director of the Office of Cancer Survivorship, and both of them work in the Division of Cancer Control and Population Sciences at the National Cancer Institute, National Institutes of Health. Welcome.  Dr. Emily Tonorezos: Thank you for having us. Shannon Westin: So, let's get right into it. I want to level set first. I would love for one or both of you to speak a little bit about the state of cancer survivorship currently. What's the prevalence of cancer survivors here in the US? Globally? What do we expect as time passes? Dr. Emily Tonorezos: Thank you for starting with this question. In the Office of Cancer Survivorship, we use a definition of cancer survivor that we got from the advocacy community many years ago. We use a definition that says “a person is a cancer survivor from the time of diagnosis through the balance of life.” That means in the United States, we estimate that we have a little over 18 million cancer survivors, and globally, it's a little more difficult to estimate those numbers. Not every country has a cancer registry to count the number of cases, but we think there are upwards of 53 million cancer survivors diagnosed within the last five years in the world. Shannon Westin: Wow. And so this is why it's so important, such a large number, and that's just an estimate. And we know this is only going to be growing. I personally learned so much from your manuscript, which is critically based on the understanding that our beliefs as practitioners truly impact the way we care for our cancer survivors. I admit, I definitely held or hold some of these beliefs, and I'm certainly grateful that you're providing that objective evidence to support or refute these claims.  So, with that being said, let's tackle the first one that you all approached: Shared care results in the best outcomes for cancer survivors. I think first I'd love to hear about what your definition of shared care is. What does that really mean in the context of cancer survivorship? Dr. Michael Halpern: Shared care is a deliberate process to coordinate and integrate components of survivorship care between specialty, in this case, oncology providers, and primary care providers. And part of the issues with this belief about shared care being the best have to do with the broad practice experience of survivorship care. While the ideal definition is this integrated and coordinated care, shared care can range from one extreme to being essentially oncologist-led care - where the oncologist also sends information to the primary care providers; and to the other extreme - care led by primary care providers and an oncologist is available to answer questions as needed. So part of the issue with the available literature is that there is a tremendous range in terms of the definition of shared care that's being used in studies. Shannon Westin: So, understanding those limitations, obviously, based on what you just said, what have we seen in some of the studies that have been exploring shared care and what it might mean for cancer survivors? Dr. Michael Halpern: So there have been some wonderful studies and some very well-done research in shared care. The majority of it indicates essentially no benefits, not any worse, but definitely not any better than other survivorship care models among multiple domains, quality of life, patient preference, clinical outcomes, in some cases, costs. So there isn't at this point a rationale for believing that shared care leads to better outcomes than does other types of models of care. And that's not to say that we don't think that shared care is a valuable model, that it's potentially very useful and beneficial for certain groups of cancer survivors. It's just that at this point, we don't have evidence to say who it is going to have optimal outcomes for compared to other kinds of survivorship care models.  Shannon Westin: And that makes sense. I mean, I think we're seeing this over and over again in all aspects of cancer care that one broad stroke or one broad plan isn't right for everybody, whether that's therapeutic or surgical or prevention, so it makes sense to me that that's what we're seeing here in survivorship as well. So I see this manuscript as a call to action about what are we missing, what data do we need to generate to really be able to move this care forward. So that makes total sense to me. And I guess in line with that, another belief, and I've heard this all the time from my patients, too, is this idea that primary care providers feel unable to provide survivorship care. They're not comfortable. “Oh, you have a diagnosis of cancer. You have to be seen there at the cancer center.” What does our evidence demonstrate here? Dr. Emily Tonorezos: This is another belief that was found to be a presumption. So that means that this is a belief that we think was true, but which convincing evidence does not confirm or disprove. So what the available evidence tells us is that primary care providers do have challenges in taking care of cancer survivors, particularly with regards to certain cancer-related care needs. But at the same time, we found lots of evidence that primary care providers are more than willing and able to take care of cancer survivors. They express confidence in their skills. They think that they are capable of taking care of cancer survivors. And especially for survivors of more common cancers, primary care providers, in general, express a lot of confidence in their ability to take care of those patients. What they might lack could be things along the lines of survivorship-specific knowledge. So that is a gap that we identified. But this idea that primary care feels unable to take care of survivors really was not supported by the evidence. Shannon Westin: I mean, and that makes sense, right? If we're seeing more and more cancer survivors, primary care is going to adapt to that. We adapt to the things we see commonly in our clinics, and that goes across all specialties. So that certainly makes sense. I guess you've already kind of said this, and I'll just highlight it for the listeners. You know, clear guidelines seem to be a clear, nice option to potentially improve this situation.  So let's discuss this next myth that you all identified, that oncology providers are hesitant to transition survivors to primary care. Now, I understand this one because I definitely, we get this a lot, and I'm a center medical director in GYN, and we've definitely tried to put patients that are free of disease out back in the community to be able to free up space for other patients. And we definitely get pushback because seeing patients that are in this state of being free of disease and they're living their life, it's inspiring. We remember why it is we're doing the things we do. What did the data show us about this myth? And are we creating barriers to this transition to survivorship care outside of the oncology centers? Dr. Emily Tonorezos: Exactly. So this belief is a myth. We found evidence that this belief is not true, and it seems to be one of those things that feels true, that oncologists want to take care of cancer survivors, that it contributes to the joy of medicine. But that evidence really does not suggest that that's the case. In fact, the opposite is true in the evidence. We found when we looked at the available research Oncologists want to take care of people who are diagnosed with cancer and need treatment. That is really what they think their role is. That's what they feel they're contributing. And so, even though there is a pleasure in seeing a person who has finished treatment, most oncologists say that the amount of time that they spend taking care of people who are done with treatment is appropriate - meaning they're not looking to expand their panel of post-treatment patients. They really want to take care of people who need treatment currently and then perhaps have a little bit mixed in of people who are done with treatment or who are in that survivorship phase. We found a lot of evidence, also hard evidence, that oncologists are, in fact, transitioning survivors to primary care. There is a lot of evidence that people who have been diagnosed with cancer are being seen in primary care and that that proportion increases over time. So if oncologists were really creating these insurmountable barriers to transition to primary care, we would not be seeing so many survivors in the primary care setting. But the fact is they're there, and they are being moved there by their providers. Shannon Westin: I love hard evidence. I do have a few patients that have said, "Can I just come see you every once in a while?" And I love seeing them, but I agree, we can't fill our panels with that. So that makes good sense.  So the next topic centers around finances, and this is the idea that survivorship clinics lose money. What truth did you all discover here regarding reimbursement for this type of care?  Dr. Michael Halpern: We discovered that this is a presumption. It's a belief that there isn't compelling evidence one way or the other. Part of the issue with this is probably some confusion about what constitutes survivorship care. There are certainly difficulties in obtaining reimbursement for certain survivorship services, such as sexual health and fertility counseling, and wellness and exercise services. It's understandable that there may be problems getting reimbursement or appropriate reimbursement for those. But when looking at overall survivorship care, there are actually very few studies that have done a financial analysis of the cost of providing that care versus the reimbursement. And those that have done more detailed analyses generally show that the reimbursement for survivorship care is greater than the cost. Survivorship care clinics actually do break even or make money.  Now, it's also true that providing survivorship care likely doesn't provide the same level of reimbursement as providing oncology treatments, which involves administering systemic agents and different kinds of imaging or diagnostic procedures. And so there are other streams of reimbursement possible for that. But overall, there really isn’t compelling evidence to indicate that survivorship clinics lose money. There is a concern that having this widespread belief that they do may be a disincentive for hospitals or healthcare systems to start different kinds of survivorship clinics. Shannon Westin: I think this is an area where it would really behoove us to do more work so that we can encourage institutions to do this. And, I know in our center, the things that you're mentioning, it's exactly like the problems that these people are having around sexual health and fertility and exercise, wellness in general, I mean, those are the soft things that I feel like it's harder to kind of gain momentum to really develop established programs that really make an impact. And so I was so glad to see that you mentioned that in this paper, and I hope it will encourage people to really move that forward.  So finally, I was interested in this presumption around the shared electronic health records and how that might help with survivorship care coordination. Is this our solution for smooth communication and care of these people? Dr. Emily Tonorezos: This one was actually almost something that's sort of funny to think about, how naive we were about electronic health records. We found a number of examples from five or ten years ago where leaders in survivorship research and clinical care were saying, "Well, once we have electronic health records, we will not have these same problems of care coordination or communication." And that has just not been true, unfortunately. So this one was also a presumption, meaning the evidence of a benefit for electronic health records just was not out there. So we know that consolidation and transfer of diagnostic and treatment information can increase knowledge. So you can show that you can increase knowledge about diagnosis and treatment with a shared electronic health record. So the primary care provider is able to look, for example, at the pathology from the original diagnosis. But whether that actually results in anything in terms of improved care is an open question. Shannon Westin:I think that's what we've learned a lot about electronic health records in general. I remember when we were transitioning to our new system, and everyone thought, "Oh, this is going to be the end all, be all." And it has been good in a lot of ways, but it certainly hasn't been the cure for everything that ails us.  Well, I'm just so thrilled. Thank you all so much. This has been really educational and so important, given what we've already talked about, about the increasing population of cancer survivors that we're seeing in the clinic and globally. I think just to kind of tie a bow on it, I would just love to hear each of your bottom lines regarding kind of where we are right now with the care of our cancer survivors and what we need to be addressing maybe in the short term to move things forward. Dr. Emily Tonorezos: So I'll go first. I just want to say it's really important, I think, when we are around other investigators and in our meetings and talking about clinical care, that we think critically about the things that we hear people saying. This idea, especially the one that oncology providers don't want to transition their survivors to primary care, but the others as well. I think the way that we need to address this or carry this forward is to just be aware when we're in those settings and we hear people say things, to ask the question, "Is that really supported by the evidence?" And you may find that there are even more of these commonly held beliefs that really aren't supported by the evidence or that deserve a little bit of a deeper dive. Dr. Michael Halpern: I very much agree with that. And it's critical that we be willing to question some of these beliefs, be willing to discuss them, and not accept them as facts in order to be able to develop new research programs, hypotheses, to explore really what can help produce the best outcomes for survivors, because that's really what we're all about.   The other bottom-line issue, I think, one, Dr. Westing that you brought up, is that survivorship isn't a one-size-fits-all. The best survivorship care is the care that is tailored towards the survivor - the individual needs and wants. What kind of supports will be most effective in terms of enhancing their health? So, we really need to pay attention to the individual and, most importantly, what outcomes for survivorship care matter most to the survivor? What do they want to see happen? What do they want their subsequent future to look like? And how do we measure those outcomes to ensure that they get the best care on the terms that they want?  Shannon Westin: Well, great. I think that's a perfect place to end. I just want to, again, thank my guests. This went by so fast, and I learned a ton, and I hope all of you did as well. Again, we were discussing the Comments and Controversies manuscript "Myths and Presumptions about Cancer Survivorship" published in the JCO on November 16, 2023.  Thank you again to our listeners for joining JCO After Hours. And please do check out our other offerings wherever you get your podcasts. Have an awesome day.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      
4/11/202417 minutes, 37 seconds
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JCO Article Insights: Long Term Follow Up of the RESORT (E4402) and LYSA Study

In this JCO Article Insights episode, Alexandra Rojek provides a summary on two long term follow studies: "Long-Term Follow-Up of Rituximab Maintenance in Young Patients With Mantle-Cell Lymphoma Included in the LYMA Trial: A LYSA Study" by Sarkozy, et al published on December 18th, 2023 and "Long Term Follow Up of the RESORT Study (E4402): A Randomized Phase III Comparison of Two Different Rituximab Dosing Strategies for Low Tumor Burden Follicular Lymphoma," by Kahl, et al, published January 9, 2024. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Alexandra Rojek: Hello and welcome to JCO Article Insights. I'm your host, Alexandra Rojek, and today we will be discussing two clinical trial updates published in the March 1st issue of JCO, focusing on the long-term outcomes of rituximab therapy for patients with lymphoma. The first paper discusses the use of maintenance rituximab for mantle cell lymphoma patients in the LYMA trial, and the second paper addresses rituximab dosing strategies for low tumor burden follicular lymphoma in the RESORT study. The first article by Sarkozy et al. for the LYSA group is titled "Long-Term Follow-Up of Rituximab Maintenance in Young Patients with Mantle Cell Lymphoma Included in the LYMA Trial: A LYSA Study." The LYMA trial was designed to answer whether the addition of the CD20-targeting monoclonal antibody rituximab provided additional benefit for patients with mantle cell lymphoma who achieved a response to induction chemoimmunotherapy, followed by consolidative autologous stem cell transplant in randomized patients, maintenance rituximab for three years versus observation alone. The primary analysis of the LYMA trial was published in 2017 and showed that the primary endpoint of four-year event-free survival or EFS was met at 79% in the maintenance rituximab arm compared to 61% in the observation alone arm. Additionally, there was a four-year overall survival or OS benefit of 89% versus 80% in favor of maintenance rituximab. Thus, on the basis of the LYMA trial primary analysis, the use of maintenance rituximab after consolidative autologous stem cell transplantation has become the standard of care in the field for these patients.  The long-term safety and efficacy data presented in this clinical trial update for the LYMA study continue to demonstrate ongoing EFS and OS benefit for patients randomized to maintenance rituximab. Patients were initially enrolled between 2008 and 2012, and 240 patients were randomized to either arm. EFS in this study was defined as absence of disease progression, relapse, or death, severe infection, or allergy to rituximab. The data cutoff for this updated analysis was April 2019, with a median follow-up from randomization of seven years for living patients with a note that this is prior to the COVID-19 pandemic. For those in the maintenance rituximab arm, the seven-year EFS was 76% compared to 46% for those under observation. For those on the rituximab arm, the majority of relapses occurred within three years of randomization and thus while on maintenance rituximab, which the authors suggest does not show an increase in incidence of relapse after the end of maintenance therapy. The seven-year overall survival was 83% for those on the rituximab arm compared to 72% for those on the observation, with a log-rank p-value of 0.08. There was no difference in causes of death between the treatment arms noted.  Notably, the patients who received maintenance rituximab after induction and transplant experienced a shorter second OS after relapse therapy, with a median OS2 of 1.1 years compared to 4.6 years favoring those on the observation arm, without impact of the type of salvage therapy received. Although this study was conducted before BTK inhibitors were approved in France and thus used at a low rate for patients who relapsed after initial therapy. This suggests that those who relapse after maintenance rituximab were those with the most aggressive disease biology. The authors also identified a group of patients who experienced progression of disease within 24 months of initial therapy or POD24 and showed that a Ki-67 score greater than 30% and high MIPI score were prognostic of POD24 events. For those who experienced POD24 within the rituximab arm, they also experienced a shorter OS2 compared to those on observation, again suggesting that those whose disease relapses after maintenance rituximab tend to have more aggressive and difficult-to-treat.  While the interpretation of post-relapse outcomes and therapies needs to be interpreted in the light of a different era of available therapeutic options in more recent years, particularly the newest generation of BTK inhibitors, this updated follow-up of the LYMA study provides additional strength to the standard of care established through the trial's primary analysis of the benefit of maintenance rituximab after induction therapy and consolidative autologous stem cell transplantation for patients with mantle cell lymphoma. Although the extended follow-up was conducted prior to the COVID-19 pandemic, during which increased risk of infection was shown for those undergoing B-cell depletion with agents such as rituximab, this extended follow-up of the LYMA study continues to show that the optimal therapy for mantle cell lymphoma should include maintenance rituximab after transplant. Studies since the design of the LYMA trial have sought to address whether consolidative transplants are necessary when BTK inhibitors are added to induction therapy, and ongoing studies in this era of newer treatment agents will continue to challenge and potentially redefine this now well-established standard of care. The second article by Kahl et al. is titled "Long-Term Follow-Up of the RESORT Study: E4402, a Randomized Phase III Comparison of Two Different Rituximab Dosing Strategies for Low Tumor Burden Follicular Lymphoma." The RESORT study, conducted by the Eastern Cooperative Oncology Group, was designed to address whether rituximab-responsive low tumor burden follicular lymphoma patients benefit from maintenance rituximab until progression versus a rituximab retreatment approach at the time of progression. The primary analysis of the RESORT study, published in 2014, did not show a difference in the primary endpoint, which was defined as time to treatment failure. The five-year risk of treatment failure for those on a maintenance strategy was 53% compared to 50% for those on a retreatment dosing strategy. At the time of the primary analysis, letters were sent to participants and providers, and thus the data was locked for further primary endpoint analysis in late 2011. The data lock for long-term follow-up presented in this paper was continued through 2021.  The authors looked at several endpoints in this long-term follow-up. They found that freedom from first cytotoxic therapy, at a median follow-up of almost nine years, favored the maintenance group over the retreatment group, with 83% versus 63% of patients free from chemotherapy or radiation at year seven. When looking at response duration, the analysis also favored a maintenance over retreatment approach, of 66% versus 30% for 10-year response duration, with a median follow-up of 12 years. However, when looking at overall survival at 10 years, there was no difference between rituximab dosing strategies, with a 10 -year overall survival of 83% for those receiving maintenance versus 84% for those receiving retreatment. While this extended follow-up of the RESORT study was not able to assess the long-term follow-up of the primary endpoint, the secondary endpoints suggest that while a maintenance dosing strategy was superior for prolonging time to first cytotoxic therapy and response duration, this again did not translate to an overall survival benefit. The authors conclude that they continue to recommend a rituximab retreatment strategy for these patients instead of a maintenance strategy, in the absence of a survival benefit, particularly with the high response rates observed with next-line treatment strategies for follicular lymphoma patients.  Similarly to the LYMA study discussed in the first paper, the treatment arms of the RESORT study were completed prior to the COVID-19 pandemic. B-cell depletion, such as with prolonged rituximab therapy, is known to negatively impact the ability to combat viral infections such as SARS-CoV-2. Thus, the authors conclude that, in light of current and future infectious concerns, the extended follow-up of the RESORT study does not support the use of maintenance rituximab for patients with low tumor burden follicular lymphoma. Other studies have also evaluated modified and abbreviated maintenance rituximab dosing strategies for this same population and have also not shown a survival benefit, thus further strengthening this recommendation of favoring a retreatment approach over maintenance therapy. Together, the extended follow-ups of the LYMA and RESORT studies, while addressing different questions regarding the use of maintenance rituximab in mantle cell lymphoma and follicular lymphoma, support the primary endpoints of each respective study. There is a clear role for the use of maintenance rituximab therapy to promote improved event-free and overall survival, as the LYMA study has shown for mantle cell lymphoma patients. However, this does not extend to low tumor burden follicular lymphoma patients in the RESORT study. The updated analyses of these two studies provide additional strength to the nuanced and targeted application of this stalwart of lymphoma therapy that is rituximab, in the modern treatment era. While ongoing studies will aim to address how we optimize therapies with new agents for each subtype of lymphoma patients, the LYMA and RESORT studies continue to guide best practice and standards of care.  This is Alexandra Rojek, thank you for listening to JCO Article Insights. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.  The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  
3/25/202410 minutes, 5 seconds
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Pembrolizumab in Patients With Advanced Cancers With HTMB

Dr. Shannon Westin and her guests, Dr. Herbert Duvivier and Dr. Geoffrey Oxnard, discuss the paper “Pembrolizumab in Patients With Tumors With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry Study” published in the JCO. TRANSCRIPT The guest on this podcast episode has no disclosures to declare.  Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in-depth into articles published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncologist and Social Media Editor of the JCO. As always, it is my pleasure to serve and bring this information to you.  Today, we will be discussing, “Pembrolizumab in Patients With Tumors With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry Study.” And this was published in the JCO on August 10th, 2023.  None of the authors have any conflicts of interest to disclose.  Joining me today are two of the authors, Dr. Herbert Duvivier, the principal investigator of this arm of the TAPUR trial. Welcome. Dr. Herbert Duvivier: Thank you.  Shannon Westin: And then, of course, many of you know Dr. Richard Schilsky, who is the former CMO and Executive Vice President of ASCO and a principal investigator on the TAPUR study.   Dr. Richard Schilsky: Thank you, Shannon.  Shannon Westin: So, let's get going. I think the first thing would be great is to level set and make sure everyone knows exactly what this TAPUR basket trial is, the Targeted Agent and Profiling Utilization Registry study. Can you guys give the audience a brief description of the objective of TAPUR and maybe how it came to fruition?  Dr. Richard Schilsky: Sure. This is Richard Schilsky. Maybe I can start with that. The TAPUR study is a prospective, phase II, multi-basket, multi-center genomic-matching trial. Its primary objective is to identify signals of drug activity for targeted agents that are already marketed. But in the TAPUR study they are being used outside of their FDA-approved indication. The study, as you may know, was conceived in 2014, launched in 2016, and is still enrolling patients across the country. Really, the genesis of the study came from the fact that it began at the time where genomic profiling of patients with advanced cancer was becoming more commonplace. Genomic alterations that could be targeted by already marketed drugs were being identified. However, patients and doctors were having difficulty accessing these drugs because they were not used on label and were unlikely to be covered by insurance. And moreover, even if they could access the drugs, there was no organized mechanism to collect outcome data and report on the results of the patient experience receiving that treatment.  So those factors led to the development of TAPUR, which attempts to solve both the drug access problem by having collaborating pharmaceutical companies donate their drugs to the trial so they’re available to patients at no cost, but also implements a structured data collection mechanism so all of the relevant clinical outcomes with the patients can be collected and ultimately reported. And that’s how TAPUR came about. Shannon Westin: Well, it was so necessary, and I think we do so much of our oncology treatments off-label, but as we get more and more expensive drugs when we move away from chemotherapies and more targeted immunotherapies, it’s very hard to get those drugs off label. So this was such a relevant and necessary trial that had to happen, and it's a great example of leadership that you had the vision to put this together through ASCO.  I think the natural next question for me is having not put patients on the TAPUR study, how does a patient join this study? How do they get started? Walk us through that. Dr. Herbert Duvivier: At our institution, normally, all the physicians are aware of the TAPUR trial through internal conversations. When they have patients who have been treated with multiple lines of standard therapy, usually the next step for them is to get NGS testing. We have a research team that reviews all NGS testing for these patients and knows the open arms of the TAPUR trial. And if there happens to be a particular patient who may match with one, they will inform the physician. It is then up to the physician to speak to the patient about that option.  Shannon Westin: Do you have people come looking for the TAPUR trial or are these generally more established patients? Dr. Herbert Duvivier: From my perspective, I think it is usually established patients. Shannon Westin: I think what I love about this trial, and I have spoken about this trial in lectures around baskets, it’s such a pragmatic design making it as straightforward as possible to really implement across different centers, whether academic or community, or wherever they are. I guess one of the questions always around these targeted therapies is the molecular selection. How do you make sure that people are being appropriately molecularly selected and how do you decide which testing to utilize?  Dr. Richard Schilsky: As you pointed out, Dr. Westin, the goal of the study from the beginning was to have a very pragmatic design, in a sense to have this study attempt to replicate the way oncologists were deploying precision medicine in their practice. The study has broad eligibility criteria, it has minimum necessary data collection, it uses conventional clinical evaluations, there are no additional clinical evaluations required that are not part of routine clinical care. And it just makes it easy to embed the study into the clinical workflow. The study is based largely at community sites, about 85% of the 268 participating sites are located in smaller communities. The study has a set of genomic matching rules that are listed in the protocol and baked into the IT platform for the study as a rules engine. For every treatment available in TAPUR, there is a set of genomic inclusion and exclusion criteria.  So in essence the way it works, the physician determines that NGS testing is appropriate for their patient and can use any NGS test they want, as long as the test is performed in a CLIA certified, CAP, or New York State-accredited laboratory. They select the test, they select the biospecimen to be tested, they get the results, they look at the results, and they determine if there is a genomic alteration in the patient's tumor that is targeted by one of the study treatments in the TAPUR study. They can enter that into the rules engine, the rules engine will confirm or not that the appropriate alteration of treatment has been selected. If it is confirmed, then the patient can immediately be enrolled in the study if they meet the clinical inclusion and exclusion criteria.  If the rules engine does not confirm the treatment match is appropriate, or in some cases there are multiple possible treatment matches, if there are multiple alterations that can be targeted, or another case is the doctor is simply uncertain about which alteration is best to target, then the clinical site can send that patient case to the TAPUR molecular tumor board. A group of experts convenes weekly that reviews the clinical history, the pathology report, genomic test report, the prior therapy the patient has received, and they make a determination as to whether or not there is an appropriate therapy that’s available on TAPUR for the patient. And if not, then are there other potential therapies  that are available that could be considered. That information is sent back to the treating physician who determines whether or not here she feels that treatment option is appropriate for their patient, and if so, the patient can then be enrolled and receive the therapy. Shannon Westin: So awesome. I love the idea. If we don’t have an arm for you on our trial, we can help assist you potentially determine an option for your patient outside of that. That’s so clever.  Okay. So let’s get into this particular arm. Obviously, our audience is quite savvy and are aware of the role of immune checkpoint inhibition across a number of solid tumors. Could you describe what you sought to determine in this particular arm of the TAPUR study?  Dr. Herbert Duvivier: I think one of the most important things to remember about this study is that this study was opened and accruing prior to pembrolizumab becoming FDA approved in, I think, June of 2020. So prior to June of 2020, there was no indication for pembrolizumab in high TMB tumor types and the goal of the study was to determine if pembrolizumab had any overall response rate, duration of responses, progression-free survival, or overall survival advantage over what would be considered standard chemotherapy at that time in patients with high TMB. Dr. Richard Schilsky: Yeah, that's exactly right. And in this paper that we're discussing, we're reporting on two different groups of patients. So there's a group of 28 patients, all with colorectal cancer, all of whom had high tumor mutation burden, as defined by the protocol. And that's one group. Then there's a second, larger group of patients, which is a very heterogeneous group of solid tumor patients. And the reason that that group is reported is there were patients who were being enrolled with multiple different tumor types with high tumor mutation burden. Each tumor type determined a specific, tumor-specific cohort in the study, and they were enrolling at different rates depending upon how common the particular tumor type was. But once the FDA approval for pembrolizumab, for any tumor with a high tumor mutation burden, was granted, then all of those cohorts essentially had to close to new enrollments because there was no longer an off-label use for pembrolizumab in that setting - everything was now on the label.  The result was that we then basically collapsed all of the open cohorts that were not then going to be able to complete into this one large, heterogeneous cohort that's being reported in this paper. And going back to the colorectal results, in the paper, we describe a disease control rate of 31%, an objective response rate of 11%. There were three patients who had partial responses lasting 12, 27, and 97 weeks each. And I think it's important to point out that in this particular cohort, essentially all of the colon cancer patients were microsatellite stable. So that's an interesting nuance here because we know that pembrolizumab is active and has an FDA approval in microsatellite high tumors. But this particular group of patients was essentially all microsatellite stable, suggesting that even in that population, if the tumor also has a high tumor mutation burden, the patient has the potential to respond and benefit from the treatment. Shannon Westin: I found that very intriguing. And, of course, as a gynecologic oncologist that treats endometrial cancer, I'm always thinking about MSI and microsatellite stability. So I was very intrigued by this. We are not seeing a ton of TMB high in our population, but there are some patients that do have that.  So let's talk a little bit about the results for the collapsed all solid tumor group. What did you find there? Dr. Herbert Duvivier: In the histology pool cohort, there were 47 patients representing 21 different tumor types, with a median tumor mutational burden of approximately 13 mutations per megabase with a range of 9 to 228. 40 of 47 patients had MSS disease, microsatellite stable disease. 6 of the 47, MSS was not reported, and 1 case was ambiguous. The disease control rate was about 45%, and the objective response rate was 26%. There were 3 complete responses: 1 in bladder, 1 in parotid, and 1 in squamous cell carcinoma. 9 partial responses and 9 stable disease 16 plus weeks. Of interest in the patients that were responding, 10 out of the 21 patients had POLE or POLD1 mutations, and 9 of the 21 patients had BRCA1 or BRCA2 mutations, although most of those mutations were classified as variants of uncertain significance. Shannon Westin: That's really interesting. We've seen pretty good data for POLE and benefit from immunotherapy, although at least in the GYN tumors and especially in endometrial cancer, those patients usually do well no matter what you do with them. And so they don't often make it to get immunotherapy because they have a complete response up front to their surgeries. So very intriguing to see that driving benefit. I'm just interested to see because it seems like there's a range that you were quoting of what was considered to be TMB high. So did you see a correlation for response to therapy based on how high the tumor mutational burden was in a given tumor or tumor type? Dr. Herbert Duvivier: Yes, actually we did see a moderately negative correlation between maximum percent change from baseline in a tumor and increasing TMB, which indicated an association between a higher TMB and greater shrinkage of tumor lesions. Dr. Richard Schilsky: I should point out, by the way, that when we introduced this arm into the TAPUR study, this high tumor mutation burden arm, as Dr. Duvivier has already pointed out, it was prior to, of course, the FDA approval, and the FDA approval is for tumors that have at least 10 mutations per megabase. It was also prior to the adoption of that threshold of 10, based on work by Friends of Cancer Research and others as sort of the convention for what defined a high tumor mutation burden. So when we put this into TAPUR, we essentially consulted with some of the testing laboratories. We consulted with Merck, the sponsor for pembrolizumab and actually in the TAPUR study, we defined a threshold of 9 mutations per megabase as defining high tumor mutation burden.  Now, as Dr. Duvivier said, there's a broad range of tumor mutation burden represented in this population, and there does seem, if you look at, if the readers want to look at figure 4 in our paper, there does seem to be a general correlation between best response and number of mutations per megabase, which also holds true in a modest way for both progression-free and overall survival. So, TMB is somewhat predictive of favorable outcomes. It's not a perfect biomarker by any means, but generally speaking, if you have enough patients, you can define this sort of trend to support the notion that the more mutations, the greater the likelihood of benefit. Shannon Westin: That makes a lot of sense. One other thing that I just wanted to comment on before we kind of bring the podcast to a close is I was really struck by the high proportion of underrepresented minorities in this arm of TAPUR, and I just would love to hear your thoughts on how the design improves recruiting in this population of patients. Dr. Richard Schilsky: This was a goal of the study, very intentional. When you look at the overall study demographics, there are about 2800 patients now that have been enrolled on TAPUR overall. Almost 12% are black, about 6% are Hispanic, about 4% Asian. The median age is about 64. So it's a slightly older population. The goal always was to enroll a population of patients in TAPUR that was broadly representative of the patients that oncologists treat in practice. In the way we accomplished what we've accomplished, we still have work we can do to improve it. But the clinical sites were carefully selected and vetted. We focused on sites that served a significant fraction of minority patients. We made the eligibility criteria simple and broad, so many of the eligibility criteria that might typically exclude minority populations or older patients from clinical trials are not exclusion criteria in TAPUR. We made the operations of the trial simple, so patients really aren't asked to do much more than what they would normally be asked to do in the course of their routine cancer care. So I think all of those things together have made it possible to attract and enroll a more representative patient population in the study. And we're very gratified by that because when you look at many of the registration trials for many cancer drugs, minorities and older people are terribly underrepresented. So we feel that TAPUR is adding value there and adding useful information. Shannon Westin: I think it's so generalizable and really the way people are practicing, and so to see similar results or concordant results, despite not as much of the rigorous testing and potentially exclusion of certain patient populations is really reassuring and certainly very exciting.  The last question is what's coming next? What other arms are coming soon? And can sites still join? Is this something where it's ongoing enrollment and participation? Dr. Richard Schilsky: So sites can still join. There's a place on the ASCO website where sites can find more information about TAPUR, and there's essentially a form available where sites can indicate their interest in joining the study. And then those sites are then evaluated by the TAPUR study team to determine if they meet the minimum necessary requirements to qualify to join the study. There's a lot more data coming out, many more papers that are in press and being written. There are two abstracts that will be presented in April at the AACR meeting. There are three abstracts that have been submitted for the ASCO annual meeting. So a lot more data to come.  This is a study that, at least hypothetically, could continue in perpetuity as long as we're able to continue to attract new drugs and new treatment combinations onto the TAPUR study platform. So the TAPUR team is always on the lookout for drugs that are about to get an FDA approval and that could be appropriate for the TAPUR study and continue to talk to many pharmaceutical companies about their interest in potentially putting their drugs on the platform. Shannon Westin: Well, great. Thank you both for taking the time. I know you're both incredibly busy.  Again, this has been “Pembrolizumab in Patients With Tumors With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry Study.” I'm your host, Shannon Westin, and I'm so grateful that you joined us on JCO After Hours. Please check out our other offerings on the website or wherever you get your podcasts. Have an awesome day.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Duvivier's COIs: Speakers' Bureau Company name: Guardant Health Company name: AstraZeneca Company name: Regeneron  Schilsky's COIs: Leadership Company name: Clarified Precision Medicine Company name: Leap Therapeutics Stock and Other Ownership Interests Company name: EQRx Company name: Leap Therapeutics Consulting or Advisory Role Company name: Cellworks Company name: Scandion Oncology Company name: Bryologyx Company name: Illumina Company name: EQRx Company name: Syapse Company name: Zephyr AI Company name: AADi Research Funding Company name: AstraZeneca Company name: Bayer Company name: Bristol-Myers Squibb Company name: Genentech/Roche Company name: Lilly Company name: Merck  
3/14/202419 minutes, 56 seconds
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JCO Article Insights: Axillary Soft Tissue Involvement and Breast Cancer Prognosis

In this JCO Article Insights episode, Giselle de Souza Carvalho provides a summary on  "Pathologic Exploration of the Axillary Soft Tissue Microenvironment and Its Impact on Axillary Management and Breast Cancer Outcomes" by Naoum, et al and "Optimization of Breast Cancer Regional Nodal Management" by Braunstein et al published in the January 10, 2024 issue in Journal of Clinical Oncology. The original report discusses how the examination of axillary soft tissue beyond lymph nodes is often omitted and it predicts breast cancer outcomes and need for nodal radiation. TRANSCRIPT The guest on this podcast episode has no disclosures to declare.  Giselle Carvalho: Welcome to the JCO Article Insights episode for the February issue of the Journal of Clinical Oncology. This is Giselle Carvalho, your host, one of the ASCO editorial fellows at JCO this year. Today, I'll be providing a summary of an article focused on “The Association of Axillary Soft Tissue Involvement on Outcomes for Breast Cancer Patients.” It was published in November 2023 and was partially presented at the 64th Annual ASCO in October 2022. Although lymph node involvement in breast cancer patients is correlated with a worse prognosis, the impact of extracapsular involvement is still a matter of debate, and the implications of axillary soft tissue involvement are still not fully understood. There is some evidence indicating a decrease in disease-free survival for patients with less than four lymph nodes and with extracapsular extension, while other studies show that extracapsular involvement has no prognostic role in these patients and that the number of positive lymph nodes might matter more. Patients with node-positive disease may present with only lymph node involvement or lymph node involvement plus extracapsular extension and/or axillary soft tissue involvement. The axillary soft tissue involvement can result from either direct lymph node extension through the capsule or direct microscopic spread from the primary tumor. It is pathologically defined in this article as axillary lymphatic channel invasion, axillary soft tissue deposits, axillary blood vessel invasion, or any combination of these. This was a retrospective study of patients with invasive breast cancer who received treatment at Massachusetts General Hospital in Boston, Massachusetts, from 2000 to 2020. Lymph nodes and surrounding adipose tissue were submitted in their entirety for histopathologic evaluation using hematoxylin and eosin stain, and immunohistochemical stains could be added at the pathologist's discretion. Eligibility criteria included primary breast cancer and positive lymph nodes without prior or contralateral breast cancer. 2,162 patients were included. They were divided into four groups according to their axillary pathology: the first group was composed of patients with positive lymph nodes with no additional axillary involvement; the second group of patients with positive lymph nodes and extracapsular involvement; the third group of patients with positive lymph nodes and axillary soft tissue involvement but with no extracapsular extension; and the fourth group of patients with positive lymph node and both extracapsular extension and axillary soft tissue involvement. Primary endpoints were 10-year rates of local-regional failure, which was defined as recurrence in the breast or chest wall or ipsilateral axilla, axillary failure, and distant metastasis. Among 2,162 patients, 58% had lymph node involvement only, 25% had lymph nodes with extracapsular extension, 3.5% had lymph node involvement with axillary soft tissue involvement, and 14% had lymph node involvement with both extracapsular and axillary soft tissue involvement. 51% of cases of axillary soft tissue involvement were in the form of axillary lymphatic channel invasion. The median follow-up was 9.4 years, and 74% of the cohort had hormone receptor-positive breast cancer, 10% had triple-negative disease, and 16% had HER2-positive disease. The groups with axillary soft tissue involvement, extracapsular extension, or both had more advanced tumor pathologic features when compared to the lymph node-only group, including a higher median size of breast tumors, a higher number of malignant lymph nodes, and an increased likelihood of breast lymphovascular invasion. Additionally, more patients in these three groups received mastectomy, axillary lymph node dissection, regional lymph node radiation, and systemic therapy. The lymph node-only group had the lowest 10-year incidence of distant failure, 13%, while the group with extracapsular extension and the group with axillary soft tissue involvement both had a 23% rate of distant failure at 10 years. The risk of distant failure reached an impressively high rate of 42% for the group with both extracapsular extension and axillary soft tissue involvement. Considering 10-year local-regional failure, the first group had a 6.2% rate, the second group a 5.7% rate, the third group a 10% rate, and the group with lymph node positivity with extracapsular extension and axillary soft tissue involvement had a 14% rate. The 10-year axillary failure rates were only 1.6% and 0.8% for the groups with no axillary soft tissue involvement but rose to 4.6% and 4.5% for the groups which did have axillary soft tissue involvement. In multivariable analysis, including tumor size, grade, number of positive nodes, and receptor status, axillary soft tissue involvement remained significantly associated with distant failure with a hazard ratio of 1.6, local-regional failure with a hazard ratio of 2.3, and axillary failure with a hazard ratio of 3.3. Of note, the number of axillary failures was overall low, only 4.6% in the group with both lymph node and axillary soft tissue involvement. Delivery of regional lymph node irradiation, defined as treatment of axillary, supraclavicular, and internal mammary nodes, was associated with improved local-regional outcomes in patients with extracapsular extension or axillary soft tissue involvement with a hazard ratio of 0.5 and a p-value of 0.03 but was not associated with any improvement in distant failure. The authors described the main limitations of this study as the retrospective nature and the absence of genomic marker results. In summary, although current guidelines do not emphasize axillary soft tissue examination, this study shows the importance of reporting axillary soft tissue involvement beyond the number of positive lymph nodes and the presence of extracapsular extension, as there is an increase in local-regional, and axillary failure rates for patients with axillary soft tissue involvement even without extracapsular extension. Therefore, both extracapsular extension and axillary soft tissue involvement should be consistently reported in large randomized trials as we continue to work to tailor local therapy to individual patient risk. This is Giselle Carvalho. Thank you for your attention and stay tuned for the next episode of JCO Article Insights. The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.        
2/26/20248 minutes, 31 seconds
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Omission of Radiotherapy after Breast-Conserving Surgery

Dr. Shannon Westin and her guest, Dr. Reshma Jagsi, discuss the paper "Omission of Radiotherapy After Breast-Conserving Surgery for Women With Breast Cancer With Low Clinical and Genomic Risk: 5-Year Outcomes of IDEA" recently published in the JCO. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth with manuscripts that were published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncologist and Social Media Editor for the JCO. It is my pleasure to speak with Dr. Reshma Jagsi. Hello, Dr. Jagsi. Dr. Reshma Jagsi: Hello. Thanks for having me. Shannon Westin: I am so excited that you're here. Dr. Jagsi is the Lawrence W. Davis Professor and Chair of the Department of Radiation Oncology at Emory University School of Medicine, Winship Cancer Institute. She is going to be talking about her incredible work, "The Omission of Radiotherapy After Breast Conserving Surgery for Women with Breast Cancer with Low Clinical and Genomic Risk: Five-year Outcomes of IDEA," which was published in JCO in February 2024.  All right, let's get right to it. First, I want to levelset. Can you run us through some brief facts and figures about breast cancer just to make sure that all the listeners are on the same page?  Dr. Reshma Jagsi: Breast cancer is the most common cancer in the world. It’s 12.5% of all new annual cancer cases worldwide and is the most commonly diagnosed cancer among US women. About a third of all newly diagnosed cancers in women are breast cancer, and about 13% of US women develop invasive breast cancer over their lifetime. In 2023, there were nearly 300,000 new cases of invasive breast cancer. The median age of breast cancer diagnosis is 62, meaning an awful lot of people are getting diagnosed with breast cancer in the population that we specifically chose to study.  Shannon Westin: Wow, you're really good at this. That's like the perfect transition to move to the next piece. So, first, I think I'd love to hear about the standard of care for the population that you were studying and how we got to this point.  Dr. Reshma Jagsi: We offer women who are diagnosed with early-stage invasive breast cancer the option of breast conservation, and we encourage breast conservation because, of course, it is a better-tolerated surgery than mastectomy. Many women are eligible for breast-conserving therapy. And years ago, we as radiation oncologists encouraged our surgical colleagues to refer to breast-conserving therapy as lumpectomy plus radiation, just as one set. Because the studies that have been done in the 1970s and 1980s to establish that breast conversation was equally safe and effective in treating breast cancer relied on radiation therapy to minimize in-breast tumor recurrence rate, which one of those trials independently showed that there was no difference in survival. But the ones that compared lumpectomy surgery alone to lumpectomy followed by radiation therapy did show a pretty substantial improvement in local control with the addition of radiation treatment. And so radiation treatment became a part of a parcel of breast conservation in the early 1990s when consensus statements came out favoring breast conservation as a treatment approach.  And so the net analysis has combined all of these studies together and showed that overall, without radiation treatment, a patient treatment with a lumpectomy had a 30% risk of in-breast tumor occurrence in those historical studies. And it was reduced by about two thirds to about 10% when that lumpectomy was followed by radiation in those historical randomized trials. But of course, we’ve made many advances in our understanding since that time, and so that’s what this study is seeking to build on. Shannon Westin: It makes sense. We all know that radiotherapy can lead to other issues, acute and chronic morbidities, as well as cost and having to do the treatment itself. So we're all interested in de-escalation of therapy. Tell me, prior to your study, what data were out there potentially supporting the de-escalation and avoiding radiotherapy in that specific population? Dr. Reshma Jagsi: In the ‘90s, after those landmark foundational historical trials have been completed, there was a lot of interest in seeing if we could identify a population of patients in whom the risk of local recurrence was sufficiently low that they might safely choose to omit radiation therapy. All of these randomized trials have shown very consistently that there is a relative risk reduction. Whatever your risk is without radiation, radiation reduces that risk. The overall disease recurrence risk is cut in half with the addition of radiation treatment. But, if I told you that your overall risk was 1%, and I could cut that in half with radiation, you might say, “I might be willing to tolerate the 1%.” At least some women might be willing to tolerate that. So can we find a population in whom the risk is low enough that at least some of those women say, "Look, I want to go without radiation." And of course, the balance of where that number should be changes as we get better and better at delivering radiation. So you mentioned, radiation comes with toxicity, comes with burden and yet, there have been some tremendous advances, and particularly in recent years, to shorten the course of radiation. We have evidence that we can treat partial breast radiation safely in five treatment fractions. We have five-year data that we can treat the whole breast in five-treatment fraction. We certainly have long term evidence that we can the whole breast with 15 fractions from many patients diagnosed with breast cancer. So the burden has decreased. We’ve also found that with hypo fractionated shorter courses of radiation, the toxicities are much lower, patients tend to tolerate radiation treatment both in terms of acute side effects and long term side effects extremely well.  So that balance of what is low enough is changing with time.  But the trials that were started in the 1990s included the CALGB 9343 trial, a landmark trial published in the New England Journal of Medicine, with its five-year results showing only a 4% risk of recurrence at five years in patients who were 70 or older with clinical stage one disease that was hormone receptor-positive if they received a lumpectomy and tamoxifen alone, not receiving radiation - that risk, if we added radiation in this randomized trial, was only 1%. So there was still a substantial relative risk reduction with radiation treatment. This was published in 2004 in the New England Journal of Medicine.  At the same time, there was a Canadian trial that was published, and in that trial that included women who were 50 years of age and older, there were more concerning results with, even in a very favorable prespecified subgroup of patients who had node-negative breast cancer and T1 hormone receptor-positive tumors, the risk of ipsilateral breast tumor recurrence was 15% at eight years. So that started to feel excessive for women 50 and older.  Meanwhile, we went on to get the update of the CALGB trial, and the 10 -year results showed that the risk was, in the women 70 and older, was only about 10% without radiation. It was 2% with radiation. So again, there was a benefit from radiation, and it's up to each individual woman to decide whether they'd prefer to proceed and minimize their risk, or would be willing to tolerate something like a 10% risk. More recently, just this past year in the New England Journal, the PRIME 2 study from the United Kingdom, looking at women 65 and older, again, early-stage node-negative hormone receptor-positive tumors, and very similar results - 10% versus 1% local control at 10 years.   So you get an improvement with radiation. But there are some women who are 65 or 70 and older who say, I'm willing to tolerate the 10% risk. And so the question was, could we identify some patients who are younger than 65 to 70, but still postmenopausal, like in that Canadian trial, who might actually have similar outcomes - low risks at five and ten years - such that they might want to entertain the option of omitting radiation therapy, which right now is not standard or in any guidelines? So we have some promising information from some retrospective analysis of that Canadian trial that suggested that looking at biology might help. And in fact, the LUMINA trial, published just this year from Canada, did a prospective cohort study selecting patients based on immunohistochemistry, and suggested very low risks, five years in patients who were somewhat younger, although it ended up that the median age of the patients in that study was 67. So we still sort of had this question of what about the younger postmenopausal patients? And that's what took us to IDEA.  Shannon Westin: And just for my education and for the education of the listeners, when you have an in-breast recurrence, how likely are you to be able to cure that? Is that tough to cure, or can you usually get control again? Dr. Reshma Jagsi: It's an excellent question. And so often these recurrences are caught early and are still completely curable with additional intervention. Now, there can be an impact, of course. You can talk to any survivor about the devastating impact of being diagnosed with breast cancer recurrence, and no one wants to go through that. And so there are reasons that people will want to reduce that, and there are implications for breast conservation because it may be that the remaining breast tissue is insufficient to allow a second breast conserving surgical procedure. It may also be that when one experiences recurrence, one decides, "I'm done with this. I'm having a mastectomy at this point." So, in-breast recurrences are very meaningful to patients and something that we should not take lightly. Shannon Westin: It seems, though, the majority of the studies that you were talking about, aside from the LUMINA study, were predominantly based on those clinical features like stage and things like that. So, can you talk a little bit about the role of molecular features, genomic testing, things like that, to select patients?  Dr. Reshma Jagsi: Yeah. So, we have seen a tremendous change in the way we think about breast cancer in recent years, with a real focus on tumor biology, rather than classic clinical pathologic features alone to help us make decisions about systemic therapy. And so, there is a body of work that suggests that genomic assays, including the 21-gene recurrence score, that's commonly used for treatment decision making already ordered in many of these patients and available to us, that it may be useful in understanding patients' risk of local recurrence, both when they are treated with radiation and when they are treated without radiation. So, Terry Mamounas did some wonderful work looking at NSABP data where you know that the mastectomy patients at the time of the studies that were included were not receiving radiation treatment. And it did appear that the 21-gene recurrence score was helping to discriminate for local regional recurrence risk, suggesting it might be useful to use that to select patients who might be at lower risk.   Shannon Westin: All right, perfect. So, that leads us to your study. So, let's talk a little bit about the design and the population and kind of how you put it together.  Dr. Reshma Jagsi: This was really a true collaboration, a partnership across multiple 13 collaborating sites, where my colleagues, the lead investigators at each site, were extremely committed to this question. And we sought to do a preliminary cohort trial, really involving 200 patients. And over the course of three years, we enrolled those 200 patients who were aged 50 to 69 years old and had unicentric invasive breast cancer and lumpectomy surgery that led to negative margins of 2 mm or greater. And their disease needed to be PR positive, HER2 negative, it needed to be node negative, pathologically node negative, and the Oncotype DX 21-gene recurrence score needed to be less than or equal to 18. And then these patients were offered the opportunity to consent and register on a trial to receive five years of endocrine therapy as standard of care alone, and 10 years of surveillance on study, or to proceed with the standard of care treatment off trial, which would have been a recommendation to receive radiation treatment. And so, we ended up with patients with a mean age of 62 years, which, as I said, that's really more mapping the overall population of patients in the country. And we were able to report our results at the San Antonio Breast Cancer Symposium and with simultaneous publication in JCO, with a median follow up of 5.2 years. Shannon Westin: Okay, and let's talk about a little bit about your major findings. Tell us what your good work demonstrated. Dr. Reshma Jagsi: So, the overall and breast cancer-specific survival rates at five years were both 100%, and the five-year freedom from any recurrence was 99%, with a 95% confidence interval that went from 96% to 100%. But I want to emphasize that these are five-year data in a younger postmenopausal population, where five-year data are not typically sufficient to guide decision making. So, I really want to emphasize that these are very early results. But really, what happened here was we only had a couple of patients who had recurrences before five years, two patients, and that was one isolated ipsilateral axillary recurrence, and one ipsilateral breast event. But we also did see six additional patients who recurred later than five years after breast conserving surgery. And because we don't have much long-term follow-up, it makes it incredibly important for us to continue to follow this cohort over time before people make any Monday morning practice implications of offering this cohort of patients, or patients like this cohort of patients, omission off trial.  The good news is that there are ongoing trials that are building on this work, including NRG-BR007, the DEBRA ,that includes a population of patients really similar to those enrolled on IDEA and randomizes them to radiation or no radiation, which is actually incredibly important. Because what we want to understand is also the quality of life effects of omitting radiation therapy because what we don't want is to inadvertently cause an increase in worry about recurrence. Or, you could imagine that patients who omit radiation treatment then feel really stuck with their endocrine therapy. Now, endocrine therapy is the standard of care, but if they're experiencing terrible endocrine therapy side effects and they didn't get radiation treatment, are they more likely to persist with that endocrine therapy and to be miserable because they omitted a treatment that, as I mentioned earlier, can be administered now in five days or less?  And one of the questions that keeps coming up from older patients that I treat, where we already offer the option of omitting radiation, those CALGB and PRIME II patients, those patients will often say to me, "I’ve got to say, Doc, that whole experience of radiation that you described for five days, and the toxicity, and that doesn't sound so bad to me. What sounds bad to me is multiple years of endocrine therapy." And so, there are also ongoing trials in Europe, and I hope one day in the United States, also looking at older women and offering them a de-escalation of a different sort. Now that we have made so many advances in radiation treatment, maybe the optimal monotherapy for an older adult is actually, for many patients, given their values and preferences, going to involve omission of endocrine therapy. And we need to find out if that's safe. And again, Europa in Europe is investigating that question, and I hope that the American cooperative groups take up something similar. Shannon Westin: That’s awesome! And what else is going on in this space? Any other trials? That was like, such a great review of ongoing trials, and I'm sure our listeners would love to have your expertise. Anything else that you're looking forward to that might impact the treatment landscape here? Dr. Reshma Jagsi: Absolutely, and if there are listeners in other parts of the world, there are trials going on also looking at this. There is PRIMETIME, which is a cohort study designed, but with a much larger cohort that's going on in the United Kingdom. There's the EXPERT trial that is randomizing patients to radiation treatment or not in Australia and New Zealand. So, there are many trials that are ongoing, again, looking at de-escalation of radiation therapy. And I want us all, regardless of our specialty, to think about ways that we can de-escalate and optimize the options that are offered to our patients. And I think there's a tendency for patients to be very scared of radiation, sometimes, for our colleagues to be very scared of radiation. I mean, we are the only specialty that has a special “danger radiation sign” that comes to mind when you hear the word radiation therapy. So, it can be this very frightening thing that we often leap to efforts to avoid.  And what I don't want to be the conclusion of this is, “Isn't it great? Radiation oncologists themselves recognize that radiation is terrible and that you should avoid it.” That's not the case. What I hope people will say is, “Isn't it great that radiation therapists are trying to offer as many options to patients as possible?” Because it means a lot to a patient who's had the sense of power and control and autonomy ripped away from them by a breast cancer diagnosis, to be given many options to articulate their values and their preferences and to decide what treatment makes most sense for them. I think, for a lot of patients, that involves radiation treatment. And I think what we need to do as physicians is think about what other things are our patients really concerned about.   Our medical oncology colleagues have done tremendous work to de-escalate systemic therapy in the form of chemotherapy. Our colleagues in surgery have, again, de-escalated mastectomies, axillary dissection. So, there are these ongoing efforts, and I do honestly believe that the next frontier is endocrine therapy and optimization of endocrine therapy. It is so powerful. It is why we have such wonderful outcomes. We know that we should have a healthy respect for ER-positive cancer, which can recur in the long term. We don't want to throw out the baby with the bathwater, but baby steps towards understanding what happens if we peel back our treatments is our obligation.  Shannon Westin: I think this is a perfect place to end/ I agree - less is more is really becoming a resonant statement across all of our different subtypes. We're certainly seeing it in GYN oncology, and just like you said, systemically or even surgically. So I agree. I think we have a call to action to really assess what we've always done and make sure that we're not over-treating patients for whom it's inappropriate.  So I think this is great. And I just want to commend you again on your work. These types of multicenter trials are really hard to do, and getting it done in such a short period of time and really getting the data out to patients is so important. And I appreciate what you're saying about needing more follow-up, but it is certainly very reassuring and very in line with what we've seen. So congratulations on your work. Dr. Reshma Jagsi: Thank you. And I just again want to thank all the patients who enrolled, the Coleman Foundation for their support, the University of Michigan for doing the multi-site coordination and the biostatistic support, and all of the collaborating investigators. I mean, this was a labor of love for everyone involved. Shannon Westin: Yeah, these types of trials definitely take a village. Well, great work. Thank you for taking the time. I know how busy you are. So again, we are so honored and so excited to talk about "The Omission of Radiotherapy After Breast Conserving Surgery for Women with Breast Cancer with Low Clinical and Genomic Risk: Five-year Outcomes of IDEA,” just published in print, February 2024 in the JCO. Definitely check it out. And please check out our other episodes of JCO After Hours. We'd love to have your feedback. Take care. The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    Dr. Jagsi: Stock and Other Ownership Interests Company name: Equity Quotient Research Funding Company name: Genentech"
2/22/202420 minutes, 42 seconds
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Costs of Cancer Prevention in CDH1 Variant Carriers

Dr. Shannon Westin and her guests, Dr. Jeremy Davis and patient advocate Kathryn Carr, discuss the paper "Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy" recently published and printed in the JCO. TRANSCRIPT Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, a professor of GYN Oncology at MD Anderson, and the JCO social media editor. I am so thrilled to have wonderful authors here today who do not have any conflicts of interest. We are going to be discussing the “Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy.” This was published in the Journal of Clinical Oncology online on October 30, 2023, and in print on February 1st, 2024.  And I am excited. I am accompanied by the lead author, Dr. Jeremy Davis, who is an Associate Professor and Surgical Oncologist at the NIH, National Cancer Institute Intramural Research Program. Welcome, Dr. Davis.  Dr. Jeremy Davis: Thank you. Shannon Westin: If it is okay with you, I'll call you Jeremy. Dr. Jeremy Davis: Yes, please.  Shannon Westin: Fabulous. We also have patient advocate Kathryn Carr, who is a board member for No Stomach for Cancer. Welcome, Kathryn. Kathryn Carr: Thank you so much.  Shannon Westin: So let's get right into it. I think this is really thought-provoking work. First, I'd love to level set. So this was work around hereditary diffuse gastric cancer syndrome. Can we get a little bit of information about what causes this and how common it is? Dr. Jeremy Davis: So, hereditary diffuse gastric cancer syndrome, also referred to as the diffuse gastric cancer and lobular breast cancer syndrome, is basically early-onset diffuse gastric cancer and in women, lobular type breast cancer attributed to germline mutations in the CDH1 gene. If we look at all cases of gastric cancer in the United States, only about 1-3% may be considered hereditary in nature. But when we do study hereditary causes of cancer, it is by far the most common one that we are aware of. Shannon Westin: What is the likelihood that someone who is a carrier of a germline CDH1 variant will develop gastric cancer? Dr. Jeremy Davis: That's a good question. Early on, when the syndrome was first described, the estimates of cancer risk were quite high, probably upwards of 70-80%. The good news is that more current estimates published in the last few years suggest that that risk in a lifetime is probably in the 25-40% range. It’s interesting, we do have our own data that are under review right now, where in some families where there’s no history of stomach cancer, that risk of stomach cancer in a lifetime getting a CDH1 mutation might be as low as 10%. So I think the takeaway is that there’s clearly a spectrum and that spectrum of risk is probably based on factors that we don’t quite yet understand. Shannon Westin: What are the options for management of this hereditary syndrome, really focusing on the gastric cancer syndrome portion today? How good does it do to reduce the risk? Dr. Jeremy Davis: The options are really two. One is probably the prevailing recommendation that most people would be aware of, is to prophylactically remove the stomach, and we choose to use the term most often ‘risk-reducing gastrectomy’, but to remove the entire stomach and really eliminate the risk of cancer from ever developing. The other option is enhanced surveillance, and people might think of this as akin to other high risk cancer syndromes. But for this we would do yearly or annual endoscopic surveillance. Many people think that that may not be the best option, but it is certainly an option. We discussed some of that in the paper about what are the risks and benefits of gastrectomy, and then what may be the benefit of enhanced surveillance for some people. Shannon Westin: Well, I would love to hear Kathryn. I think this is a perfect opportunity to hear a little bit about your journey with carrying this variant, as much as you are willing to share with our listeners. Kathryn Carr: Yeah, absolutely. So I found out that I have this spicy little gene back in 2019. My whole family got tested so the gene comes down from my paternal great grandmother. There are five of us who actually all had our stomachs removed by Dr. Davis. Within a year, he had five Carr stomachs. For me when I found out, I was extremely overwhelmed. I mean, “You want to take my stomach out? Like, what do you mean?” But after talking to Dr. Davis and his entire care team, I knew for me, having the total gastrectomy was the only option simply because I know my personality type enough that I was not going to be able to move forward with life unless I got rid of this overwhelming worry. Shannon Westin: Yeah, I think that makes sense. I'm a GYN oncologist by trade, so I often reference all things surgery around that. We have the same thing when we talk about risk-reducing surgeries for endometrial and ovarian cancers. This seems more like what we do in Lynch syndrome, where patients are at risk for endometrial cancer. Removal of the uterus is almost definitive in its ability to reduce that risk, but it's obviously a very large surgery. Jeremy, can you review the gastrectomy in general? What are the most common short-term and long-term adverse events? What did you have to discuss with Kathryn and her five family members around what they could expect from this surgery? Dr. Jeremy Davis: Yeah, I think this is a great question because it's the thing at the top of most patients' minds. When I sit down to talk to somebody about gastrectomy, usually a lot of the conversation initially centers around ‘how long does the operation take, how long am I at the hospital, and what are the most likely risks of the operation?’ The good news is that as operations go, it can be done in two to three hours, and most people are in the hospital for maybe five to seven days. The risks of this operation, however, at least during the operation or immediately afterward have to do with how we have to reconnect everything and reconnecting the intestine to the esophagus so that people can continue to eat. Because I think a lot of people wonder, "Well, how am I going to eat?” The stomach's gone, but we recreate intestinal continuity. We put things back together in a way that people can eat and absorb their food.  But that connection we make between the esophagus and intestine is almost like the Achilles heel of this operation. It's the one thing that keeps surgeons up at night, and it's probably the one thing that causes the most trouble in terms of immediate risks, like leaking. If that connection leaks, it can lead to infection. There are other aspects of the operation that relate to any kind of intestinal surgery, such as leakage, blockage, or narrowing or something like that. So these are the things you need to worry about in the short term. But you mentioned the long-term consequences, and that was really one of the reasons why we wrote the paper. If you look in the literature, the focus is on the acute problems, things that happen within 30, 60, or 90 days of the operation. Which, yes, those are very, very important. But since we're talking about an operation that's supposed to prevent cancer and therefore allow the patient to live a long and happy life, I think it's important for us to think about what happens well beyond the time that the patient essentially heals from the operation.  Shannon Westin: It's so critical. And I think before we go into the work that you did and what you all found, Kathryn, I would love to get your perspective. Having gone through the procedure, what was your experience? Give us as little or as much detail as you want, whatever you're comfortable with. But also, what did you wish you had known? What surprises kind of came up during the course?  Kathryn Carr: I'm going to quote Rachel, who works with Dr. Davis at the NIH. She's the clinical dietitian. And my question to her was, "Seeing all the patients you've seen and knowing all that you know, what would be the advice that you would give me?" She told me to have the patience to get through the first year. I think that really set my expectation of, "Okay, this is not just a surgery where in a week or two weeks I’m going to be up skipping along." It is a marathon. I really worked hard with Dr. Davis in the hospital. I'm allergic to everything. I was convinced that my spleen was erupting. I think I scared many fellows, and they were like, "That's actually not where your spleen is. It's fine. You're okay. Stop getting on WebMD." But once I got home, those first eight weeks, they’re hard. There were several moments where I would just sit and stare off into space and think, "Oh my gosh, what have I done?" But for me when Dr. Davis called to tell me the pathology report and that they did find some signet cells, I was 100% sure that I made the right decision. I would have been worried every second of every day that my body was going to turn on me. So once I kind of had that relief, it was like, "Okay, my body can do this. We're built to do hard things." Then it was just getting through the first six months, learning what I could eat, what I couldn't eat, working with Rachel on different strategies of, “Okay, I’m going to maximize my protein in the morning and then maybe get a little more adventurous as the day goes on.” But what I wish I had known before surgery, because I'm a planner, I want everything scheduled and figured out. I was in the hospital, I had a different outfit for every day, and I just wanted it to go perfectly. I think taking away the expectations of what your journey is going to look like would be the best advice I could go back and give myself. Because I am very competitive, and my dad and I were separated by seven months of this surgery. He can do things that I still can't do, and that's okay. Everyone's healing journey is going to look very different because everybody is going to respond incredibly different. It's like the body is doing roll call and the stomach is nowhere to be found, and everybody is going to respond totally differently to that. Shannon Westin: That's so insightful. I really appreciate that.  I guess now it's a good time to turn to the work that you did, Jeremy, and you kind of already hinted at what your objectives were, but can you maybe walk through your primary objectives in the way you designed the study. Dr. Jeremy Davis: You know, I think as somebody who trained to take care of people with cancer and do big operations to cure people, this was a little bit of a different experience in the beginning for me. Because here I was taking ostensibly normal people - Kathryn may argue with that statement - but normal people, and I was going to take them to the operating room and do something to them to prevent a problem. And this is not a minor thing, it's a big deal. What I learned pretty quickly was how much I was disrupting people's lives. And what I mean by that is that a patient comes to clinic three or six months after surgery. We all document the typical things. They are healing well, they are recovering as expected, their incisions are healed and all this stuff. But it was the stuff that didn't always go down in the medical record. The comments that the patients made to my team, the nurses, the dietitian, about how their lives were being disrupted. And this started to change my viewpoint on, “Oh my goodness, we're paying attention to important things, but we're really not paying attention to what's happening.” So, the idea behind the study was really to explore those consequences that don't get talked about a lot. That was the nature of the idea behind the study. It was easy enough for us to conduct the study because my research at the NIH is about gastric cancer, but more specifically, this hereditary form of gastric cancer. We have a natural history study that allows us to follow people for a long time, not just within three or six months of surgery, and then we're done. So that longitudinal aspect of the study is really what allowed us to accomplish that. Shannon Westin: What I thought was really interesting here is how many different types of questionnaires you were able to utilize to really assess beyond kind of the straightforward quality of life Yes/No. Can you speak a little bit about some of the questionnaires you chose and why?  Dr. Jeremy Davis: My concern going into this was that I had read a lot of the literature related to quality of life after gastrectomy for gastric cancer. There are certainly these validated questionnaires out there. And my sense was, having read those questions and papers, that those validated typical questionnaires- I'm referring to the FACT-G or the FACT-Ga might not capture the things that we wanted to capture. So, I spoke to our palliative care service here at the NIH clinical center, which is the hospital here on campus in Bethesda. They had developed a questionnaire many years ago that they called the NIH HEALS or Healing Experience of All Life Stressors. They designed that to identify stress causing changes associated with chronic illness. You might argue that having a germline mutation that puts you at risk for cancer is kind of a chronic condition. So, we thought we would use that.  And then the last part was we just sat around the table and we thought, “Well, jeez, what are all these things that people are telling us that would never be captured in almost any questionnaire?” And that's when we designed a series of questions that we thought were relevant to our patient population because we wanted to capture all the things that people had told us. Those were things like, “I had to change my job because I couldn't do the same work anymore, right?” Or, “My partner, our relationship changed substantially, and we grew apart, and we ultimately got divorced.” How do you capture that? So that's how we designed it. We basically looked at all the patients that we had done the prophylactic gastrectomy on and applied all of those validated and unvalidated questionnaires. Shannon Westin: That's so great. And I bet, Kathryn, you participated quite a bit in that, in addition to other people in the study. Kathryn Carr: I did, and I'm so grateful that Dr. Davis is doing this study because it is so important to look at what life is like without a stomach. You have this immediate thought of, “Okay, I just want to save my life. I want to make my life longer. But how is it going to change my life? How is it going to alter my day-to-day?” Because even Dr. Davis has said it would be weird if it didn't change your life. I mean, you're taking away a very important piece of the puzzle. So, I think this study is going to help people make more accurate decisions. I don't doubt my decision to have my gastrectomy at all, but this is beautiful information just so that you can be more well-prepared to walk into the surgery of, “Okay, now I have a very clear understanding of what my life could look like.” I've been very fortunate that I have not had a lot of the physical problems. I don't deal with a lot of bile reflux. My weight has stabilized, so I am very blessed in that way. But emotionally, this has been a really tough surgery. You start to feel misunderstood, like you have to walk into every day being very prepared of, “Okay, every two hours I have to eat something or else I get real hangry, not just a little hungry, real hangry. Also, my body will start to shake.” That's how I get my hunger signal. My whole body will start shaking, which is very scary. It's very unpleasant. I'm almost four years post-op, and so I lean into my schedule and routine.  One piece of advice for anyone walking into this surgery is to make sure you're anchored in something. For me, my faith anchors me, but if you're not anchored in something that is secure and true, like, you are going to float away, because this is a storm.  Shannon Westin: Jeremy, do you want to just pass on a few of the key findings? I encourage everyone to read the paper. There are so many different things that were explored and identified as part of this study. It's amazing with the number of patients that were involved, what the depth of the findings was. But perhaps you can kind of hit some of the major high points. Dr. Jeremy Davis: Yeah, I think the key takeaways for me, and obviously I'm still learning from all of this, is that I think we talk a lot about the surgery, in this case especially, but we don't talk enough about what life is like afterwards. I've started to talk to people about how much you think your stomach plays a role in your life, and you think about how much of our life centers around eating and drinking and holidays and family gatherings. And you have to imagine that means those activities are potentially disrupted. So for me, the key takeaways from this are, number one, we have to be aware. We have to be aware that risk reducing surgery of almost any kind has consequences. Yes, we want it to have a positive impact on the patient, but we have got to be aware of the negative impact. This is like systemic chemotherapy. It can do a lot of good, but toxicities are real. In terms of the specific findings from this study, listen, 94% of people in the study, 126 of people, 94% had some long term consequence. And it wasn't just like some long term, “Oh, I don't like my scar.” No, it was 94% of people had a long term problem, such as “I have daily bile reflux that interferes with my activities of daily living.” Something like that.   And I think the range of consequences is really important, too. And so, again, they range from things like GI symptoms, which you would imagine would be quite typical for a gastrectomy, but mental health, right? People talking about worsening symptoms of anxiety or depression, some substance abuse. Whether it was alcohol or otherwise, disruptions in relationships, I mentioned earlier, and even occupation change. I can't physically do the job that I used to do. So I think as clinicians, as surgeons that walk into this, yes, we need to focus on the surgery and the immediate consequences, but we also need to think, “How am I going to change this person's life? Not just for the better, but how might I really impair their life in the long term?” Kathryn Carr: Well, in one, just very simple example. So like going out to eat with people. There's a natural cadence of conversation. I take a bite, you talk and vice versa. But when you're chewing your food to the nth degree it interrupts that natural cadence. I avoid dinner dates because then I have to talk about my stomach on a first date or going out to dinner with friends. It's nice if there's a group of us because then other people can carry the cadence but then you kind of feel left out of the conversation because you're like, “Oh, well. I’ve got to eat, otherwise I'm going to pass out.” So that's just like a very simple, you wouldn't think of, “Okay, I'm going to dinner at 7:30 so I should probably eat a snack before I go because I might not get my food until 8:00 or 8:30.” So it's just like you're constantly thinking about, “Okay, I've got to make sure that I have food in my body.  Shannon Westin: It’s so critical.  Well, this has been an awesome discussion and I'm sad that it's coming to a close. I guess just final thoughts around what's next in this space. Like what are you working on now, Jeremy? Dr. Jeremy Davis: I'm a cancer surgeon and a cancer researcher so my goal is to find a way for us to prevent stomach cancer that doesn't require me having to take out somebody's stomach. So in the laboratory that's what we're doing, right? We're working on finding a way to prevent stomach cancer so that I don't have to do this operation anymore. But on the clinical side of things, the next thing that we're exploring is how do patients think about, talk about, or express concerns to their physicians about reproduction - reproduction in the setting of a cancer predisposition syndrome. And I think that's going to be really important work.  Shannon Westin: That's great. Kathryn, any thoughts? Kathryn Carr: I know that being four years out, I'm not like an old timer, but I do just want to help anyone who's at the beginning stages of this journey and just making other patients feel less alone. I told Dr. Davis I just entered the world of TikTok to talk about gastrectomy and just opening up a conversation of what does life without a stomach look like? And just making people feel less alone and more understood throughout this process. Shannon Westin: Thank you both for the work you're doing, and thank you to all of our listeners for tuning in to JCO After Hours. Again, we were discussing the “Costs of Cancer Prevention: Physical and Psychosocial Sequelae of Risk-Reducing Total Gastrectomy.” Please do not be a stranger to our podcast. Check out our other offerings and reach out to us on X and Instagram if you have other topics you want us to cover. Have an awesome day. The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.     
2/8/202423 minutes, 33 seconds
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JCO Article Insights: Low and Moderate Grade Adverse Events and the Patient Experience in Clinical Trials

In this JCO Article Insights episode, Subodh Selukar summarized findings from the original article published in the January 2024 JCO issue: “The Importance of Low and Moderate Grade Adverse Events on Patients’ Treatment Experience and Treatment Discontinuation” and accompanying editorial “Patient Experience, Adverse Event Reporting, and Clinical Trial Design”. The summary provides information regarding low and moderate grade adverse events and the patient experience in clinical trials. TRANSCRIPT Welcome to the JCO Article Insights episode for the January 2024 issue of Journal of Clinical Oncology. This is Subodh Selukar, your host, and today I will be providing a summary on 2 articles focused on low and moderate grade adverse events. The first article, titled “The Importance of Low and Moderate Grade Adverse Events on Patients’ Treatment Experience and Treatment Discontinuation” by Dr. O’Connell and colleagues, investigated low and moderate grade adverse events and the patient experience in clinical trials. Their article is accompanied by an editorial entitled “Patient Experience, Adverse Event Reporting, and Clinical Trial Design” by Dr. Neuman.  In clinical trials, a standardized system for reporting adverse events is the Common Terminology Criteria for Adverse Events (or “CTCAE”) established by the NCI, the United States National Cancer Institute. The CTCAE categorizes adverse events at 5 severity grades across 26 system organ classes. However, some clinical trials may only report adverse events at grade 3 or higher, with one possible rationale being that low and moderate grades are unlikely to affect patient safety or key trial endpoints. In Dr. O’Connell’s article, the team investigated how the numbers of grade 1 and 2 adverse events related to patient self-reported side-effect burden and treatment discontinuation. To do this, they analyzed data from the Phase 3 trial E1912 conducted by ECOG-ACRIN comparing two treatments for chronic lymphocytic leukemia. They chose this trial as an example because the study data included all adverse event grades throughout the duration of treatment for each patient. The authors studied side-effect burden based on GP5, which is the fifth item in the FACT-G subscale in the Functional Assessment of Cancer Therapy. GP5 rates the patient’s agreement with the statement “I am bothered by side effects of treatment” in the past 7 days, and it has previously been connected with adverse event grade and treatment discontinuation. For treatment discontinuation, the authors focused on those discontinuations that were recorded as being due to “adverse events, side effects or complications.” They found that, for each adverse event grade, there were, on average, more adverse events in cycles that ended with a patient discontinuing treatment compared to other cycles. Next, they used Bayesian models to assess how the numbers of grade 1 and grade 2 adverse events in a treatment cycle were associated with the odds of higher side-effect bother and odds of treatment discontinuation, after adjusting for cycle number, treatment and occurrence of grade 3 or higher adverse events within the cycle. Baseline GP5 was also included in the models, and these models also accounted for the inclusion of multiple cycles for each patient. When adjusting for baseline GP5, treatment, cycle and presence of grade 3 or 4 adverse events, both the number of grade 1 and the number of grade 2 adverse events were each strongly associated with increasing side-effect bother. The adjusted odds of treatment discontinuation were also higher with more grade 2 adverse events. However, with the same adjustment variables, the odds of treatment discontinuation were actually lower with larger numbers of grade 1 adverse events. In their primary analysis, they focused on adverse events that were attributed to treatment, so they excluded non-treatment-related adverse events from the counts. Sensitivity analyses including these adverse events have similar conclusions but with a weaker magnitude of effect. They attributed this to issues like existing adverse events not causing new bother. Next, the authors analyzed whether symptomatic versus asymptomatic adverse events affected these results by re-fitting the models and separating the predictors into numbers of asymptomatic and symptomatic grade 1 or 2 adverse events. In these results, they found no evidence for associations between numbers of asymptomatic adverse events at any grade and side-effect bother. On the other hand, they found strong evidence for associations with symptomatic adverse events of grade 2 and 3 or higher both for side-effect bother as an outcome and with treatment discontinuation. Asymptomatic grade 2 adverse events were associated with treatment discontinuation but not side-effect bother, and symptomatic grade 1 adverse events were associated with side-effect bother but not treatment discontinuation.  ·       The authors conclude that adverse events of all grades, especially symptomatic adverse events, should be recorded regularly in cancer clinical trials. Formal patient reported outcomes are not typically collected as frequently as adverse events are recorded, so identifying patients with a high number of lower grade adverse events could be used to facilitate early supportive care to improve patient quality of life and reduce the likelihood for treatment discontinuation. ·       They also highlight their result identifying lower odds of treatment discontinuation with larger numbers of grade 1 adverse events. They provide one explanation that patients may perceive grade 1 adverse events being associated with treatment efficacy, but this perception changes with higher grades.  In their call to collect more lower grade adverse events, the authors acknowledge that recording more adverse events may be time-consuming and burdensome for sites and recommend cost-benefit analyses to develop future guidelines. ·       This balance between the benefits and costs of increased adverse event data collection is the focus of Dr. Neuman’s editorial. Dr. Neuman acknowledges that Dr. O’Connell’s article provides a convincing argument for how low grade adverse event information is valuable, but notes the clinical trial context that current efforts at the NCI are to more efficiently conduct cancer research, which could be supported by streamlining data collection. ·       Requiring the collection of low grade adverse events could have important impacts to trial logistics. Due to the high volume of low grade adverse events, reporting all low grade events could delay reporting higher grade and more serious adverse events; and it would require an increase in the effort of clinical trial research staff, which would be difficult if not accompanied by an increase in reimbursement to sites. ·       Dr. Neuman suggests 3 approaches to balance the costs and benefits of collecting low and moderate grade adverse events. First, investigators could consider limiting low-grade adverse event reporting to the experimental arm. The standard of care regimens may not always have low-grade adverse event data available, but this may still be justified when there is extensive clinical experience with the standard of care. However, this approach is only practical when the experimental arm is not blinded. ·       A second approach for moderating the effort in collecting low-grade adverse events is to limit collection to symptomatic adverse events, connecting with Dr. O’Connell’s example E1912 dataset. This approach could be addressed by prespecifying types of symptomatic adverse events that would be most impactful during the trial design phase. ·       Dr. Neuman’s third suggestion is to plan for a follow-up study after the phase 3 trial to collect low-grade adverse event data and their impact on patients’ experiences and treatment discontinuation. This would be beneficial by only requiring low-grade adverse events in an experimental regimen that has successfully passed phase 3. However, a new study would require funding and site enthusiasm, which could prove challenging. ·       Overall, Dr. Neuman emphasizes that investigators should develop trial-specific considerations and engage with the relevant stakeholders during study design. Because of the complexity of adverse events in these patient populations, the best uses of grade 1-2 adverse events will likely continue to develop in the future. In their article, Dr. O’Connell’s team studied grade 1 and 2 adverse events as separate predictors, but I would be curious to know how the accumulation and trajectory of these adverse events affect the patient experience. For example, even if the severity does not rise to grade 3, an increasing trend in a patient’s adverse event severities could signal the treating physician to modify study dose or to discontinue the treatment. I’m not sure if that type of information was available in their trial E1912, but perhaps that could be a factor to consider for the future. And, of course, it will be important to assess how these grade 1-2 adverse events relate to the patient experience in different studies, especially across different cancer patient populations, acknowledging that this is inherently challenging to study because the data to inform this research is not universally available. As Dr. Neuman indicates, trial-specific goals and expertise will remain critical when considering the data collection for a given trial.  That concludes this episode of JCO Article Insights regarding a summary of the article “The Importance of Low and Moderate Grade Adverse Events on Patients’ Treatment Experience and Treatment Discontinuation” by Dr. O’Connell and colleagues and the editorial entitled “Patient Experience, Adverse Event Reporting, and Clinical Trial Design” by Dr. Neuman. This is Subodh Selukar. Thank you for your attention and stay tuned for the next episode of JCO Article Insights.
1/29/20249 minutes, 50 seconds
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Debunking Sex and Disentangling Gender From Oncology

Dr. Shannon Westin and her guest, Dr. Ash Alpert and Spencer Adams, discuss the paper "Debunking Sex and Disentangling Gender From Oncology" recently published in the JCO. TRANSCRIPT The guests on this podcast episode have no disclosures to declare. Shannon Westin: Hello and welcome to JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I'm your host, Shannon Westin, Social Media Editor and GYN oncologist by trade. I'm so excited to be discussing a very important manuscript. This is "Debunking Sex and Disentangling Gender from Oncology," which was published in the JCO Online on May 26, 2023. So I'm joined by two of the authors here today on the podcast. First is Dr. Ash Alpert. They are an instructor of medicine and hematology at Yale Cancer Center. Welcome. Dr. Ash Alpert: Thank you. Shannon Westin: And we also have Spencer Adams. They have a bachelor's in public health, are a certified health education specialist, and are currently pursuing a master's in public health at Western Michigan University. Welcome, Spencer. Spencer Adams: Thank you for having me. Shannon Westin: So let's get into it. I'm so excited. First off, I just want to say thank you because I learned a ton from this paper, and I'm hoping to be able to implement some of these changes that we're going to discuss over the next few minutes at my own institution. So I wanted to just make sure we kind of level set and everyone's on the same page. So let's start off by discussing ontological oppression. Can you explain to the listeners what this means and how it relates to sex and gender and oncology? Dr. Ash Alpert: Sure. So, ontological oppression is actually a concept from one of my colleagues at Yale, Robin Demroff, who's a philosopher. Ontology is a way of thinking about what exists and how we categorize what exists. And so ontological oppression is discrimination or stigma that happens because of the ways people imagine us fitting or not fitting into social categories. For example, if we think that people are women or men based on their sex assigned at birth, then it makes sense that we would think of transgender people and nonbinary people as abnormal, weird, or pathologic. In oncology, if we think of ovarian cancer as something that happens to women and a man with ovarian cancer comes into our clinic, we may be confused or uncomfortable. We may respond to those feelings by denying his identity, for example, thinking he's actually a woman or using the wrong pronouns or name for him or even potentially denying him care. And we have some data to suggest that clinicians respond to lack of knowledge about transgender people by treating them as abnormal, weird, or bad in some way.  Spencer Adams: Yeah. And to add to that, when we consider how we classify people, first, there's a problem within that. There's an ethical problem within that, but it's an idea or a construct that society has created and wants people to fit into these nice little boxes just because it's easier to digest, or you make the person more palatable if they're able to do these things. And life is not like that. We have differences, and we have things that make people fit outside the box. And I believe that when we keep reminding people that a box exists or a social construct exists, you're stifling who they are, their personality, their guiding light. You're stifling a lot of things about that person and ignoring something that's incredibly important to them. Shannon Westin: I think that along those lines, kind of taking that to the next step, it would be really helpful to discuss a little bit more around this interaction between sex assigned at birth and gender and what assumptions are made. And I think you kind of started along this, like, how that impacts oncology care. But in your paper, you did, I think, a really great job of really laying out a lot of the problems that happen in this space, and I'd love to explore that more right now. Dr. Ash Alpert: So sex is a designation made when a baby is born by somebody viewing that baby's external genitalia. And so I think we all, as doctors, know that that designation doesn't necessarily tell us what that person's karyotype is, what their later hormonal milieu will be, what their internal anatomy is, and it certainly can't tell us anything about their gender, which is how someone sees themselves as a man, woman, nonbinary, or something else, and usually develops around the age of four. And even though I think that we all know that, we're so used to sex and gender being used interchangeably, not just in the ways that we talk to each other, but in everything about the way that we do our work. And so it becomes very difficult to disentangle these concepts for ourselves.  And we have used sex in particular as a proxy for so many other factors where it doesn't necessarily function. And parts of medicine are based on that. So it's very hard to start to unpack and disentangle those things. For example, the ways that we talk about certain types of cancer can be linked with gender, like we were talking about earlier, women with ovarian cancer, men with prostate cancer. And that's the way that we talk to each other. But it's also in our clinical trial eligibility criteria, sometimes, it's in our patient facing materials, it's in the ways that we name our clinics, the ways that we talk about our work. So then even just sometimes occupying space to get oncology care can be a form of being misgendered.  Spencer Adams: Yeah, I think it's dangerous to conflate the two, sex and gender. As Ash was saying, that one is a visual inspection, the other is who the person is. And if we claim to be an institution that does patient-centered care, how can we be patient-centered if we are not properly respecting the patient? And to do that, you have to respect their gender as well. I see also one of the things that I want to add to the list is clothing that the patient is offered, especially going to a "women's clinic." We can change that to "reproductive health clinic," but usually the clothing is pink and that may be dysphoria-causing for some of our transgender and gender nonconforming friends. So it truly is in everything that is client facing, that is how the structural building is made. It truly is not just how we talk to each other, but how society runs.  Shannon Westin: Yeah, let's talk a little bit more about training because I think that will be pretty important as we try to change these things. So the way we're trained in medicine and oncology, regarding sex, regarding gender, how does this negatively impact the health? We've talked a lot about the mental health, definitely impacts, but also, I think, overall physical health. Dr. Ash Alpert: Well, I think something that we started to talk about, but didn't talk about in detail is not just the conflation of sex and gender, but the ways that this concept of sex is used as a proxy for a number of other factors, including anatomy, hormonal milieu, karyotype, and body size. One of the ways that this becomes problematic is in our laboratory values for example. Laboratory values are developed, as far as I understand it, based on looking at large studies of people that are categorized as women or men and looking at averages. So, averages are helpful, but they can't necessarily tell us about disease or no disease. So, for example, if a large number of cisgender women have iron deficiency that is undiagnosed, and we use their averages, then we're going to continue to underdiagnose iron deficiency anemia going forward.  So, the ways that we've tried to use sex as a proxy for a number of things doesn't just hurt trans people, but potentially leads to very imprecise data in general. Specifically for trans people, we know that many trans people have negative experiences with care, that this leads to people avoiding care and likely leads to decreased screening for cancer and delayed cancer diagnoses. So we don't have a lot of data about this, but we do have some data to suggest that transgender people may present later with later stage cancers, be less likely to be treated, and have poorer outcomes than cisgender people. Spencer Adams: And I think it's important to add that there are physicians who will - we call it like, “the trans illness" - but they will blame everything that you're experiencing on the fact that you're transgender or the fact that you're on hormones or the fact that you had the surgery, and say that you need a specialist. So you can't just go to your primary care physician anymore for the flu because they'll just blame it on your medical transition. When we take that into consideration, I think there's a whole host of physical ailments that come from just being denied care. I don't know if that is from the physician's own personal stigma around trans people or just them not being trained in trans healthcare to where they feel confident in going into that room. So it's a twofold attack. First, we need to make doctors who are competent in trans healthcare, and then second, we need to have more inviting spaces for trans and gender nonconforming people. Shannon Westin: I think the next step is really better understanding this idea around degendering care, specifically in oncology, but I could really talk about medical care as a whole, but let's focus on what you all brought forward in the paper. I would love to hear how we think this idea of degendering care will promote better healthcare. And then, I think, some practical actions. What can we do on a day-to-day basis? And you've already started peppering this through this discussion but I’d love to like bullet point it out for the listener.  Dr. Ash Alpert: Yeah. So the way we described it on our paper was: “disentangling oncology is a conscious and explicit disentanglement of gender, anatomy, hormonal milieu, karyotype, and other biological factors. In oncology, diagnoses, epidemiology, and knowledge production. As well as,” - and I think this is an important part and that's maybe the harder part of the paper - “eliminating sex from our conceptual framework of bodies and disease”. So, in other words, we're really trying to say that not only do we need to disentangle gender and sex, but we need to debunk the idea that sex is an immutable fact of the body that says something important about a person and their biology. Instead of thinking about sex as this immutable fact of the body, can we really break down and think about what exactly are we measuring? Is it anatomy, hormones, karyotype, size, or stigma?  In terms of practical actions, some of the things we had in our paper include that oftentimes, the words "woman" or "man" can be replaced with the word "people." So like a very easy change. And actually, ASCO and the NCCN, both in the last few years, have worked to degender their guidelines by doing just this simple change. Then we also need to do this on our websites, in our patient education materials, and in our clinical trial eligibility criteria. Because if you have a trial for prostate cancer that says that one of the inclusion criteria is being male, then whether or not you actually mean that as an inclusion criteria, a transgender woman or her physician may see that as a barrier to enrollment.   Ensuring that, as Spencer was saying, that gowns, binders, and wigs are available that are gender-neutral are available for all genders. Ensuring that people have access to bathrooms, so making sure gender-neutral bathrooms are available. And often, this is as simple as taking a one-style bathroom and putting a sign on it that says "gender-neutral." Ensuring the names of clinics, mammography suites, and titles do not contain gender. Ensure that intake forms don’t conflate gender with biological factors. For example, in a clinic I used to work in, one of the questions on the intake form was, "If you are a woman, when was your last menstrual period?" Which if I’m a man and I have a period, it might be hard to figure out how to answer that question.   Spencer Adams: One of the biggest barriers for trans and gender nonconforming people is that intake form. It is the first person that you meet or see when you go to any healthcare establishment because that sets the tone for whether or not this establishment is trans-friendly. If you have, as Ash said, a "for women only" box or descriptor on your intake form, that is a sign that maybe they're not as trans-friendly as they could be. Or if you see "women's clinic" instead of "reproductive health clinic" or whatever, that could be a sign that they may not be as gender-friendly as they could be. These little changes actually make such a big impact on the trans community, and it's something that I believe would be very much appreciated and would close the gap between trans and gender nonconforming people and the medical community. Dr. Ash Alpert: I know that for me, going to a doctor's office, these small moments, although they may seem small to other people, really add up in terms of stress. People talk about microaggressions, and I think that's really a good way of conceptualizing what it's like to have these little irritations or hits that happen over and over again throughout a clinical encounter. And I think in particular, for folks who are dealing with a cancer diagnosis and treatment, which can be experienced as a traumatic event, having these recurrent denials of identity on top of that can lead to additive trauma in a way that can be very distressing and have negative sequelae for patients. Shannon Westin: Yeah, we're trying to look around this idea of allostatic load and how we can actually measure this because I think when we talk to policymakers about this, around not just the trans community, but also around underrepresented minorities, and the stresses that impact their risks of cancer, and how it's not just their race or ethnicity that's driving it, it's all of these microaggressions and everything. We get a lot of like, "Really? That's not science." So, I definitely think doing a better job around being able to objectively measure these other things and move forward in a very objective direction is going to help. Because if one of those things we know it's there, but for people who aren’t as ready to believe or understand that, it helps to have and embed that objective data. So that gets into the epidemiologic potential and cancer prevention. Dr. Ash Alpert: Yeah. In some ways, we can't do much about the data that have been collected in the past, but we can start to think about them more critically and describe what we think is really going on in what we were calling sex or gender categories. But going forward, we can really think about collecting data on our clinical trials and in our large population-based surveys that actually speak to biological factors. So, if what we're concerned about is whether or not someone has ovaries, we can ask for an anatomy inventory. And when we're interested in hormonal milieu, we can check hormone levels. When we want to know about chromosomes, we can check a karyotype. And if what we're interested in is stigma, then we can ask about stigma, or we can ask about things that we think may cause someone to infer stigma. Once we have data that’s much more nuanced and granular, we’ll be able to better extrapolate it to all people in a much more rigorous and precise way, including trans people. Spencer Adams: When it comes to cancer treatment and diagnosis within the trans community, it's such a unique thing because we have to consider also the social determinants of health. And this built environment that we've created, such as a hospital or cancer wing, or whatever you want to call it is directly impactful. As you were saying before, this microaggressions that add on and on to our trans friends. So, I think that when we look at the data and we look at stigma, we also have to look at where people are– We have to meet people where they are. It's going to be very difficult to bridge the gap between the medical community and the trans community when it comes to stigma. But if we have competent doctors trained in trans care and not always pushing off for a specialist, then I think we'll get better data.  One thing that happens to trans people is doctors feel as if they cannot diagnose because being trans is seen as a disorder that they see as out of their wheelhouse. First, they classify it as a disorder, and secondly, they think it's outside of their wheelhouse. So they would refer to an endocrinologist or someone else to provide the care that the person is seeking. We call it the "trans disease" or the "trans injury,” because if I come in with a broken leg and the first thing you say to me is to go to an endocrinologist because we don't understand how hormones work, that's not care, and that's not patient-centered care. And that's what we're all moving towards, I believe. All hospitals are moving towards this patient-centered care. And to do that, to be patient-centered, you have to understand the person as a whole, and you have to be able to treat the whole person and then make a treatment plan that is specialized and custom to that person. This may involve different routes people take in order to feel comfortable or achieve what outcome that they wish to achieve. But it's really a patient-centered approach that we have to drive home in order to make some change.  Shannon Westin: My last question is, what's next, and how do we get this information out? How do we actually enact? I mean, obviously this podcast reaches a lot of listeners, but beyond that, how can we educate people so that we can make these changes? This is something that hits close to home for me. I recently took over the gynecologic cancer center, which is where we house all below the belt malignancies. But there's work in progress, and we're discussing an overarching center to cover breast and gynecologic malignancies. And there's a discussion around how to title that. One of the suggestions was that it should be a "women's center," or something like that and that is not in line with what we've just been speaking about. So I think, certainly, that kind of individualized, like boots on the ground, people that are willing to speak up and say things and try to change these types of things, and I fully intend to do that - fingers crossed that it won't be me just waving my tiny fists in the air.   But more broadly, I’d love to see more education at ASCO, large oncology symposia and conferences. It needs to go to the people who are not aware. It can't just be an echo chamber of people who have already been talking about this and are already knee-deep. It needs to reach the broader oncology community so that people realize that this is an issue that involves all of us and that we all need to be addressing. And like you said, even simple things around replacing language and saying people and making sure that the trial eligibility are broad, those simple things that individuals can do can. But I also think like NCCN and ASCO, we have to do something around the organizational levels to really make an impact.  Dr. Ash Alpert: Yeah. And I think that the things that we talked about the we can do as individual clinicians, there’s the things that large institutions like NCCN and ASCO can do to sort of send out the inclusive messaging that is needed. And I think in the middle, we can create teams that are institutions of folks who we can be in allyship with to think about what are the most urgent changes that need to happen and the most feasible changes and start with those and then just keep going. Some of the changes that we make now will help us in the years to come, so I think being focused on the now and the future at the same time is helpful.  Spencer Adams: I think that the teams within our individual institutions is really a great approach to this. When it comes to figuring out the next steps to be more gender-inclusive, I really think that institutions should get data from their community. They should understand the makeup of their community and see if that is something that aligns with the makeup of their hospital. Because we can go and talk about doctors getting training in trans care or more doctors of color being in your hospital to make the BIPOC community feel more accepting. But if we don't have teams whether it’s diversity, equity, and inclusion teams, or whatever you want to call it, that are willing to push to make policy change within the hospital, then there will be no movement. So, we really need to get people within their hospitals to give them the power to really push what has been taught for so long and really challenge the status quo and allow us to move forward with gender equity. Shannon Westin: Well, I think that is the perfect mic drop moment, and I just want to thank both of my guests. Spencer, this was awesome and I always take copious notes when I talk with you all because I learn so much. It inspires me to try to do what I can at my institution and within the field of gynecologic oncology to make things better. So I hope that others who are listening are just as inspired as I am. And to our listeners, thanks again for tuning into another episode of JCO After Hours. Please check out our other podcast offerings wherever you get your podcasts. Have a wonderful day. The purpose of this podcast is to educate and inform. It is not a substitute for professional medical care and should not be used for the diagnosis or treatment of individual conditions.    Guests on this podcast express their own opinions, experiences, and conclusions. These opinions do not necessarily reflect those of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an endorsement by ASCO.      
1/25/202423 minutes, 9 seconds
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Germline EGFR Mutations and Familial Lung Cancer

Dr. Shannon Westin and her guests, Dr. Judy Garber and Dr. Geoffrey Oxnard, discuss the paper "Germline EGFR Mutations and Familial Lung Cancer" recently published in the JCO. TRANCRIPT The guest on this podcast episode has no disclosures to declare.   Shannon Westin: Hello, and welcome to JCO After Hours, the podcast where we get in-depth on articles that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, Social Media Editor for the JCO and Gynecologic Oncologist by trade. And it is my great pleasure to speak today with you about an amazing manuscript entitled, “Germline EGFR Mutations and Familial Lung Cancer.” It was published in the JCO on August 14, 2023.  The authors have no conflicts of interest, and they are Dr. Geoffrey Oxnard, he's a Thoracic Oncologist and Associate Professor, Hematology and Medical Oncology at Boston Medical Center.  Welcome, Geoff. Dr. Geoffrey Oxnard: Hi, Shannon. Thanks. Shannon Westin: And Dr. Judy Garber, the chief of the Division of Cancer Genetics and prevention at the Dana-Farber Cancer institute in Boston. Welcome, Judy. Dr. Judy Garber: Thank you. Hi, Shannon. Hi, Geoff.  Shannon Westin: So excited you both could be here. Let's get started. So first I just want to levelset for our audience. Can you speak just a little briefly about the incidence and mortality of lung cancer and how that's been changing over time? Dr. Geoffrey Oxnard: Sure. Lung cancer is common and it's deadly, more than 200,000 cases a year in the United States, more than 100,000 deaths a year in the United States. But I think importantly, it's evolving. Its biology is evolving as smoking incidence goes down. We've identified these genomic subtypes of lung cancer that are sort of increasingly apparent and important as we think about its treatment. Outcomes are changing with emerging therapies, presentation is changing with lung cancer screening and with a growing ability to now find cancers early and prevent them. And so it's in that setting of a very dynamic disease that we chose to study a really unique little slice of it, which is germline risk. Shannon Westin: So let's take that one step further because I think that's really interesting. You mentioned the genomic aberrations and kind of how you're using that to target. Can you expand upon that a little bit more for me? Dr. Geoffrey Oxnard: Lung cancer that I've long studied is different than breast cancer when Judy has long studied because we think about its somatic alterations, we've always thought about KRAS mutations, EGFR mutations, and smaller and smaller splice limit. ALK, RAS, RET HER2, etc. And so tumor testing in lung cancer has one of the first to be standard across on solid tumor oncology. And the germline genetics was kind of an afterthought and is the flip, I think, of how genetic testing evolved in the breast cancer space for example. Dr. Judy Garber: I might argue a little bit if breast cancer was earlier and it was subtyped some molecularly it doesn't have as many molecular subtypes yet perhaps as lung cancer. But we've all been studying the somatic space to look for targets for therapy. And the germline space, certainly in breast cancer, came much earlier. And everybody knows about BRCA1 and 2. Now, we hope everybody knows about Lynch Syndrome, but certainly not everybody's thinking about inherited lung cancer risk. Dr. Geoffrey Oxnard: Yeah, these have converged. I think 10 years ago when this kicked off, I felt like a super outlier for thinking about, wait a second, what about the genetics behind all this that is leading to this strange variable presentation of lung cancer? For example, we know that in Asian populations, one type of lung cancer, EGFR mutant lung cancer, is more common. There must be some geneticness that leads to that. What explains the sort of pattern of presentation of these genetic subtypes in the populations we see in the US, that’s pretty unclear?  Dr. Judy Garber: So, I think, Shannon one of the clues about all this came from the fact that the EGFR mutations were being identified in the tumors. And then I really should let Geoff tell this story, but as the amateur thoracic person in the room here, to me, it was so interesting that there were the EGFR mutations, then there was treatment exploiting EGFR mutations, and the most common resistance mutation was this T790M variant. But when labs started testing EGFR, there was a small group of people who had that resistance variant without ever having been treated at all. So that was the obvious question, what was it doing there? And that's where Geoffrey came in.  Dr. Geoffrey Oxnard: Yeah, this is a patient I met more than a decade ago at my fellowship in MSKCC. She'd been living with a T790M mutation in her tumor for years and years and years. I was like, “Well, I don't understand. Why is this sitting there?” And she had this sort of slightly mysterious history of lung cancer in her family. And we realized, wait a second, this T790M was behind her cancer from the beginning, and in fact, might have been the basis of why she developed lung cancer. And so that actually motivated a career development award I submitted to the Conquer Cancer Foundation of ASCO, a grant I received, and that then led to a program that I led at Dana-Farber under Judy's mentorship, where over the past decade, we sort of focused in and studied this strange, rare syndrome, really to dig into inheritedness as a kind of different flavor of lung cancer genetics.  Dr. Judy Garber: Well, and now it's really a good time to think about this because we're recognizing there are younger cancers, colon cancer, like an epidemic, and lung cancers, and we're not sure how many of them are genetic or come from other exposures. Geoff talked about the differences in Asia, some of which are certainly genetic, some which may be environmental, especially in the lung, where that's such an issue. But trying to sort these things out, you have to be willing to think a little bit differently. And that was fun when Geoff came from the lung program, interested in the germline, we said, “Oh, we have to do this.”   Shannon Westin: Well, let's talk about what you did. I would love to hear and I know the audience would as well about the design of this study, so called INHERIT study. Very good name. I love a good name. This is a good one.   Dr. Geoffrey Oxnard: Yeah. So that stands for Investigating Hereditary Risk of T790M, INHERIT. I forget where we coined that. Let me give you a case example. A patient presents in his 40s. I remember this man. He has an EGFR mutation in his tumor. He has a T790M in his tumor as well. He had routine tumor testing that lung cancer patients were getting. And he says, “Oh, also, my brother had lung cancer in his 40s just a couple of years ago. He was a smoker, though. He never had genetic testing.” And so this patient we test on the study, we hypothesized that when patients present with T790M at diagnosis, that it would be a representation of an underlying germline EGFR mutation. Our hypothesis was that about 50% of the time T790M at diagnosis would be explained by a germline behind the doll. And that that could then empower families like this one to understand the kinds of lung cancer they're getting in their family, the kinds of treatment they should be getting, and the kinds of testing they should be getting to look for lung cancer at risk early on.   It really saddens me that in a family that doesn't know about this condition, the brother would never get testing and would never think that I might be getting or might never get testing, might not be disposed to getting testing, and might not realize there's a therapy available to target that EGFR mutation if he died young without even much treatment. But this individual, we tested his lung cancer, we found him a therapy, we put him on a pill therapy that could last a very long time. And so we set up a program with a consortium alchemy, the Addario Lung Cancer Medical Institute, where we enrolled at three sites, both at Dana-Farber in Boston, Vanderbilt, and Ohio State, with some motivated investigators there that we appreciate their collaboration.  But also, again, this is now more than 10 years ago, set up shop where people could enroll remotely, that if you found a T790M in your tumor, for whatever reason, you could reach out to the team at Dana-Farber centrally and get consented online and even get counseling. And this is one of the early ways of getting this remote participation. And you can imagine, over the course of the study, we quickly ran out of individuals at any given site, but that remote enrollment accelerated and really allowed us to get to the large population of remote study. Dr. Judy Garber: We were lucky that things were happening. The things you don’t expect. So EGFR testing was not routine at that time. And the EGFR testing that had developed in Dana-Farber and NGH became standard of care at Dana-Farber so we were finding those patients, and then grew outside as well, at institutions and testing labs. And these people would somehow emerge so we were very lucky that we were able to set up remote testing. We could send and get a saliva sample and be able to test. Or these were people who got tested through their own doctors, found out they had this mutation and then went online and said, “Who knows anything about this?”  I would say that we and our amazing genetic counselors who spoke to all these patients, took their detailed family histories, got their other information, and were able then to really build out these cohorts so we can understand them. And to look at, for example, Geoff’s question, it was really his question, “Why did we have such clusters in certain parts of the country? Could it be that there were the so-called founder mutations that somebody had this mutation and they spread their genes around so that they’re around the country and that turned out to be true. Shannon Westin: It's so fascinating, and I love how you kind of almost crowdsourced getting these patients to you because I was mystified because it's such a rare aberration and you had so many patients. Let's talk a little bit maybe about your patient population and who volunteered, and is it reflective of kind of you do think, the general population? Dr. Geoffrey Oxnard: I want to give a shout out to the GO2 Lung Cancer Foundation. That really was a lot of the ‘rah rah’, getting people to know about this, having some word of mouth and spreading the word. And so certainly there are physicians around the country that have been like found patients that I've got to know because they sent us patients to study over the years. We ended up getting germline testing on 141 individuals who presented eligible for testing because of either a relative or a mutation that was suspicious for inherited. Most of those were enrolled remotely, in the end, as you might expect. We found what you might expect, that this was Mendelian in its inheritance, that if you had a first degree relatives, they had 50% chance of having this. And so we sort of slowly built these pedigrees of individuals who once they were positive, would refer in their relatives and say, “Please go get testing. Let's describe our family and help understand our risk.”   It ended up boiling down to six individuals with a germline EGFR mutation from 39 different families. I remember one family where two different cousins presented separately to the program, not knowing each other was participating. And so, of course, there's not that many of these families around the United states, but we're really very lucky to have touched so many different individuals. What did we find? That if you had a germline EGFR mutation, your tumor almost always had an EGFR mutation. That really is the dominant biology of lung cancer that presents in these affected individuals, that it presents young, that the likelihood of developing lung cancer is around 55% by age 40 to 50. So it really is– I'm trying to make sure I'm quoting that right, actually, Shannon, I'm looking at the numbers here, but it was a really broad range of diagnosis.  We had a 28-year-old who was affected and an 83-year-old who was affected. I saw a family where the grandson had lung cancer, but his father and grandfather who had germline EGFR mutations, did not. So variable penetrance. Judy, of course, told me, “Geoff, this is the way families present. Come on, Geoff.” But other families, incredible penetrance– not everyone having lung cancer, many of them smoking, some of them not smoking. But for these families, what a sense of empowerment to say, “Oh, this helps explain what's going on in our family, why this is happening at a younger age.” And helps explain the therapies that we had some concern about giving these potent EGFR inhibitors originally, understanding every cell in their body has this EGFR mutation. Are we going to somehow cause toxicity? No. These potent therapies can be effective, can be tolerated, and can work for many years. So we really feel hopeful that we've described a syndrome that's out there that people see and that has a distinct presentation, a distinct treatment pattern, and a clear association with lung cancer risk. Dr. Judy Garber: And I think that now the opportunity is to say, can you find these people before they get their lung cancers? Some of them have abnormalities on scans. Think of it's like the APC, the polyposis coli of lung cancer. You can see these adenomas forming, but we can't really predict exactly who's going to develop tumor when. And that, I think, is a challenge that families have to help us with because we need to continue to identify some of these people who have not had cancer. They have children. They want to know what to tell them besides not smoking adamantly and maybe with some hopes that we're going to do some screening.  I am afraid there probably is not good data that EGFR inhibitors could be used for prevention, but it's tempting to think that way. So there's plenty of work to do still to sort out the questions. This is the nature of genetics. We often find inherited susceptibility and people want to know, “Well, why would I want to know? What am I going to do about it?” And here I would say, “We're going to figure out what's your risk more specifically, and how can we help reduce that risk, in addition to telling you not to smoke.” Dr. Geoffrey Oxnard: I do want to allude to Judy's comment about founder effect. I didn't tell you exactly about the presentation, but these families, first off, we only found germline EGFR mutations in Caucasian individuals and in black individuals, and it was mostly in the United States and in fact, enriched in the southeast United States. And don't get me wrong, we had enthusiastic participation from Vanderbilt. But still it seemed like there was more southeast United States prevalence. And even families I met in the Boston area would say, ‘Oh yeah, I have relatives going back to Arkansas.”   And so we ended up with a bit of a suspicion for this geographic enrichment, studying the genomes of these affected individuals, and in fact did find a very large region of chromosome 7 that was shared in more than 90% of the folks we tested, suggesting a founder effect in the southeast United States, probably white and black. And that goes back hundreds of years, maybe 200, 300, 400 years, as far as we can estimate, making me think that this is a fairly unique syndrome that we're seeing in North America, but actually may not be prevalent in other parts of the globe. Though we did identify a single individual in Australia, it might be a unique phenomenon in North America. Dr. Judy Garber: At least more common. But these days, people travel, so hard to know. Shannon Westin: I don't know if you've gotten a chance to do this - any other cancer type seeming to be associated with this mutation? Dr. Judy Garber: No, fortunately not. Shannon Westin: Okay, very interesting. And what about outcome? What was the association, or was there any association of these mutations with cancer related outcomes? Dr. Geoffrey Oxnard: I would say the survival of these cancers isn't that different than EGFR mutant lung cancers. If they get to effective therapy, they can live for years on therapy. If they don't, they can do quite poorly. One interesting finding is that they can present in a multinodular fashion that might be multiple primaries. And so you can kind of use an approach of eliminating individual clones. Sometimes it's been described these different tumors have different mutations, and so you might treat them like a stage IV lung cancer, but actually they lived for a long time because actually they had multiple stage I lung cancers, so it can present a little bit differently. And then we tried to collect CT scans on affected carriers who did not yet have lung cancer to see if they might develop lung cancer. It was not required on study, and it's sort of an area of future investigation. But as you can imagine, lots of lung nodules and certainly anecdotes of individuals where we found early precancers through the screening effort, motivating the investigation that Judy was alluding to. Dr. Judy Garber: I think this is what you expect in inherited predisposition that you have an earlier chance. So some of them are younger, not the 84-year-old, but that they could be younger, that they could have multifocal disease, that their biology could be different, but could be the same, maybe accelerated, maybe not. Some of these are slower. And I think that's why we're excited to be able to continue this work with the group at Dana-Farber.  Now, Jaclyn LoPiccolo is going to lead the INHERIT study, but much of the team is the same. And now the focus will be even more on trying to really quantify the risk and help think about prevention strategies and screening for these patients. It's a little tricky to want to do too much chest CT screening. On the other hand, there are lower dose CTs now, and we hope the guidelines will clarify the role of inherited risk. At ASCO this year there were a lot of talks about inherited lung cancer risk, but nothing is quite as well characterized as, I think, the T790M population. Shannon Westin: Well, thank you all so much. This was fascinating. I learned a ton and I know our listeners did as well. And thank you to our listeners. This was “Germline EGFR Mutations and Familial Lung Cancer.” Again, published in the JCO August 14, 2023. So go check it out and check out our other podcasts on the website or wherever you get your podcasts. Have an awesome day.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  
1/11/202418 minutes, 8 seconds
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JCO Article Insights: DYPD-Guided Dose Individualization and Survival Outcomes

In this episode of JCO Article Insights, host Dr. Soldato discussed with Dr. Knikman and Dr. Cats the findings of a study that assesses the influence of fluoropyrimidine dosing based on DYPD genotype on both progression-free and overall survival. The article, featured in the December edition of JCO, presents groundbreaking and reassuring data. Furthermore, it highlights emerging research challenges aimed at refining the prescription practices of one of the most widely utilized chemotherapy agents, striking a delicate balance between safety and efficacy. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Davide Soldato: Welcome to this JCO Article Insights episode for the December issues of the Journal of Clinical Oncology. This is Davide Soldato, and today I will have the pleasure of interviewing Dr. Knikman and Dr. Cats, respectively first and corresponding authors of the manuscript titled "Survival of Patients with Cancer with the DPYD Variant Alleles and Dose Individualized Fluoropyrimidine Therapy: A Matched-Pair Analysis."  Dr. Knikman is a clinical pharmacologist and assistant professor at the UMC Utrecht, while Dr. Cats is a gastroenterologist specializing in gastrointestinal oncology at the NKI in the Netherlands.  Welcome, Dr. Knikman and Dr. Cats, and thank you for accepting our invitation today.  Dr. Annemieke Cats: Thank you so much for the invitation. Davide Soldato: So I just wanted to start by discussing the manuscript that you published. But before delving into the results of the manuscript that was published in the JCO, I just wanted to ask if you could give a brief overview of the DPD polymorphism and explain a little its relevance in the clinical practice.  Dr. Annemieke Cats: The DPD polymorphism is very important in the metabolism of fluoropyrimidines. Fluoropyrimidines have been in practice for over seven decades now in the world and more than 2 million people received fluoropyrimidines in the beginning of this millennium. The indications for fluoropyrimidines have only been extended since then, so a lot of people are receiving this fluoropyrimidines. But with the good side of that there’s also another side and that is that there are a lot of side effects encountered by this chemotherapeutic drug. In the 1990s, it became clear that DPD was a key enzyme in the metabolism of fluoropyrimidines. Dr. Jonathan Knikman: To better understand the toxicity associated which fluoropyrimidines are accompanied by, we have to take a closer look at the metabolism of fluoropyrimidines, and more specifically at the key metabolic enzyme which is dehydropyrimidin dehydrogenase, DPD in short. This enzyme breaks down the main active metabolite into inactive metabolites because 5-fluorouracil is the main active metabolite which is metabolized into inactive metabolites. However, if this enzyme does not function properly, this could lead to higher exposures of the active metabolites and subsequently more toxicity. This can be caused by mutations in the gene encoding for the DPD enzyme, which is the DPYD gene, and single nucleotide polymorphisms, so mutations in this gene can lead to less functional DPYD enzymes, subsequently can lead to more toxicity.  Davide Soldato: So basically, patients that are harboring these SNPs in the gene encoding for the enzyme have a higher risk of toxicities. I think what is really important about the manuscript you published is that, apart from looking at the toxicities, side effects and pseudo profile among these patients who harbor these SNPs you also wanted to check whether this was associated with some reduction or at least with inferior clinical outcomes. The endpoints you selected were progression-free survival and overall survival. But I was really interested, and I think our readers and listeners would be interested in understanding a little bit the methods of the study. What was the cohort of patients that was selected? Was this a cohort composed only of patients with gastrointestinal malignancy or also different types of malignancies? And in this second case, if you included the patients with different types of malignancies, did you have any methods to be sure that there was not any differences among these patients at the very beginning? So basically, how you handled all the confounding factors that could potentially impact the analysis of clinical outcomes. Dr. Annemieke Cats: To start your question, we have to go back to a previous study we performed, which was a prospective, multicenter study we performed in the Netherlands in 17 centers in which 1100 patients that had an indication for fluoropyrimidine therapy were included. In these 1100 patients, there were about 85 patients that were heterozygous carriers of a DPYD variant. What we did, we compared these two groups with each other, but before the DPYD carriers started, they had a reduced dose. The *2A variant carriers and the *13 carriers, they received a 50% dose, and the 1236 and 2846 they received a 75% dose. Those patients, a large amount of them consisted of patient with colorectal cancer, about 60%. And also breast cancer patients consist for a large amount of this group, it was about 20%. And then the rest were esophageal and gastric cancer mostly, and there was a group consisting of rare tumors as well like anal cancer.  The comparisons showed that toxicity in the variant carriers was higher in the wild-type patients that received 100% dose. So despite those reductions, toxicity was higher in the carriers. But when we compared the variant carriers with historical controls, we saw that, especially for *2A, there was a large reduction of toxicity to a lesser amount. This was also the case for the 2846 variant carrier. But to a much lesser extent, there was a reduction in the 1236 carriers which worried us and this was the basis for a Clinical Pharmacogenetics Implementation Consortium (CPIC) to give a recommendation for starting for all these variant carriers with a 50% dose when treatment with fluoropyrimidine was indicated. Davide Soldato: Thank you very much for the clarification. So basically, you started from one previous prospective study that was composed of a mix of different cancer types. And then in the study that you now published in the Journal of Clinical Oncology, you also added an additional part of patients who were carriers of this variants. I imagine that there was some variability between patients who were carrying the variants and those were not carrying a variant. So I wanted to understand a little bit, did you perform a matched analysis or did you try to be sure that there was not any confounding factors that could impact the results? Dr. Jonathan Knikman: Yes, we performed an exploratory retrospective matched-pair analysis and we used a matched-pair analysis to select patients which are comparable between the DPYD variant carriers and the DPYD wild-type patients to ensure that on the most important factors, they were comparable and outcome was also comparable. In this matched-pair analysis, we compared progression-free survival and overall survival between DPYD variant carriers treated with the reduced dose and DPYD wild-type patients treated with the full dose. We matched these patients on five matching variables which were primary tumor type, stage of cancer, age within a range of plus or minus 10 years, sex, and treatment regimen to ensure the these patients as comparable as possible.   Davide Soldato: And so now, moving on a little bit to the results, what were the results in brief regarding progression-free survival and overall survival for patients who were harboring a variant in the DPYD gene and those who were wild-type for this gene? Dr. Annemieke Cats:The results of our study showed that there was no significant difference in progression-free survival and overall survival between the DPYD variant carriers pooled as one group, treated with the reduced dose, compared to wild-type patients treated with the full dose. This suggests that DPYD-guided dosing can be performed safely without compromising treatment effectiveness. However, when we take a closer look at the individual variants, our study showed that progression-free survival and overall survival were not negatively impacted by DPYD-guided dosing in the 2846 and the DPYD *2A variant groups. However, in the group of 1236 variant carriers, we did find a significant difference in progression-free survival with a hazard ratio of 1.43, indicating that progression-free survival  was shorter compared to the matched wild-type patients treated with the full dose. However, no difference was found in overall survival.   So based on results on this study, we can conclude that DPYD-guided dosing can be used while treating patients with fluoropyrimidines without compromising effectiveness and improving safety. However, when patients do not experience toxicity or experience minimal toxicity, it is important to escalate the dose guided by toxicity to ensure maximum exposure to the treatment.  Davide Soldato: Thank you very much. That was a very comprehensive overview of the results. I was really wondering regarding the variants in the 1236. So the one that you said was associated with a shorter progression-free survival. At the very beginning, Dr. Cats very well explained that in the first prospective trial that was done, among these patients, toxicity was still higher or they experienced more severe toxicities, even with a 25% dose reduction compared to what was planned. So I was wondering if you could speculate a little bit. Do you think that this reduction in the progression-free survival might potentially be associated with these higher rates of severe adverse events, and that maybe this has created a little bit of a gap in the adherence to chemotherapy? Dr. Annemieke Cats: We looked into the mean dose that the 1236 variant carriers received, and this was about 75% of the dosage. So the dosage was what the protocol prescribed for the study. And also the number of cycles did not differ from the wild-type patients. So, I think the patients did not stop earlier with their treatment than was intended to. What we did see however is that in the whole group, only 10% of the variant carriers had some kind of dose modification, which could be both an increase of the dose or a reduction of the dose. So, there were only a few patients where the dose was modified. We know that the 1236 variant carriers are a very heterogeneous group. DPD enzyme activity also shows a wide range, ranging from normal to very low dose even we described a patient with a homozygous 1236 mutation. And we would expect that there would be no DPD enzyme activity, but there was still some activity in this patient.  Davide Soldato: That's a very good insight on this particular topic. So, just related to the conversation that we were just having, do you think that in general, for all DPD variants, and in particular, as we discussed, for the 1236, do you think that genotyping is sufficient for now to understand which is the right dose for these patients, to balance toxicities and to obtain the best clinical outcomes? Or do you think that we need more sophisticated or more integrated types of monitoring? Should we, for example, in the 1236, look more carefully at pharmacokinetics and so understand if these patients can receive higher doses because maybe, as you were saying, the activity of the enzyme is really higher than what we are expecting based on the genotype? Do you envision something like this happening in the future, or do you consider it as a potential line of research on this topic?  Dr. Jonathan Knikman: It's a very interesting question, and it's something we've thought about a lot. At the moment, I think genotyping is the way to go and is the most robust and most validated method currently available with fluoropyrimidines. And I think it's a bit of both. Currently, as mentioned, I would recommend DPYD genotyping, and also in the 1236 variant carriers, as we have seen in previous studies, that toxicity is still increased even while administering 75% dose instead of a full dose. So we see that there's still more toxicity. However, our study also shows that progression-free survival is shorter compared to wild-type patients. So, it's quite a complex situation as we still have more toxicity, but the progression-free survival is also shorter, and that's where we would advise the dose escalation part. So, I think it's a combination of genotyping and escalating the dose when possible, if there is no toxicity or limited toxicity, to ensure maximum exposure and to minimize the effect on progression-free survival while still trying to reduce toxicity. Dr. Annemieke Cats: This is a very important question because we do not completely understand why toxicity is higher in the 1236 with a 25% dose reduction that may compromise progression-free survival. So we have to look in closer detail, and currently we are looking in closer detail to what do we have for a pharmacokinetic analysis, that you mentioned. What about DPD activity, enzyme activity? Can you titrate on that? And I think for now, it still stands that we should start with a 50% dose, but with the possible effectiveness of the dose in mind, you should go with an early titration, and I would say something about 25%. Although having said that, I have no data to underline this. And if you have the possibility to go for DPD enzyme activity in addition to genotyping, that would also help you to titrate doses on that. And that's where we stand now. But we need to know why these 1236 variant carriers have such a large range in activity and toxicity. Davide Soldato: I also think, and I can ask you if you agree with me, that this analysis is really very important because I think it's one of the first reports regarding the analysis, specifically of progression-free survival and overall survival based on variants of DPD. But at the same time, I think that we also have to underline for our listeners that this was still a retrospective and exploratory analysis. So it's true that you observed this association with shorter progression-free survival. But still, I think that we will need also more core studies to validate these findings and to be really sure and also to perform additional analysis as to what the mechanism is as you were saying. I don't know if you agree on this limitation of the study, despite its importance in regarding clinical outcomes. Dr. Annemieke Cats: We certainly agree with you that we have to keep in mind that it is an exploratory, retrospective analysis. Having said that, a randomized controlled trial certainly has some difficulties in it as well. Nowadays, it is not feasible to give patients with a DPYD variant a full dose. In 2018, there was a lawsuit in Oregon, and now recently in Ontario, Canada. There's also a lot of rumor in the news because of patients getting a full dose while having a DPYD variant. So the lethality of the toxicity in some variant carriers makes it not ethical to perform a randomized controlled trial. So we have to look for different designs that reflect real-world data and learn more about the genotype and also in different ethnicities. It is also very important because what we have studied considers the white population mostly and that's also a direction that future research should go to.  Davide Soldato: Thank you very much. That was very insightful, especially the last part regarding ethnicity and the possibility that also these variants might be different according to that.  So I think that the main message that we should pass is that when prescribing fluoropyrimidines, genotyping of DPD is fundamental because toxicities among patients harboring these variants can be severe and can also be lethal. You performed this retrospective exploratory analysis that provided us with overall reassuring data. There is still more research to be done, especially for the 1236 variant. So I think that that probably is our bottom line and main message for our listeners.  And I just had one final question because in the manuscript that you published, you had localized, locally advanced, and also metastatic cancer that were all grouped together. Do you think that an additional line of research would be to specifically look at how these impactful outcomes only in the locally advanced and localized cancer compared, for example, with the metastatic? Dr. Annemieke Cats: You raised a very good point because there is a lot of variety within this study, and now you're mentioning locally advanced, local, or metastatic cancer. It's also within the cancer types. We studied different cancer types as well to reach a large amount of patients. It would be good to have a more homogeneous population that you can derive your conclusions from. So, I think that would certainly help us in the future, and we should look into whether we could do this together because before we had such a large population, we would need several countries to work together.  Davide Soldato: Yeah, you're totally right. Thank you very much for underlining that last point.  Thank you very much, Dr. Knikman and Dr. Cats, for being here with us today and for explaining to us and our listeners the results of your research. That concludes this episode of JCO Article Insights. We discussed the manuscript titled "Survival of Patients with Cancer with DPD Variant Alleles and Dose of Individualized Fluoropyrimidine Therapy: A Matched Pair Analysis." This is Davide Soldato, your host. Thank you for your attention, and stay tuned for the next episode.  The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  
1/4/202420 minutes, 40 seconds
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Negative Impact of Prior Authorization on Patients with Cancer

Dr. Shannon Westin and her guest, Dr. Michael Anne Kyle and Dr. Nancy L. Keating, discuss the paper "Prior Authorization and Association With Delayed or Discontinued Prescription Fills" recently published in the JCO. TRANSCRIPT The guest on this podcast episode has no disclosures to declare.  Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast that goes in depth on articles and manuscripts published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncologist and Social Media Editor for the Journal of Clinical Oncology. And as always, I'm so excited that you've joined us, and none of the authors have any conflict of interest today. We are going to be discussing a very exciting piece of work, “Prior Authorization and Association with Delayed or Discontinued Prescription Fills,” recently published in the Journal of Clinical Oncology. And I'm thrilled to be joined by the two authors of this important work. The first is Michael Anne Kyle. She's a PhD research fellow in the Department of Healthcare Policy at Harvard Medical School.  Welcome, Michael Anne.  Dr. Michael Anne Kyle: Hi. Thanks for having me. Shannon Westin: We're so excited. And the second is Dr. Nancy Keating. She's Professor of Healthcare Policy at Harvard Medical School and Professor of Medicine at Brigham and Women's Hospital in Boston.   Welcome. Dr. Nancy Keating: Thank you. It's great to be here.  Shannon Westin: So, we'll get right to it. First, I always like to level set because we have such an interesting and diverse audience. Can one of you describe the process and goals of prior authorization? What does this mean for our groups that maybe haven't experienced this? Lucky them.  Dr. Michael Anne Kyle: Prior authorization is- the process can take many forms. Basically, what we're describing is before you can be prescribed a treatment, in this case, we're looking at medications, you have to submit a request to the payer, to the insurance company, asking for approval to receive that treatment, or in this case, that drug. The doctor's office does have to do a ton of work, but very often, the patient also receives a lot of the communication. So, there's a lot of work for everybody in prior auth often. And the uses of it- in principle, the purpose of prior authorization is to confirm that the reason this medication or this treatment is being prescribed is because the patient meets the criteria for need. So that can mean, you want to confirm that you have the right tumor markers for the drug that's being prescribed. You want to confirm that you are aligned with guidelines. And then I think the thing that's often on many people's minds is that in the US, we don't have a lot of controls on drug pricing, but drug prices are very high. And so, I think we often think about prior auth as being a mechanism to try and contain costs.  Shannon Westin: And this isn't new, right? So, this is a process that's been going on for a while. I'd love to hear you speak a little bit about, maybe, some of the changes, like how have the requirements for prior authorization been changing over time, especially for patients with cancer? Dr. Michael Anne Kyle: That's a great question. And that was the first step we took in this work because we've heard from oncologists, from patients, from researchers, that prior auth has been increasing. And we did find, looking at Medicare data, that that is true, that the use of prior authorizations for oral oncology drugs, so that will be Part D outpatient drugs you get at the pharmacy, has been rising over the past decade. And I think what's really interesting to point out here is we found the use of prior authorization increasing both for branded drugs and for generic drugs, and for specialty drugs, which are high cost, as well as non-specialty drugs, which are typically lower cost. So, across the board, prior auth is increasing. And why is this happening really is the million-dollar question. Some of it is surely like we have accelerated approvals happening predominantly in oncology. So, you could imagine that you do need to verify some evidence of these newer treatments, but some of it is a little bit harder to interpret. And that was one of the things in our paper that we were very interested in because we also see a lot of prior auth on drugs that have a very well-established record of efficacy. And we know our first-line therapies often now include some generics, and yet we still see that they have prior auth. And the reason for that is less clear. Shannon Westin: Yeah. Just as a gynecologic oncologist, coming from this standpoint of PARP inhibitors, which have long been established as a standard of care and for years now have been a frontline treatment, we're getting so much pushback around that, and it's a huge issue because that impact of delays and things, and I know that's your work. So, I think that's one of the reasons I was very enthusiastic about this because I think it has such broad-based impact across all of our patient populations.   So, I think that kind of definitely transitions into this. What are the potential negative impacts in this process of patients? And I would say not only patients with cancer, but what do we know also in patients with other disease types that are facing this prior authorization issue as well? Dr. Michael Anne Kyle: What we were curious about is there's a sense that prior auth is increasing, the trends show it's increasing. And we were wondering, does that matter for patient care? And we could think about the benefits of prior authorization being like double-checking that you're getting the right treatment. But the negatives are that you can be delayed in getting treatment, and that can either be because you're going through the initial process or there can be some error or denial or dispute in a prior auth process that delays your access. And the clinical implications of that would vary by drug, how that would affect your treatment. In this case, in this paper, we're talking about drugs, but for any treatment, the implications would depend on what the treatment is and what the patient's condition is. But I really want to draw attention to this other piece, which is that it's stressful not to have your cancer medicine. And so even if you ultimately end up getting it, the time that you're on the phone trying to figure it out is time taking you away from other things. It's stressful. And very often, patients with cancer are taking multiple drugs and have complex health issues. So, they may be dealing with this for multiple parts of their care. And that can add up. Shannon Westin: Perfect. Thank you. So, I guess next is to talk about how you address this. Let's talk a little bit about the overall objectives of the study that you just published and maybe briefly kind of go through the design for our listeners. Dr. Michael Anne Kyle: What we were interested in doing, like I said, was trying to figure out what happens with prior authorization at the point of care. And our study looks at 11 oral anticancer drugs in Medicare Part D. And the reason for that is because data available to look at prior auth is fairly limited. And Medicare Part D for the outpatient formularies does have indicators for whether a drug has a prior auth. So, we were able to use that. The next piece is we're not inside the office understanding why these treatment decisions were made. So, what we decided to do was say, “Okay, let's look at patients who've been consistently taking this drug.” And we said, “Okay, let's say you've had to have at least three fills in the past four months.” And we sort of take that as an indicator that you're able to access this drug and it seems to be working for you. And then what we do is we look at who are patients in plans, same drug, same plan, where the plan introduced a new prior auth on this drug they're taking, as compared with patients in plans who did not have a change in their prior auth policy. And we said, “Okay, there's this new prior authorization introduced, does that affect whether you get that next fill or how long it takes to get it?” Dr. Nancy Keating: I want to emphasize Michael Anne's point about these are patients who are already successfully filling and regularly taking their drugs. And unfortunately, due to data limitations and the inability to see prescriptions that aren't filled, we would love to look at the same question with people that are starting on a new drug but weren't able to do so but would imagine that you might even see bigger impacts in those patients. We both recognize from a health policy standpoint that there could be benefits of prior authorization policies. But it's also very unlikely to think that for a patient that's regularly filling an anticancer drug over a long period of time, that there's a reason that that patient should not be on that drug. And so, this is an area where we think that there may be really limited benefits of prior authorization, but potential harms.  Shannon Westin: Yeah, it makes sense. And of course, it would be. There's always the ideal way to set research up, and then a practical way. So, I was struck by what you chose. I thought it was really very practical and rational and made a lot of sense. And certainly, there are inferences that we can make based on what you found. So, let's talk about that. Let's talk about your primary findings. What did you see as the impact of a new prior authorization policy on patient care? Dr. Michael Anne Kyle: We found that for the patients who had a new prior auth policy introduced in their plan, compared to patients who didn't have a prior auth change, their odds of discontinuation within the next 120 days increased by about 7.1 times higher odds of discontinuation. And then for delays, we found that people were delayed an average of 9.7 days from when we last saw that they were expected to run out of their drugs based on their last fill, we said, “Okay, what's the last day we expect you to have meds on hand, and then when do we actually see you fill again if we see you fill? And the average delay there was 9.7, about 10 days. And that's a fairly conservative estimate that we decided to make. And I'm sure you and Dr. Nancy Keating can elaborate on how that's not just passive time. There's a lot of people scrambling around, probably in that interval, trying to close the gap. Shannon Westin: I mean, you said it, like, 10 days. It's a huge time. And it's not just time sitting there twiddling your thumbs. They're probably stressing, anxious. They might be having side effects related to stopping their medication. They might be taking other medications and reduce the efficacy of the combination. I mean, there's so many implications here of the impact. Dr. Nancy Keating: They're also calling the office, trying to get through to the office. Then the doctors are calling, trying to get through. People are like, what's going on here? Why isn't this medicine there? And so, there's a lot of individual patient and clinician effort that's happening at this time as well. Shannon Westin: And I think, of course, you were limited by the databases that you were using and what you're able to access, but I think it really does make me wonder, what's the impact on cancer related outcomes. We know about delays in certain therapies and things and how that can negatively impact survival and response and all of those types of things. And I wish we did have access to that kind of data because obviously the time and the things that you've been able to demonstrate are important, but the more objective data we can get around patient outcomes, I think will help us impact the actual policies that are being implemented here.  Dr. Nancy Keating: Right. And just to underscore too, Michael Anne highlighted the delays, but also there was a substantial increase in discontinuation within 120 days. So, there are some people that seem to not be able to get the med, maybe found another way to get it, or maybe were able to get samples from a drug company that we couldn't observe, but that's also concerning that there might be some people who fell through the cracks.   Shannon Westin: A very good point. I think that it's hard to know, but the potential there of losing the drug that's actually working for you is really distressing for providers and patients both.   One other thing I noticed that was interesting. Can you speak a little bit about some of the other factors that were associated with these findings with the treatment delays and what other things may be impacting these outcomes? Dr. Michael Anne Kyle: We looked at some patient characteristics and insurance characteristics that may be associated with delays. And I just have to note here that our sample is fairly small because prior authorization is so prevalent. There aren't a lot of switchers. So, this sort of limited the amount of depth we could go into. But here's what we can tell you, which is that people who are under 65, so in Medicare that will typically be people who have eligibility through disability, were filling about a day later than that 9.7 average people, female sex also filling 0.7 days, nearly a full day later. Similarly, and this is compared to males and then compared to white, non-Hispanic patients, patients who are black and patients who are Hispanic Latino are filling about 0.6, 0.7 days later, which is, of course, quite concerning, given our desire to have a more equitable health care system. And then finally, we linked our data to census data. And for patients living in a residential zip code with higher rates of poverty, we found that for each 10-percentage point increase in proportion of residents in that zip below the federal poverty level, the delay was about 2.5 days. So, what you can sort of take from that is the risk factors in particular are in Medicare being younger, which I would say is having a disability, female sex, non-white, and people living in high poverty zip codes. And given what we know about racial segregation, I think the odds are likely that the patients themselves would potentially also be low income. Shannon Westin: That's what's so important about this work, is it raises an awareness of, really, who's being impacted by this. Because I just want to draw back to kind of what you said at the beginning, that this is meant to do cost containment. It's meant to help the healthcare system. But what we're seeing in practice is it may be helping in some specific areas, but it's certainly creating quite a detriment. So perhaps there are other mechanisms that we could be exploring from a policy standpoint to try to work on cost containment, but not put the burden on the patients or on the people that are giving this health care. So, I think that's why I was so struck by this work.  I guess the next question is, what are your next steps for the research, and how can we use these data to help the patients?   Dr. Michael Anne Kyle: What a great question. I'll start, and then I'll let Nancy give her thoughts too. We're lucky that prior authorization is a very active policy area right now, both at the state and federal level. There's a great deal of interest in sort of certainly improving a lot of the information systems. Perhaps we can move away from the fax machine finally in 2023. I think there's a lot of policy relevant action happening around trying to make prior authorizations electronic, and you can automate them and make a lot of this move faster. There are also larger questions about what is the right price for a drug and how do we distribute it to people that I think are a lot more fundamental than any one study, but I think this is just another way. When we think about financial toxicity, there's just many challenges that come back to some way to this root cause of care is very expensive, and this is, I think, prior auth is one of the side effects of that.  And so, hopefully, to help patients, we can get this data in the hands of policymakers who are trying to bring us to a more modern prior auth system. And hopefully also to payers, I would be very excited to see a little bit more examination of, like when is prior auth appropriate versus when is it not. I think there are cases where prior authorization is very appropriate, and we shouldn't take it away. But one of the drugs in our study is generic imatinib, and perhaps that is a lower value prior auth. And so, I'd be very interested in seeing payers think more strategically about when is prior appropriate, both to improve access and improve equity, and then also to improve the provider burnout and the poor docs who are really struggling under the weight of this. Dr. Nancy Keating: Yeah, I couldn't agree more with everything that Michael Anne said, but really, we'll underscore that last point. The prior auth policy seems like it's this very broad policy and the way that it's implemented, it's sort of like, let's just hit everything and not take a nuanced, thoughtful approach. But just like Michael Anne said, generic imatinib, really? And then back to this point of patients that are doing well on a drug, people are not going to be taking anti-cancer therapies if they don't need to. And so there just doesn't seem to be any reason to implement a prior authorization policy on a drug that is being well tolerated. And so really, I think there could be a lot more thought and nuance put into applying these policies within health plans. Shannon Westin: Yeah, I think that's a perfect way to end this. I would just add, I think this is beyond anticancer therapy for our patients with cancer. I mean, we're seeing it now with supportive care medications. And to your point, I mean, generic antiemetics, and you're like, come on, this is ridiculous. So, I think that this type of work is- the best type of work always spurs more questions and gets us fired up about what to do next. So, I just want to again commend you on all of this important work, and we need to add more data here so that policy will change. And so, thank you both for your hard work in this area and for taking the time to educate our listeners. I'm sure we're going to hear a lot of intriguing questions for you about this work, and hopefully that'll move our policy forward.   And thank you, listeners, for checking in again with JCO After Hours. Again, we were discussing prior authorization in association with delayed or discontinued prescription fills. I'm so grateful to Dr. Kyle and Dr. Keating for joining me today, and I hope you all will listen to our other podcast offerings wherever you get your podcasts. Have an awesome day.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and it is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  
12/14/202318 minutes, 19 seconds
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Role of Molecular Classification in Predicting Response to Radiation in Early Endometrial Cancer

Dr. Shannon Westin and her guest, Dr. Nanda Horeweg and Dr. Carien Creutzberg, discuss the paper "Molecular Classification Predicts Response to Radiotherapy in the Randomized PORTEC-1 and PORTEC-2 Trials for Early-Stage Endometrioid Endometrial Cancer" recently published in the JCO. TRANSCRIPT  The guest on this podcast episode has no disclosures to declare. Shannon Westin: Hello everyone, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on manuscripts published in the Journal of Clinical Oncology. I'm your host Shannon Westin, Social Media Editor for the JCO and GYN Oncologist by trade. And I'm so excited about today's topic because it is a GYN Oncologist dream. Before I start, please note that none of the authors have any conflict of interest. We are going to be discussing molecular classification predicts response to radiotherapy in the randomized PORTEC-1 and PORTEC-2 trials for early-stage endometrioid endometrial cancer. And this was published in the JCO on September 20th, 2023. And we're going to be speaking to two of the lead authors. First is Nanda Horeweg. She's a senior researcher in the Department of Radiation Oncology at the Leiden University Medical Center in the Netherlands. Welcome. Nanda Horeweg: Thank you. Happy to be here. Shannon Westin: And Dr. Carien Creutzberg. She's professor at the Department of Radiation Oncology at the Leiden Medical Center as well. Carien Creutzberg: Thank you. Shannon Westin: So, let's get into it. And I want to really level set because we have a mixed audience here. So, why don't you start by speaking about the incidents and mortality of endometrial cancer? Nanda Horeweg: Yes, of course. Endometrial cancer is the sixth most common cancer in women with around 400,000 new diagnoses made globally each year. And a woman's lifetime risk to get endometrial cancer is around 3%, and the median age, the diagnosis is 61 years. Most of the women who are diagnosed with endometrial cancer are diagnosed at an early stage, around two thirds, and they have an excellent prognosis. Actually, the five-year survival rates are around 92%. For stage 2 disease, this is actually already going down a bit to 74%. Therefore, stage 3 disease is only 48%. Women that are diagnosed with advanced disease have only a five-year survival, 15%. Shannon Westin: So, given that we know the majority of endometrial cancers are diagnosed at this early stage, prior to your evaluation, what was known about the optimal way to treat this early-stage patient population? Carien Creutzberg: Well, of course, the PORTEC trials were done … were started PORTEC-1 in the 19th of the last century, and PORTEC-2 in 2002. So, at that time, there were still many, many women treated adjuvantly with external beam radiation therapy. And we just developed risk factors to decide on their risk and the incidents for radiotherapy. And in PORTEC-2, because in PORTEC-1 we had seen that most of the recurrences in these early stage cancers were in the vaginal fold, we compared local vaginal brachytherapy only three sessions within full course of pelvic radiotherapy and showed that it had similar pelvic control and survival. Of course, this study, which Nanda conducted, was a long-term analysis with many new factors known from the translational research in the tissue samples of these patients who participate in PORTEC-1 and 2. And in the meantime, we've developed much more knowledge on the molecular factors and other important factors such as LVSI, which tell us much more about the individual prognosis to patients. So, the treatment has been developing greatly in the past 20 years. Shannon Westin: Yeah, and I think this is a great case of less is more, right? We were doing so much for so many people that really didn't need it. And so, really tailoring who needs less treatment, who doesn't need any treatment, and then also, conversely, who may need more treatment that would be missed by the traditional risk factors that you're speaking of. So, I think that brings us right into my next question, which is just bringing the audience up to date on the cancer genome atlas and how that's changed the way we classify endometrial cancer. Nanda Horeweg: Yes, I think the molecular classification of the TCGA has shaped the way we think about endometrial cancer, and has huge impact on decisions on adjuvant treatments in the years to come. The TCGA performed an extensive characterization of the endometrial cancers and found that in fact, this disease exists of four different groups. And the first of the groups I'd like to discuss is the ultra-mutated group, which is characterized by POLE mutations. And this group is shown to have an excellent prognosis in many independent studies. A second group that also has a high mutational burden is characterized by microsatellite instability, and mismatch repair deficiency and has shown to have an intermediate prognosis. Then there's another group that has a low mutational burden with high copy number alterations and frequent TP53 mutations, and these have a poor prognosis. And then lastly, there's a group that does not have any of the classifying features and is often called non-specific molecular profile or TP53 wild type. And this group also has an intermediate prognosis. And then finally, there's a small group of cancers that has more than one of these classifying features, the so-called multiple classifiers. And the WHO 2020 has developed an algorithm which can be used to classify them into the four groups. And that's first on the POLE status. And for the POLE wild type tumors, they are assigned according to mismatch repair deficiency status. And for those that are mismatch repair proficient than POLE wild type, they are classified according to the TP53 status into NSMP or p53 abnormal. Carien Creutzberg: Yeah, that is because of in the ultra-mutated and hyper mutated groups, many of the other mutations are secondary mutations in the context of the ultra-mutated stage, and they behave like the first molecular group. Shannon Westin: Yeah. So, that POLE mutation is going to trump anything else, and it's so important. And I will just say as a sidebar, it's been challenging with the price of next gen sequencing sometimes to get that for everyone. So, sometimes for us when we see a p53 mutation, we actually go back and do the full next gen sequencing to make sure that we're not going to act on that core prognostic feature when it really is in the setting of that more simplistic or that more positive prognostic place. So, this is great, we already kind of highlighted a little bit PORTEC-1 and 2, but if you don't mind, I would love to get the audience a little bit more information just maybe about the populations that were included as we were figuring out how aggressive to be with radiation just to remind people of that, or to teach them that if they haven't gotten a chance to look at those studies. Carien Creutzberg: Yeah, that's important to know because PORTEC-1 was still in the era that we also treated intermediate risk stage 1 endometrial cancer patients. So, deep invasion with grade 1 and 2 or superficial invasion with grade 2 and 3. That's what we defined at that point. Then we compared external beam radiation or no further treatment, showing no survival difference, but a higher risk of recurrence with higher risk being older age over 60, grade 3 for deep myometrial invasion. And we kept those high intermediate risk factors as also similarly found by GOG-99 at the time to do PORTEC-2. So, at the time, about 50% of patients did not have an indication for adjuvant therapy anymore, and with a high intermediate risk population for PORTEC-2, we compare external beam or vaginal brachytherapy and found the benefit of vaginal brachytherapy. A simple outpatient treatment, very short with almost no side effects ensuring local control. And nowadays, using the molecular classification of PORTEC-4a, we've compared achieving treatment with or without use of the molecular factors to designated treatment. So, the standard arm is vaginal brachytherapy and investigational arm is first, a molecular risk profile. And then we give no radiotherapy for those with a favorable profile, then a brachytherapy for the intermediate ones, and for the small group is either extensive LVSI or TP53 mutation or L1 chem overexpression external beam. And we hope to show that less overtreatment and less undertreatment will benefit these patients. Shannon Westin: Yeah, I'm very much looking forward to the results of PORTEC-4a. But let's circle back and talk a little bit about your amazing work here. So, how did you leverage those patient populations from PORTEC-1 and 2 for the current study? Nanda Horeweg: Yes. Well, the PORTEC-1 and 2 study provided a unique opportunity to look into differential treatment effects for radiotherapy. And that is because these are randomized trials, so the groups are comparable, and we have long-term follow-up data that's of very high-quality. In addition, as Carien said earlier, she had the vision already back in the nineties to directly ask the patients permission for the collection of the tissue. So, we have a broader complete biobank for both of these trials, which is quite unique. And our colleagues, Professor Smit and also Charlene Goseff from the pathology department, they have done extensive work on molecular classification, and have molecularly characterized all these cases. So, this allowed us to include 880 patients in this study, which is the largest so far. And besides like the very good starting point that we have of PORTEC-1 and 2 is that we also chose a design that was optimized to conduct like real causes, the causal effects of the molecular class on radiotherapy response. So, we tried to preserve this randomization effect, the exchangeability of the groups as much by working with the intention to treat population and not excluding any patients, except for when they did not have the molecular classification assessed. And also, we looked at areas in the body that were irradiated in one group and not in the other one to really observe the effect of radiotherapy as much as possible. So, looking to the entire pelvis, so local and regional recurrences in PORTEC-1 and looking at pelvic recurrences in PORTEC-2. Shannon Westin So, how were the intervention outcomes in this study different based on the TCGA classifiers? Nanda Horeweg: Before I tell you the results of biomolecular group, I think it's good to have the starting point of the analysis here. So, the no hypothesis of my study was to see whether there was any difference, and no hypothesis is that there's no difference. So, if we find a significant effect, then we can actually say that we found something. And if we start with the POLE group, we did not find any significant difference between the groups allocated to radiotherapy or not. But we did see not a single recurrence in any of the patients that we included from both of these trials. So, technically speaking, we did not find a predictive effect of the molecular classifier, but a prognostic effect. There's no one's having recurrence, so we can deduct from that, that radiotherapy is probably over treatment. Then for the MMRd group, we did observe some recurrences, but these were not significantly different between these three groups. So, based on this study, we cannot draw conclusions on which type of radiotherapy we should give to the patients or whether we should give radiotherapy at all. This was very different for the p53 group. There, the patients had lots of recurrences, unfortunately, as we expected, but we saw a big difference in outcome compared between no radiotherapy at all if it's vaginal brachytherapy where we still had lots of recurrences, and EBRT where we hardly saw any recurrences in the pelvis. And that difference was significantly different. So, that's an indication that these patients need more than just vaginal brachytherapy, even though it's only stage 1 endometrioid endometrial cancer. And then in the last group, the NSMPs, we saw even a different pattern where patients who had had external beam radiotherapy or vaginal brachytherapy, both had an excellent local regional control, and the ones that did not receive any treatments had more recurrences. And this was also very significant. So, there, you would conclude that both therapies are appropriate, but of course, the toxicity profile for vaginal brachytherapy is much more favorable than that of EBRT. Shannon Westin: We really are getting kind of consistent data around p53 needing more treatment. And I think the natural question that comes here, for me at least, and I know we can't answer it with the work, is would chemo be — would that be that extra treatment, when we saw with PORTEC-3 that the group needed the chemotherapy the most. So, I think we'll have to continue to work through that and determine is any more treatment what we need or specific treatments really the best. So, this is so intriguing and it's nice that it's consistent, that we're seeing that across these different studies that really kind of lends strength and validity, I think to what we're finding. So, one of the actions that we're kind of moving towards and that you advocate certainly in your paper is omitting therapy for patients with POLE mutations. Are there any ongoing studies around that that will help us confirm that this is safe for our patients? Nanda Horeweg: Yeah, that's a very good point. I think the evidence is strong enough now to conduct prospective trials. And of course, these are ongoing, the PORTEC-4a trial was already briefly mentioned there. The patients with poor mutations will be randomized between observation and vaginal brachytherapy. So, that will give us a good indication whether in this high intermediate risk early-stage group omission is safe. And in addition to that, we are also conducting with the RAINBO Consortium, the RAINBO-BLUE trial, wherein patients also with high-risk features, so non-endometrioid isotypes, LVSI and higher stages are included. And also in those patients, we investigate whether the de-escalation of treatment is safe. So, we're definitely looking forward to those results to be able to transfer this knowledge to clinical practice later on. Carien Creutzberg: And maybe it's nice to add that RAINBO BLUE is connected to the Canadian Taper trial. Taper being a general de-escalation trial where the POLE patients in that trial are also feeding into the RAINBO-BLUE. And I know that in North America, many centers will participate in the Taper trial. Shannon Westin: Yes, I think everyone is very excited and I think it'll be nice to have these two very strong studies that will help us really confirm that that is 100% a test that needs to be done, cost are not — and that will help avoid overtreatment of patients. So, in line of that, have you all experienced any challenges with implementing molecular testing across patients with endometrial cancer? Any thoughts on how we could potentially simplify? You talked about the rational promise algorithm, which I think is excellent, but I'm just curious to hear your thoughts on this. Nanda Horeweg: The implementation of the molecular classification can be challenging. We have to be honest about that. And usually, it's the assessment of the POLE status that's causing the problems because that's usually done with NGS, which is quite expensive. It requires a lot of knowledge in the laboratory and it's also a bit time-consuming. So, that is the bottleneck for most laboratories and for most settings. But this is already changing in a couple of places, like in the UK and the Netherlands, it's being reimbursed by healthcare insurances, and also, in many tertiary care centers in other countries, they're already systematically performing this test. But of course, there will always be places where this is not feasible. And luckily, there are also cheaper alternatives coming up and are already available at the moment. So, one of them is, for example, standard sequencing, which is not so expensive, but a bit labor intensive. Some colleagues we work with from India have implemented that in their clinical practice and are perfectly able to molecularly classify the endometrial cancers in daily practice. Another alternative is a test that we've developed in Leiden that's called the QPOLE test, which is based on qPCR, so that's a technology which we use for our COVID test around the world, so that can be done almost anywhere. And with that, you have a very high accuracy to detect unknown pathogenic variants. And this is also published in JCO Global Oncology, and can be implemented in any center after a local validation step. And even like more companies nowadays are realizing that this is important. So, I think commercial tests are already becoming available and very more on the market soon. So, I am really hoping that it'll be more available to endometrial cancer patients. Carien Creutzberg: And they'll offer them at a very low cost and also a rapid turnaround because NGS can take like 10 days. But realizing on a more national level, if you have found one patient with a POLE mutation, the omission of cycles of chemotherapy with all of the patient care around in the hospital is worth much more than just a few POLE tests. So, we have to look at this and that's I think why our healthcare reimbursement came through that if you look at a population level, it is cheaper, and we'll do an extensive cost analysis in PORTEC-4 just to show this. Shannon Westin: That is such a good point. I love that and all of the downstream issues that happen potentially with radiotherapy or with chemotherapy, that's really brilliant. And I'm going to take that back, I love these podcasts. I always learn stuff that I immediately start to use. So, I guess then the last question is, what's next for this particular research and how might we validate what you found? Nanda Horeweg: Yes. Well, as mentioned earlier, for POLE, we have already put the next step in place. So, PORTEC-4a has completed accrual almost two years ago, and we're very much looking forward to do the final analysis within one to one and a half years. So, that will be one of the important next step. And of course, the POLE-BLUE trial is open at the moment, and within a couple of years, we also hope to learn more about this group. So, that's very exciting. Then for the mismatch repair deficient group, while we did not find any particular sensitivity for radiotherapy, and I also don't think that we will conduct another large randomized radiotherapy trial in this group — I think the results that we've observed in the metastasized setting, were really impressive results with immunotherapy are the way forward for this molecular class. And I think the next thing we should do now is prove whether this works or not in the adjuvant setting. And if that's starting with the high-risk patients, which is something we are currently doing in the MMRd-GREEN trial, which is ongoing in the Netherlands, and soon, will open internationally. And from there on, we can work forward if we see that also in this setting the immunotherapy works well. Shannon Westin: And I think GY020 also — NCI trial is also looking at the addition of immunotherapy to radiotherapy in that irony at risk. Carien Creutzberg: Absolutely. Nanda Horeweg: Yeah. And the KEYNOTE-B21 as well — oh, well, already complete accrue. Shannon Westin: The B21, yeah. So, I think those are good. Yeah, that's a really good point for that MMRd group that the immunotherapy really is the way to go, and then more work to be done with the no specific molecular profile. Nanda Horeweg: The NSMP, I think like for the early-stage group, it's quite clear that vaginal brachytherapy is a therapy of choice. But you can of course, try to identify those at such a low risk that you could deescalate treatment. And that's of course what's being done in the Taper trial and also in part, investigated in the PORTEC-4a trial. Carien Creutzberg: And those with higher risk NSMP that we are revisiting hormonal treatments because 90% are estrogen receptor positive, and they have a clearly better prognosis than those with estrogen receptor negative tumors. So, those with estrogen receptor positive tumors can in RAINBO-ORANGE, which will be run led by the UK group, see if we can improve quality of life with less intensive adjuvant treatment. And then you came to the p53 group, that's a good one to stop with. Nanda Horeweg: Yeah, we have very good indications that radiotherapy and chemotherapy is working well for this group. And this is also in line with the guidelines that have been issued in the last few years by many societies. So, I don't think we should change this base of the treatment consisting of radiotherapy and chemotherapy. But since the prognosis is still rather poor, we need to add systemic agents to reduce the risk of metastasis. And preferably, this should be like well-designed based on a proper biological underpinning, plus something that's not too toxic since we're combining the three therapies together. So, this is what we try to do in the RAINBO-RED trial where we will investigate the addition of a PARP inhibitor to chemoradiation in the p53 group. Shannon Westin: Oh, I love that. That's been my whole career, is adding PARP inhibitors wherever I can. Carien Creutzberg): We might also want to mention the HER2 inhibitors, which are also in about 20% of the p53 group has HER2 overexpression. And there is a trial being set up in NCI with trastuzumab and pertuzumab. Shannon Westin: My only concern with that one is I think that the antibody drug conjugates are so much more powerful, the TDX data that we just saw from DESTINY is so impressive. And so, I do wonder, like if we need to move on from kind of some of the older HER2, and get with the program and use some of these more powerful drugs. But with that, I just want to thank Dr. Creutzberg and Horeweg. This was such a great discussion, and obviously, near and dear to my heart talking about endometrial cancer, but I hope our audience enjoyed as well. Just as a reminder, this was a discussion on molecular classification predicts response to radiotherapy in the randomized PORTEC-1 and PORTEC-2 trials for early stage endometroid endometrial cancer, published in the JCO on 9.20.23. I am your host, Shannon Westin, and I hope you'll check out more JCO After Hours wherever you get your podcasts. Have an awesome day. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    
11/30/202323 minutes, 6 seconds
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JCO Article Insights: Impact of Physical Activity on Mortality and of BMI on Treatment-Related Adverse Events

In this JCO Article Insights episode, Davide Soldato provides summary on two articles published in the November issues of the Journal of Clinical Oncology. The first article provides data on the prognostic effect of physical exercise on overall mortality and cancer-related mortality in a pan-cancer analysis of the PLCO study. The second article provides data regarding the impact of BMI on treatment-related adverse events and adherence to Palbociclib in the PALLAS trial. Overall, results of these study support the need to conduct studies investigating lifestyle behavioral factors and their impact on outcomes in survivors of and patients diagnosed with cancer. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Davide Soldato: Welcome to the JCO Article Insights episode for the November issue of the Journal of Clinical Oncology. This is Davide Soldato, your host, and today, I will be providing a summary on two articles focused on the impact of exercise on cancer prognosis and of BMI on treatment side effects. In the first article titled Pan-Cancer Analysis of Postdiagnosis, Exercise, and Mortality, Lavery and colleagues investigated whether higher exercise was associated with a reduced risk of mortality among individuals diagnosed with cancer. The authors conducted a pan-cancer analysis using data from the Prostate, Lung, Colorectal, and Ovarian cancer screening study or PLCO, using data from a questionnaire that was administered to participants in the study at a median of nine years after initial randomization. The questionnaire including 12 questions related to physical activity, both occupational and non-occupational. Of these 12 questions, four were used to assess the prognostic impact of moderate and strenuous exercise evaluated both in terms of frequency, so a number of sessions per week, and duration of exercise sessions. The exposure to exercise was defined according to international guidelines, and patients were so divided among those who had a moderate intensity exercise defined as at least four days per week with each session on average for 30 minutes in duration, and strenuous intensity exercise equal or more to two days per week with each session on average of at least 20 minutes in duration. So, based on this definition, the patients were categorized as either exerciser, if they were meeting the recommendation or non-exercisers. Additionally, to assess the existence over those response relationship between exercise and mortality, the authors further categorize patients on a four level scale as reporting no exercise, exercise, not meeting recommendation, meeting recommendation, or exceeding recommendation. The primary endpoint of the study was all-cause mortality, and secondary endpoints included cancer mortality and mortality from other causes. This study included more than 11,000 patients diagnosed with cancer. 38% of them reported meeting guidelines recommendation with a median of 44 and 19 minutes spent in moderate and strenuous exercise respectively. Individuals belonging to the group of exerciser were more frequently male, non-smokers, and with a lower prevalence of cardiovascular diseases. The most common cancer diagnosis were prostate cancer, breast cancer, and colon cancer observed respectively in 37%, 20%, and 7% of the participants. Patients who died within six months from the completion of the questionnaire were excluded from this study. A median follow-up time between this landmark point and the last follow-up was 11 years. More than 4,500 deaths were observed in this period, and less than half were related to cancer meeting. Meeting exercise recommendation was associated with a 25% risk reduction in all-cause mortality, a 21% risk reduction in cancer mortality, and a 28% risk reduction in mortality from other causes. In particular, five-year cancer mortality rate was 12% among exerciser and 16% among non-exerciser. Interestingly, the positive prognostic effect of exercise was observed starting within the first five years of observation, but persisted up to 20 years afterwards. An inverse to those response relationship between exercise and mortality was observed, so increasing exercise was overall associated with incremental reduction in the risk of death. The authors compared patients reporting no exercise with those reporting exercise under at the recommendation or over the recommendation. For all-cause mortality, the risk reduction was equal to 25% among those reporting exercise below the recommendation, and increased to 35 and 36% among those meeting and exceeding recommendation respectively. Similar results were observed for cancer mortality, risk reduction ranged from 19% in those reporting exercise below recommendation, up to 33% for those exceeding recommendation. Finally, the authors investigated the effect of exercise on mortality by cancer type, and observed a significant reduction in cancer mortality only for head and neck cancer and renal cancer. While reduction all-cause mortality and mortality from other causes were observed across a wide range of cancer, including breast, endometrial, and hematopoietic and prostate. The study confirms previous findings by showing an inverse relationship between higher level of exercise and lower risk of all-cause mortality, and provides novel insights on the topic by reporting that those response association, data on other causes of death, and edited analysis by cancer site diagnosis. All limitation of the study is related to the generalizability of the findings. The study included only patients that were alive at a median of 4.5 years after cancer diagnosis, which might have applied to selection of patients with good prognosis, and thus, reducing the number of cancer mortality events. Additionally, these patients were willing to complete an additional questionnaire in the context of the trial, which might be related to a higher motivation in engaging in healthy lifestyle behaviors. The study did not replicate previous findings observing a reduction in cancer mortality for breast, colon, and prostate cancer, among those reporting higher exercise. Although this might be related to the inclusion of long-term survivors in the study. In the second article titled Impact of BMI in Patients With Early Hormone Receptor-Positive Breast Cancer Receiving Endocrine Therapy With or Without Palbociclib in the PALLAS trial, Dr. Pfeiler and colleagues investigated the impact of BMI on side effects, adherence to treatment, and efficacy of palbociclib in the PALLAS trial. Just as a reminder, PALLAS is a randomized clinical trial that investigated whether the addition of two years of palbociclib to standard endocrine therapy in patients treated for stage two, three hormone receptor-positive HER2-negative breast cancer could improve invasive disease-free survival. Previous report of the trial showed that palbociclib did not improve invasive disease-free survival compared to endocrine therapy alone. More than 5,500 patients were included in this analysis, and among them, more than two third at a BMI equal or over 25 diagnoses with 32% being overweight and 30% obese. Overweight and obese patients were more frequently older and coming from North America rather than from Europe. In line with the age difference, normal weight patients were treated more frequently with Tamoxifen alone or in combination with ovarian function suppression or with aromatase inhibitors in combination with ovarian function suppression. No differences in tumor characteristics was observed according to BMI. However, there were some minor differences regarding the type of surgery and administration of chemotherapy. The authors observed that side effects of palbociclib were significantly different according to BMI and in particular, they observed a lower incidence of a hematological toxicity among overweight and obese patients. Conversely, higher rates of arthralgia, nausea and diarrhea were observed among overweight and obese patients, both in the palbociclib and in endocrine therapy alone. In particular, regarding hematological toxicity, the authors observed that overweight and obese patients experienced a significantly lower incidence of overall neutropenia, grade 3 and grade 4 episodes of neutropenia. For example, looking at grade 3 neutropenia, the incidence was equal 44% in the obese population versus 64% in the normal weight cohort. Differences in incidence of neutropenia remains significant even when adjusting for confounding factors, including previous administration of chemotherapy, age, ECOG performance status, and race ethnicity. Furthermore, a lower incidence of overall thrombocytopenia was observed in the overweight and obese cohort. The lower incidence of hematological toxicity led to significant differences in those reduction, early discontinuation, and relative dose intensity for palbociclib. At six months, only 29% of obese patients reduced to those of palbociclib compared to 50% in the normal weight cohort. Similarly, only 20% of obese patients permanently stopped palbociclib compared to 35% in a normal weight group. Finally, the risk of palbociclib early discontinuation was 25% lower for each additional 10 units of BMI, even when accounting for additional potential co-founders. As a consequence of a lower dose reduction and lower rates of early discontinuation, the relative dose intensity for palbociclib was significantly higher among overweight and obese patients compared to normal weight ones. Efficacy of palbociclib was not different according to BMI, neither in the palbociclib bar, nor when assessing patients in both arms. However, these analyses are performed with a relatively short, medium follow-up time, and a low number of events. So, in conclusion, this report from the PALLAS trial shows that higher BMI was associated with a more favorable safety profile, especially regarding hematological toxicity, and a lower risk of treatment discontinuation. These findings are in line with previous data obtaining the metastatic setting with other CDK4/6 inhibitors, and support the existence of a different pharmacodynamic profile influenced by BMI that translates in a more favorable toxicity profile. At present, differences in BMI do not seem to affect palbociclib efficacy, but further analysis with additional follow-up time and events, as well as by type of endocrine therapy administered are planned in the PALLAS study. That concludes this episode of JCO Article Insights. In these episodes, we summarized findings from two studies, the first titled, Pan-Cancer Analysis of Postdiagnosis, Exercise and Mortality by Lavery and colleagues. This trial shows that higher level of exercise are associated with lower risk of all-cause cancer specific and other cause mortality, although with some differences according to cancer site. The second article titled Impact of BMI in Patients with Early Hormone Receptor-Positive Breast Cancer Receiving Endocrine Therapy With or Without Palbociclib in the PALLAS trial by Dr. Pfeiler and colleagues observed a significant different side effect profile for palbociclib according to BMI, but no differences in efficacy. This is Davide Soldato, thank you for your attention and stay tuned for the next episode of JCO Article Insights.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions.Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    
11/27/202311 minutes, 39 seconds
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Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial

In this "Podcast Takeover," Dr. Lidia Schapira guest hosts to discuss with Dr. Shannon Westin her own JCO paper, which reports on the DUO-E Trial. Dr. Ramez Eskander also joins in this lively discussion. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I am your host, Shannon Westin, Social Media Editor of the JCO and Gynecologic Oncologist by trade. And actually, I'm super excited today because we are going to have a podcast takeover because we are discussing my own work, which was simultaneously presented at the European Society of Medical Oncology 2023 Congress and published in the Journal of Clinical Oncology on October 21st, 2023. And this was the DUO-E trial, “Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer.” Because we’re discussing this work and we wanted you to have an unbiased podcast discussion, Dr. Lidia Schapira, who is a Professor of Medical Oncology at Stanford University and an Associate Editor of JCO and the Art of Oncology podcast host, is going to take over this podcast and really just pepper me with questions about this exciting work.  Welcome, Dr. Schapira.  Dr. Lidia Schapira: Thank you so much. It's such a pleasure to be with you. Dr. Shannon Westin: And before I turn over the reins, I also want to introduce one of my colleagues, who’s going to be providing quite a bit of insight on this topic, Dr. Ramez Eskander, who is Professor of Obstetrics, Gynecology, and Reproductive Sciences at the University of California, San Diego. And you will know he’s the principal investigator of the GY-018 study, which established pembrolizumab and chemotherapy as the new standard of care in endometrial cancer. Welcome, Ramez.  Dr. Ramez Eskander: Thank you. Thank you, Dr. Westin. It's a pleasure to be here. And congratulations again to you and your study team for this exceptional work.  Dr. Shannon Westin: Thank you. And congratulations to you.  Dr. Schapira, thank you for being here and please do take it away. Dr. Lidia Schapira: So let's start by having you tell us a little bit about the standard of care for women with endometrial cancer and advanced endometrial cancer prior to this study. Ramez, I'm going to direct this question to you first. Dr. Ramez Eskander: For many years, actually since about 2012, carboplatin and paclitaxel, which ironically is a chemotherapy backbone really across all of our gynecologic tumors, emerged as the preferred doublet chemotherapy regimen for the management of advanced-stage metastatic or recurrent endometrial cancer. It evolved through a series of different clinical trials, in fact taking us from whole abdominal radiation, systemic chemotherapy, comparing single agents to doublets and then triplet regimen of TAP to carboplatin and paclitaxel, which ultimately, then, following the presentation of GOG Protocol 209 and its publication, as the chemotherapy backbone, being carboplatin and paclitaxel. And it’s been that way for many, many years. Dr. Lidia Schapira: And how effective is the regimen? Dr. Ramez Eskander: The response rates to carboplatin and paclitaxel are actually quite reasonable in the patients who have advanced-stage disease, particularly if they haven't had prior systemic chemotherapy. Response rates in the 50% to 60% range. The issue is that the responses tend to be limited and disease recurrence is an expectation in these patients who have advanced-stage disease. And so that really highlighted the importance of trying to continue to advance therapeutic opportunities in these patients to improve long-term outcomes.  Dr. Lidia Schapira: As we think about improved long-term outcomes, we're thinking about a better treatment and also a kinder treatment, perhaps one that is also less toxic. Can you talk a little bit about the population of women with endometrial cancer? Are these older women? Do they have comorbidities?  Dr. Ramez Eskander: What we’re seeing is, interestingly, there has been an evolution a bit in this space. Historically, we used to think about endometrial cancer as—the phrases we used to use are type I and type II. These type I tumors, we would say, are estrogen-driven malignancies; they tend to be seen in overweight or obese patients. And we would identify them in a theoretically younger patient population. And then we had these type II, or what we termed estrogen-independent malignancies, that we would see in an older patient population. Of course, with obesity came metabolic syndrome and other cardiovascular comorbidities, etc. But really, that narrative has evolved dramatically, and that’s really something that will be highlighted in, I think, our discussion of these studies today, where the nomenclature that we used to historically use has evolved because of our understanding of the molecular characterization of this disease. So we’ve really gone away from that, and now we understand that we’re seeing all of these different heterogeneous endometrial cancer types amongst patients of different ages, different comorbidities, different races and ethnicities. And so it’s created a more complex picture for us. But certainly, there are comorbidities that these patients face, and that’s important as we look to identify treatments strategies that are both effective and tolerable. Dr. Lidia Schapira: My final question before we jump into this very exciting study is about the Cancer Genome Atlas work. Can you tell us how that’s changed the thinking and the design of the studies? Dr. Ramez Eskander: It was a seminal publication, really, back in 2012/2013 looking at an assessment of endometrial cancers to try and determine whether or not all of these "endometrial cancers" that we used to enroll on a single study are similar or divergent. And it’s important because the study I referenced that really established the standard of care, GOG Protocol 209, as carboplatin and paclitaxel, there was no real consideration of molecular characterization at all. We enrolled all patients onto this study without thinking about these variables, of course, because it was designed, conducted, and completed before the TCGA data emerged. But what we learned from the TCGA is there appeared to be four distinct molecular subgroups. There were the POLE-mutated patient population. There was the mismatch repair deficient or MSI-high endometrial cancer population. There was the copy number-high or what we say are the p53-mutated. And then the last cohort was called the NSMP (no specific molecular profile). But now, that’s even evolved; some people term it TP53 wild type. That’s a bit of even a heterogeneous cohort amongst itself. So we’re going to take these subsets, independent of POLE and an MSI-high, and we’re going to look at TP53 or copy number-high, and that will probably be divvied out further, and the NSMP, and that will probably be subdivided. But really, it gave us these four components, which has then evolved. Many of you may have heard of the ProMisE algorithm or ProMisE Plus, which looked to take the data from TCGA so that we can start to really look at it in clinical practice. So it’s really revolutionized how we think about these patients, how we think about the disease, and how we design trials.    Dr. Shannon Westin: And I just want to add to that because I think that it's so important, what Ramez said about the way we were developing trials, the way we were designing trials. We knew that these classifiers—we were learning these classifiers are prognostic. Now what we’re really trying to hone in on is how predictive they are. And certainly, one of the major classifiers that we’re going to talking about today is mismatch repair status, and that is most definitely predictive of response to therapies. But we’re still learning about the other classifiers and how we might adjust the way we treat people, even deescalating care for certain patients. That is still being proven in clinical trials, although we suspect that it’s going to be borne out as other clinical trials report. Dr. Lidia Schapira: It's a perfect segue to this current trial. Tell us a little bit about the objectives and the design of DUO-E. Dr. Shannon Westin: As Ramez said, the standard of care was chemotherapy. And so we wanted to see if there was a way to improve outcomes for these women with advanced and recurrent endometrial cancer in a really clinically relevant, meaningful fashion for patients. And so we knew that this TCGA classifier, the mismatch repair, was so important, and we thought that the addition of immunotherapy to chemotherapy would most certainly work in that population but could even work in the entire population because, generally, endometrial cancer seems to be a little bit more responsive to immunotherapy and to activation of the immune system than, say, some of our other gynecologic malignancies. And so we set out to see what the addition of durvalumab, which is a PDL-1 inhibitor, would add to chemotherapy. And this was two chemo as well as followed by durvalumab maintenance.  But even further, we had some really kind of exciting science data from our lab that said that if we combined a PARP inhibitor with immunotherapy that we could accentuate on the response to therapy and we could get more benefit. And there's kind of a lot behind that, but essentially, what we thought was that the damage that's caused by the PARP inhibitors would create an activation of different immuno-pathways, like STING pathway and activating cytokine release, and that we would get this synergistic activity. So one of the other objectives was to see if the addition of the olaparib, the PARP inhibitor, to durvalumab in that maintenance setting could even further improve benefit. So we had a dual primary endpoint looking at progression-free survival, so the amount of time people live without their cancer coming back. And that endpoint was first, the durvalumab-alone arm to control, and then the second portion of that was the durvalumab/olaparib arm back to control. Dr. Lidia Schapira: So before you tell us about the results, tell us a little bit about the study itself. I mean, I was very impressed that you did it in so many different locations. Tell us about that effort.  Dr. Shannon Westin: This was a huge collaborative effort both with the GOG Foundation, the Gynecologic Oncology Group Foundation, as well as ENGOT, which is our European colleagues that do amazing clinical trials. But in addition to that, we really worked very closely with our industry partner to really make sure we spanned the globe. And so we had groups from all over the world that participated and really were exceptional. The care that was taken and the hard work that went into this type of study across the world really can't be overstated. We were very lucky to have a wonderful infrastructure group. We met weekly for a long time, just keeping an eye on the data and making sure that everything was as positive as possible and, of course, that we were watching the outcomes of the patients very closely and making sure that there was no evidence of harm or issue. And so it really did take a village, truly, to run this study and to ensure that at the end of it, we got really great data that we can trust. Dr. Lidia Schapira: So tell us the results. Dr. Shannon Westin: So DUO-E was positive for both of its primary endpoints, which was very thrilling. So for the first analysis, which is the durva-alone arm to control, we saw a reduction in the risk of progression of 29%, so a hazard ratio of 0.71. And then the addition of olaparib seemed to further enhance this benefit, so a 45% reduction in the risk of progression for a hazard ratio of 0.55. But what's really exciting is our follow-up time was pretty long; it was about 17 months, so we were able to look at a couple of different analyses, including an 18-month landmark analysis where we saw approximately 50% of the patients were still alive progression free at 18 months, as compared to only 21% of patients being alive progression free in the control arm. So there was a doubling in that progression-free survival time point at 18 months, which is thrilling. Dr. Lidia Schapira: So Ramez, as an expert in the field, what was your reaction when you read or heard these results?  Dr. Ramez Eskander: It's exciting, honestly. So we have gone a long time without seeing really significant successes in the endometrial cancer space, a testament to the fact that we hadn't yet developed our understanding of how we could move this needle forward. But Dr. Westin and the DUO-E team conducted an exceptional clinical trial, as you mentioned, international study, rational and important hypothesis to adjudicate. And what we saw here was both now we had other studies—the RUBY trial, the GY018 trial, the  AtTEnd—and now here DUO-E, which added this hypothesis of PARP maintenance in addition to checkpoint to try to augment response and consistent, really provocative data, exciting, in line with what we've seen and hopefully will continue to drive the science in this space, most importantly. Dr. Lidia Schapira: So let me ask you a follow-up question to that. What kind of scientific questions are in the air now as a result of this trial and what the trial found? Dr. Ramez Eskander: Oh, goodness. Shannon and I could both take this, I'm sure. But I think in the dMMR population, we recognize that there's a ton of data that is supportive of the fact that these tumors are immune responsive, particularly in dMMR endometrial cancer, whether it's an epigenetic promoter hypermethylation, or a mismatch repair gene mutation. I think the data has emerged that immunotherapy is here to stay for these patients in the newly diagnosed advanced stage, even chemo naïve, who need adjuvant therapy.   The pMMR population, this is where we're seeing more and more questions emerge because we realize that that may be a cohort of different cancers. And I'll let Shannon speak to this briefly, but even the incorporation of the PARP inhibitor, in addition to the checkpoint, there's a biologic rationale for combining those two together to augment response. And to see the benefit in that trial—arm three and arm two, we can look at descriptively and look at the differences, but who are those patients? Where is the PARP and the checkpoint most effective? How do we expand that to a larger population of patients potentially? These are questions that emerged because, as Dr. Weston will allude to, I know we also talk about HRR mutations, which are captured, but we even have a lot to understand about that in endometrial cancer, where we've had more research in the ovarian cancer space. Dr. Shannon Westin: Being mindful of time, because I have, like, 1,000 hypotheses that have been generated by this study, which, I think, shows it's a great study, right? Because you get some answers, and as our colleague Brad Monk says, “The only definitive study is the negative studies.” This most certainly was not that. But just kind of expanding on what Ramez said, the interesting thing about DUO-E is that really the biggest benefit for the combination of the durvalumab and olaparib was in that mismatch repair proficient group. And I personally thought that we were going to see accentuation of the impact in the mismatch repair deficient group based on the science, but that just wasn't borne out by the data. It doesn't seem that the combination has that much to add in that mismatch repair deficient group. And when we tease out the mismatch repair proficient group, I think that's where a lot of interesting information is going to come because, to Ramez's point, we're going to tease out: Is it driven by the P53-mutant population? Is it driven by the population that has homologous recombination deficiency? How do we even measure homologous recombination deficiency in endometrial cancer? So I'm super excited about what we found and how that may help us to make those decisions for the patient in front of us.  The other thing I think needs to be made mention of—and this was something we saw in DUO-E as well as AtTEnd—we had a large population of patients that were recruited in Asia, 30%. Interestingly, when we look at the forest plot, that group doesn't seem to benefit as much from the addition of the olaparib. So we really need to tease out what's different about that population because what Nicoletta Colombo presented around AtTEnd, it looked like they didn't benefit from the atezolizumab either in that study. So there's clearly something different about that population, and we have a really big opportunity to look at that since we had such a large proportion of patients that were enrolled there. So that's another, I think, really intriguing question. Dr. Lidia Schapira: So how does this fit in the context of endometrial cancer treatment, and what are we going to do with patients in the clinic? I'd love to hear both of your perspectives, starting with you, Ramez. Dr. Ramez Eskander: It's an evolving answer, to say the least. What we can say definitively is that we have a United States FDA approval for the regimen of dostarlimab plus carboplatin and paclitaxel in the mismatch repair deficient, advanced-stage/recurrent or metastatic patient cohort. And again, that's because the magnitude of benefit that we saw in the RUBY trial, which looked at that, was actually analogous to what we saw in 018, AtTEnd, and DUO-E, again, consistently highlighting the benefit of the IO and the dMMR. We have yet to see how this is going to evolve the landscape in the larger patient population, which is the pMMR patient population. And it may be that based on the data that we have, we will see immunotherapy plus carboplatin and paclitaxel as the new standard of care in the pMMR cohort, or it may not. That's yet to be defined. And I think Dr. Westin will add to this, but I think that's also going to depend on the perception of how we view the cohort. Is it one group of patients? Are we going to have to think about subsets within the pMMR population? That is an active conversation. Dr. Shannon Westin: I would just add, having treated patients on this combo regimen with the durvalumab and olaparib, I have multiple patients that still remain on study, and this—we're looking at three and four years out. I just never saw anything like that before with standard chemotherapy, so there's definitely something here. So I want to know who those patients are, who benefits really the best from the combination, and who could we just give the immunotherapy to and get that same benefit. So we obviously always want people to live as long as possible. That's the bottom line. But we don't want to overtreat. And so I think balancing that is really important. Dr. Ramez Eskander: The point that was made earlier: We have yet, aside from MMR response to checkpoint, within the pMMR population, we understand that there may be subsets, but we have yet to prospectively validate that these molecular cohorts within the pMMR population are truly defining response to a particular therapeutic strategy. So we have to be cautious not to limit the treatment opportunities for these patients without having the data that we need to do so because, as Dr. Westin mentioned, for us—whether it was the Gy018 trial, the RUBY, the DUO-E trial—what we saw is there are pMMR patients who have a dramatic response even though they are “biomarker negative.” They're pMMR, they're TMB low, they're not POLE mutated, but yet they still derive a dramatic benefit. And so that goes back to the hypothesis about why we're even combining checkpoint with chemotherapy in which, for example, in lung cancer, there's been established success and approval. So I think we're all eager to see these strategies emerge as treatment opportunities for the pMMR patients as we work to still develop additional effective opportunities. Dr. Lidia Schapira: So, based on all of this and sort of the new twists on the scientific hypotheses that are now generated, what are the next steps? Dr. Shannon Westin: Well, I think we have to see if these drugs are available for patients. So looking at things like compendium listing and regulatory approvals obviously is going to be very important. But from the things that I can control, we are looking at the different molecular subtypes and understanding the different mutation status and trying to tease out who may be driving the biggest benefits so that we can help advise and make sure that we're doing the right thing for the patients. Dr. Lidia Schapira: And wearing my supportive care hat, I have to ask you, Shannon, about the tolerability. We often find that the quality of life and studies come out after, sometimes months or years after, the original trials are published. So let me take this opportunity to ask you now: How did women tolerate these drugs? Dr. Shannon Westin: The bottom line, Lidia, is, as expected, when you add additional drugs, you see additional side-effects. I think the good thing is that we're very comfortable with immunotherapy and we're very comfortable with PARP inhibition in gynecology because we have had access to these agents and so we know how to manage the toxicities. And so, from a standpoint of incidence, there was a higher incidence of grade three and higher adverse events in the group that had durvalumab/olaparib. But this was primarily driven by anemia, which is as expected and is usually pretty time-limited at the start of olaparib. From a long-term standpoint, there was a slightly higher proportion of patients that discontinued therapy, but it actually wasn't as much as I was worried about. So we saw a 19% discontinuation rate in the group that was just the control arm, and that went up to 24% in the dual arm, so definitely higher, but not that much higher. And when we moved to maintenance, which is really where—that's where the arm becomes unique, it was much lower at about 12%. And so that's exciting to me, that patients were able to stay on a drug and were able to tolerate it.  And then, to your other point, we do have a very nice patient-reported outcomes plan, and that is actually being analyzed as we speak with the hope of presenting it at the next major meeting, our Society of GYN Oncology meeting in March. So not right away, but I think in a pretty timely fashion, we'll have those data. Dr. Lidia Schapira: Congratulations, Shannon, on leading and presenting this wonderful study. So it's been a real pleasure to chat with the two of you. Dr. Ramez Eskander: Thank you. Dr. Shannon Westin: Thanks so much, Lidia. I really appreciate it. Thanks, Ramez, for being here.  And I will just say thank you to all of our listeners. We really hope you enjoyed this episode of JCO After Hours, where we discussed the DUO-E trial, which is a phase III trial evaluating durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer. And again, please do enjoy this publication that was online at the Journal of Clinical Oncology on October 21st, 2023. And do check out our other podcast offerings wherever you get your podcasts. Have a wonderful day. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      
11/5/202323 minutes, 23 seconds
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JCO Article Insights: Safety and efficacy of a Novel ADC Targeting TROP-2 in Metastatic Non-Small Cell Lung Cancer (NSCLC)

In this JCO Article Insights episode, Davide Soldato interviews Dr. Jacob Sands, medical oncologist at Dana Farber Cancer Institute (Boston, MA) and Assistant Professor at Harvard Medical School, on their paper “First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01”. The interview offers a deep dive into the safety and efficacy data of this novel drug and puts these data in the context of the current treatment landscape of NSCLC and of the revolution that ADC are bringing into the oncology world. TRANSCRIPT Davide Soldato: Welcome to this JCO Article Insights episode for the October issue of Journal of Clinical Oncology. This is Davide Soldato, and today I will have the pleasure of interviewing Dr. Jacob Sands, co-author of the manuscript titled, “First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01.” Dr. Sands is a Medical Oncologist working at Dana-Farber Cancer Institute in Boston and Assistant Professor at Harvard Medical School. His main field of research and clinical interests revolve around improving screening and diagnosis of lung cancer and also on developing novel therapeutic agents for this disease.  So, welcome Dr. Sans, and thank you very much for accepting our invitation today.  Dr. Jacob Sands: Happy to join. Thanks for having me. Davide Soldato: I just wanted to start with a very general question because I think that we are going to discuss a very important study and the manuscript that you co-authored is going to look at the safety and the efficacy of this novel ADC datopotamab-deruxtecan that is targeting TROP2. But I just wanted to have a little bit of context before starting to discuss the safety and efficacy data. So the population that was included in the study included more or less 60% of patients that received three or more lines of therapy and also 20% of patients who received five or more lines of therapy. So I think that this is a very particular population, especially considering that we are speaking about non-small cell lung cancer. And so I wanted to get from you like a general context, like what are the therapeutic options for these patients normally in clinical practice and what do we expect in terms of outcomes and in terms of toxicity? Dr. Jacob Sands: Yeah, so as you point out, this is a highly pretreated population in general, which is to say that they've really gotten the most effective lines of treatment up to this point. Now, we certainly do see some efficacy from some of the later lines of therapies in some patients, but inherently there is a decreasing response rate and decreasing durability of these responses as patients get further along in their treatment courses as far as lines of therapy. So it's generally considered to be a challenging clinical scenario, which is part of what makes the data that we're going to discuss, I think, so meaningful.  Davide Soldato: Yeah, I think that especially if we look at the population that was included first, I think that the very particular thing is that included both oncogene-addicted and non-oncogenic addicted patients, and also the great majority of these patients received the most effective treatments that are available because they all received more or less immunotherapy and platinum-based chemotherapy, if I'm not mistaken. Dr. Jacob Sands: That's right. And that's an important distinction that you're drawing in the patients with oncogenic drivers and, of course, there's plenty of data with this compound with Dato-DXD in that population as well. But broadly speaking, in the non-oncogenic actionable alterations where they've gotten chemo-immunotherapy, those really are the most meaningful. Of course, docetaxel has been a long-standing second line that I'd say there is less and less enthusiasm about that as a line of treatment as we've seen some of these other more novel therapies that have just a better toxicity profile in particular, but also some with really durability that we don't quite see with docetaxel as well. And so once you're getting past that, you're really now reaching a bit deeper to then have something that is well tolerated and has efficacy. That's a setting where we really need it even more.  Davide Soldato: So, going back to the results of the study, as we kind of pointed out, this was a very standard classic with a Bayesian design, phase I dose escalation and dose expansion study of this novel ADC datopotamab-deruxtecan. So I just wanted to go over with you and to provide our listeners a little bit with some data regarding the doses that were explored and then what were the doses that were selected for the expansion. And also to discuss a little bit the safety data. We were discussing the tradeoff between risk and benefit, especially in patients that are very pretreated, searching for these kind of sweet spots between the toxicity and the efficacy. So I just wanted to put in context a little bit the data that you reported in the manuscript. Dr. Jacob Sands: Yeah, that's right. So, like phase I’s go, we started with a low dose at 0.27 milligrams per kilogram, and dose escalations occurred up to 10 milligrams per kilogram. The 10 milligram per kilogram dose did have toxicities that really made it not considered to be tolerable, and that mostly being mucositis and skin. And so it was then back down to 8 milligrams per kilogram. And then there was a dose expansion at 4, 6, and 8 milligrams per kilogram. The 4 and 6 milligram per kilogram doses had 50 patients enrolled within those cohorts and 80 patients within the 8 milligram per kilogram cohort to then get much more data, of course, for efficacy and tolerability within those levels. Ultimately, each of them really demonstrated some efficacy as well as general tolerability. The 6 milligram per kilogram dose was really the one selected overall for further testing and future trials based upon the data out of this one that we're going to discuss further. Davide Soldato: What were the main side effects that you observed in the trial? And particularly, do you think that there is some kind of special toxicity that should be looked at when using this novel type of ADC? Dr. Jacob Sands: Certainly there are some novel toxicities to really pay attention to. And maybe I'll just point out before diving into the toxicities, that this is in many ways chemotherapy. The antibody drug conjugates, as listeners probably know, are an antibody that has a linker bound to chemotherapy, what's called the payload. And in this case, it's a topoisomerase I inhibitor with the antibody, the TROP2. So the cells on the surface, when there's TROP2 expression, the drug binds to that, gets pulled into the cell and releases that chemotherapy intracellular, but it is still chemotherapy. And so some of the toxicities are things that we commonly see with chemotherapy drugs. Although, broadly speaking, I would say we're able to deliver higher doses of that chemo to the cells in this kind of targeted dosing of chemotherapy to give the chemo intracellular.   Now, that being said, some of the toxicities that we see from this drug in particular that are a bit different is the stomatitis, mucositis. That is something that has occurred. Now, I've found that if it's really severe, then with a dose reduction that has really substantially improved any toxicities with future dosing. And at a 6 milligram per kilogram dose, a dose reduction to 4 milligram per kilogram is still within a dose range where we saw plenty of efficacy within the trial that we're discussing. That being said, if one can help patients tolerate it better, if it's more mild symptoms, if it's not severe, then that's better in maintaining that dose. And interesting things like ice chips at the time of infusion, so cold within the mouth, kind of like the cold caps to try to reduce alopecia at the time of infusion of the chemo may help some steroid rinses also can be helpful. But really these are things to help prevent stomatitis from being severe. It's harder when that occurs, then the treatment for improving it is a bit different.   We do know, though, that that does improve with time. So even when it was severe with that infusion, it does improve as patients get further out from those doses. Of course, another one is dry eyes or irritation within the eyes. And if that is severe, then or even mild actually, I'd say when there's any known toxicity like this is to involve ophthalmology. Now, within this trial, ophthalmology was involved and patients had to get a baseline eye exam and they would get checked at different time points throughout the course of the trial. And so they were being monitored. I did not have anyone who needed to stop the drug because of this. The patient I had with the longest standing response to therapy did have some dry eye. It was not bothering him so much. And he had this real aversion to using eyedrops. It was very hard for him to make himself use these. But when I told him, “Look, if this gets worse, you might have to come off the trial, that it might not be our decision just by the way the trial describes it, if this gets worse.” And so for him, the fear of having to come off the drug was really the thing that helped him to then start using his eyedrops, which really helped to control that a bit more. And so that is something to monitor for.  But the biggest thing really is interstitial lung disease. This is something that is a complex topic, I think because it's something that we need to be very aware of and monitor for. At the same time, a diagnosis of interstitial lung disease can be challenging. There really were not cases where we had pathologic confirmation of this diagnosis. These are clinical diagnoses in the cases on this. Now there was an adjudication committee that would review all of the data and come to a determination of whether this looked like drug related ILD or not. But for clinicians, when you see a patient whose scan shows some inflammatory markings or inflammatory appearing markings on a scan, we see that all the time with other drugs too. And so determining what is potentially incidental versus drug related, I think in most cases on a trial when we're unsure, we lean toward drug related. And in some cases there are reported out severe cases of drug related ILD.  I think the really difficult thing that I'd want people to take away from all of this, though, the bottom line is, yes, we need to be very aware of the potential for drug related ILD while at the same time, we need to not reflex, just call things drug related ILD and really make sure that we're doing a workup when feasible rather than just that bottom line conclusion. We see it at a rate related to the drug, and I do think it's real. But we also need to, when treating individuals, try to identify any other potential etiology. I did have one patient that really looked absolutely classic for this diffuse drug related ILD that ended up ultimately really being what looked more like tumor progression in just a radiographic pattern that looked more like an inflammatory process than it did the way we would typically see cancer progression. And so this has really, for me, I think, highlighted this as a topic where I'm diving a bit more into that description.  Davide Soldato: And I also think that in the population of lung cancer patients, as you were saying, this is even more complicated because frequently these are patients who had a history of smoking, who can have concomitant infections where progression is easier in the lung. If I think, for example, other ADC that have already been tested, for example, in breast cancer, it might be far easier to detect and to adjudicate an ILD to the drug that we are using compared to what could be, for example, for lung cancer patients.  So if I understood correctly, the toxicity that in your opinion as a clinician, they are more complicated to treat, let's say on a more daily basis, are more stomatitis and inflammation, but maybe the one that you experience as potentially more severe are always related to lung toxicity.  Dr. Jacob Sands: Well, I think the scary thing about the ILD is that we have higher grades of ILD, and this is a toxicity that then can become life threatening. When we see a grade I or a grade II ILD reported in numbers, where we see, okay, this looks like it's really happening, and then see some really higher grade toxicities, I think the concern amongst clinicians then is if they're seeing lower grade, which of those can potentially progress to those higher grade, which then becomes life threatening toxicities. Whereas dry eyes certainly can become a nuisance, we didn't see any blindness or something like this, and the stomatitis resolves as you hold the drug, and in some cases, really before the next cycle even comes, it's just more a matter of controlling the discomfort, which can be severe. I'm not minimizing that. I think that's why ILD stands out so much, is that that becomes a potentially life threatening thing.  And to your point exactly, these patients with a smoking history on other drugs, we see these inflammatory findings. Now, in some cases, we know it can be from the drug. In other cases, we see it and know that it's essentially incidental. And I'll say to patients, “Hey, we see this. It's something we'll monitor on future scans, and these can wax and wane.” When you have a patient on a drug with a high attention towards something like ILD, there can be- what I'm cautioning against is a reflex attribution to that drug. In all cases. I'd urge clinicians to individually assess each of these patients to get a sense of whether they think that that's going on for that person, knowing that it's often not possible to say with 100% certainty in any of these cases. But we often see waxing and waning inflammatory findings. And in many of these patients with heavier smoking histories, in particular, there can be waxing and waning respiratory symptoms. So the question is, are there instances where there is what really is an incidental inflammatory findings and incidental respiratory waxing and waning that then suddenly we call a grade II?  At the same time on the other part of that, if there is something that seems like it really may be drug related ILD, is doing that work up and really evaluating and diagnosing that before it progresses to a point that really there are severe symptoms. And it's kind of trying to do both of those things on the opposite ends of the spectrum that I'm speaking toward at the same time. Davide Soldato: Just on a personal note, do you think that, as we continue the development of these drugs that are associated potentially with lung toxicity, do you think that we also need to pay attention to the drugs that were immediately previously received by the patients? What I mean is, do you have the feeling that the previous treatment could potentially impact on the risk of developing this type of toxicity in the lung? Dr. Jacob Sands: I don't know that we yet have data to draw any real conclusions around that. But you raise an important question within this, and what potential toxicities could be related to prior treatments or synergy across those. Of course, we see inflammatory findings within the lungs and pneumonitis with prior immune-related therapies, and that it would be a good prompt to the question you're asking. And that in particular, we also see this in some of the targeted treatments, although not nearly to the same percentages. I don't know that we can draw conclusions from this. I would speculate that the mechanisms of action of each of these drugs are so different that I would not hypothesize real synergy in those toxicities. But it is certainly something to be aware of and an important question that you're raising. Davide Soldato: I think that, apart from the safety data that I think we dissected, the other end of the spectrum would be finding a drug that this very pre-treated population could still give us some efficacy data. So you already mentioned that, in the dose expansion cohorts, so 4, 6, and 8 milligrams, we had more or less signals of activity and of efficacy of these novel drugs. So the therapeutic options, as you were mentioning, are potentially docetaxel or other types of mono chemotherapy. But we know that the objective response rate is not that high, and that progression-free survival is not that long with these types of drugs. And potentially the safety profile could also be complicated in patients that are also pre-treated. So I just wanted to discuss a little bit the efficacy data and to see if there is really promise in this type of delivery of chemotherapy as you were saying with the ADC. Dr. Jacob Sands: We saw response rates of about 25% across all three of those cohorts. The manuscript outlines the 4, 6, and 8 milligram cohorts within a chart showing the efficacy outcomes. And really it's around 25% across the three of those, which in this patient population, as we've discussed, heavily pre-treated, to have a response rate of 25% is really quite promising that there really is a substantial treatment effect. On top of that, we also see a duration of response of really around 10 months. So, in the patients that are having a response, there really is some durability. Now, it's tragic that 10 months is considered durable within this population and it really highlights the ongoing need for further drug development because I don't think anyone would say that 10 months is enough, we need dramatically better. But within the context of what we currently have, a 10-month duration of response is really quite meaningful and a response rate of 25%.  Now, it also describes a disease control rate. And I always have to put a little asterisk to this. I think we see this increasingly - the disease control rate being reported - and it always looks quite a bit better than the response rate. And that's essentially incorporating stable disease. And although I would never claim that everybody with stable disease is truly benefiting from a drug, across all of the studies where this is reported out, there is a spider plot which really highlights a number of patients that are not considered responders, but with responses, a handful of them beyond six months of disease control, even though they're not considered responders, and one of them beyond a year with still ongoing disease control. So, even within that stable disease group, I'd say there are some who are really clinically benefiting from the drug, which is to say that really, even beyond the 25% response rate, we are seeing some others that are truly benefiting from this.  Davide Soldato: Yes, and I also think that for these patients, especially when they can develop very rapidly symptoms that can potentially also impact quality of life, having a drug that achieves this level of stability - with maybe no deterioration in clinical symptoms - I think that it's still probably a very meaningful objective to obtain for this type of population. Of course, I think that with future studies we will also have probably health-related quality of life data that will tell us more about the impact of this type of drug in this setting. But I still think that this could be potentially a relevant endpoint, even if we don't achieve what we officially consider as a response as per resistor criteria.  So I think that we have talked a little bit about the efficacy data. So, we are kind of entering a novel area where more and more ADCs are being tested, are being included in clinical practice. For example, if I think about breast cancer, we already have two that are approved that can be used, the same in bladder cancer. So, as you participated in this phase one trial, I just wanted to have your opinion: if you think that, in the future, we are going to evolve completely towards this type of delivery of chemotherapy, using what we call now "smart drugs" in terms of delivery of these cytotoxic agents. Dr. Jacob Sands: It'll be interesting to see. We certainly will see other generations of ADCs. I mean, I think we're really just at the beginning with this technology. We certainly have now a very solid foundation to build upon, where we have effective targets and effective payloads. We've highlighted some of the toxicities we're seeing from that. Also, I'd highlight within this drug with TROP2, the amount of expression has not seemed to really be a driver in this. And some of that may be the bystander effect, which I'd call a real benefit of the drug, where the payload as a drug goes through apoptosis and lysis, that payload that releases then into the surrounding- toward the surrounding cells is membrane permeable and crosses into other cells, leading to potentially more efficacy. That technology in itself, I'd say, is something that we may see incorporated further into next generations of ADCs. Whether there can be improvements in preventing toxic drug in other sites like the stomatitis, for example, with newer generations that evolve from this, we'll see.  I don't know that I would anticipate all chemotherapy ultimately going through ADC technology, but I certainly believe that this is the beginning of what I would call a whole new class. But would future cytotoxic treatment happen more so through ADC than just broad circulating payloads? If we can call it that. And I certainly think we'll see a lot more development like that. But you know, we may see other ways of developing the cytotoxic drugs in other forms of delivery as well. It'll be exciting to see as we go forward. Davide Soldato: I also think that one of the major challenges that we probably will have to deal with, in probably not so long, is also the sequencing of these types of agents. We are starting to have, as I was saying, accumulating data regarding the efficacy of these drugs. And some of them share either the same payload or they target the same antigen on the cell. And so, do you think that we will need as a new line of research to really go into the field of cross resistance when we are using and trying to sequence these types of novel agents?  Dr. Jacob Sands: We're seeing that across various tumor types. I mean, to stick with lung in particular and small cell lung cancer, we've seen DLL 3 really be a demonstrated target for small cell lung cancer. And now we have a handful of drugs being developed that target DLL 3. How would we potentially utilize those drugs? In what orders and which ones over others is going to be an area for discussion, much like the area you're raising here, where we see TROP2 directed treatments. And so which one would you choose? On top of the fact that there are other targets, in this case, we're talking about TROP2, but of course, there's HER3 that we've seen, and especially when we're talking about an EGFR population, EGFR mutation population, we've seen good efficacy with this TROP2 antibody drug conjugate, as well as the HER3. And so how would we order those? And they both are using the same payload.   If we're talking about both of the deruxtecan compounds, this is going to take some sorting out. I think with time, it'll be tough. I don't know if we'll end up seeing head to head studies in this or if this is going to end up being shaped more by expert committees and their descriptions. But I imagine we'll see some heterogeneity in the treatment pathways at different centers just based upon preferences and familiarity with these different drugs. Of course, assuming that they all end up ultimately being approved and then that efficacy and tolerability that we're seeing continues to pan out in future trials. Davide Soldato: So we were mentioning before that there is a very big line of development for this novel ADC. And I think that there are also some trials that are exploring the role of data DXD so the datopotamab-deruxtecan in lines where patients have received less therapy or in combination with other agents. So I wanted to ask you if you could give us some insights regarding the ongoing trials, if you know about them. And also what do you think could be the area of a met need where this drug could potentially give the most effect? Dr. Jacob Sands: It'll be interesting to see. In the first line setting we have TROPION-Lung07 and TROPION-Lung08. These are studies with PDL-1 expression of less than 50% or greater than or equal to 50%, the greater than equal to 50% being plus pembrolizumab versus pembrolizumab alone. The less than 50% essentially being an incorporation with or instead of chemotherapy along with the platinum-based therapy plus pembro. And so that one is a more complicated three-arm study. Now, essentially what this is looking at is incorporating this antibody drug conjugate in place of chemotherapy for potential tolerability when given concurrently with the platinum and pembro. Whether or not we'll see some synergy with the chemo and the pembro, I guess I would hypothesize that we would likely see at least similar to when giving the chemotherapy, or at least that's the hypothesis driving the trial design.   If anything, whether we note improved tolerability relative to those getting, I'd say the carboplatin component, because certainly within non-squamous, non-small cell, pemetrexed is generally very well tolerated. And so that's a bit tougher to beat out from a toxicity standpoint. The trials are really designed based upon the efficacy that we've seen from this trial you're pointing out. I think by the time that this podcast is heard, we'll have the data from TROPION-Lung01 that'll be reported out as well in the second line setting versus docetaxel as that data is near release. These are areas for ongoing attention, certainly. Davide Soldato: Thank you, Dr. Sands, for being with us today. This concludes our episode of JCO Article Insights. We discussed with Dr. Sands the results of the manuscript titled, “First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01.”  This is Davide Soldato. Thank you for your attention and stay tuned for the next episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  
10/30/202327 minutes, 37 seconds
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Economic Evaluation of a Non-Medical Financial Assistance Program on Missed Treatment Appointments Among Adults With Cancer

Dr. Shannon Westin, Dr. Stephanie Wheeler, and Dr. Caitlin Biddell discuss the paper "Economic Evaluation of a Non-Medical Financial Assistance Program on Missed Treatment Appointments Among Adults With Cancer," a simultaneous publication, podcast, and presentation at the ASCO Quality Care Symposium.
10/28/202324 minutes, 24 seconds
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Disparities in End-of-Life Cancer Care

Shannon Westin speaks with Holly Prigerson and Alfred Neugut about their thought-provoking editorial, "You Get (Offered) What You (Can) Pay For: Explaining Disparities in End-of-Life Cancer Care."  
10/12/202326 minutes, 1 second
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Advance Care Planning in Adolescents and Young Adults with Cancer

A variety of perspectives are explored as Dr. Westin speaks with Dr. Jennifer Mack, Dr. Chun Chao, and Mallory Casperson about end-of-life care planning in adolescent and young adult cancer. TRANSCRIPT The guest on this podcast episode has no disclosures to declare.  Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get down and dirty with manuscripts that are being published in the Journal Clinical Oncology. And I am your host, Shannon Westin, GYN Oncologist and Social Media Editor of the Journal of Clinical Oncology. I am so very excited to have a number of guests with us today to discuss a very important paper entitled “Discussions About Goals of Care and Advanced Care Planning Among Adolescents and Young Adults with Cancer Approaching the End of Life.”  And I'm joined by several of the authors of this important paper. The first is Dr. Jennifer Mack. She is the Associate Chief in the Division of Population Sciences, an Associate Professor at Harvard Medical School and Senior Physician in Pediatric Hematology Oncology at the Dana-Farber Cancer Institute. Welcome, Dr. Mack. Dr. Jennifer Mack: Thank you. Dr. Shannon Westin: We also have Mallory Casperson. She is the cofounder and CEO of the Cactus Cancer Society. They provide online support programs and resources to young adult cancer survivors and caregivers in the comfort of their own homes. Welcome.   Mallory Casperson: Thanks for having me. Dr. Shannon Westin: And then, finally, last but not least, Dr. Chun Chao. She is a Senior Research Scientist in the Division of Epidemiologic Research in the Department of Research and Evaluation at Kaiser Permanente Southern California. Welcome.  Dr. Chun Chao: Thank you. It's a pleasure being here. Dr. Shannon Westin: So I want to get right into this. I think that there certainly has been a lot of discussion, at least at our institution as well as at the ASCO level, around advanced care planning across all patients with cancer and anyone with a diagnosis of cancer. And I would love to just start and level set and make sure all of our listeners are all on the same baseline around the incidence and prevalence of cancer in adolescents and young adults. Like, first, define what are the age groups that we're looking at here? How common is cancer in this population? Dr. Jennifer Mack: Right. For this study, we defined adolescents and young adults as individuals aged 12 to 39. And right now, about 90,000 adolescents and young adults are diagnosed with cancer in the United States each year. Those numbers are also rising, so more and more are diagnosed each year, and because of that, we think it's increasingly important to pay attention to the needs of this population. This population really experiences a whole range of different cancer types, some of which are more common in children, some of which are more common in adults, but the most common ones include breast and gastrointestinal cancers, sarcomas, germ cell tumors, leukemias, lymphomas, and brain tumors. Dr. Shannon Westin: And your manuscript notes that adolescents and young adults seem to receive medically intensive measures at the end of life. Now, how common is this across this group? And do you all have a sense of some of the reasons that we see this increased use of these measures? Dr. Jennifer Mack: That's a great question. We and others—actually, the early work that led to this study was done with Chun. We had previously found that most adolescents and young adults receive at least some kind of medically intensive care at the end of life. And that includes things like being hospitalized, being in the intensive care unit, receiving chemotherapy, and spending time in the emergency room near the end of life. And so, if you take all of those together, about two-thirds of adolescents and young adults receive at least one of these near the end of life.  And we don't know the reasons for this. There are probably complex reasons. Some adolescents and young adults may actually want to receive these kinds of measures, maybe because they're young and they want to do everything they can to live as long as they can. And some patients in this age group are parents to young children, and they may be making choices to prolong life and be there for their kids. But we also know that if we look at older adults, most people who know they're dying don't want to receive this type of care, which is also associated with more suffering and with poorer quality of life. So it's also possible they're making these choices because they don't fully recognize they're approaching the end of life or because they haven't had opportunity to plan for this time through conversations with their medical teams. Mallory Casperson: I think the conjecture, too, that a young adult is likely to focus on extending life, even in a situation where palliation is the stated goal, is a really great conjecture. This population is really burdened by these unique psychosocial issues that are driven by the extreme disruptions that cancer has on major life milestones. Like Jenny said, they may have young children at home, they may have a new spouse at home, still be trying to advance at work, you name it. So this period of young adulthood is really characterized by constant change. And it's possible that these young adults are being driven to stay present in their lives for really as long as possible to reach some of these goals or even just to support their young families as they reach their own goals. Dr. Shannon Westin: I really appreciate that context, and I'm going to always bring it back to what I know as a provider of gynecologic cancer care, where we see quite a bit of young people at the beginning of their life, at the beginning of their fertility. And I think it is so important to keep that context in mind as we're designing interventions and studies and things like that. So I really appreciate that, having the ability to kind of see from that standpoint. So I think you guys have convinced me this is important. We know the reasons. So why don't we just lay out the objectives of this particular study and give our listeners a brief review of how it was designed? Dr. Jennifer Mack: Great. We wanted to know how often adolescent and young adult patients with incurable cancer have discussions about prognosis and end-of-life care planning before they die. And a secondary goal was to understand whether having earlier discussions would change the type of care that's delivered. So, for example, having those discussions about goals of care earlier in their illness, could that make them less likely to receive intensive measures?  So, to do the study, we conducted a retrospective review of health records for nearly 2,000 adolescents and young adults who died between 2005 and 2019 after receiving care in one of three centers—the Dana-Farber Cancer Institute, Kaiser Permanente Southern California, Kaiser Permanente Northern California—and looked for documentation of discussions about care planning. For this study, we focused on patients who either had stage IV disease at diagnosis or who had experienced a recurrence because we wanted to ensure that we had a population of young people who were living with advanced disease and not people who might have died suddenly and unexpectedly during treatment, because they might not have had the same opportunity for end-of-life care planning. So we really wanted to focus on those who had the poorest prognoses. Dr. Shannon Westin: It's a really large group of people and, I think, hopefully fairly representative. I guess my question is, when you're looking at the group that you were able to kind of pull from in this retrospective database, which I think can sometimes be limited, do you feel like it was fairly representative of the population that's out kind of across the States, let's say? Dr. Chun Chao: So I think it's a real strength that we included two different care settings in this study, so a tertiary cancer center and community-based cancer care. Therefore, patients who seek care in each of these settings are representative in our study. I think this design really increased the generalizability of our findings. And on a further note, in this study, we actually observed very similar care patterns across all three study settings. So that was quite reassuring. Dr. Shannon Westin: So reassuring. And I think it brings up a point that I wanted to make, and I also agree was a strength of your study, is having that across the academic center and then a large integrated health plan. And I guess I'm just curious how your collaboration came to be to kind of come across different groups and, of course, the inclusion of Mallory from the patient advocate side. I think this is a testament to your powers of collaboration. I'd just be interested in how that kind of came to be. Dr. Chun Chao: So this goes back to almost 10 years ago. I think, at that time, people started to really recognize that adolescent and young adults with cancer were a very understudied group, but they are also very challenging to study. So, for example, AYA cancers, adolescent and young adult cancers, are fortunately not very common. Although the number is increasing, you do need a large population base to study them. So, at that time, researchers at Integrated Health Systems started to really see that we had an opportunity here to really contribute to this knowledge gap, leveraging the resources that we had at these health systems, especially the ones that have a very large membership and a long-term retention of these members and also a comprehensive electronic medical record system.  At that time, my colleague and I published a study that demonstrated the feasibility of using these resources to do follow-up studies of long-term health outcomes of AYAs with cancer. And I think that we might have attracted people's attention to utilizing the resources at these health systems to do such studies. So Jenny was the one who really saw the need or the lack of data or the need of high-quality data to really improve care for our AYAs who are at that end-of-life stage. So she reached out to a research network called the Cancer Research Network, who I think that the people there connected Jenny with me because I was also starting to work on long-term health outcomes of AYA cancer survivors, adolescent and young adults. After we talked, we were like, “We have to get this funded. We have to get these questions answered. These questions are so important.” So, as Jenny mentioned, we did a pilot study that really showed there is a lot of burden of medical intensive care at the end of life for our young patients. And, as often is true with research, this opens up a lot more additional questions that we needed answers for. So we have been working together since then.  Mallory Casperson: I came into this group sort of by accident. My background is in engineering. I was about halfway through a PhD when I needed to leave a couple years outside of my first cancer diagnosis. And I was at ASCO staffing a booth for my organization and just happened to meet a researcher from Kaiser Permanente Northern California, and the rest is history. That introduction sort of got me into this world, and, once you know one person, you get to meet others. And it's just been a really, really wonderful opportunity to help, I think, insert the patient voice. But also, for me, I just love research and data. And so getting to help advance the conversations happening around adolescent and young adult care in this research setting and in these settings where we are getting to look at very large datasets has just been really, really wonderful. Dr. Shannon Westin: These are my favorite parts of these podcasts, these stories of how things kind of came to be. And, at the risk of taking too much time there, I love the story, and I'm so in awe of you guys.  I guess, let's get to the bottom line. What did you guys find? Did you find what you expected in regards to advanced care planning and goals of care in this population? Dr. Jennifer Mack: So we felt that most patients had documented discussions about prognosis, about goals of care, about palliative care, hospice, and their preferred location of death before they died. Dr. Shannon Westin: So I was actually kind of impressed at that. It seemed like a lot. I was expecting—I don’t know what I was expecting, but I think I was expecting less documented discussions because, in my own practice, I don't necessarily think I do a great job of this. So was that in line? Were you expecting to see such kind of high levels of documentation? Dr. Jennifer Mack: I really agree with you. I was impressed with the fact that most patients had these discussions. Many of them had more than one discussion about their goals of care. So their providers were going back and having follow-up discussions, making sure that their goals of care were the same and weren't changing over time. So I agree. I was pleasantly surprised with how often these were happening.   I would say I'd love to see these discussions either happening with everyone or at least offered to all patients so that they can say whether they want to have them or not. So, in this study, 17% of patients never had a discussion about goals of care. And non-white and Hispanic patients had lower rates of discussions than white patients. So there are some potentially important gaps here that need attention. But I also think you're right; there's a lot of good news here. Clinicians are making consistent efforts to talk with patients about their wishes for care, and then they're documenting them, which is an important thing because it allows those wishes to be known by everybody on the care team and helps to ensure that they're going to be carried out. Dr. Shannon Westin: I was also intrigued by the finding of the younger patients having earlier discussions around advanced care planning and hospice and goals of care. Any thoughts as to why that might be? Again, I felt like it was a little bit opposite of what I was expecting, not having a ton of background in the area.  Dr. Jennifer Mack: I was surprised, too. We had to check the numbers a couple of times just to be sure because it wasn't what I was expecting. And we don't know for sure what the reason for this is, but I think one possibility is that some of these discussions with the youngest patients, or for the youngest patients, are happening with family members, maybe their parents. And it's possible that clinicians are a little more comfortable or more likely to talk with parents than with the young patients themselves. And so that could actually increase rates of discussions for that group.  One thing we didn't assess was who was there for the discussions. It's not always documented. There's more to learn there about who was there and more about what was discussed. But that was our guess is that these may be family discussions more so than patient discussions. Dr. Shannon Westin: That really makes a lot of sense. And then I guess the next natural question is when we have these earlier goals-of-care discussions or when we have these discussions at all, what did you guys see on the impact of those kind of medical interventions that happened after? Dr. Jennifer Mack: Yeah. We found that when goals-of-care discussions happened earlier, more than a month before death, that adolescents and young adults were less likely to receive some of these intensive measures that we've talked about, so less likely to receive late-life chemotherapy, care in the intensive care unit and emergency room, and less likely to be hospitalized in the last month of life. So, even though these findings were observational, it creates the potential that having discussions earlier can help reduce some of these intensive measures and refocus care on palliation, if that's what patients are looking for. Dr. Shannon Westin: I think that's a really important point because we often bring our own thoughts and beliefs into the care of our patients and think, “Well, I wouldn't want those things.” And I think making sure we know where the patient is—and Mallory, I'd just be interested to get your thoughts here. How do we best approach those things and try to avoid—you know, we want to give advice where advice is needed, and we want to make it clear what the goals or what the potential successes might be. But I'd be really interested to hear your thoughts around framing those discussions and making sure that people understand what can be gained from those types of intensive treatments. Mallory Casperson: Yeah. I think it's important with patients in this situation—and it was discussed in the paper, but the idea of timing, how frequently are we having these care preference types of conversations, and how often are we reframing things with the patient based on how goals might be changing? I think that's a huge piece of the equation because, especially when we're talking about 30 days before death, 60 days before death, things might change quite rapidly from week to week and so having some of those things in mind.  And then it wasn't discussed as much on this paper, but it definitely has been in other work by both of these authors, as well as other just end-of-life research, but this idea of who is in the room for these conversations, I think, is another really important piece of this. Because a caregiver might have different preferences and goals than a patient. If a patient is 15 versus a patient is 25 versus a patient is 39 is also going to change things, and it's going to change the perspective that their caregivers bring to the equation. And so I think who is in the room and how are we doing that very difficult thing of weighing people's opinions in the situation, I think, is very complicated and also very important to figure out. Dr. Shannon Westin: And I think that that leads to my next question: How do we get more of that information? What do you think are the next steps for this particular work? And also, I would just say, how do we guide that? I mean, I struggle with these conversations. It doesn't matter if my patient is 22 or 82. I think trying to meet people where they are is one of the critical pieces. So what's next for this work? How do we help inform these discussions for the caregivers and for their providers? Dr. Jennifer Mack: I think you're right that we do think an important next step is promoting earlier discussions about goals of care and advanced care planning, partly because it gives patients time to reflect on what's important to them, to digest the news, and then make thoughtful decisions that are best for them. But from a research perspective, I think, as we do that, we need to understand more deeply what adolescents and young adults want from these conversations. What topics should be addressed, with whom, and how should they be discussed? And we've also learned from other work, including work that the three of us have done together, that goals of care for adolescents and young adults aren't always as simple as wanting care focused on palliation or prolonging life, this kind of binary thing. Often, there are these other equally important goals, like making sure their loved ones are okay, what's going to help them the most, having opportunities to nurture and deepen their relationships, and finding ways to attain their life goals and meaning while they're living with advanced disease.  So all of these different aspects, which aren't always a typical part of goals-of-care conversations, could be integrated to help support the kind of wider goals that are held by adolescents and young adults with cancer.   Mallory Casperson: I think, too, adding to that, we've talked about how AYA patients' goals of care have changed over time. So I think timing is a thing that could be added into future work, which is a difficult thing, I think, to gather from some of these records sometimes. But also, I think thinking through what these different words mean to different populations and how we're defining them is really important, too. So just an example outside of end-of-life care: When you tell a 30-year-old who's going through cancer that exercise is important during treatment and you talk to a 70-year-old going through cancer that exercise is different, that means different things, and they themselves have different context around what that word means in their normal life. And so I think when we throw out words like “palliation,” “palliative care,” and just general end-of-life conversations, that the same context applies. When an AYA agrees that maybe palliative care is the goal, what does that mean to them, and what are they bringing to the conversation in terms of their younger perspective than an older population that we're potentially more used to working with? So I think framing these ideas and how they might differ between populations is another thing that would serve as future work in this AYA end-of-life care space. Dr. Shannon Westin: Great. Well, thank you all so much. The time just flew by. This was such a great discussion of an incredible topic, and I just want to thank you all again for your hard work in this space.   And thank you to all of our listeners. Again, we were discussing the manuscript “Discussions About Goals of Care and Advanced Care Planning Among Adolescents and Young Adults With Cancer Approaching the End of Life.” And this is published in the JCO, so go check it out. And please do go check out our other podcast offerings and tell us what you think on Twitter. We'll see you next time. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
9/28/202322 minutes, 13 seconds
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JCO Article Insights: Improving Lung Cancer Screening Using Blood-Based Biomarkers

In this JCO Article Insights episode, Davide Soldato summarized finding from the original article published in the September JCO issue: “Mortality Benefit of a Blood-Based Biomarker Panel for Lung Cancer on the Basis of the Prostate, Lung, Colorectal, and Ovarian Cohort”. The summary provides information regarding the ability of a blood-based panel of 4 biomarkers in improving the identification of individuals at risk of developing lethal lung cancer and potential of combined screening strategies to improve trade-off between potential harms and benefit of the screening process.
9/25/20237 minutes, 50 seconds
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Impact of Smoking Cessation on Mortality From Kidney Cancer

Dr. Mahdi Sheikh and Dr. David Zaridze join Dr. Shannon Westin to discuss how quitting smoking after diagnosis may impact survival in kidney cancer. TRANSCRIPT  The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello everyone, and welcome to another episode of JCO After Hours. This is the podcast where we get in-depth on manuscripts that have been published in the Journal of Clinical Oncology. As always, I'm your host, Shannon Westin, Gynecologic Oncologist and Social Media Editor for the JCO. And I am so excited to be here today. We are going to be discussing the paper, “Smoking Cessation After Diagnosis of Kidney Cancer Is Associated With Reduced Risk of Mortality and Cancer Progression: A Prospective Cohort Study,” which was published in the JCO on March 29, 2023. And this very intriguing paper, I have two of the major authors from this paper. First is Mahdi Sheikh, who is a scientist and epidemiologist at the International Agency for Research on Cancer, the World Health Organization in Lyon, France. Welcome, Dr. Sheikh. Dr. Mahdi Sheikh: Thank you very much, Dr. Westin, and thanks for having us. Dr. Shannon Westin: And then with Dr. Sheikh is Dr. David Zaridze. He is the Director of the Department of Clinical Epidemiology at the N.N. Blokhin Russian Cancer Research Center in Moscow and also the President of the Russian Cancer Society. We are with greatness today. Dr. David Zaridze: Thank you. Thank you very much. Nice to be with you. Dr. Shannon Westin: Very nice to be with the two of you. So, let's get started. I first wanted to just level set. Could one of you review just the overall incidence of kidney cancer and what proportion of patients with kidney cancer are known to be smokers at diagnosis? Dr. David Zaridze: The figures I'm going to present are rates. They are adjusted to standard world population. Why am I saying that? Because in America you sometimes use adjustment to the US population. These figures will be different from what you are accustomed to see. Okay, incidence of kidney cancer in Russia, in men, 14.1 per 100,000. I compare this with the United States of America, men, 16.5. Very small difference. Women in Russia, 8 per 100,000. In the United States of America, 8.8 per 100,000 of population. Exactly the same. Very close. These rates are sort of high-ish, but there are very high rates, for example, in the Czech Republic, where rates are more than 20 and other Central European countries. In Russia, kidney cancer mortality in men is 6 per 100,000. In USA, 3 per 100,000. In women in Russia, 1.9. In the United States, 1.3. I would say that there is a difference in mortality in men, not much in women. The incidence of kidney cancer is increasing in Russia sharply, sharply. Since 1990 it has increased - it’s tripled. It increased from 5 per 100,000 in 1990 to 14 per 100,000 in 2019. Mortality is stable or declining. This is suggesting that kidney cancer is overdiagnosed in Russia and probably elsewhere. But this is not a problem of our discussion now. The frequency of the prevalence of smoking in kidney cancer patients. It is estimated that 15% to 20% of patients with kidney cancer smoke. In Russia, we have results only from our study. 18% of patients smoked at admission to our cancer center. Dr. Shannon Westin: Got it. Okay, good. Well, that's really helpful, especially to those of us that don't take care of patients with kidney cancer every day. It helps us just understand. And I guess the next question is what do we know about the impact of tobacco cessation on the risk of kidney cancer? So you were talking about that increasing incidence. How does tobacco cessation impact that? Dr. Mahdi Sheikh: Tobacco smoking is a known risk factor for kidney cancer and an estimated 17% of the kidney cancer burden worldwide can be attributed to tobacco smoking. There is a recent meta-analysis of 56 studies that was published a few years ago that clearly showed a dose-response relationship between smoking and kidney cancer, meaning that the more cigarettes a day you smoke, the risk of kidney cancer will go up. For example, the risk that was shown for five cigarettes per day was 20%. It goes up until 70% for 30 cigarettes per day. And also with a duration, the more years you smoke, the risk for kidney cancer will go higher. However, the good news is that when you quit smoking, there is strong evidence that the risk for developing kidney cancer will be lower compared to if you continue smoking. And there is some evidence that shows again dose-response relationship, meaning that the more years you spend in quitting smoking, the lower your risk would be for developing kidney cancer compared to if you continue smoking. So this is not only about renal cancer or kidney cancer but also true about many other cancer sites as well. Dr. Shannon Westin: Okay, that's super helpful. And then I guess prior to your study that we're about to talk about, did we have any information on what happens when patients quit smoking after their diagnosis? Any limitations to those data that were available? Dr. David Zaridze: You mean the data which was prior our study? You know, the negative effect of smoking after diagnosis has been shown nearly three decades ago. The information exists already for thirty years, but it was largely ignored not only in clinical practice but also in clinical trials. And I have to stress that in clinical trials this information is still ignored. I came across these studies and decided to review them some time ago. All they were case-control studies and to my knowledge, none of them assessed the effect of quitting smoking. I decided to review these studies and included this review in my book, Smoking: A Major Cause of Cancer, which was published in 2012 and was dedicated to Professor Richard Doll's anniversary. In fact, this was a stimulus for the study we are discussing. And in fact, the component of this study we are discussing today was built in and baked into the existing cohort study to which we added the active follow-up component for assessing the changes in smoking habit and disease status. Dr. Mahdi Sheikh: If you review the evidence, before publishing this study just like a few years ago, we find that there are many studies published talking about the effects of smoking cessation on cancer survival. However, as David mentioned when you go deep into these studies, you’ll find a lot of limitations. First of all, most of these studies are retrospective studies, which means that either case-control or retrospective course that patients developed the outcome, and then some investigators came to see their records to assess or ask family members before they developed the outcomes. There are a lot of biases with these types of studies. And with the epidemiologic study, perspective study that we did, has less limitations compared to retrospective ones. Another one is that when we go into the study you see, they only assess a small number of patients, small sample size. Some studies just assess 10 smokers, some assess like 30. By this study we try to assess a large number of smokers who quit smoking after diagnosis. Another limitation is that– First, let's see what exposure and what setting we are talking about. We're talking about smoking which is a very dynamic behavior. People quit smoking and they relapse smoking and they quit smoking and so on. So if you access this exposure for only a limited time, for example, for one year, then you may miss what happens after that which results in misclassification of some of the participants. So repeated assessment was not done in other studies that we did here in this study. Another one, you are talking about special setting patients who are diagnosed with cancer. These patients have special circumstances, they have treatments, they have family support, they might go under the stress of cancer, and all these different stages at diagnosis. And most studies that are available, they didn’t account for this. They didn't adjust or they didn't try to understand the role of these compounding factors, as we call it in epidemiology, on that, the thing that we're trying to address. And a prospective study, as I said, long follow-up time. Even the very few prospective studies that were available for other cancer sites that have only one year or maximum two years of follow-up with this type of exposure, so it is important to follow them for a long time. Another thing I would say was exposure assessment. Not only did we repeatedly try to assess exposure among participants, but try to call the people– David and his team who did the study in the field, called the participants and tried to ask the family members and sometimes their physicians about their smoking behaviors. When you go to current evidence you see, mostly smoking behavior was assessed using the record that is available like treatment records or patient records, which again has some limitations if you do not assess exposure among qualified participants. Finally, we're talking about a dynamic behavior in the follow-ups. Some people might change smoking. But there is a very important thing, in this study, we also collect at the time of quitting smoking. There's a very important thing in statistics we call Survivorship Bias, meaning that, if you were assessing an exposure doing the follow-up and if you do not pay attention to this, you will assess an exposure that is a proxy of people who lived longer. Meaning that people have enough time, they have a long time, and those who have longer time, will have more time to quit smoking. And then you will be assessing this, actually, not the exposure, but you're only assessing people who quit smoking, and then whatever you assess, you would end up with a beneficial effect. But if you have the time of quitting smoking and follow up and all these statistical things and lower sample size, you are able to account for this very very important bias in epidemiology. Dr. Shannon Westin: Before we go further, I'd love for just a bit of a description of exactly how you laid out your study to really add to where this data are so limited around survival and tobacco cessation. So maybe review the primary/secondary objectives, basic design, just to make sure our listeners are all on the same page. Dr. David Zaridze: The study has classical prospective cohort design that the study, which was basically a basic study, in which the new component was built in. This study used a user’s questionnaire-based exposure assessment and molecular epidemiologic approach. I mean that, in addition to the questionnaire approach, we collected blood and tumor tissues for molecular studies. All patients with kidney cancer admitted to the cancer center were interviewed at admission before receiving any treatment. A structured lifestyle questionnaire was used. Participants were asked about their lifetime smoking history which included questions about the duration and frequency of smoking cigarettes, the average number of cigarettes smoked every day. They were also asked about their lifetime history of alcohol drinking. The questions included questions about exposures to carcinogens other than smoking, and health conditions, including chronic kidney diseases, hypertension, diabetes and so on. Height and weight were measured. Today, this study generated and continues to generate plenty of results and papers published in most prestigious journals such as Nature Genetics, for example. So, as you know, we started from 2012, we started the follow up of the cohort members, we were focusing on Moscow residents and the follow-up includes regular annual contacts with the patients personally or via telephone or with patients’ household members, etc. Again, we collected information about changes in smoking behavior and disease status. We also used information from the regional cancer registry to confirm the information obtained from patients. The average period of follow up was eight years. And this is quite a long follow-up. Repeated assessment of smoking status reduces the likelihood that exposure to smoking was misclassified. However, regrettably, the self-reported information on smoking was not supported by biochemical tests, for example, by blood cotinine testing. To my knowledge, this is the only prospective cohort study in patients with cancer, not only with kidney cancer that have collected data on participants' smoking status prospectively for quite a long time. The average follow-up time was eight years. Dr. Shannon Westin: That was incredible. That definitely caught my eye. And I was looking, I was like, “Oh, how many did they lose?” And you guys kept 80-100% of the patients. I just was so impressed by that. And now hearing the mechanisms in which you did that, it makes sense. You were very diligent, multiple ways to contact patients and confirm the data. So you really are to be congratulated for the work that you're able to achieve. Dr. Sheikh, I'd love to hear, you talked a little bit about how some of the studies didn't really think about confounding variables. Can you kind of highlight some of the confounding variables that you all controlled for in order to really assess the impact of the cessation on survival? Dr. Mahdi Sheikh: Thanks to the high-quality data and also the large sample size and the way the study was designed, we were able to adjust for a lot of confounding. So we tried to adjust for all these things. So we used three approaches. The first approach was adjustment. When you ran this in the analysis, we tried a statistical model, we tried to adjust for these confounders like age, sex, treatment, socioeconomic status, smoking intensity, alcohol, and other factors. This is one effect, one approach. The second approach was stratification, meaning that we come and see the effect within people who have been diagnosed with only earlier stage tumors to see if the effect among people with earlier stage tumors differs with the effect that we see among people with higher stage tumors. But again, if you read the paper, you see that we saw the protective effects of smoking cessation on both groups of people, those who were diagnosed at earlier stages and those who were diagnosed at later stages. And also heavy smokers or mild to moderate smokers, again, we tried stratified analysis excluding those heavy smokers and saw the effect, again, among those who were light smokers or moderate smokers and also with the heavy smokers. I want to say that we tried all these types of analytical approaches and we really saw the protective effects across all patient subgroups. Finally, I talked again about the survivorship bias. So we used really strict statistical approaches to address this confounding, and because we had the time of quitting, we had the follow up time and all these things. And, again, whatever we did in the study we still could see the effects of smoking and all this is due to the good design, the large sample size, and the good questionnaire data that we have. Dr. Shannon Westin: That's awesome. I think, of course, now let's get to the bottom line. 40% reported that they quit smoking after diagnosis with none relapsing during the time period. And what did you see was the impact on overall survival as well as cancer-specific survival? Dr. Mahdi Sheikh: So we tried several outcomes - overall survival, cancer-specific survival, but also progression-free survival. And then because we had the large sample size we could assess all this. Interestingly, we saw the effect on all the three outcomes that we assessed. So the overall survival was better among those during the quitting time and also the cancer-specific survival was also better and also progression-free survival was better among all these participants. Dr. Shannon Westin: I think most people that have read this paper - and if you haven't read this paper you should run to read it right now - I really was impressed with that kind of clear benefit across cancer-specific mentality across all subgroups regardless of how much they smoked. So I don't know why you get a sense of like, “Oh, if you smoke a little bit you wouldn't see as big of an impact,” but a very clear impact. And I would love to hear why you think smoking negatively impacts these outcomes. How does the cessation help? This is a perfect time for that. Dr. Mahdi Sheikh: When we review the evidence about how smoking cessation may be beneficial for patients, for the survivorship of patients with cancer, we come to five mechanisms that are suggested in the literature. So the first one can be, is suggested, that is altered cancer biology. Smoke and tobacco smoke contain numerous carcinogens and mutagens. So it has been shown that cancer cells that are exposed to tobacco smoke, they may become more aggressive and the risk of metastasis might go higher and also, angiogenesis and all other effects on the biology of cancer cells. So it may affect the cancer cell biology. Another suggested mechanism might be altered immune response. So tobacco smoking affects the immune system and then the immune response among those who are exposed to tobacco might be affected by tobacco smoking. So their response to the cancer cells but also other bacteria, viruses, and other things might be affected as well. The third possible mechanism suggested altered drug metabolism. It has been shown that tobacco smoke and smoking can affect some of the enzymes that have metabolic responsibilities and metabolism of the drugs. So that can affect the washout period for the drug. It might not stay enough in the blood or vice versa as well. It might affect the toxicity. There is some evidence about this. The fourth mechanism suggested is about increasing treating-related complications or treatment-related complications. People who smoke have delayed wound healing, they have more complications, the surgery, the time they spend at the hospital might be longer. And this is also part of which smoking may affect the outcomes that we saw here. And finally, that is we are talking about tobacco smoking and patients with cancer are human beings with all these systems. So we know that smoking causes damage to the cardiovascular system, to the pulmonary system and also to the lungs and other things. So this is why we see different outcomes are affected by cancer. Dr. David Zaridze: I was impressed by the data that exposure to tobacco smoke condensate induces changes in tumor microenvironment. For example, it inhibits formation of interferons, interferon alpha and gamma, inhibits the migration to tumor microenvironment of the immune cells. The number of CD8+ T lymphocytes, T killers, are significantly lower in the tumor microenvironment of current smokers compared to former smokers and never smokers. And even more interestingly, the number of PD-L1+ cells are also lower in the tumor microenvironment of current smokers than former or never smokers. This is probably very important in terms of effectiveness of impairment by smoking of the immunotherapeutic approaches in cancer treatment. Dr. Shannon Westin: That's very important and we know the microenvironment has a huge impact on just the way the cells respond to treatment and develop resistance and so that makes a lot of sense. Okay, well, this has been amazing and I think one thing that you just said just struck me, Dr. Sheikh, that you've obviously shown this in lung cancer and you're looking at this in other cancers. I guess the question is: What should we be doing? How should we be implementing tobacco cessation efforts across all cancer diagnoses to help all patients that have really any diagnosis of cancer? Dr. David Zaridze: Let me first underline the clinical importance of these results. The benefits from quitting smoking are comparable or even superior to those recorded in the clinical trials of modern kidney cancer treatments such as immune checkpoint inhibitors. I refer to the results of pivotal trials in advanced renal cell cancer in the frontline setting and these results were reported at ASCO Meeting 2023 recently in May. If you compare the results of our study with results of these pivotal trials, it is very impressive. It is clear that our findings strengthen the case for making tobacco cessation treatment a standard part of the routine health care for all people with cancer, however, smoking is still quite high in cancer patients. And I would like to quote Peter Shields who is saying that, in the United States,10% to 50% of cancer patients smoke. As far as Russia is concerned, in our study, 80% of kidney cancer patients smoke, and in our lung cancer study, 58% of cancer patients smoke.  The barrier is that the oncologists do not believe or are accepting with a great deal of skepticism the results of our study. They don't believe the idea that anything else besides surgical, radiological, or medical treatment could improve the outlook of cancer patients. It's difficult for them to apprehend. Many of them think that smoking cessation after diagnosis is simply a waste of time. Many patients simply don't know that smoking cessation after diagnosis may be beneficial for them. In addition, they are pessimistic and they feel discouraged to quit smoking, as they might think it is too late. I would like to quote my favorite quote: “Smoking cessation treatment has to become the fourth pillar of cancer treatment, one that could affect cancer treatment outcomes as powerfully as surgery, chemotherapy, or radiation therapy.” This is Dr. Fiore, 2019. Dr. Shannon Westin: Thank you so much. And Dr. Sheikh, anything to add there around cessation efforts? Dr. Mahdi Sheikh: As we saw the results of these studies that smoking cessation is feasible and it is accessible at a minimum cost for many patients, it should really be integrated in the  management of patients with cancer. It is feasible, it is cheap, it is accessible. But unfortunately, when we review the evidence we see that only less than half of the physicians, like around 40% of physicians, send the patients to tobacco smoking cessation services. And even some do not discuss this issue. And as David mentioned, they do not know the effect of smoking cessation. So when you go through these studies to find the major barriers, in addition to what David had mentioned, we find two important points. First one is lack of education or experience in providing tobacco cessation interventions among those who deal with patients with cancer. So they do not have the education. And second is lack of available resources for referrals. Now we’re not only talking about the United States but also many other countries even high-income countries, we do not see the resources for referrals on smoking cessation services in cancer care settings. The take home message probably from this study and also from these barriers, would be for three groups. First, for the policymakers, we would recommend sustainable funding should be dedicated to tobacco cessation services. As we saw, the effect is huge and seems to be a very big effect and it is cheap so why not implement this smoking cessation service within cancer care settings.  And the second one, tobacco treatment training programs for healthcare providers. This is also very, very important that we try to implement this training program in the curriculum of healthcare providers, especially those who deal with cancers and tobacco-related outcomes. And also for physicians, we recommend that physicians should assess and address tobacco use in all patients with cancer. They should talk about this topic and also show the benefits of quitting smoking. And patients with cancer who smoke should be supported to stop smoking at any time and each visit after diagnosis is not like some time pass, as we saw, all patient subgroups could benefit from smoking cessation. This is important.  But something also very, very important that we shouldn't forget that cancer itself causes a lot of fear and anxiety and stress. And smoking cessation sometimes may be associated with stress and more anxiety. So it is very, very important to think about this point and provide the psychosocial support to patients who quit smoking. Sometimes they may relapse just because of the fear and anxiety they have. So it's not only showing the evidence, but also supporting these patients, telling them how to do that and also supporting them emotionally and also psychosocially. And finally for the patients, I would like to give this message that we see and we know that it is never too late to quit smoking. As David said, patients may feel like, “It is too late now I've developed cancers,” but no, it's really not too late. And if you quit smoking at any time after diagnosis, you would benefit a lot from smoking cessation. Dr. David Zaridze: In the United States there are guidelines, several guidelines for smoking cessation, specifically for cancer patients because smoking cessation in cancer patients is very different from smoking cessation in general population. In the general population, we more or less succeeded, I would say, and we have to look now at this direction to the smoking cessation in cancer patients. And this is a message to WHO, that countries, members of WHO, based on the recommendation guidelines of WHO, develop their own specific guidelines for smoking cessation in cancer patients. And that should be used in all cancer clinics and that should be a must, absolutely important part of anti-cancer treatment. And as I already told, it should be the fourth pillar in cancer treatment, as treatment, as surgery, chemotherapy and radiation. Dr. Shannon Westin: Thank you both. That was such a great discussion, and I hope that we've convinced everyone that this is a critical effort that they need to be addressing every day.  I just want to thank everyone who listened. This has been "Smoking Cessation after Diagnosis of Kidney Cancers Associated with Reduced Risk of Mortality and Cancer Progression: A Prospective Cohort Study", again published in the JCO on March 29, 2023. Thank you guys again for listening to JCO After Hours. Please check out our other podcast offerings. You can check them out on the website or wherever you get your podcasts and let us know what you think about the podcast on Twitter. Dr. David Zaridze: Thank you. Dr. Mahdi Sheikh: Thank you very much.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  
9/14/202329 minutes, 37 seconds
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HER3-DXd in EGFR-Mutated NSCLC: HERTHENA-Lung01

Dr. Shannon Westin and her guest, Dr. Helena Yu discuss the paper "HERTHENA-Lung01, a Phase 2 Trial of Patritumab Deruxtecan (HER3-DXd) in EGFR-Mutated NSCLC Following EGFR TKI Therapy and Platinum-Based Chemotherapy" published in the JCO during the World Conference on Lung Cancer in Singapore.     
9/10/202316 minutes, 22 seconds
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JCO Article Insights: Introducing The Childhood Cancer Data Initiative

In this JCO Article Insights episode, Emily Zabor interviews Dr. Gregory H. Reaman, the Scientific Director of the Childhood Cancer Data Initiative at the National Cancer Institute, on their paper titled  “The Childhood Cancer Data Initiative: Using the Power of Data to Learn From and Improve Outcomes for Every Child and Young Adult with Pediatric Cancer”. Dr. Reaman introduces us to the initiative, its goals and structure, and what has already been achieved since its launch. TRANSCRIPT The guest on this podcast episode has no disclosures to declare.  Emily Zabor: Welcome to this JCO Article Insights episode for the August issue of JCO. This is Emily Zabor, JCO's Biostatistics Editorial Fellow. And today I am interviewing Dr. Gregory Reaman, the Scientific Director of the Childhood Cancer Data Initiative at the National Cancer Institute, on their paper titled “The Childhood Cancer Data Initiative: Using the Power of Data to Learn from and Improve Outcomes for Every Child and Young Adult with Pediatric Cancer.” Dr. Reaman, welcome to our podcast. Dr. Gregory Reaman: Thanks very much, Emily. Appreciate the invitation. Emily Zabor: Dr. Reaman, could you start by introducing yourself and describing your involvement in the Childhood Cancer Data Initiative? Dr. Gregory Reaman: I'm Gregory Reaman. I'm a Pediatric Oncologist. And I guess my involvement with the CCDI began shortly after the initiative was announced at the State of the Union media address in 2019, which was followed shortly thereafter by the formation of a working group by the NCI's National Cancer Advisory Board Board of Scientific Advisors. Given my role at the FDA at that time as Associate Director for Pediatric Oncology in the Oncology Center of Excellence, and the fact that I was the founding Chair of the Children's Oncology Group, I was an ex-officio member of this working group. So from very early on, I had involvement. I formally joined the NCI in November, left the FDA to assume the position as Scientific Director of CCDI. Emily Zabor: That's great. So you've really been involved from the start. I had not really been familiar with the initiative until I read this paper. And as a cancer biostatistician, I was really excited to learn about this initiative, which sounds like it will ultimately create a very valuable data resource to be used for research purposes, among other things. So I think it's a really interesting project. So for our listeners who may not be familiar, could you describe the motivation for and goals of the Childhood Cancer Data Initiative? Dr. Gregory Reaman: As I mentioned, this really is a very unique initiative, venture, if you will, on the part of the Cancer Institute and in large part driven by this fortunate infusion of funds to support childhood cancer research. And given the fact that pediatric oncology is very much a collaborative enterprise, it really does sort of follow that data sharing and using the power of data, its ability to be used by multiple investigators, irrespective of the source, aspirationally can improve outcomes for children cancer. The three primary objectives– actually, this working group that I mentioned earlier put together a white paper that had 24 specific recommendations to the NCI. But there were three foundational objectives or goals. One was to learn from every child diagnosed with cancer, irrespective of the institution where they were diagnosed to receive therapy, to develop an ecosystem that would enable the submission, aggregation of data, and harmonization in a federated system that could then be accessed and used by investigators and analyzed to ultimately improve outcomes. And then one objective, which was a little bit more specific, and that was to really focus on the opportunity to genomically classify tumors from newly diagnosed pediatric cancer patients, because this was something that obviously is much more widespread in the adult population, given the advent of targeted therapy and precision oncology and its more widespread use in medical oncology than pediatrics. And although many large academic institutions do have resources, the majority of smaller institutions do not. And when it's necessary and preferable to accurately and timely identify or diagnose a child's cancer that may actually provide information on treatment recommendations, the ability to do that and have it covered by insurance is sometimes problematic. So developing a program that would not cost patients or institutions anything and then make that data available to patients, families, and providers, as well as making it available for secondary research use, was a major goal and objective. Emily Zabor: Yeah, that sounds like such an important initiative. The Molecular Characterization Initiative, which I understand has already enrolled and characterized the genomics of 751 participants just in the first year, I think is what the paper reported? Dr. Gregory Reaman: That's correct. That was in the first year. We're now beyond the first year and we're approaching 2000 patients that have had their tumors genotyped and about 1500 results that have been returned to patients and providers. Emily Zabor: That's fantastic. So with this linkage to the clinical data, that's going to be an extremely important data source. And I understand that the participation is currently limited to members of the Children's Oncology Group, which consists of over 200 children's hospitals, universities, and cancer centers. Can you describe in more detail what information it currently provides and how this initiative is going to be advertised and implemented to ensure complete participation across all of these member sites? Because that sounds like a really big challenge. Dr. Gregory Reaman: Limiting the participation to the Children's Oncology Group initially was in no way meant to be exclusionary, but really provided an opportunity for linkage to clinical data. Since the Children's Oncology Group really represents nearly all of the pediatric cancer programs in the United States and some programs even outside the US, in Canada, and a couple of European sites, Australia and New Zealand, it was felt that given the resources that currently exist within the COG for specimen procurement, specimen submission, and then DNA and RNA extraction through the COG's Biopathology Center at the Nationwide Children's Hospital would really facilitate having the sequencing done at a single site, single institution, using a single platform. And also it provided an opportunity for some clinical data, including demographics, diagnosis, radiographic data, and treatment data that could be collected somewhat longitudinally from patients enrolled on the MCI. Looking to make this as broad as possible since the objective of the CCDI is to learn from every patient, and every patient that we're concerned about not being able to capture adequately within the Children's Oncology Group are older adolescents and young adults with cancers that are more frequently seen in the pediatric population. So we are looking at ways to work with the COG's Biopathology Center to see if we can create systems that we can actually have specimens submitted from patients seen at institutions outside of the COG and molecularly characterized the same way. And that will be important as we launch another new planned initiative called the Coordinated National Initiative for the Treatment of Rare Pediatric and Young Adult Cancers. Emily Zabor: Okay, that makes sense. So those adolescents and young adults are harder to capture since they're not being seen at those COG member institutions. Okay, well, that sounds like a big challenge to find those patients at their institutions and get them involved, but I think it's an important piece of this for sure. Dr. Gregory Reaman: I should also point out that there were opportunities for some of the larger well, for all of the NCI-designated cancer centers, the pediatric programs associated with those cancer centers, to submit genomic data on newly diagnosed patients. That was something that actually transpired early on in the history of CCDI. So those data are in the CCDI's ecosystem. Emily Zabor: Oh, that's great. So you collected the existing data. Dr. Gregory Reaman: Right.  Emily Zabor: That kind of leads into my next question about aggregating data sources. With these disparate sources of pediatric cancer data, it seems like the aggregation is a lofty and important goal, but once that's complete, you're going to have this data ecosystem, which you said was one of the main goals of this initiative. I was wondering if you could tell us who will have access to this data ecosystem and what will be required for individuals to gain access. Dr. Gregory Reaman: All of CCDI was predicated on this really being a community initiative if you will, so multidisciplinary and community-based. So patients, families, advocates, clinical researchers, physician providers, basic and translational researchers, researchers in public health and epidemiology. So there will be different levels of data that will be available to specific individuals. Patient-level data will be deidentified through a system of APIs that will be used that will enable the association of clinical data to existing molecular data and outcome data that might be available in the ecosystem. Those data will be- there are many data in the ecosystem that will be open source and available to anyone who is interested. This includes data from the NCCR in the Childhood Cancer Data Catalog, which is basically a listing of some close to 300 pediatric cancer databases that are available. The patient-level data will be sort of a controlled access. So there will be a requirement for individuals, investigators who wish to access that data, to sort of be certified, if you will, utilizing NCI and NIH data sharing requirements. Emily Zabor: That makes sense. Yeah, you mentioned deidentification, but especially when we're dealing with these kinds of rare diseases, patient privacy does seem like it could be a concern. So what exactly are you doing to ensure that that is not something that gets violated through this process? Dr. Gregory Reaman: I think there's every attempt to eliminate any PPI, HPI, obviously. So, again, most of the clinical data that are being provided currently are data that's coming from the Children's Oncology Group, where for every patient enrolled or registered through the COG and enrolled on a clinical trial, there is a COG ID number that is associated and that will be available only to the NCI and the CCDI to link it to unique specimen identification numbers, which are the only numbers that will be available to any investigator. So no one will be able to make the connection from the specimen identifier to the unique patient identifier in the COG. Emily Zabor: That's great. And that way, you can really get access to all of the detailed data without concerns about privacy. Dr. Gregory Reaman: Correct. And then being able to link all of these disparate data sets will really require the identification or the development, I should say, of a participant index. So that is one of our highest priorities right now in developing a CCDI participant index so that we would be able to link the identifier or clinical data with any research data or biologic data that may be available on patients to facilitate research plans and programs. Emily Zabor: And through that process, is there also some method involved for identifying duplicated data? Because I assume some of these patients may get seen at different institutions over time, and that could be a concern that they end up in the database multiple times. Dr. Gregory Reaman: That's exactly why I think developing the participant index is so critical to, number one, link, and number two, to avoid, prevent duplication, because you're absolutely right. There may well be the same patient data in multiple data sets, which are, of course, disparate. And the only way that they're going to be really utilizable and made interoperable is by linking them to the specific patient or individual patient. Emily Zabor: Great. And do you have an idea of the timeline when that part would be complete and this data ecosystem would be available to researchers?  Dr. Gregory Reaman: The ecosystem is already available to researchers. We launched several months ago the CCDI hub, which is sort of the entryway or entry point, if you will, for access to the ecosystem. We hope to actually have the participant index up and running, and it's something that we've been working on for over a year, but actually available and utilizable within the next several months.  Emily Zabor: That's fantastic. We'll have to go check out the CCDI hub that's already out there then. Before we end, is there anything you'd like to share with our listeners that we haven't already discussed? Dr. Gregory Reaman: Well, I think the one program that I mentioned just briefly, the Coordinated National Initiative for Rare Pediatric and Young Adult Cancers, we see there's a real opportunity to address a major unmet need. Fortunately, all pediatric cancer is rare, but there are some cancers that are extremely rare and for which there are, in many cases, no defining standard of care, and in many cases, there are no treatment protocols because of the difficulty mounting studies with such small patient numbers. So we see this as an opportunity to actually develop a registry that will provide, hopefully, natural history data that will inform clinical trials. All of these patients will be enrolled on the Molecular Characterization Initiative. So there will be the opportunity to hopefully learn if there are specific molecular drivers of some of these cancers that could inform the use of targeted drugs in a therapeutic approach to some of these. And we're looking to do this international collaboration with colleagues in the EU as well. So that is something that we just launched a task force  to develop a listing of core critical data elements to collect on patients and then developing the registries for a number of these rare cancers. Emily Zabor: That sounds like it's going to be a really valuable resource for planning and designing future clinical trials, so I'm glad to hear about that. Dr. Gregory Reaman: And we would invite anyone who's interested to find out about the CCDI, to find out more about the CCDI, which they can do through cancer.gov/ccdi. There is an opportunity for people to register for newsletters. We have a series of webinars, many of which are designed now to actually provide training on some of the resources and platforms that are available currently through the ecosystem and things that we have all planned for future developments and use. So as I said, this is a community venture and we look to expand the community in every way possible. Emily Zabor: That sounds great. So hopefully our listeners will take note of some of those resources in addition to this paper being out there, which will guide some people in the right direction to learn about this really great initiative for childhood cancer.  So, Dr. Reaman, it has been a pleasure speaking with you. And thank you so much for joining me today on this episode of JCO Article Insights. Dr. Gregory Reaman: Thank you very much. It's been great to be here. Appreciate the opportunity.  Emily Zabor: This concludes this episode on the article, “The Childhood Cancer Data Initiative Using the Power of Data to Learn from and Improve Outcomes for Every Child and Young Adult with Pediatric Cancer.” Thank you all for listening and please tune in for the next issue of JCO Article Insights.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  
8/28/202318 minutes, 41 seconds
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Impact of Heatwaves on the Care of Patients With Cancer

Dr. Shannon Westin, Dr. Abbas M. Hassan, and Dr. Leticia Nogueira discuss the impact of heatwaves on cancer care delivery and what can be done about it. TRANSCRIPT The guests on this podcast episode have no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on manuscripts that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncologist and Social Media Editor for the Journal of Clinical Oncology. I'm so excited to be here today to discuss a very thought-provoking manuscript. This was published on June 10, 2023, in the Comments and Controversies section of JCO, and it’s entitled “Impact of Heatwaves on Cancer Care Delivery: Potential Mechanisms, Health Equity Concerns, and Adaptation Strategies.”  And I am thrilled to tell you I am joined today by two of the authors of this very important manuscript. Dr. Abbas Hassan is an intern in the Division of Plastic Surgery, Indiana University School of Medicine. Already reaching for the stars, publishing in the JCO as an intern, that has to be a record. Congratulations and welcome, Dr. Hassan. Dr. Abbas Hassan: Thank you for having us. Appreciate it. Dr. Shannon Westin: And with Dr. Hassan is Dr. Leticia Nogueira. She is now the Scientific Director of Health Services Research at the American Cancer Society. Welcome, Dr. Nogueira. I'm so excited to have you. Dr. Leticia Nogueira: Excited to be here. Dr. Shannon Westin: Let's get right to it. This topic is very timely. We are currently enjoying several weeks of greater-than-100° weather here in Texas, where I am, and across the United States. Why don't we start by just defining heatwaves in general and what their global impact is on morbidity and mortality? Dr. Abbas Hassan: Yeah. So, I mean, it's the Texas heat, right? It's hard to ignore it when you're sweating buckets, right? So this kind of extreme heat isn't just a Texas problem. It's happening everywhere, so from Australia to Europe and across the US. And what we're experiencing, my friends, are heatwaves. They're like the unwanted guests at a barbecue, showing up uninvited, hanging around for at least two straight days. Now, defining a heatwave isn't straightforward as it might sound, with various different definitions across studies and policies. But one thing that is clear: heatwaves aren't just about discomfort. They're deadly. They're claiming more than 5 million lives globally every year.  Now, let's just imagine for a moment the year 2020. Not exactly a walk in the park. And on top of that, everything else, heatwaves cost over $4.5 billion in damages in the US. And that's probably just the tip of the melting iceberg, considering the tricky task of identifying exact heatwave periods. Dr. Shannon Westin: And you said it's really hard to define, so I imagine that that makes it really difficult to study. Hopefully, I think we've already gotten our first call to action is coming up with some type of consistent definition so we can truly look at this in a scientific fashion. I guess I'm asking you to predict, but I'll do it anyway. What do we expect to happen over the next 30 years in regards to the climate change we're seeing and maybe overall temperatures across the globe? Dr. Abbas Hassan: The way things are going, we're probably going to need a lot more sunscreen and a lot more ice cream. In all seriousness, the outlook is pretty stark. By 2023, we're looking at 8.1 million of our fellow Americans facing temperatures hotter than 125°F. And fast-forward to 2053, the number skyrockets to like 100 million. So that's a 13-fold increase. Remember when we thought 2014 was hot? And then 2015 came in, then 2016, and now all the way to 2020. Each year seemed to outdo the last, making the past seven-year span the warmest we've ever experienced. So we're not just dealing with a few off years. We're in the midst of a trend that's heating up our planet and impacting our health at an alarming rate. Dr. Leticia Nogueira: Yes, I would like to add to that, exactly what Dr. Hassan said. We don't really need to worry about or focus on what temperatures are going to be in 30 years. It is here now. The threats of climate change are here now, threats of extreme heat, no matter how we define it, right? Because it could be number of days above a certain temperature threshold, and that threshold is usually established by the previous 30 years. And we've already seen these jumps in temperatures in the previous 30 years, especially in most recent years. So these hazards, these threats, are already here. No future projections necessary to understand the hazards and the detrimental consequences of exposure to extreme heat due to climate change. Dr. Shannon Westin: Well, let's talk a little bit about that. And specifically, I would love to hear kind of what we've been seeing as far as the impact of heatwaves on health outcomes. I think our group would be interested in knowing, what are some of the things that you're seeing and you’re experiencing? And then further, what are the things that make people more vulnerable, let's say, to the climate hazards? Dr. Abbas Hassan: Yeah, let's dive in a bit more into what makes us vulnerable to these heatwaves. When you think about vulnerability, the key elements are, one, increased exposure; two, increased sensitivity; and three, decreased ability to adapt. So think about it this way: Let's say you’re—not sure if you guys play this—let’s say you're playing a game of tag, and the sun is it. Now the sun is pretty good at tag, so anyone spending a lot of time outside—that's increased exposure—is more likely to get tagged. Then you have some players who are, for various reasons, they’re slower or less agile. So this can be due to age, health conditions, or other factors that make them more sensitive to heat. They're not able to dodge the sun as quickly. So that's increased sensitivity. And finally, imagine some players are dressed up  in heavy clothing, unable to change into something cooler. They don't have the resources to adapt. So that represents that decreased adaptive capacity. While everyone playing this game can feel the burn, there are some who are more at risk.  So, for example, individuals with cancer are particularly at risk because they have various physical, psychological, socioeconomical consequences of their diagnosis, treatment, and even their path to survivorship. And this can include everything from weight loss to tumor, compromised immunity, side-effects from medications, and even financial stressors, making their game of sun tag especially challenging. So when we talk about the impact of heatwaves on health, it's not a one-size-fits-all issue. Our vulnerability is a complex combination of various factors that can leave some of us more at risk than others. And it's this understanding that can help shape our approach to tackling the challenges that climate change brings. Dr. Shannon Westin: That was very well stated, and I think I want to dig in a little bit deeper on some of the broad factors you covered, especially as it relates to patients with cancer, who obviously fit in the category of vulnerable to really all those pieces. So I'd love to dig in a little deeper. So let's talk a little bit more about age. I know that certainly patients with cancer can be any age, but it does seem to affect patients that are older or more elderly. How might that impact sensitivity to these heatwaves? Dr. Abbas Hassan: Okay, so dig a little deeper here. The reality is that getting older comes with its fair share of challenges, and one of them is increased sensitivity to heat. So as we age, we become more susceptible to heat. And this is particularly true for individuals over the age of 65, many of whom are also dealing with a cancer diagnosis. In fact, the number of seniors with cancer is expected to nearly double by 2060. So heat sensitivity in this group is due to several factors. First, our body's ability to regulate heat, or thermoregulation, declines with age, much more like an old car cooling system not working as it once did. So this means we're less able to handle extreme heat, making us more vulnerable during heatwaves. And this vulnerability is especially concerning for older cancer patients because some cancer treatments can cause additional complications, such as kidney injury, which can impair our cooling systems even further.  Additionally, these treatments can lead to dangerously high levels of hypernatremia and hyperkalemia, and this can lead to serious complications like cardiac arrhythmias. So in other words, the aging process coupled with cancer and its treatment can make older folks more susceptible to the harsh impacts of heatwaves. Dr. Shannon Westin: That makes sense. So you started to touch a little bit on comorbidities with discussing heart disease and arrhythmias and how that might impact. Are there other comorbidities that are certainly quite common in patients with cancer that can impact health conditions related to climate change? Dr. Leticia Nogueira: Yes. So, in addition to, as Dr. Hassan mentioned, some chemotherapy drugs inhibiting thermoregulation makes it harder for people to control their body temperature, several cancer treatments also impact kidney function, and kidneys are important organs for body temperature regulation. Even some cancer treatment drugs also lead to cognitive impairment, which makes it harder to recognize heat stress and heatstroke symptoms. It could also impair mobility and the ability to go look for a cooling, safe space. There are several other cardiorespiratory comorbidities that can also impact sensitivity to extreme heat. And we cannot forget that cancer diagnosis treatment comes with socioeconomic consequences as well, because it impacts the ability of individuals to remain employed or maintain the same level of income. And these socioeconomic consequences also impact the adaptive capacity that Dr. Hassan was mentioning, such as installing air conditioning or improving insulation during a heatwave or throughout the year, which makes individuals diagnosed with cancer more vulnerable to these threats. Dr. Shannon Westin: You had mentioned some of the economic challenges here. I'd love to speak a little bit more about that, and I think we certainly see this in vulnerable populations just in general, being able to receive their cancer treatment or make it on time for their treatments. In addition to that, are there limitations around accessing resources or things that would help protect people during these heatwaves? Dr. Leticia Nogueira: Yes, we see a lot of barriers in access to resources in communities that have been targeted for marginalization or they are experiencing barriers in access to resources. Right? We can start with some of the ways that our urban centers are built. Concrete and asphalt trap heat in urban centers, leading to this effect called the urban heat island. So you see almost a 20° difference between urban centers and more suburban or rural areas when it comes to these hot days. And that, of course, increases exposure to extreme heat, which is one of the components of vulnerability.  Then you have sensitivity. If there are barriers in access to healthy resources, healthy foods, places to exercise, and there are, for example, an increase in targeted advertising for tobacco or alcohol outlets in the neighborhood, that has been shown to be associated with an increased prevalence of several chronic health conditions. And as we were discussing, these chronic health conditions also increase sensitivity to climate hazards.  And then, of course, there is adaptive capacity. We were mentioning the challenges faced by people who have been diagnosed with cancer in being able to afford some of the infrastructural updates that are necessary to cope with extreme heat. And the same challenges apply for people who are experiencing other types of socioeconomic distress, making it harder for these communities to prepare and respond to the challenge posed by heatwaves.  Oh, there's one more thing. I just wanted to mention that this is a concern, the adaptive capacity, not only for these communities that are facing barriers in access to resources. With climate change, there's been an increase in power outages. So, even if you can afford to use AC, it does not mean you're going to be able to use it during a heatwave because these power outages are becoming more frequent, especially as people turn up their AC and overwhelm the electric grid. So this is a concern for all US residents, not just people from lower socioeconomic levels or cancer patients. Dr. Shannon Westin: You are speaking my language, coming from Texas, where our grid is a constant source of-- Dr. Leticia Nogueira: I lived in Texas for a while. Yes. Dr. Shannon Westin: I know you did. I saw that in your bio. Okay, well, I think we got the scope. I'm appreciative of the level of detail that you all were able to cover in such a short period of time. So I think now let's move towards the kind of action items, like what can we do? How can we mitigate some of these issues, or all of these issues? Start wherever you think your lowest hanging fruit is, I would say. Dr. Abbas Hassan: Okay, absolutely. So addressing the challenges that climate change presents, especially for vulnerable groups like cancer patients, is, I would say, a lot more like putting together a jigsaw puzzle. It requires us to work on multiple fronts at once and fit all the pieces together to form a complete picture. So let's walk through this puzzle together. So picture this: Our first puzzle piece involves upgrading our healthcare infrastructure. We need to gear up our systems with surveillance, monitoring, and even staffing to swiftly detect and respond to heatwaves. The second part of the puzzle is that our healthcare workers, or providers, need to become more aware of climate change. They need to provide guidance to their patients that suits their cultural context and language, discussing things like what they need to wear during a heatwave, the best way to travel, even what changes to make in their diet. But how would our healthcare providers turn into these warriors? Well, that brings us to our next piece, like continuing medical education. So, by providing education opportunities into medical and public health curriculums, we can create a force of well-prepared healthcare providers and professionals ready to fight the challenges of climate change.  And also considering how heatwaves can affect our medications. As temperatures rise, we need to think about developing thermostatic medications that can withstand the hotter conditions. It's like equipping our medications with their own little heat shields. Lastly, I think, which is perhaps most importantly, we need to be stewards of our own environment with our own healthcare systems. This includes reducing our carbon footprint and advocating for heat equity. So a concept that ensures that everyone, irrespective of their socioeconomic status, has access to and protection from heatwaves’ related risks. So, just like that jigsaw puzzle, every piece plays a crucial role. By working on those front lines simultaneously, we can build a more resilient, equitable healthcare system ready to face the rising temperatures. Dr. Shannon Westin: Okay, you absolutely win on JCO After Hours for the best examples. The puzzle pieces. I’m just—I am, like, obsessed. This was—you're amazing. Dr. Leticia Nogueira: Playing tag, right? He's a natural. Dr. Shannon Westin: Playing tag, the sun exposure. I was like, this is like… I have to say you are very well suited for this type of work. Dr. Abbas Hassan: You're too kind. Thank you. Dr. Shannon Westin: And honestly, I think when you put it like that—sometimes these kind of problems seem so big and overwhelming, but when you kind of break it down into those chunks, it does seem doable. And I think almost every time on this podcast I bring this up, but I'm going to do it again. What can we do to change policy, right? We need a policy change. Like, some of what you mentioned is medical education, things like that. But really, what about lawmakers? What do we need to be talking to our lawmakers about so that we can get broad-based policy changes that will help us enact some of these strategies that you just so well described? Dr. Leticia Nogueira: I also wanted to add something I think is relevant to both here, and that is that the United States healthcare system is the second largest industry when it comes to emissions in the US. Emissions from the US healthcare system alone surpass emissions from the entire United Kingdom. So there is a big component of this strategy here to recognize that it is anthropogenic, manmade emissions that are causing climate change and leading to these detrimental health consequences. In our role, there are only so many Band-Aids we can put on this side before we start evaluating how we’re actually contributing to the problem.  And here is where this jigsaw puzzle and the policy and “I'm getting overwhelmed” kind of all comes together because there are several different efforts that are both climate mitigating and also improve climate adaptation. For example, switching towards clean energy sources that are generated on-site at healthcare systems can decrease the emissions of these institutions and also make them more resilient to power outages that, as we talked about, are only becoming more frequent. And there are several other examples. And you were asking about policy. I think that one of the recent advances when it comes to policy-level interventions comes from the Inflation Reduction Act, where we have a lot of incentives for shifting towards more clean energy sources and decreasing our environmental impact with our professional activities that we need to keep in mind as we're trying to protect the health and safety of cancer patients. Dr. Shannon Westin: Great. Thank you so much. And I guess that we're getting towards the end of this. It's gone by very fast, and I personally am writing down my to-do list of things I need to do tomorrow. What is next for you all for your work in this space? Dr. Leticia Nogueira: I think that, as a researcher, there’s a few different things that we can do. Similarly, as you are a clinician or a psychooncology or any of these other professions. One of them goes back to Dr. Hassan was saying surveillance and measuring the effects because that increases awareness and provides the background evidence that's necessary for developing and implementing solutions, right? And then, of course, being champions within our own institutions so that we are both trying to solve the problem when it comes to protecting the health and safety of patients. Is it possible to use electronic health records to identify those who are most vulnerable? Can we expand on data sharing and information sharing so we can build on lessons learned from previous heatwaves and do better next time? And then how, of course, can we contribute to reducing the emissions from our own institutions so we stop contributing to the problem we're trying to solve? Dr. Shannon Westin: Well, this was so educational, and I am so pleased that we had an opportunity to talk to you about this really important paper. I just want to thank, again, Dr. Hassan and Dr. Nogueira for taking the time to review this and really for thinking through this very important problem. And I hope it inspires all of you to look at what your institutions are doing and determine what strategies you might be able to utilize to start to mitigate some of these problems.  Again, we were discussing the Comments and Controversies manuscript “Impact of Heatwaves on Cancer Care Delivery: Potential Mechanisms, Health Equity Concerns, and Adaptation Strategies,” which was published in the Journal of Clinical Oncology June 10, 2023. If you haven't read it, run, don't walk, to do so. And please do check out our other JCO After Hours podcasts on our website. And if you have any problems, reach out to me on Twitter. I'd love to chat. Have a great day. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  
8/2/202320 minutes, 31 seconds
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JCO Article Insights: Immunotherapy in People Living with HIV and Cancer

In this JCO Article Insights episode, Davide Soldato interviews Dr. Naqash  from University of Oklahoma. Dr. Naqash provides insight into the original article published in the July JCO issue: “Safety and Activity of Immune Checkpoint Inhibitors in People Living With HIV and Cancer: A Real-World Report From the Cancer Therapy Using Checkpoint Inhibitors in People Living With HIV-International (CATCH-IT) Consortium”. The interview offers a deep dive into the manuscript results on efficacy and safety of Immune Checkpoint Inhibitors in this specific population and offers insights on future research direction in this space.
7/21/202325 minutes, 14 seconds
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Racial/Ethnic Differences Discovered in Multigene Germline Testing of Early-Onset Colorectal Cancer

Dr. Shannon Westin and her guest, Dr. Andreana Holowatyj, discuss the paper "Clinical Multigene Panel Testing Identifies Racial and Ethnic Differences in Germline Pathogenic Variants Among Patients With Early-Onset Colorectal Cancer," recently published in JCO. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of the JCO After Hours podcast, the podcast where we get in-depth on manuscripts and interesting papers that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, and it's my pleasure to serve not only as a GYN Oncologist but as an Associate Editor for Social Media for the JCO. And as always, I'm super excited about the paper that we're going to discuss today. This is “Clinical Multigene Panel Testing Identifies Racial and Ethnic Differences in Germline Pathogenic Variants Among Patients With Early-Onset Colorectal Cancer.” This has been published in the JCO. And I am so excited to be accompanied by the last author, Dr. Andreana Holowatyj, who is an Assistant Professor of Medicine and Cancer Biology at Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center.  Welcome. Dr. Andreana Holowatyj: Thank you, Dr. Westin, for having me. I'm really excited to get to talk about this paper. Dr. Shannon Westin: So are we. And please note that we do not have any conflicts of interest with this work.  So let's get started. First, early-onset colorectal cancer is any colorectal cancer diagnosed before age 50. So I just wanted to level set. Can you give us a bit of background on the incidence of early-onset colorectal cancer? Dr. Andreana Holowatyj: Sure. All of the attention recently has been drawn to the fact that in contrast to incidence of colorectal cancer decreasing among adults over age 50, we've seen over the last several decades, this uptick—alarming uptick, in fact, in colorectal cancers among individuals diagnosed younger than age 50 years, or, as you point out, we call early-onset colorectal cancer, largely with reasons that are unexplained overall, which has drawn a lot of concern and attention as to what are the factors driving this marked increase in early-onset colorectal cancer both in the United States and globally. Dr. Shannon Westin: And what do we know about the burden of early-onset colorectal cancer across different racial and ethnic groups? Are there disparities in survival like we've seen in some of the other cancer types? Dr. Andreana Holowatyj: Yeah. So recently, a paper published demonstrating this greater shift towards early-onset colorectal cancer, where now we're seeing approximately 1 in every 8 adults with colorectal cancer being diagnosed under age 50. Add to that prior studies have shown that the proportion of early-onset colorectal cancer cases or incidence is actually higher among individuals who identify as non-White compared to those who identify as non-Hispanic White. We previously published in JCO a paper that assessed disparities in survival among early-onset colorectal cancer patients and strikingly found that individuals who identify as non-Hispanic Black had poorer survival compared with non-Hispanic Whites, both in colon and rectal tumors, specifically for young individuals. However, and of striking interest, we did not see these survival disparities between Whites and individuals who identify as Hispanic, which further led us to question what may be some of the biological, environmental, and other factors that may actually be driving some of these disparities by race and ethnicity, both in incidence but also in outcomes. Dr. Shannon Westin: So that kind of brings us to this study. Will you walk us through what the objective of this study was? Dr. Andreana Holowatyj: Yeah. So the underlying question really is what could be the role of germline genetic features or germline predisposition in early-onset colorectal cancer disparities? We know from prior studies published in JCO and other journals that about 14%-25% of early-onset colorectal cancer cases have a germline predisposition. However, these populations have been of limited size and, more importantly, of limited diversity. So we really wanted to tackle that question to understand what is the prevalence and spectrum of germline genetic features in early-onset colorectal cancer by race and ethnicity. Are there differences? Where do these differences lie? And what can this information really tell us in better understanding the early-onset colorectal cancer burden? Dr. Shannon Westin: Well, now, well, just talk us through the design that you employed to achieve these objectives. Dr. Andreana Holowatyj: We were fortunate to partner with a nationwide clinical testing laboratory to identify individuals who were between the ages of 15 and 49 years when diagnosed with the first primary colorectal cancer over about a five-year study period. We were able to identify around 4,000, or specifically 3,980 individuals, who identified as non-Hispanic White, non-Hispanic Black, Hispanic/Spanish or Latino, Asian, or Ashkenazi Jewish who had clinical multigene panel testing uniformly for 14 genes that have a known susceptibility to colorectal cancer overall, to really examine the prevalence and spectrum of genetic features across these self-identified racial/ethnic groups.  Dr. Shannon Westin: And what was the overall prevalence of germline mutations in this population? And did it differ kind of overall in the different racial and ethnic groups? Dr. Andreana Holowatyj: Overall, the prevalence of germline genetic features when assessing 14 colorectal cancer susceptibility genes in this population was pretty consistent with prior studies at 12.2%, seeing about 1 in every 8 patients present with germline genetic predisposition. However, when we teased these numbers apart across racial/ethnic groups, what we saw is the prevalence of these germline genetic features ranged from 9.5% in individuals who identified as Asian to 10.3% of individuals who identified as Black, 12.4% as White, 12.7% for individuals who identify as Ashkenazim, all the way up to 14% of individuals who identify as Hispanic within this population. So we saw a wide—a decently wide breadth of prevalence across these racial/ethnic groups overall. Dr. Shannon Westin: And of course, as a gynecologic oncologist, I'm always centering myself and thinking about Lynch Syndrome. So how did the prevalence of mutations in the mismatch repair gene differ between racial and ethnic backgrounds? Dr. Andreana Holowatyj: So really interesting question. Overall, about 7% of individuals in our cohort presented with a pathogenic or likely pathogenic variant in the mismatch repair gene. But what we saw is that the prevalence of Lynch Syndrome varied from 3% or so of Ashkenazim individuals all the way up to 9.9% of Hispanic individuals. We saw that variance in MLH1 strongly differed across racial/ethnic groups, particularly in the Hispanic population, that accounted for some of these differences. Dr. Shannon Westin: And then were there any differences in some of the other germline mutations that you explored? Dr. Andreana Holowatyj: Yeah, we also observed differences in the prevalence of APC mutations, although largely attributable to the p.I1307K variant in Ashkenazim individuals, as well as CHEK2, monoallelic MUTYH, and PTEN. Dr. Shannon Westin: Okay. Interesting. I was intrigued about those findings for the monoallelic MUTYH variants. Do you think we should be potentially doing increased screening in specific populations based on your results? Dr. Andreana Holowatyj: Yeah, so I think to kind of put this into context, most people probably know that biallelic MUTYH variants yield MUTYH-associated adenomatous polyposis and, of course, confer a strong increased risk of colorectal cancer development. In monoallelic carriers of MUTYH variants, there really is limited evidence to guide clinical management, and this is an evolving area. Per NCCN guidelines, unaffected individuals with a monoallelic MUTYH pathogenic variant and a family history of colorectal cancer in a first-degree relative are recommended to get colonoscopy screening every five years beginning at age 40 or 10 years prior to the age of that first-degree relative of colorectal cancer diagnosis.  However, for individuals with a monoallelic MUTYH variant and no known family history of colorectal cancer, it's inconclusive as to whether specialized screening and surveillance are warranted. Current studies conducted in European or predominantly White populations have reported conflicting evidence as to whether there is an increased colorectal cancer risk for carriers of a monolithic MUTYH pathogenic variant. I don't think we're quite there yet to make a conclusive decision on whether increased screening is warranted in the population or not. I think the evidence is leaning towards potentially seeing not a strong increased colorectal cancer risk, but we'll have to wait and see on some additional studies to be conclusive in that area. Dr. Shannon Westin: I was also intrigued—the lack of difference in germline features between Blacks and Whites was stark. I mean, why do you—what do you think might have led to us not seeing a difference there? Dr. Andreana Holowatyj: I think there's potentially two avenues for this. I want to caveat the fact that this could be attributable to a limited sample size. Although we had about over 1,000—just over 1,000 individuals who identified as non-White, there's still potential selection bias in this cohort. However, we have included about a comparable number of individuals who identified Blacks and Hispanics herein, which does raise this question of we see differences in germline genetic features between Whites and Hispanics, but the lack of difference between individuals who identify as White and Black kind of yields possibly two avenues. If germline genetic features do contribute to racial/ethnic differences in early-onset colorectal carcinogenesis and outcomes, then there's a chance that we have not yet identified ancestry-specific variants associated with early-onset colorectal cancer. This has marked implications in the development and equitable design of multigene panel tests.  However, we also know that beyond genetics, the interplay with biology, social determinants of health, and behaviors could also underlie these distinct patterns. We recently demonstrated in a separate paper that we see actually differences in the tumor mutation burden between individuals who identify as Black or White, which is supporting the idea that a distinct tumor biology may be driving early-onset colorectal cancer disparities. And if there are no germline genetic features, then the question is really how does that interplay of the environment—some of these other complex interrelated factors, how could that be driving disparities in early-onset colorectal cancer incidence and outcomes, particularly for individuals who identify as Black? Dr. Shannon Westin: And I guess that kind of leads to my next question. The testing platform that you studied, is it all-inclusive? Are there other mutations that might be relevant, or just we don't know yet? Dr. Andreana Holowatyj: Yeah. So I think one of the advantages of this study is that all individuals had clinical multigene panel testing for the 14 genes that we evaluated overall. However, while that's a strength of the study, it's also a limitation, given that we only queried 14 genes with unknown colorectal cancer susceptibility, which really is a first step, yet a key step, in further studies and supporting further discovery of potential ancestry-specific variants or genes associated specifically with early-onset colorectal cancer predisposition. Dr. Shannon Westin: That makes a lot of sense. And I guess that's the next kind of natural question is so what do we do next, right? Where do we go? How do we move this forward? Dr. Andreana Holowatyj: Yeah. So I think one of the advantages of this approach and being fortunate to partner with the clinical testing laboratory is that the study was nationwide among individuals who, of course, had multigene panel sequencing. But at the same time, we were able to accumulate a sufficient number of cases to be able to study these patterns across population groups. I think the natural next step from multigene panel testing is based upon these findings to move into clinical exome sequencing to be able to not only move towards identifying genetic ancestry, since that's, of course, the biological construct—and I would be remiss if I didn't acknowledge that race and ethnicity is a social construct but was all that was available in the context of this present study—but also will allow us to query the entire exome and understand and dive deeper into some of these questions: variants of uncertain significance and also potential ancestry-specific variants. Dr. Shannon Westin: Well, great. Well, this is super intriguing, and I know this is going to get a lot of excitement and attention from our readership. So I just want to thank you again for taking the time to review this really important paper, “Clinical Multigene Panel Testing Identifies Racial and Ethnic Differences in Germline Pathogenic Variants Among Patients With Early-Onset Colorectal Cancer.” Again, I'm Shannon Westin, and I'm just so grateful that everyone came to listen to JCO After Hours. Please do check out our website for other podcasts you might have missed. Have a great one.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  
7/13/202314 minutes, 45 seconds
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JCO Article Insights: Two New Prediction Models for Risk of Venous Thromboembolism in Cancer Patients

In this JCO Article Insights episode, Emily Zabor summarizes two original articles from the June 1st, 2023 Journal of Clinical Oncology issue: “A Clinical Genetic Risk Score for Predicting Cancer-Associated Venous Thromboembolism: A Development and Validation Study Involving Two Independent Prospective Cohorts”  by Muñoz et al,  and “Derivation and Validation of Clinical Risk Assessment Model for Cancer Associated Thrombosis in Two Unique Healthcare Systems” by Li et al, as well as the accompanying editorial “Fine Tuning Venous Thromboembolism Risk Prediction in Patients with Cancer” by Jean Marie Connors. The original reports describe the development and validation of two new risk prediction models for venous thromboembolism in cancer patients and the editorial puts them into context of existing tools. TRANCRIPT  The guest on this podcast episode has no disclosures to declare. Emily Zabor: Welcome to JCO Article Insights for the June 1st, 2023 issue of JCO. I'm your host, Emily Zabor, JCO Biostatistics Editorial Fellow. Today, I will be providing summaries of three articles.  The first article, titled “A Clinical Genetic Risk Score for Predicting Cancer-Associated Venous Thromboembolism: A Development and Validation Study Involving Two Independent Prospective Cohorts” by Andres Muñoz and colleagues, describes the development and validation of a risk score for venous thromboembolism in oncology patients based on both clinical and genetic features, called the ONCOTHROMB score. In developing this model, the authors sought to address the fact that venous thromboembolism is among the leading causes of death among patients with cancer. Whereas hospitalized cancer patients are typically treated with thromboprophylaxis, outpatient treatment with thromboprophylaxis is only suggested for patients at high risk for venous thromboembolism identified according to the Khorana score.  The authors sought to determine whether incorporation of known genetic risk factors along with clinical factors would result in improved predictive accuracy. The risk score was developed in a cohort of 364 patients and was validated in an external cohort of 263 patients. The primary outcome of interest was venous thromboembolism within six months of a cancer diagnosis. The authors used logistic regression with backward selection with a p-value threshold of 0.25 to first select the genetic variants to include in the genetic risk score and then to separately select the clinical features to incorporate. Then the genetic risk score and clinical features were combined into a single multivariable logistic regression model, and backward selection was performed again.  The final model included nine genetic variants, tumor site, TNM stage, and a BMI of greater than 25. In the validation data, the ONCOTHROMB score using a threshold selected with the Youden index resulted in an AUC of 0.686 as compared to an AUC of 0.577 for the Khorana score with a threshold of 3. The ONCOTHROMB score had statistically significantly higher sensitivity, whereas the Khorana score had statistically significantly higher specificity. The authors conclude that the ONCOTHROMB score demonstrated improved predictive ability and should be investigated further in clinical trials.  The second article, titled “Derivation and Validation of Clinical Risk Assessment Model for Cancer Associated Thrombosis in Two Unique Healthcare Systems” by Ang Li and colleagues, describes the development and validation of a risk assessment model for venous thromboembolism, pulmonary embolism, and lower-extremity deep vein thrombosis in oncology patients undergoing systemic therapy. The authors developed this model to address the increased morbidity and mortality associated with venous thromboembolism among cancer patients and the fact that risk reduction for use of thromboprophylaxis as well as the efficacy-safety trade-off, and cost-effectiveness have been shown to be higher among patients selected as high risk for venous thromboembolism.  The primary outcome was venous thromboembolism within six months of treatment initiation. In the development data set, the authors used lasso-penalized logistic regression analysis to shrink some of the covariates to zero as a form of variable selection, then a multivariable logistic regression model was fit to the remaining covariates and those with an estimated odds ratio greater than 1.2 or less than 0.8 were retained in the final model. A linear risk score was created from the resulting beta coefficients. The risk assessment model was developed in a cohort of 9769 patients and validated in an external cohort of 79,517 patients. The final model included eleven factors: cancer subtype, pre-therapy BMI greater than or equal to 35, pre-therapy white blood cell count greater than 11, pre-therapy hemoglobin less than 10, pre-therapy platelet greater than or equal to 350, cancer staging 3 to 4, targeted or endocrine monotherapy, lifetime history of venous thromboembolism, history of paralysis and immobility in the last 12 months, recent hospitalization lasting greater than three days in the last three months, and Asian Pacific Islander race.   The final linear risk score was stratified into six categories and then dichotomized based on overall venous thromboembolism incidence of 7%, resulting in about half of the patient population being classified as high risk for venous thromboembolism. In the validation data, the model was associated with a c-statistic of 0.68 as compared to 0.6 for the Khorana score with a threshold of 2. Sensitivity analyses demonstrated that the model had similar discrimination in subgroups according to age, sex, and race-ethnicity. The authors conclude that their new risk assessment model has the potential to improve patient selection for thromboprophylaxis. The third and final article titled “Fine Tuning Venous Thromboembolism Risk Prediction in Patients with Cancer” by Jean Marie Connors, is an editorial accompanying the two previously summarized articles. Dr. Connors emphasizes that venous thromboembolism is the second leading cause of death in cancer patients, second only to cancer itself, and that while treatment with thromboprophylaxis has been shown to significantly reduce the occurrence of venous thromboembolism in randomized controlled trials, since the overall risk of venous thromboembolism is so low, treating all patients would result in significant overtreatment. Therefore, prediction tools are needed and many have been developed, with the Khorana score being the most widely used because it is the best validated and easy to calculate.   Dr. Connors observes that in the risk assessment model by Li and colleagues, more granularity is added to the  Khorana score by stratifying gastrointestinal cancer subtypes and by adding aggressive NHL, myeloma, brain tumors, and sarcoma, and also incorporates additional cancer-specific and patient-specific risk factors. But while this risk assessment model reclassified approximately 25% of patients in both the development and validation sets, as compared to the Khorana score, there was only modest improvement in discrimination. With the c-index improving from 0.65 to 0.71 in the development set and from 0.6 to 0.68 in the validation set from the Khorana score to the new risk assessment model.   On the other hand, the ONCOTHROMB score developed by Muñoz and colleagues contains fewer clinical features as compared to the Khorana score but adds a genetic risk score based on eleven genetic variants. The Khorana score performed quite poorly in both the development and validation data in this study, with AUCs of just 0.58 and 0.56, so improvements to 0.781 and 0.720 were relatively large. Connors notes that prospective validation of both scores is still needed, especially of the ONCOTHROMB score in more diverse populations, as allele frequencies can vary widely and the studied populations were predominantly Western European. Connors cautions that there is still a need to demonstrate mortality benefit from venous thromboembolism prophylaxis and that the risk of bleeding and other complications must be properly weighed against the benefits.  That concludes this episode on the articles “A Clinical Genetic Risk Score for Predicting Cancer-Associated Venous Thromboembolism: A Development and Validation Study Involving Two Independent Prospective Cohorts” and “Derivation and Validation of Clinical Risk Assessment Model for Cancer Associated Thrombosis in Two Unique US Healthcare Systems,” and the associated editorial, “Fine Tuning Venous Thromboembolism Risk Prediction in Patients with Cancer.” Thank you for listening and please tune in for the next issue of JCO Article Insights.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Like, share, and subscribe so you never miss an episode and leave a rating or review.  Editorial:   Fine Tuning Venous Thromboembolism Risk Prediction in Patients With Cancer Derivation and Validation of a Clinical Risk Assessment Model for Cancer-Associated Thrombosis in Two Unique US Health Care Systems A Clinical-Genetic Risk Score for Predicting Cancer-Associated Venous Thromboembolism: A Development and Validation Study Involving Two Independent Prospective Cohorts Original Report:   Find more articles from the June 1 issue  
6/26/20238 minutes, 39 seconds
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Olanzapine for Chemotherapy-Related Anorexia

Dr. Shannon Westin, Dr. Lakshmi Sandhya, and Dr. Prasanth Ganesan discuss the use of olanzapine to treat chemotherapy-related anorexia, as recently published in JCO. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on manuscripts published in the Journal of Clinical Oncology. As always, I'm your host, Dr. Shannon Westin, GYN Oncologist and Social Media Editor for JCO. I'm very excited to be here today.  And please note that our participants do not have any conflict of interest.   So we are going to discuss a really exciting paper today entitled the "Randomized, Double-Blind, Placebo-Controlled Study of Olanzapine for Chemotherapy-Related Anorexia in Patients with Locally Advanced or Metastatic Gastric, Hepatopancreaticobiliary, and Lung Cancer." And this was published in the JCO on March 28, 2023, and has gotten a lot of excitement.  And so I'm very thrilled to have two of the authors with me today. First is Dr. Lakshmi Sandhya. She's a Junior Consultant at the SVICCAR Hospital in Tirupati, India. Welcome, Dr. Sandhya. Dr. Lakshmi Sandhya: Thank you so much for the opportunity to be here. Dr. Shannon Westin: And I also have the senior author here today, Dr. Prasanth Ganesan. He is a Professor in the Department of Medical Oncology at JIPMER, which is the Jawaharlal Institute of Postgraduate Medical Education and Research in Puducherry, India. Welcome, sir.  Dr. Prasanth Ganesan: Thank you. Thank you very much, Dr. Westin. It's good to be here. Thank you very much.  Dr. Shannon Westin: Great to have you both. So we're going to get right to it. I think this is an excellent paper and certainly something we see across many of our patients who are diagnosed with cancer and who are receiving treatment for cancer. But first, I want to level set. What is the true definition of chemotherapy-related anorexia, and really approximately how many patients do you think it impacts?  Dr. Prasanth Ganesan: As you know, anorexia itself is very common in advanced cancers. Almost like maybe 80%, 90% of patients have some form of anorexia. But at diagnosis, it depends on the type of cancers. Very high in upper GI cancers, esophagus, stomach, pancreas, or lung cancer. But when we talk about chemotherapy-related anorexia, we specifically mean anorexia that is brought on or probably worsened by chemotherapy. So this depends a lot on the regimen that is used. So studies in lung cancer, upper GI cancer that have used something like platinum agents, maybe as high as 50% to 80%. Now, the challenge is how much of it is contributed by the underlying cancer itself and how much of it is worsened by the chemotherapy. It's tough to say, but I think we all have seen that chemotherapy does kind of really increase the anorexia in many of these patients. So I would say the problem is common. Depends on the type of cancer, the type of agent being used, and also sometimes on how intently we are looking for it. Dr. Shannon Westin: You bring up a great point in really kind of making sure that we're screening our patients for it and understanding who's actually experiencing those things. And I do think putting it on our list of things that we, on a day-to-day basis, discuss with our patients is really relevant, although I will say sometimes we haven't done that because we don't have a good treatment. So that's what makes your paper so exciting. But before we get into the results of the paper, why don't we talk a little bit more about some of the factors that contribute to anorexia? Dr. Sandhya, I don't know if you want to elaborate a little bit on some of those. Dr. Lakshmi Sandhya: Yeah. So most important would be the cancer type and the type of chemotherapy agent being used. So, as we mentioned, some cancer types have high anorexia incidence even at baseline. So the most important and prominent would be the upper gastric cancers and the pancreatic and lung cancer. Among the chemotherapy types, I think the platinum agents are known to cause anorexia more often and also associated with nausea or vomiting. So anorexia and weight loss is not very common in other cancers like breast, if you see, or ovarian cancer during the therapy. In fact, there has been weight gain in most of the patients with breast cancer, and most of the data which comes from breast cancer show that weight loss is experienced only by around 5% of the patients. So we would say the factors contributing most commonly would be the type of cancer and the chemotherapy that is being used.  Dr. Shannon Westin: Yeah, I think it's a great point. As a gynecologic oncologist, we do a lot of platinum, but we balance it, especially in upfront with paclitaxel or taxanes and we're giving steroids as premeds for them. And so we definitely see patients expecting to lose weight and instead actually getting hungry with the steroid use and eating to some degree.  Dr. Prasanth Ganesan: So I just want to add that even targeted agents, when you use something like sunitinib or everolimus, some of these agents, even they have got anorexia, probably 20% to 30%. So we did not include them in our study, but I'm just saying that even with targeted agents, we do get anorexia, at least some of them. So it's a problem across them. Dr. Shannon Westin: Yeah, we've been using PARP inhibitors and definitely can see that nausea, vomiting, and anorexia in that population. So I appreciate you making a point that that wasn't included but could be potentially extrapolated here. And then I guess the other question that I have is how does anorexia impact cancer-related outcomes? Does it have an impact in that way? Dr. Prasanth Ganesan: I believe it does, but it's probably not in a direct sort of way. So anorexia is strongly associated with weight loss and some amount of cachexia, and weight loss per se has been associated with poor outcomes across the board. There's a lot of data, especially in lung, upper GI cancers, and even head and neck cancer where weight loss before or during therapy has been associated with poor survival impact. So, again—in pancreatic cancer, it’s associated with poor survival. So it’s difficult to pin the weight loss only on anorexia here because weight loss is often multifactorial, but yeah, anorexia is probably a significant factor which is also adding to that. So I would say indirectly, yes, anorexia has an impact on cancer-related outcomes. Yes.  Dr. Shannon Westin: And I guess just getting into kind of what we can do before we get into the novel findings in your study, I know we've tried to talk about some dietary-related interventions that we can utilize to combat anorexia. Anything that you all have found to be most helpful from a diet standpoint?  Dr. Lakshmi Sandhya: So, from the diet standpoint, I would say dietary counseling is generally recommended for all the patients. To be very frank, we don't usually have a dietitian to spare at our outpatient clinic to counsel all the patients. So this is not something we are able to practice in the clinic. But in this trial, of course, we had a dietitian who counseled all the patients, and she gave them a diet chart to follow and gentle advice on what item to use and which is good, specifically emphasizing on high-calorie and high-protein diet. So we did not find that any particular dietary intervention is impactful. If you’ve seen various studies on dietary intervention, they have shown mixed results on improvement of anorexia or weight gain. So we're not sure whether dietary counseling particularly has impacted the results. Dr. Prasanth Ganesan: Yes. Dr. Shannon Westin: Okay. And then I imagine that would be one of the reasons that led to your exploration of this agent of olanzapine to treat chemotherapy-related anorexia. And can you just walk us through any data that existed kind of prior to your study to support this work? Dr. Prasanth Ganesan: Yeah, definitely. I think olanzapine has been in the news for the last decade or so because we've been using it consistently for vomiting and nausea in patients getting emetogenic therapies. So there are at least three studies which we found for olanzapine in cancer anorexia. I think one was from Dr. Navari, and he had done a randomized trial comparing megestrol with megestrol plus olanzapine. And this was done in patients with advanced cancers, and they found about 35% of the patients in the olanzapine group had additional weight gain. So it was useful. And this was not a very recent study. It's almost done about 10 years back. Dr. Shannon Westin: Oh, wow. Dr. Prasanth Ganesan: Then, after that, there was an interesting phase I study by Dr. Naing, and that was from MD Anderson, and that looked at various doses of olanzapine also. And that was interesting for us because that's where we got our starting dose of 2.5 mg because even at this dose, there was an effect on anorexia. So that was a very useful study because we were also trying to figure out what is the best dose to use in our trial. So that's why we went with the 2.5 mg.  Dr. Shannon Westin: That's great. I know everyone's excited to hear about the results. So, Dr. Sandhya, do you want to walk us through the design of the study and maybe how you chose your patient population? I think you've already kind of hinted at it, taking people that at baseline have high levels of anorexia.  Dr. Lakshmi Sandhya: Yes, sure. So this was designed as a phase III randomized blinded trial. So we used olanzapine in one arm and the matched placebo in another. So we gave olanzapine at a dose of 2.5 mg once a day for 12 weeks. And similarly, a placebo which looked similar was given to the other group. So we assessed for weight gain as an objective measure and improvement in appetite as one of the endpoints, which is more of a subjective measure. And we wanted to focus on population where the problem of anorexia was maximum. So we focused on upper GI, lung and pancreas, and biliary tract cancers to make it more uniform when it comes to anorexia. Dr. Prasanth Ganesan: Just to add a point that, even though we had included three or four types of cancer, almost 60% of our patients were actually gastric cancer patients because that probably reflects the profile of patients that we see at our center. It's a very common cancer in our place, and the next common was the lung cancer. We had only about 15% of patients who had pancreaticobiliary cancer. Dr. Shannon Westin: That makes sense. Obviously, wherever we're enrolling is what we're going to see, but I think hopefully these data can be extrapolated across all cancer types. So you mentioned that your primary endpoint was weight loss as well as the improved appetite. Can you walk us through, Dr. Sandhya, what you found? What were your results? Dr. Lakshmi Sandhya: So we had two primary endpoints. One was weight gain, and the other was improvement in appetite. So we wanted to use weight gain, as I said, since we felt that it is more of an objective measure than measuring anorexia. And olanzapine in our trial improved weight more than 5% from baseline in 60% of the patients in the olanzapine group and 9% in the placebo. Correspondingly, we have also measured improvement in appetite by using various questionnaires, which are validated. So one was visual analog scale, and the other was FAACT AC subscale, which we used during this trial. So yes, olanzapine worked well. We had hoped to show improvement in weight in about 30%, but surprisingly, we found that the weight gain was about 60% in the olanzapine group.  Dr. Shannon Westin: That's so great. It's always nice when you outperform your wildest dreams. So congratulations. Were there other secondary endpoints you observed that were impacted by the olanzapine?  Dr. Prasanth Ganesan: Yeah. So we did have a bunch of secondary endpoints because, again, we were worried when we started off because this is a subjective endpoint and we're not really sure how it's going to pan out. So we looked at some endpoints like quality of life, obviously, and we also had some nutritional assessment with the SDA and consistently, all of these showed improvement with the olanzapine. And what is most interesting for us was the grade III/IV side effects of the chemotherapy regimens, and these were reduced in the olanzapine. So this was something which we were looking for because consistently—we had also done some earlier studies in elderly populations where we found that the nutrition was an important factor in determining the toxicities of therapy. So that's why we wanted that as an endpoint.  And in fact, we found that patients who started at lower doses in cycle one due to poor performance status and nutrition, many of them could actually increase their dose in their subsequent cycles and this was more commonly seen in the olanzapine arm. So this was something which was very pleasant and which was something which we found was very interesting. So we could deliver more better chemotherapy intensity in these patients, thanks to their better nutrition.  Dr. Shannon Westin: That's so exciting. Such a nice concrete thing for patients as well. I mean, obviously being able to gain weight is something that they could see and having that appetite, but knowing that they had less side effects from their chemo as well is such an important impact. I guess, on the converse side, were there any negative impacts to the olanzapine?  Dr. Lakshmi Sandhya: Not really. We specifically asked patients about olanzapine-induced side-effects like drowsiness. At this dose of 2.5 mg per day, we found very little side-effects which would be attributed to olanzapine. As we mentioned, overall side-effects were also lowered in olanzapine arm. So with short duration of three months and at this dose, we believe that olanzapine is fairly safe. Dr. Shannon Westin: And that’s great. And I’d be remiss—especially here in the States, this is high discussion around financial toxicity. As I recall, it’s a pretty inexpensive agent. Is there any kind of negative financial impact for the use of this drug?  Dr. Prasanth Ganesan: Yeah, this is the best part. In India, for three months, olanzapine costs about 300 rupees. That would be like $4 or something for three months of therapy. I think that's pretty easily affordable across the board. Most patients here can easily buy this. And I'm not sure about the cost in the US, but I'm guessing it would not be too high. It's been around for some time. It should be out of patent and things like that. So I think it's a very inexpensive drug.  Dr. Shannon Westin: Yeah, we like that, like reuse of an old drug to do something good. The other question I had for you all is just any thoughts about how these results might compare to other things that we use, like glucocorticoids or progestational agents? I know we didn't have that as a comparator, but just your thoughts on that. Dr. Prasanth Ganesan: So, in terms of efficacy in reducing anorexia, it's difficult to compare because, if you see the studies of steroids and megestrol, most of them have been done by patients with more advanced cancers, not necessarily patients who are getting chemotherapy in the front line. But we think the side-effect profile is what gives an advantage to olanzapine because three months of steroids, even if you say lower doses of dex at 4mg or something, which I would want to use in a newly diagnosed cancer patient. Megestrol also seems to have problems like DVT and is actually much more expensive, at least in our context. I mean, if you compare with these aspects, I would definitely put olanzapine ahead, but as you said, this is not a direct comparison between those so-called existing agents. Dr. Shannon Westin: Yeah, I think that's a very thoughtful answer, but I think something we just needed to cover, even though we know that it wasn't a randomized trial between those two. Any limitations, Dr. Sandhya, on these results? Anything that you wish you had done a little differently? Dr. Lakshmi Sandhya: Yeah. As such, it is applicable only in the context of upper GI and lung cancers, as we have mostly included upper GI and lung cancers, and most of the patients, almost two-thirds of the patients included in our study, were gastric cancers. So also the duration that we used was only for 12 weeks. So we don't know whether longer duration will benefit more or harm. And the sustainability of weight beyond 12 weeks, we have not actually looked into. So, yeah, maybe these are few limitations that we can think about. Dr. Shannon Westin: That's very true. And I think that—I mean, obviously, when we design trials, we have to have a limit. Do you have plans—are you able to follow these patients out a little further? Do you know if clinically they're continuing it off-trial?  Dr. Prasanth Ganesan: So we have done that. So we have been following them for their survival data, and we just completed the analysis. So I think we have to really publish that next. So it is looking interesting. So some interesting data there. So that's something which we found it very exciting. Dr. Shannon Westin: Okay, good. Dr. Prasanth Ganesan: So that is something which is out there. And we also looked at some data on improvement of their muscle mass and on their CAT scans, we looked at that. So that's also something which we are trying to analyze and see whether we can have more concrete or objective endpoints in terms of improvement of the muscle mass and adipose tissue and things like that. Dr. Shannon Westin: Okay, good. Well, we'll look forward to that in a future version of the JCO, I hope. I guess the last thing is where do we go from here? You kind of hinted at this a little bit. I'm kind of bummed because I was ready to start implementing this in my clinic tomorrow. Dr. Prasanth Ganesan: So it's just safe, it's effective, and it's cheap. So I don't see any reason we should not start implementing something like this straightaway. I use it quite commonly, definitely for patients who are part of the trial population. And even for any patients with advanced cancer on or off chemotherapy with anorexia or weight loss, I'm comfortable to use olanzapine at least for a short term. And many patients at least they come back and say that it does help them. And I've not seen any side-effects at this dose of olanzapine. So it seems very safe to use. I'm comfortable to put it in the clinic right away.  Dr. Shannon Westin: Dr. Sandhya, what do you think?  Dr. Lakshmi Sandhya: I feel, in this trial, we came across the safety part of it and also the affordability part of it, and definitely it has been very encouraging results, so yeah. So, day-to-day practice, it can be used. Dr. Shannon Westin:  Well, great. I think this is super-educational, and I hope everyone else is just as convinced as I am how important this work was and how potentially impactful it will be for our patients. I just want to again thank these wonderful physicians and researchers. Dr. Sandhya, Dr. Ganesan, thank you so much for your time and a little bit of a late time for this taping across the globe. So thanks again for being here. Dr. Prasanth Ganesan: Thanks, Dr. Westin, for giving us this chance.  Dr. Lakshmi Sandhya: Thank you so much. Dr. Shannon Westin: So, again, y’all, this has been JCO After Hours discussing the important paper, "Randomized Double-Blind Placebo-Controlled Study of Olanzapine for Chemotherapy-Related Anorexia in Patients With Locally Advanced or Metastatic Gastric, Hepatopancreaticobiliary, and Lung Cancer,” published March 28th, ‘23. We are just so grateful that you joined us and hope you'll check out the other podcast offerings on the website. Take care. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  
6/22/202319 minutes, 2 seconds
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PROSPECT Trial (Alliance N1048): PROs During and After Treatment for Locally Advanced Rectal Cancer

Host Dr. Shannon Westin interviews guests Dr. Ethan Basch and Dr Deborah Schrag on their JCO simultaneous publication paper at ASCO's 2023 annual meeting: "Patient-reported outcomes during and after treatment for locally advanced rectal cancer (Alliance N1048). TRANSCRIPT The Disclosure for guests on this podcast can be found in the show notes  Dr. Shannon Westin: Hello, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on articles that are published in the Journal of Clinical Oncology. It is your host, Shannon Weston, GYN Oncologist and Social Media Editor for the JCO. And I'm so thrilled to bring you our first podcast that will be a simultaneous podcast JCO publication and ASCO presentation at ASCO 2023, dropping on June 4, 2023. And it is an exciting one. We'll be discussing “Patient-reported Outcomes During and After Treatment for Locally Advanced Rectal Cancer: The PROSPECT Trial Alliance N1048” (10.1200/JCO.23.00903)  And let me introduce both of these amazing people that are going to be with us today. First is Dr. Deborah Schrag. She's the chair in the Department of Medicine at Memorial Sloan Kettering Cancer Center in New York City, New York. Welcome. Dr. Deborah Schrag: Thank you.  Dr. Shannon Westin: And then I'm also accompanied by Dr. Ethan Basch, the Chief of the Division of Oncology and Physician in Chief at NC Cancer Hospital at the University of North Carolina, Chapel Hill, North Carolina, my alma mater. So welcome.  Dr. Ethan Basch: Thanks, Shannon. Nice to be here. Dr. Shannon Westin: And this is a good one. I was really intrigued by this work and I can't wait to talk about this with the audience, and I think that you're going to get a lot of excitement around this. So let's dive right in. I think we should start, first, let's speak a little bit about the role of patient-reported outcomes, assessing patient experience, especially as it relates to the evaluation of new therapies. Dr. Ethan Basch: Yeah, I'm happy to take that question, and thanks for asking it. All of us who practice oncology or accrue to trials recognize that patients receiving cancer treatment are highly symptomatic, either from their disease or from the sequelae of treatment. And as such, assessing and managing symptoms is really a cornerstone of what we do as oncology providers or investigators. But unfortunately, there's now abundant evidence that we as clinicians or investigators miss many of the symptoms and side effects that our patients experience, in fact, up to half of them. And so over the years, there have been a number of strategies developed to try to bridge this gap to fill in the pieces. And patient-reported outcomes is the one that has emerged to fill this gap, by informing us about the experiences of our patients. And without patient-reported outcomes and trials, we really have an incomplete understanding of the properties of products, the experiences of patients. And so when we are trying to do a risk-benefit assessment, for example, from data in a clinical trial, if we don't have patient-reported outcomes, we actually have an inadequate assessment of what was happening on the ground in that trial, particularly when it comes to adverse event assessment.   Dr. Shannon Westin: I think it's been great how we've been able to start incorporating these more. But before we go too far down that line, this study was particularly done in rectal cancer and we have a very diverse audience. And so just to level set, can one of you speak a little bit about the current standard of care for locally advanced rectal cancer?  Dr. Deborah Schrag: So, rectal cancer has a nasty tendency to come back in the pelvis. And Shannon, you're an OBGYN, so you know how miserable that can be. These are called locally recurrent cancers and they are just miserable. They cause a great deal of symptoms and a great deal of suffering. And back in the 1970s and ’80s, a strategy to treat pelvic or local recurrence of rectal cancer was developed and that strategy was radiation. And it used to be that 10%, 20%, even 30% of patients who had rectal cancer surgery would have a cancer come back. And these were people who couldn't sit down, constant pain, leaking, trouble urinating, trouble moving their bowels.  Radiation was a tremendous innovation. Radiation has been part of the management of locally advanced rectal cancer since 1990. Since 2004, we've given that radiation before surgery in the neoadjuvant setting. So this has been the predominant way that we treat these cancers really for the last two decades. We give about five and a half weeks of chemotherapy and radiation. Patients then have surgery, recover from the surgery, and many, not all, go on to receive some postoperative chemotherapy. It depends a little bit on what's found at surgery. But those three phases, the chemoradiation phase first, followed by surgery, followed by chemotherapy has been the prevailing care standard.  When we launched this trial, we wondered whether we could improve upon that and whether we could capitalize on some of the innovations and discoveries, and advances that have taken place in the past couple of decades. Development of better surgical technique, better chemotherapy, better imaging. And that was really what this trial was about. But the key thing is really what Dr. Basch said at the outset. We cure these patients. More and more often, we cure these patients. And so we want people to live not just long, but well. And so we really have to pay close attention to the symptoms. And the only way we could do that was by actually asking patients to tell us what their symptoms were, both during the acute phase of treatment as well as longer-term as they were followed up and recovered.  Dr. Shannon Westin: Thank you so much. So I think this is a great time for us to just talk very briefly about the overarching PROSPECT trial. What were the two arms and how did it impact standard of care? Dr. Deborah Schrag: Essentially, the two groups in PROSPECT were a chemo first and radiation only if you need it group, that was the experimental group. And the standard control group was the chemotherapy and radiation for everybody. So the chemo and radiation therapy group involved our typical 5040 centigrade worth of pelvic radiation given over five and a half weeks. So Monday to Friday for five and a half weeks with some sensitizing fluoropyrimidine chemotherapy, and physicians and patients could choose whether that was given as oral capecitabine or as intravenous 5-FU, they work just the same, followed by surgery. So that's the standard group. The experimental group received six cycles of a very common chemotherapy regimen used in gastrointestinal cancer, FOLFOX, and gave that regimen six times two weeks apart, followed by restaging with a pelvic MRI and examination by the surgeon. If patients were responding and the tumor had decreased in size by at least 20%, patients could go straight to the operating room. But if patients were poor responders to chemotherapy, they had a second chance, if you will, to get the chemoradiation. We call that group the chemo first with selective chemoradiation group. That was the intervention. And we followed patients and our outcome was disease-free survival. And we have about five years of follow-up in our patients. So this is a very mature study.  Dr. Shannon Westin: And what happened? What were the results? Tell us, how did this impact standard of care?  Dr. Deborah Schrag: So the upshot is it was designed as a non-inferiority trial and it met the prespecified non-inferiority hypothesis. The exact point estimates were that at five years, essentially 80.4% and 78.6% of participants were alive and disease-free in each group. So that's really almost exactly the same at five years. And the results for overall survival and for local recurrence were also nearly identical. Dr. Shannon Westin: So congratulations. Why don't you now, if you could, walk us through how you assess the patient experience on this particular trial? So specifically looking at the endpoints that you assessed and also the time points that you chose.  Dr. Ethan Basch: Thanks for the question. I'll take that. So in this trial, particularly because it was a non-inferiority trial being conducted in a curative context, we really wanted to get a sense of the adverse effects, the side effects of the treatment that are most salient in this population. And so to do that, we used two different approaches. The first was that we selected 14 symptomatic adverse events from the patient version of the CTCAE, also known as the PRO-CTCAE. The patient version of the CTCAE was developed about ten years ago. The purpose of it is to enable the patient voice to be brought into clinical trials around those side effects for which patients are in the best position to answer. But this was really the first large randomized trial into which the PRO-CTCAE was integrated. So this is really a landmark for that tool which is maintained by the NCI. Dr. Deborah Schrag: The PRO-CTCAE was developed by Dr. Basch, and I was his partner. So I'm going to say that Dr. Basch shepherded this tool. This was his brainchild, this was his project, this was his labor of love. He had this vision that we could do better in oncology by engaging patients in reporting their own symptoms and way back in the mid-aughts when both he and I had less gray hair. He worked really hard to develop this system. Its precursor was developed at Memorial Sloan Kettering when Dr. Basch and I worked there in the aughts, and it was tested and found to make a difference, it was very well received by patients. The NCI was persuaded that Ethan was on to something and issued a contract, a large contract, which engaged, I believe it was eight cancer centers around the country. And it took a huge amount of work.  This system was developed with a way to get the right words so that patients would understand, so that we have things like construct validity, content validity, so that it would work in Alaska and Maine and Hawaii and New Mexico. The system has now been translated into over 30 languages, but this has really been a career-defining endeavor and labor led by Dr. Basch. He's had wonderful assistance from Amylou Dueck, amazing statistician who's helped, and I've been a good partner to him as well, and many others along the way. But this is really the culmination of a vision that it took more than a decade, almost two decades to realize.   And I would just say to any junior investigators out there with a good idea, sometimes you have to be patient and just keep at it, as Dr. Basch has. And now we're starting to see that PRO-CTCAE is becoming standard. It's integrated in many trials. He didn't start a company. It's freely available. The NCI has it. It's NCI intellectual property. Again, available around the world. I'm just very proud of my colleague and academic partner. Dr. Shannon Westin: It's a great, inspiring story, and I love how you spelled out the timeline because it's so true. Sometimes the best ideas do take a long time to get to fruition, so I love that story. Dr. Ethan Basch: The truth of the matter is that this idea of patients reporting their own adverse events was really hatched in conversations that Deb and I had together more than 20 years ago at a coffee shop on the Upper East Side. And I think the observation at that time was that we use the CTCAE for clinical investigators to evaluate patients' adverse events on trials. But that doesn't really make sense for highly subjective phenomena like nausea or fatigue. I mean, the only way an investigator can know about a patient's fatigue is if the patient themselves reports it. And it was our empiric observation in the many clinical trials that we had been involved with that it just seemed like that stuff was being underreported, and so then we subsequently unmasked that, in fact, is the case. In looking at multiple instances perspective, we found that, indeed, there's a massive underreporting of patients' symptomatic side effects in clinical trials.   This has been a partnership that Deb and I have had with other colleagues, again, for more than two decades. And so it is really gratifying in the PROSPECT trial to see this coming to fruition. I think the other piece of this, though, as long as we're handing out compliments or accolades, is that Deb has been working for more than a decade on the PROSPECT trial because of a belief that over-treatment or that treatment could be peeled away to improve the experience of patients. And I think the reason why Deb has had an interest in employing the PRO-CTCAE in this trial is because I think it's been her belief that what it's really about is the patient experience, especially in the non-inferiority setting. What's more important than what patients report themselves? And so Deb has championed this and made this happen. And it's no coincidence that Deb's PROSPECT trial is the first major trial the PRO-CTCAE was in, it's because she's a champion for the patient experience and the patient voice. So right back at you, Deb.   I would say the Pro CTCAE now is embedded in hundreds of clinical trials throughout the industry. I mean, it's really been widely proliferated. It's gratifying, and it shows the power of an idea. I'd say the PROSPECT trial is really the alpha for this approach. Dr. Deborah Schrag: I just would like to inspire physicians. I know there are doctors out there and investigators out there who have different ideas that are not mainstream or they want to take risks, and not everything is going to work out. And some kooky ideas are just that. They're kooky or different, and they're not going to work, but sometimes you’ve just got to hang in there. Dr. Ethan Basch: I think it does show the power of an idea, or certainly the power of an idea that Deb Schrag is involved with, which is always one to bet on, for sure.  Dr. Shannon Westin: I would like to get some advice here because we build in these types of PROs, we always are worried about how much burden is too much. How many things can the patients be asked to do and we don't want to put too much burden? You all had a really nice participation rate. I think it was like 83%. Any tips that you have for keeping patients engaged and encouraging participation and kind of walking that balance between how much is too much? Like, we want to get all the data we want to get, but how do we meet that balance?  Dr. Ethan Basch: So as Deb alluded to, we've come really far in 20 years, and the idea of engaging patients directly through connected health technologies, it's in the zeitgeist now. I mean, it's just a given. I mean, we're all connected in so many ways. And even patients who formerly have been so hard to reach generally can be reached with one interface or another. So in this trial, we used a strategy that I would really advocate for. So first we had an electronic PRO platform that could be accessed through the web or through a handheld device. But there was also what we call an automated telephone system or an IVR system, an interactive voice response system like what the airlines use when you get the electronic voice and you can use the push buttons or speak into it. And so we gave patients a choice of using either of those, the idea being to meet people where they are.   And then for those patients who did not report at the expected times, a CRA actually called them to recapture the information that was missed. And so by using this kind of strategy, we had a very high adherence rate and very little missing data. Just as a couple of quick asides, in this and other studies, we found that the patients who choose the telephone-type interfaces tend to be more rural. They have lower health literacy, lower SES, lower educational attainment. And so you really need to think about that with any technology like this one because there is a risk that this digital divide will increase disparities or representation in how we capture data or administer care. So the way that we did in this trial, I think kind of got it right in many ways and I think as an exemplar for other studies.  Dr. Shannon Westin: Thank you for that. That's I think hopefully helpful for all the young investigators in the audience that are designing these types of trials. On that same note, around the population, what about the population that participated in this trial? Again, as a GYN Oncologist, I'm always intrigued by our different areas of solid tumors. Do you think this trial is pretty representative of the population and specifically the group that participated in the PRO outcomes? Dr. Deborah Schrag: So the first part of your question I will answer second. The patients who reported are highly representative of the total population. So I don't think there's any issue there. If you look at what's called Table 1 for the trial overall and Table 1 for the patients who participated in PRO reporting, the characteristics, and attributes are the same. So the results generalized. So that's very good. The bigger issue was upstream with the participants who went in the trial. And I think the biggest place where we need to make improvements is to recruit populations of patients to clinical trials who are more representative of the United States of America. And we did not achieve that. We tried in this trial, but we did not succeed. So we have unacceptably low participation from African Americans. And the racial and ethnic diversity in the clinical trial does not reflect the racial and ethnic diversity in the United States or more importantly, of patients who get rectal cancer. This is for all kinds of reasons, people are marginalized, we've got structural racism that persists. We've got issues related to mistrust. And I would just say we need to do a hell of a lot better. We didn't fail here because we're bad or because we didn't try. It's a challenging, pernicious, and persistent problem, but it is an important one and it's an important deficit.  Dr. Shannon Westin: 100%. Yeah, I think across the United States this is an issue, globally as well, but especially I think we have an opportunity within our recruitment within the United States to really provide that diversity. So I think we're all familiar with the NCI and the push to have those plans, but yeah, I don't think no one would think you didn't try hard enough. I think it's definitely something that we are systemically dealing with. Dr. Deborah Schrag: Yeah, getting cancer treatment is hard. Getting cancer treatment when you're living with a lot of challenges, for example, poverty or single parenting or living in a marginalized community or with poor transportation access, or food insecurity is even harder, if not impossible. And because of the way these cooperative group trials are funded, we didn't provide any support for transportation or food or any of the other things. This was a publicly sponsored trial and I think it is worth us having a very serious conversation about what we need to do to subsidize and support trial participants to ensure that we do have more representative participation. We fell short here. Dr. Shannon Westin: Can you walk us through a little bit of the PRO findings during that, the new adjuvant chemo versus the chemoradiation group? What did you conclude? Dr. Deborah Schrag: We've got an OBGYN interviewing us here. The genesis of this trial for me personally, colorectal cancer is occurring more and more in young patients, and you can't carry a pregnancy to term once you've had pelvic radiation and it usually tips you into early menopause. And this is a real concern when we have 35-year-old women with rectal cancer.  Dr. Ethan Basch: So Deb already noted the non-inferiority results in the study, and I think in the setting of a non-inferiority result, the PRO findings become of interest. And in fact, the PRO results in the two arms are quite different from each other. The two key periods when we evaluated PROs were first during neoadjuvant therapy and then in the period following surgery, one-year post-surgery, and then 18 months post-surgery. So during neoadjuvant therapy, we evaluated PROs in the two groups, which again were chemotherapy alone with selected use of radiation, which in the end, very few patients required, versus the prior standard of chemoradiotherapy. What we found was during active neoadjuvant treatment, almost all symptoms were worse with the investigation arm with chemotherapy alone, in fact, eleven of the symptoms were worse. Now, this is not a big surprise because it's FOLFOX therapy and these are the symptomatic adverse events that we would expect to see being worse during FOLFOX chemotherapy. However, diarrhea was better with FOLFOX than it was with the standard of chemoradiation. And I think that, again, intuitively, is what we might expect.  What becomes interesting is the period 12 and 18 months after the surgery. And what we found in that in those time points was that the symptoms were either the same between groups but for three key symptomatic adverse events, they were significantly worse with chemoradiation therapy. And those specifically were neuropathy, fatigue, and sexual function. And Deb made a point earlier about one of the reasons that she conceived of the trial being concerned about sexual function or the ability to carry a pregnancy in young patients who undergo chemoradiation. And in fact, we see, perhaps not that surprising that sexual function is significantly better with the chemotherapy alone arm and that's durable.   I think there's a question mark about sensory neuropathy. We saw that neuropathy was better in the FOLFOX  arm and the chemotherapy arm at both 12 and 18 months. And one could see that as a little bit of a head-scratcher because we might expect to see that neuropathy would be worse in a FOLFOX arm because of the exposure to oxaliplatin as opposed to radiation. I think that that will warrant some further evaluation. But the empiric finding is that the late effects are in fact significantly worse in the chemoradiation arm for those three areas. Dr. Shannon Westin: Yeah, I was intrigued by the neuropathy because that's why in my experience, we don't use a ton of FOLFOX, but occasionally we'll treat our patients with mucinous ovarian cancer, and I feel like the neuropathy is a really difficult strategy. But I'm especially interested in those long-term adverse events after radiation. We do a ton of radiation for patients with cervical cancer and other of our cancers and I was really intrigued by this opportunity to potentially lose some of those long-term side effects. Any thoughts as to why there really wasn't a difference in that overall health-related quality of life at all these time points?  Dr. Ethan Basch: Yeah, it's a great question. So in this study, we did use an overall quality of life or health-related quality of metric and it was no different at any time point between the two arms. I think it's a limitation of the tool that was used. The tool that was used when this study was designed, it's called the EQ-5D. It's used in a lot of health economic evaluations for cost-effectiveness analyses in Europe, in clinical trials. So it gets dropped into a lot of studies but it really is not sensitive to the nuances of symptoms like we see in this trial. It asks about overall global physical function, anxiety, depression, but it really doesn't get into the weeds of neuropathy or sexual function, some of the domains that really were most important here. So I think some of this is that the tool just wasn't sensitive enough to pick up that nuance.  On the other hand, I think it's reassuring that a very high-level global health-related quality-of-life tool was no different. It suggests that big, big picture, there's not a huge difference in the overall functioning of people between these two potential treatment approaches. But when you get into the more detail, we do see the differences in those individual symptoms.  Dr. Shannon Westin: And then I guess the bottom line, how are we going to use these results to inform what we do for this patient population? Dr. Ethan Basch: Yeah, I think it's nuanced. I think that goal of collecting this kind of information, like any information on trials, is that when one of us walks into the room with a patient, we sit down to make a choice when there are different options is to say what are the pluses and minuses of each. So for a patient who's really concerned about those short-term acute toxicities like nausea and fatigue during neoadjuvant treatment, then they might want to go with the standard of chemoradiation. But if they're really concerned about bowel function, or if they're really concerned about long-term sexual function or to some extent neuropathy, then probably the better choice for them would be FOLFOX alone, chemotherapy alone, the investigational approach. But really it's more information for that shared decision-making. It's a little more nuanced, it's a little bit more for us to think about in those conversations with our patients, but it really helps patients ultimately to make an informed decision so they can know what to expect.  Dr. Shannon Westin: Well, I just want to say congratulations. I know you've convinced me, and I bet you've convinced everyone listening that we need to be incorporating the PRO-CTCAE in all of our upcoming large practice-changing trials. So congratulations on your work, not only in this trial but with that measure as a whole. It's really exciting.  Dr. Ethan Basch: Thanks so much. The evidence really does suggest that without employing a tool like the PRO-CTCAE or another PRO tool in a trial to understand the symptomatic adverse events from the patients directly, we will have an incomplete understanding of what's going on in that trial. And it's really to the detriment of us as investigators or to drug developers not to include these kinds of tools because we really won't understand the impact on the ultimate end users of the treatments which are the patients. Dr. Shannon Westin: Well, thank you so much, and thank you to our listeners. We have been hearing about the simultaneous publication of JCO and presentation at ASCO 2023 of the Alliance N1048 Trial: Patient-reported outcomes during and after treatment for locally advanced rectal cancer from the PROSPECT trial.   I'm so grateful for all of you who've listened. Please check out our other podcasts on the website and wherever you get your podcasts and otherwise. Hopefully, we'll see you around ASCO 2023. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Show Notes: Like, share and subscribe so you never miss an episode and leave a rating or review. Guest Bios: Ethan Basch is the Chief of the Division of Oncology and Physician in Chief at NC Cancer Hospital at the University of North Carolina. Deborah Schrag is the chair in the Department of Medicine at Memorial Sloan Kettering Cancer Center in New York City, New York.  Article: Patient-reported outcomes during and after treatment for locally advanced rectal cancer (Alliance N1048)  
6/4/202328 minutes, 27 seconds
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JCO Article Insights: Smoking Cessation for Patients with Cancer

In this JCO Article Insights episode, Davide Soldato summarizes three articles from the May 20th, 2023 Journal of Clinical Oncology issue: “Smoking Cessation After Diagnosis of Kidney Cancer Is Associated With Reduced Risk of Mortality and Cancer Progression: A Prospective Cohort Study, “Efficacy of a Smoking Cessation Intervention for Survival of Cervical Intraepithelial Neoplasia or Cervical Cancer: A Randomized Control Trial” and “Integrating Tobacco Treatment into Oncology Care: Reach and Effectiveness of Evidence-Based Tobacco Treatment across National Cancer Institute Designated Cancer Centers.” The articles discuss clinical outcomes in survivors of cancers who quit smoking, efficacy of a novel smoking intervention and implementation of tobacco treatment programs. TRANSCRIPT Davide Soldato: Welcome to this JCO After Hours issue summary for the May issues of the Journal of Clinical Oncology. This is Davide Soldato and today I will be reporting results from three articles published in the May issue of JCO. Today's episode is focused on smoking cessation, impact on clinical outcomes, efficacy of novel smoking interventions, and implementations of tobacco treatment programs.  The first article by Dr. Sheikh and colleagues is titled "Smoking Cessation after Diagnosis of Kidney Cancer is Associated with Reduced Risk of Mortality and Cancer Progression: A Prospective Cohort Study". We know that smoking is a relevant risk factor for development of renal cell carcinoma, and previous retrospective studies showed better survival among patients who quit smoking after diagnosis. However, prospective data on the topic were lacking up until this point. The study by Dr. Sheikh and colleagues included patients diagnosed with renal cell carcinoma who were current smokers at the moment of diagnosis and that were followed prospectively for an average of eight years. At study inclusion, patients responded to a structured questionnaire investigating smoking habits and other behavioral factors. Furthermore, clinical pathological data were extracted from medical records.  Subsequently, after inclusion, patients provided yearly information regarding smoking status and if applicable, date of smoking cessation. Follow-up information on vital status, eventual disease recurrence, and treatments were collected both from patients and from medical records. The study reports results among 212 patients who were current smokers at diagnosis; the majority were diagnosed with stage I tumors and had a high-level education. Over the eight-year average follow-up, 40% of patients reported quitting smoking, more than half of them shortly after diagnosis. Demographic, social, and tumor characteristics were comparable between patients who quit and those who continued smoking.  Smoking cessation was overall associated with improved outcomes. Five-year survival rates were significantly higher in patients who quit smoking compared to those who continued (85% versus 61%). This higher probability of survival was observed across all evaluated subgroups, including light versus moderate and heavy smokers, and patients with early and late-stage tumors. Similarly, five-year progression-free survival rates were significantly higher among patients who quit smoking (80% versus 57%). In multivariable, time-dependent regression models adjusted for age of diagnosis, presence of other chronic health conditions, number of pack years, alcohol drinking status, tumor stage, and treatment received during follow-up, smoking cessation was significantly associated with a lower risk of all-cause mortality, disease progression, and kidney cancer-specific death. The results were comparable when excluding from the analysis patients who quit smoking three and twelve months after diagnosis, and this is important because inclusion of these patients might have biased results considering that these patients might have survived longer and thus had more chance to quit smoking.  So, in conclusion, smoking cessation among patients diagnosed with renal cell carcinoma was associated with a 50% lower risk of death, a 46% lower risk of cancer-specific death, and a 55% lower risk of disease progression. These results are extremely important and informative as they reinforce the need to promote smoking cessation among patients diagnosed with renal cell carcinoma since the observed clinical benefit was at least similar to that of currently employed or emerging targeted and immunotherapy treatments. The second article by Dr. Vidrine and colleagues is titled "Efficacy of a Smoking Cessation Intervention for Survival of Cervical Intraepithelial Neoplasia or Cervical Cancer: A Randomized Control Trial". As for many other cancers, we know that smoking is a significant risk factor for the development of cervical cancer. Furthermore, smoking after a diagnosis of cervical intraepithelial neoplasia or cervical cancer was associated with poor treatment response, increased risk of recurrence and development or worsening of other chronic diseases over the survivorship period. Cervical cancer frequently affects younger women, those with low socioeconomic status, and also minority groups. Previous data obtained specifically in these groups showed reduced access to smoking cessation intervention and consequently worse consequences from continued smoking. Consequently, the development of effective interventions to improve smoking cessation in these populations is of critical importance. The study by Dr. Vidrine and colleagues included smoking patients diagnosed and treated for cervical intraepithelial neoplasia or cervical cancer, and not already using nicotine replacement therapy. As per clinical guidelines, patients received 12 weeks of combination nicotine replacement therapy with a patch plus lozenge, and with randomized one-to-one to a standard treatment group that received educational material and a letter referring to states’ tobacco cessation quick line at baseline three and six months or to the experimental intervention group. The experimental group received the standard treatment plus a novel 12 months intervention based on the Motivation and Problem-Solving approach or MAPS, aiming at facilitating and maintaining behavioral change. The intervention was co-developed with survivors of cervical cancer who smoked to target specific needs regarding smoking cessation, healthy behaviors, and other survivorship issues. The intervention was articulated on six telephone counseling sessions that were delivered over 12 months based on the needs of each patient. After randomization, patients were followed up prospectively at 3, 6, 12, and 18 months. The primary outcome of the study was self-reported seven-day point prevalence abstinence from smoking at 18 months, so, six months after the end of the intervention. The secondary outcome was biochemically confirmed seven-day point prevalence abstinence evaluated on saliva.   The study published in JCO reports results among 194 patients. The majority were non-Hispanic White, had low socioeconomic status, and were diagnosed either with cervical intraepithelial neoplasia or stage I cervical cancer. Unfortunately, the trial failed to demonstrate its primary outcome. At 18 months, the percentage of patients who quit smoking was similar, 14% in the MAPS group versus 12% in the standard treatment group. However, when examining longitudinally the percentage of patients who quit smoking at each of the four-time points, a significant interaction was observed between the smoking condition and the timing assessment. Consequently, the authors decided to investigate the percentage of patients who quit smoking at every single time point. In this analysis, a significantly higher percentage of patients who quit smoking was observed at 12 months in the experimental group, equal to 26% for the MAPS group intervention versus 12% in the standard treatment group. Furthermore, patients who completed at least four MAPS sessions had a significantly higher abstinence rate at twelve months, 38% compared to 8% for those who completed zero to three sessions.  So, in conclusion, this trial and the MAPS intervention resulted in a higher rate of abstinence at 12 months, although a considerable number of survivors relapsed six months after the end of the intervention, thus dissipating the overall effect. However, the results of this trial are extremely important because they highlight the need for further research in the field, first to improve patient engagement to smoking cessation intervention, and second, to promote sustained behavioral change that can be maintained even after the end of the active intervention phase.   Finally, the third article by Dr. Hohl and colleagues is titled "Integrating Tobacco Treatment into Oncology Care: Reach and Effectiveness of Evidence-Based Tobacco Treatment across National Cancer Institute Designated Cancer Centers." As highlighted by the previous two articles, smoking cessation is paramount for patients diagnosed with cancer and survivors of cancer. Despite the existence of specific NCCN guidelines on the topic, there is considerable evidence that smoking cessation is not commonly addressed in cancer care. So, as part of the Cancer Moonshot program, the Cancer Center Cessation Initiative was launched in 2017 with the objective of integrating evidence-based tobacco treatment into cancer care. The study by Dr. Hohl and colleagues aimed to assess the reach and effectiveness of tobacco treatment programs across NCI-designated centers included in the Cancer Center Cessation Initiative using six months of data collected from January to June 2021.  This cross-sectional study focused on two main outcomes. The first one, treatment reach, was defined as the proportion of smoking patients who received at least one tobacco treatment component over the total number of patients who reported current smoking examined in the included NCI centers. The second outcome was smoking cessation effectiveness, defined as the proportion of patients who reported seven-day point prevalence estimates of smoking cessation over the total number of patients who received at least one tobacco treatment component in the centers.  This study examined data from 28 NCI-designated centers where more than 600,000 patients were evaluated and treated. Median smoking prevalence was 7%, median reach was around 15%, and median effectiveness was around 18%. Some differences in reach and effectiveness were noted according to center characteristics, tobacco treatment program characteristics, implementation strategies, and components of the tobacco treatment programs. Smaller centers had higher reach but lower effectiveness, whereas the opposite was observed for larger centers. Additionally, centers with higher smoking prevalence had both higher reach and higher effectiveness. The centers that were implementing tobacco treatment programs center-wide had higher reach and similar effectiveness compared to centers where these programs were implemented only in part. A slightly higher effectiveness was observed in centers that targeted only outpatients, possibly due to different patterns of care and clinical outcomes among inpatients. eReferral systems to smoking cessation quick lines that were used by 90% of the centers were associated with increased effectiveness when a closed-loop system was implemented.  Regarding the type and the component of the tobacco treatment programs, almost all centers offered at least four quick line referrals at the second higher median reach of 17% and also effectiveness 19%. Face-to-face counseling with tobacco treating specialists had the highest median effectiveness, almost 20%. All the other components, including pharmacotherapy, telephone-based counseling, and point-of-care counseling, had similar median reach and effectiveness.   Overall, these results are important as they are able to inform future resource allocation, tobacco treatment program design, and implementation according to center characteristics in order to improve reach and effectiveness of these tobacco treatment programs.   This is Davide Soldato, and in this episode of JCO Article Insights, we discussed three articles on the topic of smoking cessation. The first article, by Dr. Sheikh and colleagues, described clinical outcomes among patients who quit smoking after a diagnosis of renal cell carcinoma and demonstrated that those patients who quit had increased survival benefits. The second article, by Dr. Vidrine and colleagues, reported the efficacy results of a novel intervention to promote smoking cessation among patients diagnosed and treated with cervical intraepithelial neoplasia or cervical cancer. The second article showed that, although the primary outcome was not reached, a higher percentage of patients quit smoking with this novel intervention at twelve months. Finally, the third article, by Dr. Hohl and colleagues, examined characteristics and implementation strategies of tobacco treatment programs among NCI-designated centers, and the results of this study will be important to improve the reach and effectiveness of this program over the years.   Thank you for your attention and stay tuned for the next episode of JCO Article Insights.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  Show Notes: Like, share and subscribe so you never miss an episode and leave a rating or review. Articles Smoking Cessation After Diagnosis of Kidney Cancer Is Associated With Reduced Risk of Mortality and Cancer Progression: A Prospective Cohort Study Efficacy of a Smoking Cessation Intervention for Survival of Cervical Intraepithelial Neoplasia or Cervical Cancer: A Randomized Control Trial Integrating Tobacco Treatment into Oncology Care: Reach and Effectiveness of Evidence-Based Tobacco Treatment across National Cancer Institute Designated Cancer Centers. Find more articles from the May 20 issue.  
5/29/202313 minutes, 18 seconds
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JCO Article Insights: Use of Independently-Assessed vs Investigator-Assessed DFS in the APACT Trial

In this JCO Article Insights episode, Emily Zabor interviews Dr. Gulam Manji from Columbia University Irving Medical Center. Dr. Manji provides insight into his editorial published in the April 10, 2023 JCO issue: "Adjuvant Gemcitabine and Nab-Paclitaxel Misses the Target in Pancreas Adenocarcinoma: Or Did an Effective Therapy Fall to the Definition of Recurrence?” (10.1200/JCO.23.00039). His editorial focuses on the JCO Original Report, “Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial” by Tempero, et al on the APACT Trial. TRANSCRIPT The guest on this podcast episode has no disclosures to declare.  Emily Zabor: Welcome to this JCO Article Insights episode for the April issue of JCO. This is Emily Zabor, one of JCO's editorial fellows. And today I am interviewing Dr. Manji from Columbia University on their editorial titled “Adjuvant Gemcitabine and Nab-Paclitaxel Misses the Target in Pancreas Adenocarcinoma: Or Did an Effective Therapy Fall to the Definition of Recurrence?” Dr. Manji, welcome to our podcast. You wrote this editorial to accompany the article, “Adjuvant Nab-Paclitaxel plus Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results from a Randomized Open-label Phase III Trial by Dr. Margaret Tempero and Colleagues.” That trial, called the APACT Trial, investigated the efficacy and safety of adjuvant nab-paclitaxel plus gemcitabine compared to gemcitabine alone in patients who had undergone resection for pancreatic ductal adenocarcinoma. So I wanted to ask if you could start by giving listeners a quick overview of the study design and the main findings from that trial. Dr. Gulam Manji: Yeah, sure, Emily. So, as you pointed out, it was a randomized phase III study in patients who had resected pancreatic carcinoma. The primary endpoint was independently assessed disease-free survival. Additional endpoints included investigator-assessed disease-free survival, overall survival, and safety. And we'll get back later on as far as the importance of investigator-assessed versus independently-assessed disease with survival because I think that that's the main point of discussion for today. The enrollment criteria were fairly stringent and included patients with macroscopic complete resection, ECOG performance status of either 0 or 1, and the peripheral tumor markers of CA 19-9 being less than 100. And patients were required to initiate adjuvant chemotherapy within 12 weeks. Patients received standard gemcitabine at 1000 milligrams per meter square, either with or without nab-paclitaxel of 125 milligrams per meter square once weekly for three weeks during every four-week cycle. Emily Zabor: Great. So I think that the main thing that we wanted to talk about today, and one of the main points you discuss in your editorial is the difference between the primary endpoint of independently assessed disease-free survival and the secondary endpoint of investigator-assessed disease-free survival. So can you describe the difference between those endpoints, how they were defined, and how they differed? Dr. Gulam Manji: Sure. So, independently-assessed DFS was determined by a radiologist who was blinded to treatment assignment, and new lesions followed RECIST 1.1 criteria. In contrast, the investigator-assessed recurrence was determined by the treating physicians using all available clinical information. So that could be abdominal pain, anorexia, probably elevation of peripheral tumor markers. And the other important aspect to the study is that the independent review was not performed in real-time to confirm investigator assessments. So patients who started subsequent therapy after recurrence by treating investigators were censured for the independently-assessed DFS analysis. So in this trial, 866 patients were randomized. And patients who are randomized to the experimental arm had a median independently assessed DFS of 19.4 months, while patients randomized to the control arm, which was gemcitabine alone, had a median DFS of 18.8 months. Now, when we compare that to the investigator-assessed DFS, the data looks quite different. Where the DFS was 16.6 months in the experimental arm compared to 13.7 months in the control arm. That is consistent with the five-year follow-up looking at the median overall survival, which was 41.8 months for the combination arm compared to 37.7 months for the gemcitabine alone arm. Emily Zabor: Okay, so there's some really interesting differences there. And I noticed that there were only 439 events according to the independently-assessed DFS versus 571 according to the investigator-assessed DFS. So that's a big difference in the number of events that I guess is coming from that additional censoring that was occurring due to the delay in the independently assessed endpoint. Is that right? Dr. Gulam Manji: Exactly. So you could envision a scenario where patients received chemotherapy and then on the investigator-assessed DFS, the investigators decided that the patient had recurred. However, that patient probably did not meet the RECIST or radiological criteria to determine that that patient had recurred. And hence, since it was not done in real-time, there was censoring that occurred for the independently-assessed DFS. So that's the reason why there was a difference in that number as you pointed out.  The decision to use independent DFS, disease-free survival, really was to remove investigator-associated bias and increase rigor to the study, which is commendable. However, unfortunately, that's not how we normally treat patients with aggressive cancer who have undergone surgical reception. And knowing that imaging modality is limited in identifying those patients, particularly in those that have peritoneal disease, or even more importantly, the patients who have recurrence within the surgical bed, I think is the issue.  Emily Zabor: Right. So the motivation behind selecting that endpoint was really good and well-motivated. Everybody wants to reduce bias and make sure we're taking out those kind of more subjective parts of identifying that. But it, unfortunately, missed some events as a result. Dr. Gulam Manji: Correct. I think that it delayed those events and that's what compromised the analysis because it was the limitations of the available modalities to determine when recurrence occurs. Emily Zabor: So how do these different definitions compare to other trials or previous trials? Dr. Gulam Manji: So previous trials that I'm aware of, it was the investigator-assessed DFS that had been used. And when you look at the data that was used in this trial, that concurs with what has historically been seen. And what I mean by that is that the original assumptions regarding DFS when this trial was being designed, used historical outcomes. Investigators see that DFS with adjuvant gemcitabine ranged anywhere from between 13.4 to 14.3 months. And the study had aimed to achieve a DFS improvement from 13.5 to 18.5 months. When you look at the investigator-assessed DFS, the ballpark of gemcitabine is very much in line with the previous historical data. So I think that the key discrepancy between the two DFS endpoints was likely a delay in accurately assessing disease recurrence when using the blinded radiological modality alone. And the second thing is, as you pointed out, a greater proportion of patients who were censored for independent assessments compared with those for investigator assessments was different. So that was between 40% versus 34%. So those two points, I think, were the key points that show the difference between independent versus investigator-assessed DFS and also that the independent-assessed DFS was not done in real-time. Emily Zabor: Yeah, that's really interesting and such a good point. And I think it really emphasizes how important it is to think carefully about these endpoint definitions in the design stage of these clinical trials and especially to think about when and why patients are getting censored and how that might impact the results.  So how do these results of this trial then, given the negative result of the primary endpoint, but that positive result on the secondary investigator-assessed endpoint, how do these fit in with other trials? And what do you think that means for patient treatment recommendations? Dr. Gulam Manji: Excellent point. So just to be clear, the APACT study did fail to meet its primary endpoint and hence gemcitabine and nab-paclitaxel were not indicated for patients in the adjuvant setting. The current standard of care are either modified FOLFIRINOX or gemcitabine combination with capecitabine. And those two regimens really remain a standard of care for patients. So what I do is for fit patients, I prefer modified FOLFIRINOX. However, in patients who are not as fit, gemcitabine in combination with capecitabine is the alternative.  Now, one could envision a scenario where gemcitabine and nab-paclitaxel may become relevant. It is, but only when I'm really pushed to do so, where I feel like there is no other regimen available optimally for a patient. And one could envision a scenario where you could have a patient who does not have the performance status to tolerate modified FOLFIRINOX and then you start that patient on gemcitabine in combination with capecitabine. However, I have experienced that that combination results in significant myelosuppression in patients in the United States. And then we have to do significant dose reductions or interruptions.  Now, in that case, where I feel like I'm reducing the dose of capecitabine to a point where the patient may not be potentially benefiting from that regimen, it's impossible to determine what dose would be efficacious when you're doing those dose reductions. That is the only scenario where I may be able to be pushed to consider gemcitabine and nab-paclitaxel, but only after also discussing with the patient the results of the current data and there being limited efficacy. Emily Zabor: That makes sense. So the treatment you would select would really depend on some patient characteristics and then how they do on the different treatments. Dr. Gulam Manji: Correct. Emily Zabor: So what do you think are the next steps for research in this area and in this disease?   Dr. Gulam Manji: I think that this clinical trial really demonstrated our inability to accurately pinpoint the time of disease recurrence using imaging modalities alone. And for patients who treat pancreas cancer, they would know that the recurrence patterns usually are either to the liver or to the peritoneum, or to the lung. However, in about 25% of the cases, the recurrence may be at the surgical site, and that's when things become tricky. After patients have undergone surgery, their scar tissue and the pancreas tumor is very dense, so it's difficult to determine that there's actually tumor growth. So that's where you really need help from other modalities. So should we get a PET scan? Is the patient symptomatic? Is a tumor marker going up in the absence of biliary obstruction? So all of those things need to be taken into account to truly pinpoint whether the patient has recurred or not. In peritoneal disease, you may need to ask the surgeons to help and have the patient undergo a laparoscopy to truly determine whether there is a peritoneal disease. And lastly, I think that incorporating ctDNA to better define whether there is a minimal residual disease will likely be a standard in the future. Emily Zabor: I see. Yeah, that makes sense. Incorporating some ctDNA biomarker information along with these really detailed clinical and possibly imaging assessments to determine recurrence seems like it would be really important in future trials to make sure you're capturing all of those recurrences accurately. Dr. Gulam Manji: Yeah, I think that that's critical before you can say that an adjuvant treatment is truly helping the patient. Emily Zabor: That's great. Well, I really learned a lot reading this article and speaking to you today. But before we end, is there anything else you'd like to share with our listeners?  Dr. Gulam Manji: Yeah, so I think we know that for a majority of patients who undergo curative resection, unfortunately, the disease recurs. And I think that that implies that, really, pancreas cancer is a systemic disease at the time of diagnosis. And despite aggressive adjuvant therapy, the median DFS, OS, and five-year survival rate show that we are impacting only a subset of patients with six additional months of chemotherapy. So I think that identifying predictive markers of response to systemic therapy, better selection of patients for surgery, perhaps using total upfront neoadjuvant therapy, an institution of maintenance therapy, and patients who are at high risk for recurrence, perhaps using ctDNA as a marker to determine who those high-risk patients are, all leads to help better design and identify patients who should really be treated systemically and patients who should undergo surgery. And lastly, with some glimmers of success from personalized vaccines may be on the horizon. And I'm hoping in the near future to treat minimal residual disease so that we can get the best outcome with minimal toxicity for our patients. Emily Zabor: That's great. That sounds like an exciting development for a disease that seems really tricky. Dr. Gulam Manji: Agreed. Emily Zabor: Well, thank you so much. It has been a pleasure speaking with you, Dr. Manji, and thank you so much for joining me today on this episode of JCO Article Insights.  This concludes the episode on the article “Adjuvant Gemcitabine and Nab-Paclitaxel Misses the Target in Pancreas Adenocarcinoma: Or Did an Effective Therapy Fall to the Definition of Recurrence?” Thank you for listening and please tune in for the next issue of JCO Article Insights.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement. Show Notes: Like, share and subscribe so you never miss an episode and leave a rating or review.  Guest Bio: Dr. Gulam Manji, MD, PhD is a medical oncologist at the Columbia University Irving Medical Center in New York.  Articles: Editorial: Adjuvant Gemcitabine and Nab-Paclitaxel Misses the Target in Pancreas Adenocarcinoma: Or Did an Effective Therapy Fall to the Definition of Recurrence? Original Report: Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial Find more articles from the April 10 issue.  
5/15/202314 minutes, 26 seconds
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Peritumoral Anesthetic Infiltration Impacts Survival in Early Breast Cancer

Dr. Shannon Westin, Dr. Rajendra Badwe, and Dr. Alastair Thompson discuss the JCO paper "Effect of Peritumoral Infiltration of Local Anesthetic Before Surgery on Survival in Early Breast Cancer." TRANSCRIPT The guests on this podcast episode have no disclosures to declare.  Dr. Shannon Westin: Hello, and welcome to another episode of JCO After Hours, the podcast where we get in-depth on manuscripts that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, gynecological oncologist by trade, but serve as our JCO Social Media Editor. And I'm super excited to talk to you about a paper that was just published online, April 6, 2023, entitled “The Effect of Peritumoral Infiltration of Local Anesthetic Before Surgery on Survival in Early Breast Cancer.”   Before we start, I just note that our guests have no conflicts of interest.   And so I'm accompanied by two greats in the field. First is the principal investigator on this trial, Dr. Rajendra Badwe, who is the Director and Head of Surgical Oncology Division at the Tata Memorial Center in Mumbai.  Welcome. Dr. Rajendra Badwe: Thank you. Dr. Shannon Westin: And then, of course, I'm joined by Dr. Alastair Thompson, Co-Director of the Lester and Sue Smith Breast Center and the Section Chief for Breast Surgery at Baylor College of Medicine here in Houston, Texas. We should have met in person. Dr. Alastair Thompson: Great to be with you today, both of you. Thank you. Dr. Shannon Westin: So this is an exciting topic, and of course, as a surgeon, I'm super intrigued. So let's get started. First, I would love for you all to tell me about the rationale for modulating events at the time of surgery to improve survival in any cancer, but specifically in breast cancer as it was in this study. Dr. Rajendra Badwe: So we have been working on events at the time of surgery for quite some time. And for the first time, when I walked through the gynae OPD in Guy's Hospital, there was this cartoon of the cell being extruded for ovulation, and I felt a cell moving from one organ to the other is actually metastasis. And that's how we started working on it. And in the past few years, we have been—a decade or so, we have been publishing changes induced by event of surgery.   So what we did earlier before beginning this trial is picking up a core biopsy before I start surgery. So it's normoxic, well-ventilated as well as well-nutrition-provided tumor, and I do a core biopsy and send it for expression profile on next-generation sequencing. Then, when 50% of the tumor surface is denuded from the opposite side, which is not denuded, I do other core biopsy. And the third core biopsy is when the tumor is in my hand in breast conservation surgery.  So first was normoxic, second was hypoxic, and the last was completely anoxic tumor. And we found that the middle sample, which has never been studied, all our understanding of biology of breast cancer is based on the first core biopsy or the whole tumor sample post-surgery. The middle sample had approximately 800 genes going up and down on the next-generation sequencing mRNA, and majority of these were epithelial-mesenchymal transition, proliferation, invasion, motility. You name the hallmark of metastases, and they were up in the middle of surgery at least in 30% of the tumor. Now, if the cell surface on one side in a three-centimeter tumor ring to the cell at the other end of the tumor as to some invasion has happened, how quickly can it happen? The difference between the two biopsies was just about five minutes.  Obviously, it was some kind of an electrical stimulus that went across the tumor. That's what our assumption was. And if it was to happen through the voltage-gated channels, the downstream effect of voltage-gated channel being depolarized was the same channels that I mentioned, the hallmarks of metastases that I mentioned. And if we were to block it, it was easiest possible by local anesthetic. So that's how this trial was originated. And we did in 1600 patients local anesthetic, half of them randomly allocated to receive lidocaine 0.5% versus not. Dr. Shannon Westin: That is so intriguing. I have to look up this work. I definitely agree with you. We do a lot of pre-biopsies and post-biopsies, but the intra-tumor biopsy is so novel with being able to study the anoxic tissue. I'm so interested. And you kind of started to get into this. Can you dig in a little bit more around that role or how the mechanism of action of this peritumoral anesthetic infiltration might work in preventing metastasis and preventing some of the changes that you were able to see? Dr. Rajendra Badwe: So if adequate amount of local anesthetic injected would paralyze or block the voltage-gated channels, sodium channels, and if the sodium is not allowed to get inside the cell as a gush, the first depolarization does not happen. And the downstream effect of such voltage-gated channels being stimulated is induction of proliferation, induction of invasion, and increased motility of the cell, everything that is necessary for metastases to set in. In fact, somewhere close to about 200 genes that belong to the pathway that allows a cell to express epithelial-mesenchymal transition were upregulated during this hypoxic episode. And hypoxia also is known to produce these changes. So we now, out of these 1583 patients, in about 100 patients, we also have the middle sample. And that's being looked at on the third-generation—next-generation expression profile to see whether the effects that I mentioned just now, are they abrogated by local anesthetic as the underlying mechanism of reducing the metastatic potential or upregulating pro-metastatic pathways in cancer cells. Dr. Shannon Westin: It's so intriguing. I guess I wonder if you or Dr. Thompson can speak a little bit about the results of any studies looking at peritumoral anesthetic infiltration prior to the work that we're going to discuss today. Were there smaller studies that looked at this? Dr. Alastair Thompson: There have been a number of studies over the years, particularly some small studies from the Republic of Ireland, which have suggested that the use of local anesthetic in breast surgery might be beneficial. And then there have been some other larger studies really more thinking about the block of the surgical stimulus to the surgical site, for example, using paravertebral blocks. And we are aware that what is given as an anesthetic, whether it's an agent, intravenous agent, like propofol, or a gaseous agent, may also have some effect on the metabolic response to the trauma of surgery. So there's quite a building logical background to this particular trial. But to my knowledge, this is a unique trial which a group of surgeons have been able to implement a fairly simple technique, taking a very short period of time, but with almost as much impact as some of the major drug trials in terms of disease freedom and overall survival.  Dr. Shannon Westin: Great. So, yeah, let's get into—do you want to take us through the design of the study, Dr. Badwe? Dr. Rajendra Badwe: Yes, thank you. We had 1583 patients who were randomly allocated. These are women with early breast cancer, so essentially, T1, T2 breast cancer with or without lymphadenopathy in the armpit, and metastatic, disease-wise, M0. And these individuals, these patients, were randomly allocated on table to receive local anesthetic versus not. 796 women received local anesthetic, and 804 women did not receive local anesthetic. The adequacy of this local anesthetic was 0.5% of lidocaine being injected on all surfaces of the tumor as if from one pole of the tumor, I would open an umbrella, a needle going in all directions all around the tumor from one side and then from the other side. And if the tumor was larger than being covered by these injections, additional points of injections were done on all surfaces of the primary tumor. The adequacy was tested by inability of the surgeon to use electrical diathermy for dissection. So the surgeon had to use knife to get the tumor out. Because of so much of water content in the tissues, the diathermy would not work. And if it worked, that would mean the amount of local anesthetic injected was inadequate. So that was the quality control parameter.  Postoperatively, patients received standard treatment. We had assessment of the hormone receptors, HER2 receptors. And postoperatively, they received standard chemotherapy, which is—in great majority, was epirubicin or Adriamycin with cyclophosphamide, four cycles, followed by 12 weekly paclitaxel injections. And those who were hormone receptor-positive, premenopausal received tamoxifen, and postmenopausals received either letrozole or Arimidex. All patients who were more than four centimeter positive in tumor size or had lymph nodes positive received postoperative radiotherapy, irrespective of whether they had conservation or mastectomy. And all individuals who had conservation received postoperative radiation, which was the standard protocol.  Talking about those with HER2 positive or triple-negative or ER/PR positive, their distribution on either side was identical, very, very close, no different at all. 35% of those who were HER2 3+ or FISH positive received trastuzumab for a year on either side, but two-thirds of them did not receive trastuzumab because of the cost constraints in India. But the distribution of those who received versus not was identical on both sides. So that's the kind of general demographics of the women who were on the study. Dr. Shannon Westin: Great. I think now—I think everyone's ready for the good news. So how did the infiltration impact outcomes in these patients? Dr. Rajendra Badwe: The primary endpoint was disease-free survival. There were a total of 255 events, 109 events in local anesthetic arm and 146 events in the no local anesthesia arms. That gave us a 26% reduction, a relative reduction of 26%, which reached statistical significance at P 0.01. And at the same time, for overall survival, which was the secondary endpoint, there was a 29% relative reduction in deaths related to breast cancer, and majority of the patients who died died of breast cancer. The other cause of mortality was very little—to be precise, less than 1.5%, and that was also equally distributed on—identically distributed on both sides. So approximately 4% reduction in disease-free survival absolute and a similar 4% reduction in overall survival and the number of deaths. So this was the first trial that looked at preventing metastases than treating micrometastases. Dr. Shannon Westin: Yeah, and I think I would just call on Dr. Thompson here because I think you already started saying this. I mean, when you look at the simplicity of the intervention and the low-cost nature of the intervention and the impact as opposed to some of our “incremental benefits” that we see with different very expensive targeted therapies and immunotherapies, I'd love just to get your thoughts on that. Dr. Alastair Thompson: So, of course. I think this is an extraordinarily well-designed, very balanced trial. Yes, you can say that not all patients are treated the same way around the world. But there's been a rigor about this which is very attractive, and I think it's one of the reasons the Journal of Clinical Oncology has published it.  What is perhaps astonishing is that if we try to first do no harm, we're actually doing a very simple intervention, low cost, relatively easy. The patient is asleep, so it's not painful in any way. It's not toxic at the sort of levels of local anesthetic being administered. And yet we're managing that for every 25 patients who have this addition to their procedure, one of them is going to be disease free and one of them is going to be alive as a consequence in the relatively short term. So, in terms of balancing the issues of trying to implement something versus the benefits to a patient population, the balance is very much in favor of this really quite minor change in practice to give us quite a major, by modern standards, difference in outcomes.  Dr. Shannon Westin: Yeah, I think it's incredibly exciting, and I think, to your point around is it applicable, is it generalizable, I'd love to hear what you all think. I mean, is this something that we should be implementing across the globe? Dr. Alastair Thompson: Well, I think sometimes, we don't always do in our own practices what has been led and demonstrated to be effective elsewhere. And we need to really pause and, I would suggest, think hard whether such a simple intervention could be implemented on our next working day.  Now, many of us do use local anesthesia in the setting of breast surgery, whether it's mastectomy, axillary lymph node surgery, or lumpectomy. But the difference might be that instead of putting this local anesthesia towards the end of the operation, thinking about doing things up front and maybe, therefore, having an even bigger impact than simply good quality pain control and good quality patient care.  Dr. Shannon Westin: I would love also, just as we're kind of coming to a close here, to get both of your thoughts about how we might implement this. And again, this is coming from a somewhat selfish standpoint. How could we implement this in other solid tumors? So is there a way to replicate? Obviously, breast has a very local disease spread pattern. Is there a way to potentially replicate this in other cancer types?  Dr. Rajendra Badwe: So we have begun a similar study in my hospital for squamous cell carcinoma, as well as lung cancer. And I'm sure there will be efforts to replicate in many other cancers where it is possible to inject local anesthetic all around before we start the resectional procedure. But at the same time, we need studies to confirm that this is actually happening. If I were to take a step further and wait for the expression profile of those who have received local anesthetic versus not in this trial, and if it shows that the abrogation of effects related to the downstream stimulation of VGSC, the voltage-gated sodium channels, then it might just be a good idea to use something else. Because if local anesthetic is effective to the extent, say, about x amount, cannabis has about 200x effect on stabilization of voltage-gated channels. So that could be another intervention that can be explored in trials in any site. Dr. Alastair Thompson: So that's a good point. Where do we go from here? And I would suggest that perhaps thinking about which local anesthetic to inject—would a longer-acting local anesthetic be just as effective from a prevention of shedding of metastatic cells, would that give longer additional pain relief? Would it be possible to think about other tumor sites where we're doing a local reception, for example, in the gastrointestinal tract, elsewhere in the body, including lung, for resections? There's just a huge amount of potential which this landmark, practice-changing trial has really pointed us to. And I would envisage that in future podcasts, Shannon, you're probably going to have a lot of people talking with you about other trials that have followed on from this. Dr. Shannon Westin: I hope so because that will mean we're impacting our patients in a positive way. I'm just so thrilled to have the two of you here. This was such a fascinating discussion. It went by so fast, and I hate to bring it to a close. But I encourage our listeners to definitely read this incredibly important manuscript and communicate with us online on how we can move this forward.   Again, this has been JCO After Hours, and we've been discussing “The Effect of Peritumoral Infiltration of Local Anesthetic Before Surgery on Survival in Early Breast Cancer,” published online April 6, 2023. I'm so thrilled that you joined us today on the podcast, and I hope you'll check out our other podcast offerings. Have a wonderful day. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      
5/11/202319 minutes, 23 seconds
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Intensive Caring: Reminding Patients They Matter

Dr. Shannon Westin and her guest, Dr. Harvey Max Chochinov, discuss his article "Intensive Caring: Reminding Patients They Matter." TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and thank you so much for joining us for another JCO After Hours podcast. This is the podcast that gets in depth in manuscripts published in the Journal of Clinical Oncology. I'm your host, Shannon Westin, GI oncologist by trade and honored to serve as the Social Media Editor for the JCO.  And today we're going to be discussing a really exciting paper in the Comments and Controversies section called “Intensive Caring: Reminding Patients They Matter.” This has been recently published, and I'm so excited to have the author of this paper join us today, Dr. Harvey Max Chochinov, who is a distinguished professor in the Department of Psychiatry in the University of Manitoba, senior scientist with Cancer Care Manitoba Research Institute, and the cofounder of Canadian Virtual Hospice.   Welcome. So great to have you today.  Dr. Harvey Max Chochinov: Thanks, Shannon. Dr. Shannon Westin: And please note neither of us have any conflicts of interest, so we'll just get right started. So first, I just wanted to explore the title of your paper, “Intensive Caring.” Can you describe a bit about what that means? Dr. Harvey Max Chochinov: Well, we know that in medicine there are occasions when patients find themselves in such medical dire straits that they require intensive care. They've reached the stage where they certainly can no longer help themselves, and they require this kind of intensive approach that medicine is capable of offering. But intensive caring is meant to acknowledge that there are times when patients can be in such dire emotional straits that we need a way of being able to address that degree of abject suffering. So the idea of intensive caring was to try and provide language to describe that approach and, within the paper, as we're going to discuss, also to describe the ways in which we can actually deliver that kind of caring. Dr. Shannon Westin: Can you tell me a little bit about kind of when and where your inspiration for this work arose? Dr. Harvey Max Chochinov: The inspiration actually came from Dame Cicely Saunders. Dame Saunders was the founder of the modern hospice movement. There's a famous quote or adage that she said: “You matter because you are you, and you matter to the last moment of your life.” And this has really become kind of a central philosophical tenet of palliative care. But yet it struck me that although it describes this philosophical approach, implicit is also perhaps a clinical approach which says how do we, in fact, show patients—how do we demonstrate to patients or practice medicine in a way that actually affirms that patients matter? So that's where the title came from: “Intensive Caring: Reminding Patients They Matter.” Dr. Shannon Westin: There are so many pieces to this. I was so struck by what you said about these emotional dire straits. That's the best way I've ever heard it described. I feel like one of the major areas is that loss of hope and that feeling that you don't matter anymore. So what can we do? How do we, as practitioners, act and intervene to change that feeling? Dr. Harvey Max Chochinov: That's a wonderful question. The paradigm of contemporary medicine is we examine, we diagnose, and we fix. And yet, when it comes to addressing many elements of human suffering, it doesn't lend itself well to that paradigm because, of course, we know that there are things that are beyond the realm of fixing. So what we need, then, is to understand a way of approaching patient care where fix really is beyond our reach. How do we do that? It's by understanding that by being with the patient, by things like non-abandonment, all of these things are ways of maintaining patient engagement.  There was a wonderful study a number of years ago by Kelly Trevino in which she looked at the associations between suicidality and the intensity and the quality of the connectedness with the medical oncologist. And it turns out that that was the single most predictive factor regarding suicidality over psychological interventions or over psychotropic medication. So the way in which we start to address this kind of abject suffering, maintaining hope, is to understand that and acknowledge that there are things that we may not be capable of fixing. But the provision of intensive caring—and, again, the elements of intensive caring that I described in the article—give us ways of being able to be with patients that don't require fixing but require presence, require involvement, require ongoing commitment to the well-being of that individual.  Dr. Shannon Westin: This is a perfect segue because I was struck by that tenet of non-abandonment, you know, really committing to ongoing care. I wonder about this because we do have patients that transition to hospice, and often, in our group, they'll have an entirely new care team. And that's just part of that intensive caring that the hospice group provides. But I guess, in seeing it in these terms, I'm feeling a little bit like that may not be the ideal way for that transition to happen. So any thoughts on how we kind of combat that? Or how can we work together with hospice so that the patient feels still supported but still gets that hospice care that they so desperately need? Dr. Harvey Max Chochinov: Oh, for sure. Well, I mean, listen, we know that transferring of care is a technical task that can be accomplished by a single stroke of our keyboard on our computer. We transfer care. But there's nothing technical about the issue of caring, connectedness. And so it's unrealistic, and I don't think patients expect that all expertise resides in the hands of one individual or one team. But the reality is that when we've been looking after somebody for days, weeks, months, even years and they now have to transition to other care providers, although care can be transferred, I think there is still this human expectation of ongoing caring.   And caring doesn't necessarily require a great deal of time. It can be accomplished in really nuanced and subtle ways that really, I think, are within our grasp. Picking up a telephone, dropping by for a visit, putting a note in the mail simply to acknowledge that “I understand you're in hospice. Just want you to know that you've been on my mind. Hope things are going as well as they can for you and your family.” That demonstrates continued caring. It doesn't raise expectation that I, your medical oncologist who know you very well, am going to now intervene and take over your care. Dr. Shannon Westin: That's perfect. And I'm actually taking notes myself to—have a couple patients that I need to call today. So moving on to some of the other tenets, the Patient Dignity Question was really, I felt like, a revelation for me. It's so simple and so straightforward, and I feel like many of us, myself definitely included, don't feel like there's enough time, right, to dig into the details of every patient, kind of where they are in their process. Do you think this is something that everybody should implement today? Dr. Harvey Max Chochinov: So maybe backing up just for listeners to understand that the Patient Dignity Question asks patients, “What do I need to know about you as a person in order to provide you the best care possible?” We have done studies of the Patient Dignity Question, or PDQ, and there have been multiple studies and multiple translations around the world, probably the largest study being one that came out—Hadler, first author—several thousand patients at Memorial Sloan Kettering who were asked the Patient Dignity Question as part of the regular kind of palliative care consultation. I think the message that I take out of the PDQ research is that personhood should always be on our radar. And the reality is that if we don't understand at least the essence of who that person is, we can give lip service to providing person-centered care and lip service to maintaining dignity and all of those wonderful things that we say in position statements, but none of it will ring true if we don't have personhood on our radar. And it simply means that we need to be mindful of personhood.  I've asked patients, “So what do I need to know about you as a person to take the best care of you possible?” I've had people tell me, “I'm afraid to die alone.” I've had people tell me, “I am the victim of childhood sexual abuse.” I've had people tell me, “I'm a survivor of the residential school system.” One man said “I'm a former department head of medicine.” In fact, he was just a lovely man. He said when he was being treated for his cancer, he wanted to hang a sign on his bedpost that said, “PIP, Previously Important Person.” But what it says to me is that if we fail to acknowledge personhood, then essentially we're operating in the dark. When you have that kind of information about personhood, it just changes the way you see and experience that person, which makes for better patient care. Families are more satisfied. There's less discordance when it comes to goals of care, less likelihood of litigation because the reason that most people litigate is not because of medical misadventure. It's because they don't feel like they were treated like a person. They somehow feel like that was not acknowledged.   The other interesting piece of data out of the PDQ research is that when clinicians acknowledge personhood, they also report greater job satisfaction. So the reality is—and we know that one of the signs of burnout is emotional disengagement. So what our research has found is that if you give clinicians a way of at least maintaining some emotional engagement by finding out who this person is, not only are patients and families happier, but healthcare providers report greater satisfaction in the work they do. So the short answer is “Yes, I think we should be putting personhood on our clinical radar and finding ways that are feasible of making that happen.”  Dr. Shannon Westin: There's so many interesting tenets in this article and so many parts to the intensive caring. Some do seem to be elements of palliative care practice as well. So how would you say this is different or complementary?  Dr. Harvey Max Chochinov: I'd say indeed you're correct. I mean, some of the elements are probably ones that people in palliative care would recognize. And I don't necessarily think that that's a criticism or necessarily a bad thing. If some elements of intensive caring are accused of being old wine in a new bottle, a new bottle is something that can be very attractive. And if this can bring people back to understanding the human side of health care, well and good. I suppose what is unique about intensive caring are the constellation of elements that are described in the article—and all of the elements, by the way, are empirically based. So the article does lay out various elements of intensive caring and points out the empirical basis of each of those elements.   I think maybe the other thing that's unique about intensive caring is it begins to provide us a language for ways of being able to approach patients who are in these circumstances. Usually, in the face of this kind of abject suffering, our temptation is to feel the need to withdraw, maybe feelings of impotence, maybe feelings of failure. So intensive caring addresses all of those head-on by saying here is a way that you can effectively be with your patients, that you can mitigate their suffering, without feeling that your mandate is to examine, diagnose, and fix. It is a different paradigm, which says you can be present with and provide comfort to. Dr. Shannon Westin: Great. Now, what about therapeutic humility? Can you speak of it like that? I think many of us come into medicine because we like fixing problems. So how does this concept turn the paradigm on its head? You kind of already talked about it a little bit, but I think it's important to mention specifically.  Dr. Harvey Max Chochinov: I think anybody who's been practicing medicine for any period of time has had the experience of confronting things that don't lend themselves well to fixing. Let's take the instance of somebody who is near end of life, or even the instance where a patient has died, you're standing outside of their room, and the family is still there. You have some choices. You can either withdraw, just say, “There's nothing I can do; I've got other things that are more pressing,” or you can go into that room. Now, when you go into that room, you need to be able to put on the shelf any idea that you have the right words that are going to fix what ails this now bereft family.  But I think wise and seasoned clinicians—and I would put to you, see, clinicians who have therapeutic humility would say you go into the room. Why? Because being there, just being present with, acknowledging the loss—and it's not about what you say. Again, if you feel like you have to wait till you have the right words, you never will go in there. But if you just go in empty-handed and allow yourself to be in the presence of that kind of suffering, what any clinician who does that will say is it's of critical importance. It matters. It makes a difference. And so that is one example of therapeutic humility. And again, there are others because there is so much that we deal with. For those of us who deal with patients with chronic illness or incurable illness, the fact is that if you're not humble, you're going to find yourself perpetually feeling like you are failing, like you are not meeting patients’ expectations. What patients expect is not that you can fix what's not fixable. They expect you to be involved. They expect you to care. You will be there for them in times that are tough. Those are elements of intensive caring that are worth taking forward into practice. Dr. Shannon Westin: Well, this has been so educational. I feel like I could talk with you for another hour. But why don't we end by just speaking about the next steps for this work, and how can we make everyone aware aside from publishing in the JCO and putting out this podcast? What else can we do? Dr. Harvey Max Chochinov: Well, hopefully, the approach gives people both the language and the ways in which we can start to implement this in practice. I would hope that it kind of catches or takes hold in medical curricula, but not only in medicine but really in any setting where individuals are being trained who have access to patients. This is not just about doctors. This is about anyone and everyone who has patient contact because the reality is that irrespective of whether you're the medical receptionist or the person making the first incision, you have the ability to either affirm or disaffirm the personhood of the individual that you're in the presence of. That's both a responsibility and, as well, an opportunity. So hopefully, dissemination of this work spreads word that this is an opportunity that we can take hold of, hopefully for the betterment of patients and families and healthcare providers themselves.  Dr. Shannon Westin: Great. Well, thank you so much. You've been such an inspiration. I can't wait to start utilizing these in my clinic just tomorrow. So I really appreciate you, and I know all our listeners do as well.   Listeners, we appreciate you. Thank you so much for tuning into JCO After Hours. Again, we were discussing the Comments and Controversies article “Intensive Caring: Reminding Patients That They Matter.” I hope you enjoyed it. Please do check out the website and check out any other podcasts that are ongoing and let me know what you think. Have a great day.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.    
4/27/202317 minutes, 25 seconds
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Multiple Myeloma Joins the Car T Race

Highlighting the importance of BCMA-CAR T therapy for patients with relapsed refractory multiple myeloma and discusses future avenues of clinical investigation. Read the related article "T Cells Genetically Modified to Express an Anti–B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma" on JCO.org
5/29/20187 minutes, 45 seconds
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Exploring a New Delivery Model for Germline Genetic Testing for Patients With Ovarian Cancer

This podcast provides comment on the accompanying JCO article “ENGAGE: Evaluation of a streamlined oncologist-led BRCA mutation testing and counseling model for patients with ovarian cancer” by Nicoletta Colombo, et al and evaluates the need for new delivery models for genetic testing for oncology patients. Related Article: Evaluation of a Streamlined Oncologist-Led BRCA Mutation Testing and Counseling Model for Patients With Ovarian Cancer
3/20/201814 minutes, 37 seconds
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Is Dose-Adjusted EPOCH-R the Optimal Treatment for Children with Primary Mediastinal B-Cell Lymphoma?

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.
10/20/20218 minutes, 30 seconds
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Less is More: Precision Surveillance Imaging for Wilms Tumor

This JCO Podcast provides observations and commentary on the JCO article “Impact of Surveillance Imaging Modality on Survival After Recurrence in Patients with Favorable Histology Wilms Tumor: A Report from the Children's Oncology Group” by Mullen et al. My name is Dr. Meredith Irwin, and I am an oncologist and Professor at the Hospital for Sick Children and University of Toronto in Toronto, Canada.  My oncologic specialty is pediatric solid tumors. Wilms tumor is the most common pediatric kidney tumor. With current therapies, the 5-year overall survival for newly diagnosed patients is 90%. For the 15% who relapse, most commonly in the lung or abdomen, the cure rates still often exceed 50%. The likelihood for cure is based on a number of risk factors, including histology, stage and previous therapies. Thus, similar to many pediatric cancer patients, those with Wilms undergo surveillance imaging during and following completion of upfront therapy in order to potentially discover recurrences sooner with the hope that early identification of lower disease burden will translate to higher salvage rates. However, to date, several small studies have failed to demonstrate that early detection of recurrence by surveillance imaging is associated with better prognosis for pediatric cancers including medulloblastoma, lymphoma and neuroblastoma. Moreover, with increasing awareness of the potential risks from imaging-associated ionizing radiation exposures and associated financial costs, there is significant interest in generating evidence to determine optimal surveillance strategies and limit cumulative exposures. To address these issues for Wilms tumor, the study by Mullen et al was designed to determine whether, compared to relapses detected by surveillance with chest x-ray and ultrasound, those detected with cross-sectional CT imaging were associated with improved survival rates. To do this, four authors retrospectively reviewed flowsheets and imaging reports for patients who recurred on the 5th National Wilms Tumor Study (NWTS-5) between 1995 and 2002 to determine whether their relapses were identified by signs/symptoms or scheduled surveillance imaging.  If by imaging, they recorded the modality- CT, ultrasound and/or chest x-ray. The study cohort included the 281 patients who recurred following initial diagnosis of favorable histology unilateral Wilms. All patients underwent imaging at specified time intervals, but the modalities varied. The 5-year overall survival for this cohort post-relapse was 67%, which is similar to other studies. 48% of recurrences were detected with routine surveillance by chest x-ray or ultrasound, 25% by surveillance with CT, and 25% presented with symptoms between scheduled imaging, most commonly pain or abdominal mass. Certain characteristics differed among these groups. The CT-detected patients were more likely to be stage 4, and in the symptoms group, more relapses were extrapulmonary and occurred post-treatment.  The authors asked whether the specific method of detection of relapse impacted prognosis. Although recurrences detected by symptoms were associated with an inferior 5-year survival of 55%, versus 76% for the imaging-detected group, there were no differences in survival for patients based on the imaging modality used for detection at any point during or following therapy. There was also no significant advantage to CT over u/s or x-ray for abdominal and chest relapses, respectively. Although a higher number of foci detected at recurrence and larger relapse size correlated with inferior outcomes, analyses failed to find a significant advantage for CT use in the subgroups of lung-only relapses or advanced-stage patients. The authors also examined financial burden and radiation exposures. To determine the economic impact, the authors predicted costs based on US Medicaid/Medicare reimbursement rates.  For patients with stage III disease, more than 200 imaging studies (with estimated costs between $20,000 and $45,000) were required to identify one relapse. For stage IV, between 158 and 190 studies costing more than $15,000 were needed. Estimated radiation exposures from these surveillance protocols varied between 9.4 and 83 mSv, depending on the total number of CTs. Although it is difficult to quantify how cumulative radiation doses may impact future cancer risks, expert groups have estimated that there is a 1 in 1,000 increased risk of future cancer deaths for every 10mSv exposure at age 10, and these risks are higher for patients exposed at younger ages. Other potential negative consequences of surveillance imaging not examined by these authors include the associated psychological stress for families, which is termed “scanxiety,” and possible adverse neurological effects of anesthetic agents for young children.   The significance of this report is that it is the first study to compare the utility and cost of different imaging methods for the identification of Wilms tumor recurrences. In comparison to x-rays or ultrasounds, there was no advantage to using CT, which is costlier and resulted in higher radiation exposures. It is possible that an advantage to CT was not identified in part because only the best prognosis patients, those with favourable histology, were included. The authors excluded those with bilateral disease, who often have germline predisposition syndromes, and patients with anaplastic histology, which has a higher relapse rate Ideally, a prospective RCT design would be performed to determine whether cross-sectional imaging would be superior to ultrasounds/x-ray combinations. However, given the overall excellent survival for Wilms tumor, the number of patients required to detect a significant survival advantage would likely be very large. In addition, given the cost and potential late effects of radiation exposures, engagement from oncologists, radiologists and families might be challenging.  In conclusion, the findings in this manuscript support the recommendations by Mullen and colleagues that surveillance post completion of therapy for favorable histology unilateral Wilms does not need to include CT scans and can instead be based on symptoms and ultrasound and/or x-rays. These authors did not specify whether duration of surveillance could be limited; however, a recent publication in Lancet Oncology by Brok and colleagues supported consideration of a cut-off of two years. Their SIOP study reported that the detection of one relapse 2-5 years post-therapy required 500 scans. Importantly, it remains possible that for rare patient subsets with anaplastic histologies or other biomarkers of unfavorable disease, which may include 1q LOH, surveillance protocols might need to be adjusted. This may be similar to strategies for other tumors, such as neuroblastoma, where, in comparison to patients with high-risk disease, those with low or intermediate-risk disease with survival rates of more than 80-90% are increasingly undergoing surveillance regimens without frequent CT scans, which, in part, is determined based on clinical and biological risk factors. These approaches to risk stratification of imaging are increasingly being used. Thus, clinicians may begin to modify surveillance based on the risk of recurrence for a particular subgroup of patients, similar to precision medicine approaches for treatment. However, it will be important to perform studies similar to the accompanying manuscript to generate evidence to inform and support precision surveillance imaging recommendations that are specific to different tumor types. This concludes this JCO podcast. Thank you for listening.
10/18/20188 minutes, 35 seconds
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Prevalence of Germline Mutations in Individuals With Colorectal Cancer as Determined Using a Multi-Gene Panel Test

Summary and discussion of JCO paper by Yurgelun at al. using a 25-gene panel to demonstrate a nearly 10% germline mutation rate in colorectal cancer patients independent of high-risk factors.
1/30/20178 minutes, 19 seconds
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Minimizing Frailty in Cancer Survivors: A Meaningful Goal for All Ages

This podcast discusses the prevalence of and risk factors associated with a phenotype of accelerated aging among ALL survivors. Measurement and implications of frailty/pre-frailty are discussed.
7/13/20167 minutes, 11 seconds
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Deciphering the Heterogeneity Within EGFR-mutant Lung Cancer

A meta-analysis of 7 randomized trials comparing EGFR kinase inhibitors to chemotherapy for advanced EGFR-mutant lung cancer has shown that some populations gain greater benefit from targeted therapy – namely never-smokers, woman, and tumor harboring exon 19 deletions.
4/20/20156 minutes, 54 seconds
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Cabozantinib in Advanced Prostate Cancer: Is the Therapeutic Window Too Narrow?

This podcast discusses a phase 2 trial of cabozantinib in men with advanced bone-metastatic prostate cancer, using a novel method to assess bone scan response.
9/15/20149 minutes, 18 seconds
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Therapy Impacts Long-Term Survival for Patients in Germany With Heritable Retinoblastoma

While ten-year overall survival has increased for German patients with heritable retinoblastoma, treatment modalities including radiation and/or chemotherapy can impact overall survival.
7/5/201610 minutes, 39 seconds
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Current Status of Supplemental Screening in Dense Breasts

This podcast will review results from screening ultrasound and tomosynthesis in women with dense breasts and will discuss current and future use of MRI screening which may include average risk women.
5/23/201612 minutes, 23 seconds
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Surprisingly Good Results in BCR-ABL1-like Pediatric Acute Lymphoblastic Leukemia: What Do They Mean?

This study reports surprisingly good outcomes for children with Ph-like ALL treated on the St. Jude Total Fifteen clinical trial.
7/21/20149 minutes, 4 seconds
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When Hodgkin Lymphoma Relapses in The Older Patients

This podcast reviews outcomes for elderly patients with HODGKIN lymphoma at diagnosis and at the time of relapse.
11/4/20139 minutes, 31 seconds
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Referral Practices to Palliative Care Among Canadian Oncologists

This Podcast provides observations and commentary about referral practices of oncologists to specialized palliative care.
11/1/20128 minutes, 31 seconds
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Clinical Utility of Screening Tests in Asymptomatic Long-Term Childhood Cancer Survivors

This podcast characterizes the clinical utility of the screening tests recommended by the Children’s Oncology Group in the care of long-term survivors.
11/1/20128 minutes, 49 seconds
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"Anything You Can’t Do, I Can’t Do Either": Transplantation for High Risk AML

This is a commentary on a report from the EBMT demonstrating a higher relapse rate after allogeneic transplantation in AML patients with FLT3 ITD mutations.
1/30/201210 minutes, 28 seconds
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1 + 1 = 3. Combined Use of Anti-HER2 Agents in the Neoadjuvant Setting

The CHER-LOB trial is one of several that has demonstrated that adding lapatinib to trastuzumab and chemotherapy improves on the rates of complete pathological response among women receiving neoadjuvant therapy for HER2 positive breast cancer. Because the relationship between pCR and long-term outcomes remains ambiguous, this regimen is not recommended for ordinary use. However, these findings are a powerful support to the hypothesis that dual-modality anti-HER2 therapy is a potent combination.
4/9/20128 minutes, 54 seconds
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Solving the Mystery of Recurrence in "Surgical Cures" for Early Non-Small Cell Lung Cancer

Podcast to review the article "Occult Metastases in Length Nodes Predict Survival In Resectable Non-Small Cell Lung Cancer: Report of the ACOSOG Z40040 Trial" by Rusch et al.
10/11/20119 minutes, 28 seconds
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Advancing Treatment Options for Mismatch Repair-Deficient Metastatic Colorectal Cancers

This podcast reviews the results of KEYNOTE 164 investigating the use of pembrolizumab for mismatch repair deficient metastatic colorectal cancer, the place of this agent in the current clinical paradigm, and future directions to identify which patients are most likely to benefit from this treatment strategy. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article 'A Phase II, Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164' by Le et al. My name is Dustin Deming, and I am an associate professor at the University of Wisconsin Carbone Cancer Center in Madison, Wisconsin. My oncologic specialty is gastrointestinal oncology. Microsatellite instability high status or mismatch repair deficiency is found in approximately 15% of early stage colorectal cancers, but only 3-4% of metastatic colorectal cancer. The mechanisms by which these cancers acquire their DNA repair aberrations can vary, including germline mutations, somatic mutations and promoter methylation, which is often observed in the setting of the hypermethylation phenotype associated with BRAF mutations. This distinct colorectal cancer subtype is of particular interest for immunotherapy strategies as the lack of adequate mismatch repair can lead to 1000s of mutations and also fusions leading to the potential for expression of more neoantigens.   This world-wide phase 2, open-label study enrolled 124 patients with microsatellite instability high or metastatic mismatch repair deficient colorectal cancer following 2 or more lines of standard therapy in cohort A and following 1 or more lines of therapy in cohort B. Patients received pembrolizumab 200 mg every 3 weeks, up to 2 years, until progression, unacceptable toxicity, or withdrawal. The primary endpoint was objective response rate by Response Evaluation Criteria in Solid Tumors version 1.1 by independent central review and secondary endpoints included duration of response progression-free survival, overall survival, safety and tolerability.   At the time of this report the median follow-up for cohort A was 31.3 months and 24.2 months for cohort B. The objective response rate was 33% for both cohorts. This includes 7 patients who achieved a complete response. The median PFS was 2.3 months for cohort A and 4.1 months for cohort B. For those patients that developed an objective response the duration of response was quite prolonged with the median duration of response not reached in either cohort. The median overall survival was 31.4 months for cohort A and not reached in cohort B. This treatment was well-tolerated in this population with the most common toxicities being fatigue, pancreatitis, and increased alanine aminotransferase or lipase.   Overall pembrolizumab is an exciting addition to the treatment strategy for patients with metastatic mismatch repair deficient cancers. Based on these results, in part, this agent is now FDA approved for patients with previously treated microsatellite instability high or mismatch repair deficient metastatic colon cancers after fluoropyrimidine, oxaliplatin, and irinotecan, and for patients also for non-colorectal solid tumors following at least one prior therapy, regardless of tumor type or origin. This was the first FDA approval of a tumor histology agnostic anticancer therapy.   Long-term follow-up from this, and similar cohorts, is required to further define the duration of response for these patients, as there is hope that some of these patients could even be cured. Unfortunately, it is only a minority of patients that seem to benefit from this approach as demonstrated by the short median progression free survival in both cohorts. A better understanding of which patients are likely to benefit from immunotherapy approaches are clearly needed.    The presence of Lynch syndrome was not captured in this study to evaluate for differential response in this setting. The BRAF mutation status was collected and across both cohorts 14 patients had BRAF mutant cancers. The response rate for these patients was 43%. A similar benefit was also observed in KRAS or NRAS mutant and wild-type cancers. This study was limited in its ability to further assess those factors that could influence pembrolizumab response given the relatively small sample size and limited biospecimen collection.   Further clinical trials are investigating the use of anti-PD1 therapies for these patients in the first-line and adjuvant settings, in combination with chemotherapy and with other immune checkpoint agents, such as CTLA4 and LAG3, among others. This includes Checkmate 142, which is a phase II study that is examining nivolumab and ipilimumab in a cohort of 46 patients with microsatellite instability high or mismatch repair deficient colorectal cancer in the first-line setting. Preliminary results were presented at the 2018 European Society of Medical Oncology meeting demonstrating a 60% objective response rate and a 12 month progression free survival of 77%. These early results are promising, but further investigation is needed.   As we look forward to which factors could be leading to a lack of clinical benefit from these agents it is important to consider those factors that are intrinsic to the cancer cells, tumor microenvironment, and patient specific factors. Tumor cell intrinsic factors include important cell attributes for the immune response such as the tumor mutation burden, MHC class I expression, including beta-2-microglobulin expression, the mutation profile, including alterations in WNT signaling shown to be important for immunotherapy resistance in metastatic melanoma, and tumor heterogeneity. There is also a growing understanding of factors that are important within the tumor microenvironment for tumors to be permissive to immune cell infiltration. These factors include differences in the immune and fibroblast cell subtypes present and also the presence of certain matrix proteins. This includes a matrix proteoglycan called versican that my laboratory and others have demonstrated has immunosuppressive properties, but can be cleaved by ADAMTS proteases to an immunostimulatory fragment. Additionally, patient specific factors need to be considered such as the microbiome, immunosuppression and adverse event management.   In summary, the results of KEYNOTE 164 are a significant advance for patients with microsatellite instability-high and mismatch repair deficient cancers. Long-term follow-up from this study and further studies into the most efficacious clinical setting to use these agents will continue to advance the clinical use of immunotherapy options for these patients.   This concludes this JCO Podcast. Thank you for listening.
1/8/20208 minutes, 5 seconds
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A Deep Dive Into HLA Typing For Unrelated Donor Hematopoietic Cell Transplantation

This podcast comments on a large registry study evaluating the effect of ultra-high-resolution HLA typing on outcomes of unrelated donor transplantation.   TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article ‘Impact of Previously Unrecognized HLA Mismatches Using Ultra-High-Resolution Typing in Unrelated Donor Hematopoietic Cell Transplantation” by Mayor et al. My name is Navneet Majhail, and I am the Director of the Blood and Marrow Transplant Program and the Vice-Chair for the Department of Hematology and Medical Oncology at the Taussig Cancer Institute, Cleveland Clinic. My oncologic specialty is transplantation and cellular therapy.    For patients who are potential candidates for allogeneic hematopoietic cell transplantation, the first critical step is finding an HLA-matched donor. The HLA genes are located within one of the most gene rich regions of the human genome, are highly polymorphic, and encode proteins that critically modulate the body’s immune responses against a variety of stimuli. When selecting an unrelated bone marrow or peripheral blood stem cell donor, we typically try to identify donors who are matched at HLA genes where polymorphism is predominantly present, namely, class I genes HLA-A, -B, -C, and class II genes HLA-DRB1, -DQB1 and –DPB1. Guidelines recommend using a donor who is matched at least at HLA-A, -B, -C, and –DRB1, and preferentially at -DPB1 and -DQB1 as well.    Graft-versus-host disease or GVHD is an immune-mediated complication that continues to be a major threat to successful patient outcomes after hematopoietic cell transplantation. Better matching between the donor and the recipient lowers risk of GVHD, and guidelines recommend use of an HLA 8/8 matched unrelated donor, though in clinical practice we prefer an HLA 10/10 and even a 12/12 matched donor if one is available. In the past, HLA typing methods used ‘antigen-level’ serological testing. However, with advances in technology, the field has moved on to ‘allele-level’ or high-resolution typing which can discriminate among HLA genes that encode cell-surface proteins that ultimately constitute the antigen recognition domain, which is the functionally active portion of the HLA molecule that ultimately interacts with T-cell and NK-cell receptors. Research has shown that matching at allele-level is associated with lower risks of GVHD and better survival compared to historical serotyping-based methods, and DNA-based HLA-typing is the current standard of care.    Further advances in technology to next-generation sequencing or ultra-high-resolution typing can now allow characterization of the full HLA gene sequence. This has raised the question of the clinical significance of HLA polymorphisms in regions outside the antigen recognition domain. Prior studies in smaller cohorts of patients have raised the possibility that transplants using ultra-high-resolution matched donors may be associated with better survival and lower risks of acute GVHD. To definitively validate these findings, Mayor et al conducted a study in a cohort of >5,000 allogeneic transplant recipients from the Center for International Blood and Marrow Transplant Research. Patients had received a matched unrelated donor transplant for acute leukemia or MDS between 2008 and 2017. The manuscript that accompanies this podcast provides details of their study population, but overall their cohort was fairly representative of unrelated bone marrow and peripheral blood stem cell transplant recipients.     To summarize some key findings of their study, first, among donor-recipient pairs deemed HLA 10/10 match using high-resolution typing, 18% were found to not be a 10/10 match on ultra-high-resolution typing. Overall, only 12% of patients had a 12/12 ultra-high-resolution matched donor. Second, overall survival was comparable between patients receiving 12/12 ultra-high-resolution matched and mismatched transplants. Furthermore, there was no association of survival with the degree of ultra-high-resolution mis-match, that is, the number of loci where there was a mismatch. Similarly, when considering a subgroup of patients who were ultra-high-resolution matched at 10/10 loci, there was no difference in survival between patients who were 12/12 matched, that is, matched at DPB1, and those permissively or non-permissively mis-matched at DPB1. The authors did report an association of ultra-high-resolution matching with acute GVHD for their whole cohort, and associations with GVHD and transplant-related mortality in some subgroups, and I refer you to their JCO manuscript for details.      There are some caveats to consider in applying their findings to clinical practice, and a good study always leads to more questions. The probability of finding an adult HLA 8/8 high-resolution matched unrelated donor varies from 16% to 75% depending on recipients race and ethnicity – the chances of finding a 10/10 or 12/12 donor who is ultra-high-resolution matched is going to be significantly lower. How do we factor in the role of other known non-HLA unrelated donor selection factors such as donor age, donor sex, CMV status, ABO type, and graft source vis-à-vis ultra-high-resolution matching? Even in this highly selected cohort of patients who were actually able to get a transplant, nearly 90% did not have a 12/12 ultra-high-resolution matched donor – in this setting, how do mismatches at different loci compare with respect to outcomes? Do we change our transplant conditioning and GVHD prophylaxis regimens in ultra-high-resolution mis-matched unrelated donor transplants to reduce the risk of GVHD? Several studies have indicated comparable survival between matched unrelated donor and haploidentical related donor transplants – does the use of an ultra-high-resolution 10/10 or 12/12 HLA matched donor offer any outcome advantage compared to the haploidentical transplantation? Taken together and at this time, their findings are primarily applicable to patients who have the luxury of choosing from several young 10/10 HLA matched unrelated donors. Cost of HLA typing using next-generation sequencing is also a factor that needs to be considered.    Notwithstanding these ‘yet to be answered’ questions, there are advantages to ultra-high-resolution typing, and current technology does allow for rapid and unambiguous characterization of HLA genes with a rapid turnaround time. Many HLA labs are already implementing third-generation typing methods, and with increasing use and demand, it is expected to become cheaper and will no longer be cost-prohibitive.    Overall, with HLA-identical sibling, matched unrelated, haploidentical related, mis-matched unrelated, and umbilical cord blood, nearly all patients who need a transplant have a donor. It is heartening to see that our research has pivoted from “Is there a donor available?” to “What is the best donor?” for a given patient.     This concludes this JCO podcast. Thank you for listening. 
5/20/20219 minutes, 14 seconds
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Barriers to Clinical Trial Participation for Transgender People

What factors could be excluding transgender people from oncology clinical trials, and what can we do to make them more inclusive? Dr. Westin discusses this important issue with her guests, Dr. Ash Alpert and Dr. Lola Fashoyin-Aje. TRANSCRIPT Dr. Shannon Westin: Hello, everyone, and welcome to another episode of the JCO After Hours podcast. This is when we get down and dirty into manuscripts that are published in the Journal of Clinical Oncology. And I am so excited about our topic today. We are going to be discussing a Comments and Controversies article that was published online in JCO October 27, 2022, and it's entitled “Addressing Barriers to Clinical Trial Participation for Transgender People With Cancer to Improve Access and Generate Data.” And please note all authors do not have any conflicts of interest.  It is my great honor to be accompanied today by two of the co-authors on this important manuscript. First is Dr. Ash Alpert, and they are an Agency for Healthcare Research and Quality T32 Postdoctoral Fellow in Health Services Research at Brown University. And I'm so excited to note that they will be joining Yale as an Instructor of Medicine quite soon.  Welcome, Dr. Alpert. Dr. Ash Alpert: Thank you. Dr. Shannon Westin: And I’m also accompanied by Dr. Lola Fashoyin-Aje, and she’s the Associate Director for the Oncology Center for Excellence at the Food and Drug Administration. Welcome. Dr. Lola Fashoyin-Aje: Thank you so much. It’s my pleasure to be here. Dr. Shannon Westin: So we'll get right to it. I'm so excited. I think this is a topic that many of us, almost all of us, are needing a lot of support, needing a lot of education, and I think let's start by level setting. So what we're going to be speaking today is about transgender people. These are persons whose gender identity does not correspond with what is commonly expected for them based on the sex registered for them at birth. Do we have information about how many transgender people will be diagnosed with cancer and what are the most common cancers they face? Dr. Ash Alpert: So, given many barriers to data collection about transgender people, we actually have very little quality data about transgender people's health outcomes in general and specifically around cancer incidence and outcomes. But what we do know is that at least 0.7% of the US population is trans. And the limited data that we have suggests that transgender people don't have higher rates of cancer than anyone else. So if you look at the numbers for the US, that translates into there being about 2 million transgender people in the US and about 900,000 transgender people who are diagnosed with cancer in their lifetimes.   The other data that we have is that it looks like transgender people who are on hormone therapy and have surgeries, therefore less of a chance of being diagnosed with prostate cancer. If people have had bilateral mastectomy, they have less of a chance of being diagnosed with breast cancer. And it does seem like from retrospective data that it's possible that people on estrogen therapy are more likely to be diagnosed with a breast cancer. So basically, all things that we would expect. And given that about one in 10 transgender people in the US are living with HIV, it's likely that trans people also have higher rates of HIV-associated malignancies.  Dr. Shannon Westin: And I wonder, what about screening? I would think that this could be a real difficulty. If people are misgendered, they may not be offered the appropriate cancer screening. I know I'm getting a little bit away from the crux of your talk, but I think this is so important. Dr. Ash Alpert: Yeah. So there's a number of barriers to screening, and two of the ones that come to mind immediately are that trans people, in general, have negative experiences with physicians. So one study suggested that one in three transgender people had had a negative experience with a physician in the last year and that given this, about one in four trans people avoid necessary health care. So that automatically means that trans people aren't getting screened. And then I think the other important thing that you're bringing up is that because of the ways that certain types of health care are associated with gender—so, in other words, getting a cervical PAP smear is associated with being a woman in the ways that we talk about those tests—there are many other barriers to trans people getting cancer screenings. And we do have some data from the literature that suggest that trans people have lower rates of cancer screenings than the general population, likely because of these two, if not more, reasons. Dr. Shannon Westin: I would anticipate that this could potentially impact, obviously, diagnosis, but then also cancer-related outcomes. Do we have data on that? I know that a lot of this is a data-free zone, so I appreciate you kind of just reviewing what we do know.  Dr. Ash Alpert: So Sarah Jackson published a paper that suggested that in some types of cancer, trans people are diagnosed later with more advanced-stage disease and have poorer outcomes. But, again, it's very limited data. Dr. Shannon Westin: Anything else that you want to talk about on that second question before I move on to the next one? Dr. Ash Alpert: Yeah. I mean, I think that the question you raised about cancer screening is also true about cancer treatment. And I think we may get into this in the paper as well, that certain types of cancer—like ovarian cancer, prostate cancer, testicular cancer, and endometrial cancer—are often, in the ways that we talk about them and the ways that we write about them in guidelines, associated with specific genders. So it's not just individual oncologists, but all oncologists are steeped in this language that associates specific types of cancer with gender. And so then it becomes not just something that's happening in the language between two people, an oncologist and a patient, but also in the optics of the clinics, the names of our clinics, our titles as physicians, that all may inadvertently and implicitly exclude transgender people from care.  Dr. Shannon Westin: It's interesting. As a gynecologic oncologist, I feel like I was just talking about this with someone, about this idea of women's cancer care areas and these very specific gendered kind of comprehensive cancer centers that are incredibly exclusive to this group of people. So I'm really glad that you highlighted that. It's very timely, too, because I think our group is talking about how do we want to name our center. So I appreciate this.   So this is an area of interest greatly to me is clinical trials just in general and participation in clinical trials and encouraging inclusivity and improving representation in clinical trials. So we've seen this. We've seen this in gynecologic cancers and other cancers that, obviously, clinical trials change the standard of care, but they also provide better outcomes for patients and people with cancer. So do we know—are there any data about the current state of participation of transgender people in clinical trials? Dr. Lola Fashoyin-Aje: Yeah, I mean, thank you for that question. The fact of the matter is that we don't really know what the current state of participation in clinical trials in oncology is. This is really part of the reason why the Oncology Center of Excellence at the FDA convened the mini-symposium that we're describing in the paper and the reason why we wrote the paper. I think the assumption that we make is often that the numbers are probably not great. But since we do not routinely collect the data that would help us to identify transgender individuals as part of clinical research, even if transgender individuals did participate in a trial, we would have no way, really, of knowing.  We also do not really have great data regarding what the benchmarks for participation would be because, as Dr. Alpert mentioned before, we don't routinely collect this data as part of the epidemiologic surveys that inform our understanding regarding the populations that are affected by cancer or even at the point of care. It's really very heterogeneous, the types of data that we collect and whether the way that it's collected is optimal. So we really have an information and data deficit that is quite significant for this population that really is needed to be addressed in both sort of systemic ways, but also in our individual settings in the way that we collect data and the way we engage with this population. Dr. Shannon Westin: Are there any interventions or outreach efforts right now ongoing to start collecting these data or even to start raising awareness that these data should be included? Because I'm just thinking of all the NCI trials we do and industry trials and the data that are collected, and you just don't see this, right? This isn't part of the data dictionary typically, right?  Dr. Lola Fashoyin-Aje: Dr. Alpert can speak to some of this as well. We reviewed this as part of the paper-writing process. But there are ongoing efforts to identify the best ways to collect data and identify the opportunities where we could improve upon where some data is already being collected but also making sure that there's sort of structural measures are being taken to ensure that as we collect those data, that we are handling those data appropriately. Because this is a population that really suffers disproportionately bias, discrimination, violence. And so we want to make sure that as we are encouraging folks to provide this kind of information, because we really think that it will help improve their clinical care outcomes as well as clinical trial participation access, but that we are also, at institutional levels, addressing some of the areas that are either explicitly or inadvertently creating barriers and creating environments that are not supportive or that are not safe for this population.  And so there are ongoing efforts. I can say that at a federal level, there's increasing recognition that we really are not doing a great job. And I think there are some recommendations for how to collect these data in surveys, but it may not necessarily be applicable to what we need to know in the clinical trial setting. And so there's so much work to be done still. Dr. Shannon Westin: Great. Dr. Alpert, do you have anything to add there? Dr. Ash Alpert: This could be a very long conversation, but I'll briefly say that there are a couple of things that are happening right now that suggest that things are moving along. One is that NCI put out an administrative supplement for NCI-designated cancer centers to apply for, through which they can begin to collect sexual orientation and gender identity data at the cancer centers. So that means that now that that's happened, cancer centers across the country are testing measures with which to collect sexual orientation and gender identity data.  And at Yale, I'm a part of a research team that is beginning to collect data, both based on some national recommendations and also based on some of our individual research and ideas about how to collect this data in a way that really provides transgender people the autonomy to identify and describe themselves in ways that really feel right to them and to us. I think there are exciting things in the works. But I also really appreciate the conversation we just had about safety because in my qualitative research, what I've found over and over again is that often transgender people are put into a very difficult situation where if they come out to their clinicians, they experience stigma and sometimes violence, and when they do not tell clinicians certain things about their medical histories, including that they are on hormone therapy or that they've had particular surgeries or specific information about their anatomy, then they're put in the position where they may not be receiving the best care because their clinicians don't have all the appropriate information. It's a very difficult situation for individual patients and also for those of us who are thinking systemically and structurally about how to improve what we know about cancer epidemiology and how to provide the best care for transgender people with cancer. Dr. Shannon Westin: I mean, I think that kind of dovetails nicely with my next question, is really trying to understand how some of these structural barriers might impact participation in clinical trials. So what are the barriers that are keeping these people off of these trials? And maybe how can we start to strip those barriers away? All in that, I think, highlighting that highlight of safety and inclusion. Dr. Fashoyin-Aje: I can start by touching upon some of this. I think one important area has to do with language, the language that we use, the signage that we use. And sometimes it's not even just what is explicitly stated but also what is omitted, what is silent, which may have adverse consequences as well. And that could be even worse because then you're sort of rendering a population invisible or basically really kind of reinforcing this idea that they're just not seen.  So I think one area that is really quite relevant in the regulatory setting has to do with eligibility criteria. And I think often, those are silent with respect to transgender individuals because, number one, people just may not know, so they just could fall off, and they just are not thinking that this is a population that I need to explicitly ensure that they are invited to participate in this trial. And then I think other times, there are a lot of assumptions made about whether or not it is safe, and some of those assumptions may be supported, and some of them are not supported. So I don't want to trivialize whether or not an individual is receiving hormonal therapy, whether or not that may have adverse impact on their outcomes in the clinical trial; that could very well be the case, but we just don't know most of the time, and so we don't explicitly state one way or the other. I think the other way is just sort of the kind of language that we use. Calling individuals women may exclude certain people; they may not be sure. I think a lot of people when they hear women, they're not thinking about transgender women. So, in the paper, we really highlight opportunities where we could be more specific about the language that we use so that it is clear what we're referring to. So if you are designing a study that is meant to test a drug in patients who have ovarian cancer, say that. You don't need to say “females with ovarian cancer” if you're not really explicitly—there would really typically not be any reason to exclude people just based on that without more information. And often that more information isn't actually collected.  So I think that's sort of part of what we are trying to highlight here, that there are things that can be done at a micro level, but there are things that can be done at a macro level, and really culture change is a really important part of this, this sort of thinking like which of my neighbors might want to be included in this trial? Which one of my children's friends might want to be enrolled in this pediatric trial? And just kind of thinking a little bit out of the box and thinking of ways to be more inclusive and then have reason to exclude rather than to start from a baseline of exclusion and then inviting people. Dr. Ash Alpert: Yeah, I think we highlighted three main areas of eligibility criteria that may inadvertently exclude transgender people. One was mentioning sex or gender in the inclusion or exclusion criteria when it's unnecessary. The second is mentioning hormone therapy but not specifically and explicitly stating whether hormone therapy used for gender-related purposes would be included in that. So, for example, we, I think, in the paper, describe a prostate cancer trial that excluded people with prior hormone therapy for prostate cancer, but I think it would be very confusing for me if I were a transgender woman on estrogen therapy, whether or not that excluded me from the trial because it's not specifically called out. And then we still see blanket exclusions for people living with HIV despite all the discussion and commentary about this. And that necessarily excludes many trans people because one in 10 transgender people in the US is living with HIV.  And then I think we also, in the paper, highlight that there's actually been qualitative research done with transgender people looking into the facilitators and barriers to participating in clinical trials, and we summarize them just saying that trans people suggest that they're more likely to participate in trials that are led by or staffed by transgender researchers, that explicitly benefit transgender communities, that provide resources, that address financial barriers, barriers to transportation, and that are integrated into health care that transgender people are already receiving.  So I think there are clear ways for cancer centers, principal investigators, to think about revising their trials to ensure that they are accessible to transgender people. And I think one thing that's hinted at in those suggestions is community-based participatory research in order to really ensure that the trials that we're writing are meeting the needs of community members. Dr. Shannon Westin: I think there’s always a huge opportunity to have advocates at every level reviewing our trials and our grants. And I don't know that we always do the best job of being incredibly inclusive of who we invite to the table to review those. So that part of the paper really spoke to me as someone who sits on different—task force for ovarian cancer and through the NIH and others, making sure that we really have a representative group that is reviewing these trials and ensuring that they are appropriately inclusive. So I really always like true action items because I think we all get really frustrated when we talk about a problem and say there's a problem and we wave our hands at the problem, but what we need are really goal-based solutions. And I think that was one of the parts of your paper that really I felt like elevated this paper, and now I think we just need to get it out so that it moves on beyond this workforce, this task force, and actually gets implemented on a day-to-day basis as we're developing these trials.  So I think I have one more question that I think we've kind of highlighted, but I want to make sure to put a pretty fine point on it. And you've talked a little bit about this, but we know that many transgender people are taking hormones so they can align their anatomy and their physiology with their gender. And we talked a little bit about exclusion around this, but I'd love to hear your thoughts about how can we better address this particular issue. And I’m just thinking of gynecologic cancers. We're using hormones constantly as a treatment. Breast cancer, same. So is there a way to align the drug development in this space but allow people that are taking these hormones for a different reason, a non-cancer-related reason? Dr. Lola Fashoyin-Aje: Yeah, I think, as we discussed, these exclusions can be both explicitly stated in the protocol, like Dr. Ash mentioned before, or it can be silent, where there just isn't information that would direct a provider or investigator one way or the other as to whether or not it is safe to enroll participants on the trial who are transgender and who are receiving hormonal therapy in that context. So addressing this really takes a lot of education for each one of us. And, as I mentioned before, it's a data-free zone. And I think, ultimately, what's going to make some of these recommendations that we made in the paper sustainable is really having data.   When we were preparing the symposium and when we held the symposium, it was quite clear that some of the available data regarding the safety of hormonal therapy—like does it increase the risk of cancer, what are the impacts on an investigational therapy—there's just a lot of inconsistent information, incomplete information. And so we really need a lot of research to be done to fill those data gaps. And that's why in the FDA Oncology Center of Excellence, we actually have an active funding opportunity right now where we're requesting proposals for applied regulatory science research to really understand the factors that affect safety and efficacy of underrepresented populations in oncology therapeutic development. And we specifically call out sexual and gender minorities as part of that because we recognize that that's sort of an area where safety is always sort of invoked. But we just don't know many times if that's actually supported. And so we really do need data.   I don't have a best-practices approach. I think it's important that an investigator or provider ask their patient if they are receiving this and do preliminary basic research about whether or not there's even opportunity for drug interactions, which is something you would be concerned about, or for increasing the risk of developing tumor or tumor progression, depending on the disease. But again, we just don't know. So I think it's really challenging to offer—as a representative of a regulatory agency, it's really challenging for me to offer a best-practices approach here, other than we should just collect the information and do some research to really better understand. Dr. Ash Alpert: Another thing that complicates this whole conversation is that historically, hormone therapy and surgeries have been used as a surrogate target for transphobia. Oftentimes, trans people have the experience of presenting to care for some symptom that we're having and having that symptom blamed on hormone therapy or surgeries when it's not related. So I think that complicates the ways that we're describing our research. That complicates national conversations about the safety of continuing hormone therapy in the context of a cancer diagnosis and treatment. And it definitely complicates conversations that individual transgender people and their oncologists have about whether or not to continue hormone therapy or how to manage the timing of surgeries in the context of cancer treatment. So that's not to stop or halt these really important conversations in this data gathering, but I think those are important considerations to keep in mind as we describe these questions, collect our data, and describe our findings.   Dr. Shannon Westin: Well, great. Well, this has been amazing, and I think that we wanted to put this podcast together so that we could get your very important findings out. How else can we get this out there? What else do we need to do? What are you all doing at the FDA? Dr. Lola Fashoyin-Aje: The symposium that we organized was a huge first step, and we are having those conversations internally about what the best approach is that is data-driven approach. But to be quite honest, I think that there are so many barriers to changing the status quo. And I think what's really important is the continued highlighting of these issues at every opportunity to not leave out this population when we're talking about equity and underrepresented populations and to keep making those changes in our own particular settings about how we use language, the recommendations that we give to sponsors. I'm speaking from the FDA now about inclusion.  And our research and policy priorities really have to reflect this as well. And so, at an organizational level, what are you doing to ensure that this population is safe, has access, and that you're really engaging them in determining what—there are so many issues to prioritize. Where do you start? What are the things that are more short term, and what are the things that are longer term? And these are conversations that we have with patients at the FDA, inviting them to talk to us about them in different product development contexts, but also more generally. Dr. Shannon Westin: Any last thoughts, Dr. Alpert? Dr. Ash Alpert: I really urge readers to take these issues into consideration in their clinical trials office, to their cooperative groups, and to continue to think about them as they're writing trials. I really appreciate—I think we really appreciate the opportunity to speak on this podcast and to potentially have more people hear about these concerns and think about them. Dr. Shannon Westin: Well, I really appreciate all the time that you spent, knowing that you are both very, very busy researchers.  Thank you all for tuning in today to JCO After Hours. We've been discussing the Comments and Controversies manuscript “Addressing Barriers to Clinical Trial Participation for Transgender People With Cancer to Improve Access and Generate Data.” I am very grateful to all of you for listening. Hope you'll check out other episodes of the podcast, and we'll see you very soon. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      
4/13/202325 minutes, 38 seconds
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JCO Article Insights: Phase III POSEIDON Clinical Trial Results

In this JCO Article Insights episode, Emily Zabor summarizes two articles from the February 20th, 2023 Journal of Clinical Oncology issue: "Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non–Small-Cell Lung Cancer: The Phase III POSEIDON Study" by Johnson, et al  and "The POSEIDON Trial: Will Secondary End Points Change Our Clinical Practice?" by Remon, et al. The Original Report by Johnson, et al describes results of the Phase III POSEIDON clinical trial. The accompanying editorial by Remon, et al discusses the findings of a significant progression-free survival and overall survival benefit for the combination of tremelimumab plus durvalumab plus chemotherapy as compared to chemotherapy alone, which were secondary endpoints in the trial. TRANSCRIPT Emily Zabor: Welcome to JCO Article Insights for the February 20, 2023, issue of JCO. I’m your host, Emily Zabor, JCO Biostatistics Editorial Fellow.  Today, I will be providing summaries for two articles. The first article, titled ‘Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non–Small-Cell Lung Cancer: The Phase III POSEIDON Study,’ by Dr. Melissa Johnson and colleagues, describes the results of the Phase III POSEIDON clinical trial. POSEIDON was a randomized Phase III clinical trial in patients with metastatic non-small cell lung cancer. The trial had a three-arm design to evaluate the efficacy of tremelimumab plus durvalumab plus chemotherapy; durvalumab plus chemotherapy; and chemotherapy alone in a first-line treatment setting. The two immunotherapies were selected for study because of their complementary mechanisms of action. Tremelimumab is an anti-CTLA-4 antibody which can diversify T-cell responses and lead to increased tumor infiltration. Durvalumab is an anti-PDL1 antibody which can enhance T-cell function. Chemotherapy is still an important treatment option for early disease control and potential for immune priming. Patients in the POSEIDON trial were randomized to the three arms with equal allocation. The co-primary endpoints for the trial were progression-free survival and overall survival for the comparison of durvalumab plus chemotherapy vs. chemotherapy alone. Then, a hierarchical multiple-testing procedure with a gatekeeping strategy was used across the primary endpoints and key secondary endpoints. Gatekeeping procedures are a way of controlling the type I error rate across multiple groups of null hypotheses that have a hierarchical structure, meaning that some of the hypotheses are considered more important than others. In this case, the plan was to first test for differences in progression-free survival and overall survival between the durvalumab plus chemotherapy and chemotherapy alone arms. Then, if either of those tests had a significant p-value so that the null hypothesis of no difference between groups was rejected, tests for differences in progression-free survival and overall survival between the tremelimumab plus durvalumab plus chemotherapy and chemotherapy alone arms would be conducted. Additional levels of testing could be conducted for other secondary endpoints following significance at the previous level. These types of gatekeeping procedures are a rigorous way of controlling the type I error of the entire study at 5% while still allowing multiple tests to possibly be conducted. The efficacy analyses were conducted in the intention-to-treat population, which included 338 patients on the tremelimumab plus durvalumab plus chemotherapy arm, 338 patients on the durvalumab plus chemotherapy arm, and 337 patients on chemotherapy alone. The median follow-up among those without an event was 10.3 months for progression-free survival and 34.9 months for overall survival. The findings for the co-primary endpoints were that progression-free survival was significantly improved with durvalumab plus chemotherapy versus chemotherapy alone, with 12-month progression-free survival rates of 24.4% versus 13.1%. There was no statistically significant difference in overall survival, with 24-month overall survival rates of 29.6% versus 22.1%.  Because progression-free survival was significantly different in the durvalumab plus chemotherapy versus chemotherapy alone arms comparison, according to the hierarchical testing procedure, the study proceeded to compare efficacy between the tremelimumab plus durvalumab plus chemotherapy and chemotherapy alone arms. Both progression-free survival and overall survival were significantly higher for the tremelimumab plus durvalumab plus chemotherapy arm, with 12-month progression-free survival rates of 26.6% versus 13.1% and 24-month overall survival rates of 32.9% versus 22.1%. The tremelimumab plus durvalumab plus chemotherapy arm had higher rates of grade III or IV treatment-related adverse events and immune-mediated adverse events as compared to the other two arms. The rates of grade III or IV treatment-related adverse events were 51.8%, 44.6%, and 44.4%, and the rates of immune-mediated adverse events were 33.6%, 19.2%, and 5.1% for the tremelimumab plus durvalumab plus chemotherapy; durvalumab plus chemotherapy; and chemotherapy alone arms, respectively.  This paper also reports on a number of subgroup analyses of overall survival comparing both the tremelimumab plus durvalumab plus chemotherapy and durvalumab plus chemotherapy arms to chemotherapy alone to examine consistency of effect across subgroups of patients. The results were found to be generally consistent across subgroups according to sex, age, tumor PD-L1 expression levels, histology, planned chemotherapy regimen, smoking history, race, ECOG Performance Status, and AJCC disease stage at diagnosis. Notably, patients with less than 1% PD-L1 tumor cells had no difference in hazard of death on durvalumab plus chemotherapy versus chemotherapy alone with a hazard ratio of 0.99, but had a reduced hazard of death on tremelimumab plus durvalumab plus chemotherapy versus chemotherapy alone with a hazard ratio of 0.77. But the study was not powered to conduct statistical tests for the subgroups, so no p-values are reported, and no strong conclusions can be drawn from the subgroup analyses.  Dr. Johnson and colleagues conclude that durvalumab plus chemotherapy significantly improved progression-free survival as compared to chemotherapy alone, and tremelimumab plus durvalumab plus chemotherapy significantly improved both progression-free survival and overall survival as compared to chemotherapy alone. The authors suggest that adding a limited course of tremelimumab to durvalumab and four cycles of chemotherapy provided long-term survival benefits to patients with metastatic non-small cell lung cancer and may represent a new first-line treatment option. The second article, titled ‘The POSEIDON Trial: Will Secondary End Points Change Our Clinical Practice?’ by Dr. Jordi Remon and colleagues, is an editorial related to the first article just described. In the editorial, the authors discussed the findings of a significant progression-free survival and overall survival benefit for the combination of tremelimumab plus durvalumab plus chemotherapy as compared to chemotherapy alone, which were secondary endpoints in the trial. Recall that the POSEIDON trial had two co-primary endpoints of progression-free survival and overall survival for the comparison of durvalumab plus chemotherapy to chemotherapy alone, and the secondary endpoints were only evaluated since the co-primary endpoint of progression-free survival was found to be significant.  Dr. Remon and colleagues note that while there was no head-to-head comparison of the durvalumab plus chemotherapy and tremelimumab plus durvalumab plus chemotherapy arms, the tremelimumab plus durvalumab plus chemotherapy regimen had only a modest increase in progression-free survival and overall survival rates, but much higher rates of immune-related adverse events as compared to the durvalumab plus chemotherapy regimen. The authors suggest that following this trial, we still don't know what subset of patients would benefit from a dual immunotherapy treatment approach or what is the optimal duration of such treatment protocols. Recall that in POSEIDON, while efficacy was estimated in pre-planned subgroups, the study was not powered to detect effects within subgroups, so no statistical comparisons were made, and therefore no definitive conclusions could be drawn about whether a particular subgroup did or did not benefit from either of the experimental arms.  The authors point out that many combinations of immunotherapies have been studied for patients with advanced non-small cell lung cancer, and that there is likely little benefit from further studies where new drugs are added to current protocols in unselected patients. The authors emphasize that new predictive markers are urgently needed, especially given the financial toxicity associated with the use of immunotherapies. They propose that the study of such markers should be at the forefront of future trials. That concludes this episode on the articles ‘Durvalumab With or Without Tremelimumab in Combination with Chemotherapy as First Line Therapy for Metastatic Non-Small Cell Lung Cancer: Phase III POSEIDON Study’, and the associated editorial, ‘The POSEIDON Trial: Will Secondary Endpoints Change Our Clinical Practice?’  Thank you for listening, and please tune in for the next episode of JCO Article Insights. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  Show Notes: Like, share and subscribe so you never miss an episode and leave a rating or review.   Articles Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non–Small-Cell Lung Cancer: The Phase III POSEIDON Study   The POSEIDON Trial: Will Secondary End Points Change Our Clinical Practice?   Find more articles from the February 20 issue.
2/27/202310 minutes, 45 seconds
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Advancing Knowledge on the Use of Dexrazoxane in Children With Acute Myeloid Leukemia and Other Childhood Cancers

This podcast describes a study addressing the use of dexrazoxane as a cardioprotectant in a cohort of more than 1,000 pediatric acute myeloid leukemia patients.   Transcript This JCO Podcast provides observations and commentary on the JCO article “Effect of Dexrazoxane on Left Ventricular Systolic Function and Treatment Outcomes in Patients with Acute Myeloid Leukemia: A Report From the Children’s Oncology Group” by Getz et al. My name is Elvira van Dalen, and I am an epidemiologist at the Princess Máxima Center for Pediatric Oncology in Utrecht, The Netherlands and a Coordinating Editor of Cochrane Childhood Cancer. My oncologic specialties are cardiotoxicity and systematic reviews and guidelines in the field of pediatric oncology. I have nothing to disclose. Anthracyclines are widely used in pediatric oncology. Unfortunately, one of their most serious adverse effects is cardiotoxicity, which can occur during or shortly after treatment, but also decades later. In the Dutch LATER Childhood Cancer study, we found a 10.5% cumulative incidence of symptomatic heart failure 40 years after cancer diagnosis in survivors treated with cardiotoxic chemotherapy. The Childhood Cancer Survivor Study and St Jude LIFE show similar results. Siblings report significantly less congestive heart failure than survivors. These are high risks, especially in this young patient population. Cardiotoxicity impairs quality of life and can lead to premature death. Prevention is thus very important. Extensive research has been devoted to the identification of possible cardioprotective interventions, like liposomal anthracyclines, increasing the anthracycline infusion duration and reducing the cumulative anthracycline dose. Concerning the cumulative anthracycline dose, it should be kept in mind that there is no safe dose. Another option is the use of cardioprotective agents like dexrazoxane. As shown in our Cochrane systematic review published in 2011 which is currently being updated, it prevents cardiac damage. But unfortunately, the majority of the evidence comes from studies addressing adult patients with breast cancer and these data cannot be extrapolated to children. In children as of yet only a few randomized trials have been performed, none including acute myeloid leukemia patients. In these pediatric studies, for clinical heart failure there were no significant differences between dexrazoxane and control groups, while results for asymptomatic cardiotoxicity varied with the outcome definition used. All studies were relatively short-term, and we don’t know how longer follow-up will influence these results. Thus far only a few small non-randomized studies including 50 children or less evaluated dexrazoxane in pediatric acute myeloid leukemia, all with limitations. The article by Getz and colleagues that accompanies this podcast adds important new information to the current knowledge of the use of dexrazoxane in pediatric acute myeloid leukemia patients and pediatric patients in general. It presents the results from the Children’s Oncology Group AAML1031 trial investigating the use of dexrazoxane during frontline treatment of pediatric acute myeloid leukemia. Between 2011 and 2016, patients younger than 30 years at diagnosis were enrolled. Almost 98% were younger than 21 years. The analyses included 1014 patients, of which 10% received dexrazoxane consistently at every anthracycline course and 90% were never exposed to dexrazoxane. Anthracycline treatment involved both daunorubicin and mitoxantrone. Low risk patients received a cumulative anthracycline dose of 444 mg/m2, while high risk patients received 294 mg/m2 assuming the daunorubicin equivalency conversion employed by the Children’s Oncology Group at the time of this protocol. Patients were followed for a median of 3.5 years, with an interquartile range of 2.5 to 4.7 years. Cardiac function was assessed using either echocardiography or multigated acquisition scans which were performed at regular intervals. Compliance with cardiac monitoring was more than 90% on-protocol, but less than 60% off-protocol. Left ventricular systolic dysfunction was primarily defined as a shortening fraction of less than 28% or an ejection fraction of less than 55%. In the report by Getz and colleagues that accompanies this podcast, 26.5% of patients consistently treated with dexrazoxane and 42.2% of patients that never received any dexrazoxane developed left ventricular systolic dysfunction. The hazard ratio was 0.55 with a 95% confidence interval of 0.36 to 0.86. There was a trend towards a worse grade of left ventricular systolic dysfunction without dexrazoxane. Some evidence pointed to recovery of systolic function, but as this was based on mean values instead of number of patients below the cut-off value it is possible that patients with good and bad values balanced each other out resulting in an adequate mean value. This can give the impression that there is no problem, while for some patients this might not be true. It is important to note that this was not a randomized trial, which would have provided the highest level of evidence to answer this type of question. Dexrazoxane was administered at the discretion of treating physicians. However, characteristics like sex, age, risk group, treatment arm, compliance with cardiac monitoring and follow-up were similar in both groups. Unfortunately, cumulative anthracycline dose was not reported for both groups, but it was stated that patients completed a median of 4 courses regardless of dexrazoxane exposure. An important question regarding any cardioprotective intervention is whether it can reduce cardiotoxicity without negative effects on anti-tumor efficacy and non-cardiac toxicities. At the moment, despite its clear cardioprotective effects, at least in adults, dexrazoxane is not routinely used in clinical practice. This might be explained by the suspicion of interference with anti-tumor efficacy and the occurrence of secondary malignancies. However, as shown in our Cochrane systematic review no significant differences between treatment groups were identified, which is in line with more recently published randomized trials. Studies often do not report data on anti-tumor efficacy and non-cardiac toxicities, but fortunately Getz and colleagues did. This is important as extrapolation of many of these data to other types of malignancies is difficult. Survival and relapse risk were comparable between groups. And even though this study did report on only a few non-cardiac toxicities, those that were reported were similar. Despite the relatively short follow-up period, four secondary malignancies occurred, three in the non-dexrazoxane group. This was not statistically significant different. None of the secondary malignancies was acute myeloid leukemia, but it might have been difficult to distinguish a secondary malignancy from a relapse. In summary, although this is not a randomized trial, this large study provides new knowledge on the use of dexrazoxane in pediatric acute myeloid leukemia patients with regard to cardiac function, anti-tumor efficacy and non-cardiac toxicities. Overall, dexrazoxane seems to be cardioprotective, at least within the relatively short follow-up period of maximal 4 years, without negative effects on anti-tumor efficacy and non-cardiac toxicities including secondary malignancies. Hopefully the authors will continue to follow these patients for long-term results. Even though this study does have limitations, it definitely adds to the knowledge of the use of dexrazoxane in children. It can help to inform the development of a much-needed evidence-based clinical practice guideline that is currently being developed by the International Late Effects of Childhood Cancer Guideline Harmonization Group. This concludes this JCO Podcast. Thank you for listening.
6/11/202010 minutes, 9 seconds
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Expanding Treatment Options for Hormone Receptor-Positive, HER2-Positive Metastatic Breast Cancer

Read the related article "First-Line Trastuzumab Plus an Aromatase Inhibitor, With or Without Pertuzumab, in Human Epidermal Growth Factor Receptor 2–Positive and Hormone Receptor–Positive Metastatic or Locally Advanced Breast Cancer (PERTAIN): A Randomized, Open-Label Phase II Trial" by Rimawi et al on JCO.org.   Transcript: This JCO Podcast provides observations and commentary on the JCO article ‘First-Line Trastuzumab Plus an Aromatase Inhibitor, With or Without Pertuzumab, in HER2-Positive and Hormone Receptor-Positive Metastatic or Locally Advanced Breast Cancer (PERTAIN): A Randomized, Open-Label Phase II Trial’ by Rimawi et al.  My name is Sara Tolaney and I am Assistant Professor of Medicine at Harvard Medical School and Senior Physician at Dana-Farber Cancer Institute in Boston, Massachusetts.  My oncologic specialty is breast cancer. Since the seminal report of the benefits of adding trastuzumab to chemotherapy, we have seen an improvement in survival for patients with metastatic HER2-positive disease from approximately two years to now almost 5 years.  This dramatic improvement in outcomes can be attributed to the use of continued anti-HER2 therapy beyond progression as well as the introduction of new HER2-directed therapies.  The largest improvement in survival has come from the addition of pertuzumab to a taxane and trastuzumab as seen within the CLEOPATRA study.  This resulted in an impressive almost 16-month improvement in overall survival and established this regimen as a first line standard in the metastatic setting. While chemotherapy and dual anti-HER2 therapy is the current first line treatment approach, we are now left with the question about how best to optimize therapies available to us, and whether or not there are other first line approaches we could consider in order to lessen toxicity.  One potential alternative approach for patients with hormone-receptor positive, HER2-positive disease could be to consider the use of hormonal therapy.  There has been some concern that hormone-receptor positive tumors that are also HER2-positive may be relatively resistant to hormonal therapy.  One reason for this may be that activation of HER2 can result in direct phosphorylation and activation of the estrogen receptor.  This potential HER2 and ER bidirectional cross-talk has provided justification for combinatorial therapy targeting both of these pathways concurrently.  There have been at least three trials that have examined the addition of single agent HER2-targeted therapy to hormonal therapy.  The TAnDEM trial randomized a little over 200 patients with hormone-receptor positive, HER2-positive breast cancer to either anastrozole alone or in combination with trastuzumab as first line therapy and found a 2.4-month improvement in progression free survival, but no difference in overall survival.  The dual EGFR/HER2 tyrosine kinase inhibitor, lapatinib, has also been investigated in combination with hormonal therapy.  A phase 3 study in the first line metastatic setting found that adding lapatinib to letrozole improved progression free survival from 3.0 to 8.2 months, and another trial that looked at adding lapatinib to fulvestrant found an improvement in progression free survival from 3.3 to 5.9 months.  These three studies suggest that single agent HER2-targeted therapy adds modestly to endocrine therapy, and there has therefore been interest to see if dual HER2 targeted therapy added to hormonal therapy would result in a more significant improvement in outcomes. Since data from CLEOPATRA had suggested that the addition of pertuzumab and trastuzumab to chemotherapy led to significant improvements in disease-free and overall-survival, In the article that accompanies this podcast, Rimawi and colleagues were interested in exploring if adding pertuzumab to trastuzumab and hormonal therapy could offer additional benefits.  The PERTAIN study was a multicenter phase 2 trial that  enrolled 258 patients with locally-advanced or metastatic hormone-receptor positive, HER2-positive breast cancer who had not previously received systemic therapy in the advanced disease setting, outside of endocrine therapy, and randomized them to receive trastuzumab plus an aromatase inhibitor or trastuzumab plus pertuzumab and an aromatase inhibitor.  Patients were allowed to receive induction chemotherapy with a taxane for 18-24 weeks in combination with trastuzumab (with or without pertuzumab) at the treating investigator’s discretion; this was decided prior to randomization and patients were stratified by whether or not they had received induction chemotherapy.  The trial demonstrated an improvement in progression free survival from 15.8 months to 18.89 months with the addition of pertuzumab to an aromatase inhibitor and trastuzumab, meeting its primary endpoint.  This improvement in progression free survival was not associated with a significant improvement in objective response rate (63.3 vs 55.7%).  It is important to note that 57% of patients in the trial received induction chemotherapy, and subgroup analyses demonstrated that amongst those who did not receive chemotherapy, the addition of pertuzumab improved progression free survival from 12.45 months to 21.72 months.  In contrast, amongst those who received induction chemotherapy, the median progression free survival was similar for those who received pertuzumab compared to those who did not, 16.89 and 16.85 months respectively.  This group of patients who received induction chemotherapy had more visceral disease and a shorter medial time since initial breast cancer diagnosis.  Grade 3 and 4 adverse events were more common in those patients receiving all three agents (50.4% vs 38.7%) and the most common toxicities were diarrhea, alopecia and nausea. The PERTAIN trial represents the first randomized trial to investigate the addition of pertuzumab to trastuzumab with an aromatase inhibitor and suggests that endocrine therapy with dual anti-HER2 therapy may be a reasonable treatment approach for some patients with hormone-receptor positive, HER2-positive metastatic breast cancer.  There is also data looking at a different dual anti-HER2 therapy approach with endocrine therapy from the phase 3 ALTERNATIVE trial.  This study looked at the benefits of adding lapatinib to an aromatase inhibitor and trastuzumab and demonstrated a 5-month improvement in progression free survival, but no improvement in overall survival.  These studies suggest that upfront endocrine therapy with dual anti-HER2 therapy may offer a novel treatment option for patients that is likely less toxic and associated with a better quality of life than chemotherapy-based treatment.  One must weigh the pluses and minuses of each treatment approach when choosing the appropriate first line therapy for patients.  Endocrine therapy with dual anti-HER2 therapy has not yet been shown to be associated with a survival benefit, and is associated with lower objective response rates than that seen in the CLEOPATRA study, so it may not be the best approach in a patient with significant visceral disease at presentation, but may be an optimal approach in patients with limited tumor burden, or those who are not optimal candidates for chemotherapy.  Work is also ongoing in the PATINA trial to see if adding cdk 4/6 inhibition to endocrine therapy and dual anti-HER2 therapy, after induction chemotherapy, will have even further benefit. This concludes this JCO Podcast.  Thank you for listening.
8/14/20188 minutes, 14 seconds
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Pembrolizumab is Safe and Active in Platinum- and Cetuximab-Refractory Head and Neck Squamous Cell Carcinoma

By Amanda Psyrri  The findings of KEYNOTE-055 are summarized and compared to other immunotherapy studies in recurrent/metastatic head and neck squamous cell carcinoma. Related Article:  Pembrolizumab for Platinum- and Cetuximab-Refractory Head and Neck Cancer: Results From a Single-Arm, Phase II Study
3/22/20179 minutes, 42 seconds
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Very Late Outcomes of Wilms Tumor Survivors: British Childhood Cancer Study

3/29/20169 minutes, 20 seconds
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The First Prospective Trial of Proton Therapy for Children With Rhabdomyosarcoma: What We Learn From Preliminary Results

This is a prospective study of proton radiotherapy for rhabdomyosarcoma showing equivalent efficacy with photon treatment.
11/25/20148 minutes, 14 seconds
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An Advance for the Treatment of Osteosarcoma

This podcast provides observations and commentary on the JCO article "Randomized, Double-Blind, Phase II Study of Regorafenib in Patients with Metastatic Osteosarcoma" by Davis et al. My name is Brian Van Tine, and I am an Associate Professor of Medicine in the Division of Oncology at Washington University School of Medicine. My oncologic specialty is sarcoma. Osteosarcoma (OS) is the most common type of primary malignant bone cancer, frequently occurring in children and adolescents. It can also be found in older adults around the age of 70, but unfortunately, though rare, can be found in patients of any age. Thus, Osteosarcoma is a disease that not only do pediatric oncologists need to know about, but also adult oncologists. Osteosarcoma occurs primarily at the metaphysis of the bone, in regions of rapid bone growth, in bone-forming cells called osteoblasts. Various risk factors for the development of osteosarcoma include underlying bone pathologies, such as Paget’s Disease, prior radiation treatment, and genetic predisposition due to mutations, such as Li-Fraumeni Syndrome, caused by mutations to TP53, or in retinoblastoma mutation patients. Currently, in the curative setting, OS is treated with chemotherapy with cisplatin, doxorubicin, and high-dose methotrexate (HD-MTX), followed by surgical resection of the tumor.  Patients who relapse with metastatic disease have limited options, regiments such as ifosfamide with etoposide and gemcitabine with docetaxel are used with an expected 4-month PFS of only 12%, but the standard of care for osteosarcoma has not changed in 30 years. This is where the Sarcoma Alliance for Research and Collaboration, or SARC for short, comes in.  SARC is a non-profit organization dedicated to the development and support of research for the prevention, treatment and cure of sarcoma.  It is a collaborative group comprised of leading sarcoma physicians dedicated to performing clinical trials in rare diseases.  It is their 24th trial and is the subject of the JCO article that accompanies this podcast, where Dr. Lara Davis and colleagues report their findings of a Randomized, Double-Blind, Phase II Study of Regorafenib in Patients with Metastatic Osteosarcoma. This trial took place across 12 US centers between 2014 and 2018 and enrolled 42 patients between the ages of 18 and 76. Once again, the age distribution highlights that osteosarcoma is not just a pediatric disease, and that there is a dedication to rare disease researchers to accrue to rare disease clinical trials at SARC.   In this trial, patients were randomized one to one to either Regorafenib or placebo on a 28-day cycle and responses were assessed using RECIST version 1.1 every 8 weeks.  At the time of progression on placebo, patients were allowed to crossover to Regorafenib. Following the release of the European REGOBONE trial, a study of similar design that showed a significant benefit of regorafenib in osteosarcoma patients, an independent Data Safety and Monitoring Committee (DSMC) was convened by SARC due to concerns regarding continuing to enroll on a placebo-controlled study. The committee recommended closing the study after enrollment of 42 or the 48 planned patients.    Here is what they found.  At the time of analysis, they found a progression free survival of 3.6 months for Regorafenib and 1.7 months for placebo with a hazard ratio of = 0.42; a 95% confidence interval of 0.21-0.85, and a p=0.017.  Given the crossover design, there was no overall survival seen with a p-value of 0.62.   In addition, no new safety concerns with regorafenib treatment were identified during SARC024 and adverse events were generally manageable with dose reductions.  Notably, the median dose at the end of blind treatment was 120 mg. Taken together, this makes this the second trial to clearly show benefit for the use of single agent Regorafenib for the treatment of Osteosarcoma Highlighting the issues with using RECIST to evaluate tumors that make bone in their matrix, only 3 patients on Regorafenib achieved a partial response.  Whether this is a cytostatic response to Regorafenib or part of the bone biology of osteosarcoma will need to be determined in future work.  There are a number of meaningful observations that come from this trial.  First, and most obviously, Regorafenib is active for the treatment of osteosarcoma and it is oral.  While at this time, it is not listed in the NCCN guidelines, this publication makes the second randomized trial supporting its use.  I would hope the guidelines change to reflect these publications soon. Next, there was a very important paper published in JCO in 2016 by senior author Katy Janeway. It was a summary of seven negative phase II trials from the Children’s Oncology Group (COG) that established the natural history of unresectable osteosarcoma to have an event free survival (EFS) of 12% at 4 months.  They concluded that, “This evaluation provides a baseline for disease progression in a population of children and young adults with recurrent/refractory osteosarcoma that can be used as comparison for the design of future phase II trials in osteosarcoma.” In the current trial and the REGOBONE trial, the placebo arms of this trial and the REGOBONE study demonstrate similar rapid progression: 10% in 16-week PFS in SARC024 and 0% in 12-week PFS in REGOBONE. These become the 8th and 9th trials with a placebo arm that supports the data of the 2016 JCO publication that stated that the progression free survival of placebo for the treatment of osteosarcoma is well established. To be fair to the authors and to be clear, SARC24 was started two years before the Janeway publication, but are supportive of stopping placebo controls in phase II trials of osteosarcoma in future trial designs. Once again, the authors are to be congratulated on their findings, which I find practice changing.  Their dedication to rare cancer research is benefitting patients that agree to participate in clinical trials.  Working together they have identified an active agent for the treatment of osteosarcoma.  It will be interesting to see what the next steps are for the SARC team, as they have proposed combination studies based on Regorafenib in their discussion.  Finally, rare disease research and clinical trials in sarcoma are desperately needed to improve the outcomes of our patients.  Thank you to JCO for highlighting the work from Lara Davis and colleges and the Sarcoma Alliance for Research and Collaboration.  This national organization has sites across the country where sarcoma patients can enroll on clinical trials.  A list of adult and pediatric sarcoma referral centers and the clinical trials that are available in sarctrials.org.  This concludes this JCO podcast. Thank you for listening.
4/23/20197 minutes, 5 seconds
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Programmed Cell Death-1 Pathway Inhibitors Enter Center Stage as First-Line Treatment of Advanced Merkel Cell Carcinoma

This JCO Podcast provides observations and commentary on the JCO article Durable Tumor Regression and Overall Survival in Patients with Advanced Merkel Cell Carcinoma Receiving Pembrolizumab as First-Line Therapy by Paul Nghiem, MD, PhD et al. My name is Reed Drews, and I am a member of the Cutaneous Oncology Program at Beth Israel Deaconess Medical Center in Boston, MA. My oncologic specialty is non-melanoma skin cancers.   Merkel cell carcinoma is a rare, aggressive neuroendocrine skin malignancy with high propensity for local recurrence and regional lymph node and systemic metastases. Its incidence rises exponentially with aging and is 10-fold higher in chronically immunosuppressed patients. When Merkel cell carcinoma is advanced and/or unresectable, historical 5-year overall survival rates are low, from 14 to 27%. Cytotoxic chemotherapies, like platinum plus etoposide used in other high-grade neuroendocrine malignancies, have not yielded durable response rates.   The cutaneous cell (or cells) of origin in Merkel cell carcinoma remains controversial. Nevertheless, scientists have identified 2 pathogenetic pathways leading to Merkel cell carcinoma. In 80% of cases, clonal integration of a polyomavirus leads to Merkel cell polyoma virus-positive Merkel cell carcinoma. In the other 20% of cases, ultraviolet light-induced DNA damage leads to polyoma virus-negative Merkel cell carcinoma. Polyoma virus-negative Merkel cell tumors display predominant cytosine to thymine transitions, a signature of DNA damage from UV light, and they have a 100-fold greater mutational burden than virus-positive Merkel cell cancers. For both subtypes, loss of immune surveillance, as with aging or chronic immunosuppression, contributes to Merkel cell carcinoma development, with diminished non-self-antigen recognition of UV-induced neo-antigens in virus-negative tumors and viral oncoproteins in Merkel cell polyoma virus-positive tumors.   Given these factors, investigators have recently studied whether immune checkpoint inhibitors might hold promise for managing advanced Merkel cell carcinoma. To date, 3 antibody inhibitors of the programmed cell death-1 pathway (abbreviated PD-1), including anti-PD-ligand-1 avelumab, anti-PD-1 nivolumab and anti-PD-1 pembrolizumab, have been tested in patients with chemotherapy-refractory and/or treatment naïve Merkel cell carcinoma. The 62% objective response rate from avelumab in treatment-naïve Merkel cell carcinoma was nearly twice that observed in chemotherapy-refractory disease. In 2017 avelumab became the first immune checkpoint inhibitor approved by the FDA for advanced Merkel cell carcinoma. Nivolumab yielded similar results, as did pembrolizumab according to a 2016 report from Nghiem and colleagues of a multicenter, phase 2, non-controlled study with 26 patients.   As reported in this JCO publication, Nghiem and colleagues have now increased their cohort to 50 patients through the multicenter expanded phase 2, Cancer Immunotherapy Trials Network-09/Keynote-017 trial. They administered pembrolizumab 2 mg/kg intravenously every 3 weeks for up to 2 years. Median follow-up time was 14.9 months, with a range from 0.4 to 36.4 months. This represents the longest follow-up to date of any anti-PD-1 pathway inhibitor for first-line treatment of advanced Merkel cell carcinoma. The 50-patient cohort included 43 patients with (stage IV) distant metastatic disease and 7 with stage IIIB recurrent locoregional disease not amenable to definitive surgery or radiation therapy. All patients had normal organ and bone marrow function and an Eastern Cooperative Oncology Group performance status of 0 to 1. Key exclusion criteria were previous systemic therapy for unresectable Merkel cell carcinoma, immunodeficiency or systemic immunosuppressive therapy, active autoimmune disease, concurrent second cancer, and active central nervous system metastases.   The median age of enrolled patients was 70.5 years, with 80% age 65 or older. 64% of patients had Merkel cell polyoma virus-positive tumors. For previous management of their primary Merkel cell carcinoma, 42 patients had had surgery, and 35 patients had had radiation treatment. While no patient had previously received systemic therapy for advanced Merkel cell carcinoma, 3 patients had received adjuvant chemotherapy greater than 6 months prior to study enrollment.   Patients received a median of 10.5 doses of pembrolizumab – range 1 to 35 doses—and the median treatment duration was 6.6 months – range 1 day to 23.6 months. Radiographic responses were assessed centrally per Response Evaluation Criteria in Solid Tumors, version 1.1. Responses were generally rapid and durable with 2.8 months as the median time to response – range 1.5 to 9.7 months. The objective response rate to pembrolizumab was 56%, with complete and partial responses of 24% and 32%, respectively; 10% had stable disease; and 32% had progressive disease.   At time of data analysis, 20 of 28 responses were on-going, and the median durability of response had not been reached. The Kaplan-Mier estimation of response durability at 24 months was 79.1%. Median progression free survival was 16.8 months, and the Kaplan-Mier estimation of progression free survival at 24 months was 48.3%. Median overall survival had not yet been reached. The Kaplan-Mier estimation of overall survival rate at 24 months was 68.7%.   Tumor viral status, as determined by small T-antigen specific antibodies in serum or large T-antigen expression in tumor biopsies by immunohistochemistry, did not correlate with any study outcomes, such as progression free survival or overall survival. However, a trend towards improvement of these outcomes appeared in patients with PD-L1-positive tumors, as defined by cell-surface PD-L1 expression on at least 1% of tumor or immune cells.   The safety profile of pembrolizumab in advanced Merkel cell carcinoma was similar to that in other studies of anti-PD-1 pathway inhibitors: 28% of patients had grade 3 or greater treatment-related adverse events, causing 14% of patients to discontinue treatment. A 73-year old male patient with widely metastatic Merkel cell carcinoma and pre-existing atrial fibrillation died after developing pericardial and pleural effusions 1 day after one infusion of pembrolizumab. Other adverse events were generally manageable and typical of complications of anti-PD-1 pathway inhibitors, including adrenal insufficiency, colitis, hyperthyroidism, hypothyroidism, infusion-related reaction, myocarditis, pancreatitis, pneumonitis, maculopapular rash and thyroiditis.   With such impressive rates of durable tumor regression and overall survival, on December 19, 2018, the FDA granted accelerated approval to pembrolizumab for treating patients with recurrent locally advanced or metastatic Merkel cell carcinoma. Today’s standard of care for advanced Merkel cell carcinoma is an anti-PD-1 pathway inhibitor, and the NCCN Clinical Practice Guidelines in Oncology in 2018 recommended avelumab, nivolumab and pembrolizumab as preferred first-line therapy for advanced Merkel cell carcinoma, ahead of cytotoxic chemotherapy.   Future studies must determine what role anti-PD-1 pathway inhibitors will play in the neo-adjuvant and adjuvant settings when managing early stage Merkel cell carcinoma with high-risk features. Prior to immune check point inhibitors, neo-adjuvant and adjuvant chemotherapy were considered case-by-case, absent strong evidence for benefit.  However, now with impressive results from anti-PD-1 pathway inhibitors in advanced Merkel cell carcinoma, adjuvant nivolumab and avelumab are being evaluated in 2 randomized phase II trials. Nivolumab is also undergoing study in the neoadjuvant setting, and researchers presented promising preliminary results of a phase I/II study at the 2018 American Society of Clinical Oncology Annual Meeting. We look to Nghiem, his colleagues and other investigators to keep us informed regarding future advances, including insights into mechanisms of resistance to the immune checkpoint inhibitors.   This concludes this JCO Podcast. Thank you for listening.
3/8/20199 minutes, 29 seconds
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Don't Treat Me Like a Child: The Intensification of Conventional Chemotherapy in Adults With Acute Lymphoblastic Leukemia

GRAALL-2005 study shows no overall benefit for cyclophosphamide intensification in older adults with ALL, despite a general improvement in outcomes for the younger adults. Read the associated article by Huguet et al on JCO.org.
6/4/20189 minutes, 22 seconds
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Can We Simplify the Treatment of Myelofibrosis?

In this randomized trial, momelotinib was non-inferior to ruxolitinib for spleen response but was less effective in controlling symptoms. Related Article: SIMPLIFY-1: A Phase III Randomized Trial of Momelotinib Versus Ruxolitinib in Janus Kinase Inhibitor–Naïve Patients With Myelofibrosis
9/21/20178 minutes, 51 seconds
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How Should We Manage the Financial Toxicity of Cancer Treatment?

A study by Ramsey and colleagues suggests that extreme financial distress as manifested by personal bankruptcy might be associated with worse mortality in cancer patients. Long-term solutions have to focus on policy shifts involving how we set prices for drugs and how we design health insurance, but for more immediate solutions interventions have to focus on the oncologist and patient.
3/9/20167 minutes, 37 seconds
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FISH for Smoldering Multiple Myeloma

This podcast discusses Neben and colleagues' paper on FISH findings and smoldering myeloma.
11/4/20139 minutes, 1 second
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Should Myeloma Residual Disease Become a Standard Assay for Large Cooperative Groups and Myeloma Referral Centers?

Minimal residual disease predicts outcomes in myeloma.
6/3/20139 minutes, 9 seconds
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In a Sea of Data the Water is Still Murky: Meta-Analysis of Cognition in Breast Cancer

Cognitive impairment occurs in a subset of breast cancer survivors after chemotherapy but the incidence remains unknown.
8/27/201211 minutes, 30 seconds
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Pre-Operative Metformin in Early-Stage Breast Cancer

This podcast reviews the rationale behind evaluation of metformin as a potential anti-cancer agent in breast cancer and describes the findings of a recent window of opportunity trial looking at the impact of metformin upon proliferative indices in women with early breast cancer.
5/7/20129 minutes, 1 second
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To Biopsy or Not to Biopsy? That is the Question

Biopsy of presumed metastatic breast cancer sites confirms the diagnosis in most women and alters therapy in 14% of women in a prospective study of 121 patients but its impact on outcome could not be reliably assessed.
12/7/20118 minutes, 11 seconds
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1q Gain, a Prognostic Biomarker in Nephroblastoma, and What’s Next?

This podcast comments on two independent pediatric studies on both sides of the Atlantic showing the relevance of 1q gain in poor prognosis Wilms tumors which raises the perspectives for therapeutic modifications.
7/11/20169 minutes, 2 seconds
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Hematopoietic Stem Cell Transplant for Children With Acute Lymphoblastic Leukemia at BFM Centers: Comparable Results With Matched Sibling Donors and Matched Unrelated Donors

Review and comments on BFM experience of ALL hematopoietic transplantation.
3/19/201511 minutes, 2 seconds
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Carboplatin-Gemcitabine-Bevacizumab: Expanding Treatment Options for Recurrent Platinum Sensitive Epithelial Ovarian Cancer

Carboplatin-Gemcitabine-Bevacizumab represents an additional regimen to consider for management of recurrent platinum sensitive epithelial ovarian cancer, although it raises several questions regarding the role of bevacizumab in this disease setting.
4/23/201212 minutes, 29 seconds
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Using BCR-ABL Transcript Levels After 3 Months of Therapy on Imatinib is the Best Way to Predict Long-Term Outcome for Patients with CML Treated with Imatinib

The study by Marin et al is another milestone in our understanding how to manage CML patients on tyrosine kinase inhibitors.
1/9/20128 minutes, 55 seconds
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Targeting the Angiopoietin-Tie2 Axis: A Promising Alternative Antiangiogenic Strategy for Epithelial Ovarian Cancer

Targeting the Angiopoietin-Tie2 axis is a promising alternative antiangiogenic strategy for the treatment of ovarian cancer that exhibits non-overlapping toxicities with inhibitors of the VEGF signaling pathway.
12/19/201111 minutes, 9 seconds
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Disparities in Systemic Therapy for Breast Cancer

This podcast provides a commentary on the article by Wu et al that addresses disparities in systemic therapy for breast cancer.
12/5/20117 minutes, 43 seconds
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Obesity and Colorectal Cancer: What's the Big Deal?

This podcast summarizes the findings of this JCO article and provides commentary on its applicability to practice.
11/28/20119 minutes, 34 seconds
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Biomarker Selection for Maintenance Therapy in Advanced NSCLC

EGFR mutation is a predictive biomarker for maintenance erlotinib but its clinical application is limited. This podcast will explain why.
9/29/20119 minutes, 17 seconds
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Osteonecrosis in Pediatric Acute Lymphoblastic Leukemia

This podcast summarizes the incidence and long-term outcome of osteonecrosis in a large prospective study of children treated for acute lymphhoblastic leukemia with the dexamethasone-based Dutch Childhood Oncology Group-ALL 9 Protocol.
9/26/201110 minutes, 12 seconds
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Response to Neoadjuvant Systemic Therapy for Breast Cancer in BRCA Mutation Carriers and Non-Carriers: A Single Institution Experience

This podcast reviews the retrospective study by Arun et al. and discusses the lack of consensus regarding the relative chemosensitivity of breast cancers in mutation carriers and non-carriers as well as the optimal neoadjuvant chemotherapy for mutation carriers.
8/31/201112 minutes, 17 seconds
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Ensuring Employment After Cancer Diagnosis

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

Shannon Westin, Veena Shankaran, and Scott Ramsey discuss the issue of financial toxicity among low- and middle-income cancer patients.   TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Westin: Welcome to JCO After Hours. I am your fearless leader, Shannon Westin, the editor for social media of the Journal of Clinical Oncology, and it's my great pleasure to bring you another episode. Today, we are going to be talking about a paper published in the January 7th version of the JCO called “Risk of Adverse Financial Events in Cancer Patients: Evidence From a Novel Linkage Between Cancer Registry and Credit Records.” And none of the participants have any conflicts of interest. I am joined by two amazing people. First, let me introduce Dr. Veena Shankaran. She is a physician in the Seattle Cancer Care Alliance, professor in the Division of Medical Oncology at the University of Washington School of Medicine, and co-director of the Hutchinson Institute for Cancer Outcomes Research at Fred Hutch Cancer Research Center. Hey, welcome. Dr. Shankaran: Hi, Shannon. Thanks for having me. Dr. Westin: I'm so excited to have you. And she's joined by her colleague, Dr. Scott Ramsey, who is a professor in the cancer prevention program in the Public Health Sciences Division at Fred Hutch and the director of the Hutchinson Institute for Cancer Outcomes Research at Fred Hutch. Welcome, Dr. Ramsey. Dr. Ramsey: Shannon, great to be here. Dr. Westin: This is such an exciting paper and so very timely. We've been certainly hearing—I wouldn't say a lot but more and more about financial toxicity over the last few years, I'd say very appropriately. So, let's start with the basics. Let's make sure we level set. Can you educate our listeners on what financial toxicity is and what it means for patients with cancer? Dr. Shankaran: Yeah, absolutely. I can start. Financial toxicity, I think, is a relatively recently recognized complication, if you will, of cancer treatments. And really, I would say over the last decade or so, the literature has just sort of exploded describing kind of the various aspects of this big problem. I think one conceptual model that sort of helps me understand financial toxicity was developed by Robin Yabroff and Reggie Tucker-Seeley that really describes financial toxicity is that trifecta of material, financial hardship, kind of what we think of as out-of-pocket expenses, debt, the money that you pay to get cancer care. The other aspect is sort of the indirect coping mechanisms related to the cost of cancer care, like forgoing treatment, forgoing surveillance, cutting back on treatment-related cost concerns. So, more of the behavioral aspects. The final aspect is sort of the psychosocial-psychological aspect of financial hardship, which is really just the distress related to how am I going to pay for all of this? How is this going to affect my children and sort of our financial well-being? It's a big problem, a broad problem that touches on a variety of issues and also affects families and caregivers too. Dr. Ramsey: I would add that financial toxicity really got into the literature probably seven or eight years ago. The term itself was coined by an oncologist, Yousuf Zafar, at Duke University. He told me he actually heard it from a patient who, when he was describing all the toxicities of cancer treatments, the patient said, ”Well, don't forget financial toxicity.” And so, that's how the term, according to Yousuf, was coined. He published a series of case reports on patients who experienced financial toxicity. And our group did a study where we linked federal bankruptcy records to the cancer registry and found about a 65% higher risk of bankruptcy among cancer patients. We also did a subsequent paper looking at mortality among cancer patients who went bankrupt compared to cancer patients who did not and found excess mortality. So, we do have evidence that severe financial toxicity, i.e. bankruptcy can actually affect survival. And now, since that time, there have been other papers that have looked at quality of life, adherence to therapy and have found those as adverse impacts as well. Dr. Westin: Well, that makes sense when you're looking at that trifecta. I hadn't heard that. That was really educational for me. But looking at the ways that patients cope with this issue and actually foregoing their cancer treatment. And I think I've certainly heard about that in terms of like diabetics, like maybe taking their insulin every other day versus every day. You could see where we would see something similar in a patient with cancer. Do we have any data to know how common this is across our patients with cancer? Are there specific cancers where we see this more commonly, or is this kind of every cancer type is at risk? Dr. Shankaran: The non-adherence aspect? Yeah, I mean, I think in the studies that we've done, it hasn't been reported terribly commonly by patients. So, probably on the order of 7 to 10% of patients in the studies that we've done, though you have to imagine it's much, much more common and prevalent, particularly in cancers where people are taking oral cancer therapies, and these tend to be associated with a lot of high out-of-pocket costs, these drugs that go through the prescription plans. Actually, I mention a few papers that have been published over the years by Stacie Dusetzina, who's a wonderful colleague of ours, who's looked at how changes in copay, not even by a lot of money, but just slight increases in copays for these oral cancer medicines can significantly impact not only adherence to prescriptions that have been built, but whether or not people actually fill their prescriptions. Dr. Westin: Wow, that makes sense. So, what led you all to this particular work that's described in the paper in the JCO? Dr. Ramsey: As I mentioned, we had this bankruptcy study where we linked federal bankruptcy—and bankruptcy is an extreme form of adverse financial outcome. And I think our interest was, well, what happens with less extreme forms of adverse financial outcomes. And that led us, I think, to search for ways to characterize less severe forms, and Veena and I have done surveys over the years where we've asked patients, but it's very hard to define something that's on a population-wide level. So, we came to this idea of using credit report data and that led to a very long journey—I think it was about a two-year journey—to get one of the credit reporting agencies to agree to allow us to link their database with the cancer registry in our state. Dr. Shankaran: I always laugh when we talked about the study, because I feel like we've spent years—I mean, two years might be right, Scott, but in my head, it feels like closer to a decade—just trying to make this happen, because it was a long process trying to link the credit records to the cancer registry data. And to add to what Scott already said, part of our motivation for doing this is that there have been a lot of studies that have used survey-level data and where we've asked patients to describe what their financial burden is, and it's substantial. Sunny reports anywhere from 30 to 75% of cancer patients report financial hardship. These surveys, they're subject to interpretation, whether patients understand the question being asked. There's bias in terms of who participates in a study in the first place. And so, our feeling was, can we be a little bit more methodical in trying to understand what the impact is and looking at measures that—almost everyone has access to credit on some level or the other. So, it's a very kind of standard way of looking at people's financial status to use credit data. So, that was our goal in trying to understand, as Scott said, at a population level, what is the impact? Dr. Westin: One, that's brilliant, and that makes total sense. And anytime you can get population-level data, as opposed to the kind of trying to get people to answer questions and give you details, is always ideal. But I loved your aside about the two-year process because we have trainees listen to this or young investigators, and it's always good for them to understand sometimes the amount of time that can come—and this is obviously a really high-impact paper and so important, but even when we're doing just simple retrospective studies, the amount of time sometimes that goes into it, I love that kind of background, just to tell people it's okay if it takes a long time. It's still going to have an impact and still going to be important. That's a great segue into just really a review of some of the methods that you used for the study, what were your primary outcomes, and how you laid everything out. Dr. Shankaran: Yeah, so we essentially went to the credit agency—TransUnion, in this case—and asked them to provide us with a long list of credit attributes that we were able to link with the cancer registry. And there were many, many items that they gave us of credit data, of which we went through them all and really tried to understand the financial literature, the landscape of what credit measures are important, what indicates kind of this spiraling down towards bankruptcy, what happens first, what happens next? And so, with a lot of guidance from the economic literature and the folks from the credit agencies, we defined three categories of financial hardship that we looked at. The first one was what we categorized as severe financial hardship, which we described as inability to pay the bills as evidenced by third-party collections or charge-offs, which are basically kind of like collections where it's not worth it to the creditor to actually collect on it. The next is the kind of more of the impacts on or events that suggests potential action against a person's property. So, tax liens, delinquent mortgage payments, on to the most severe kinds of financial hardships, actually losing a home through foreclosure or repossession by the bank. And so, we took individuals with cancer, matched them by age and sex to individuals without cancer, and essentially looked to see how common these events were in the cancer population versus the non-cancer population, and then controlling for confounding factors that could also influence this association between cancer diagnosis and financial hardship. We found that cancer patients had a significantly higher, 71% greater risk of adverse financial events than individuals without cancer. Dr. Westin: That's so interesting and then can you take us through the bottom line of what y'all found? Dr. Shankaran: Well, the bottom line is that when you take people with cancer and similar people without cancer, cancer diagnosis has a significant impact on risk for major credit events that are likely to have, we think, long-term impacts on people's financial health. And that's a problem, and this does not seem right, and it should not happen that people who develop a disease, for the most part, no fault of their own. I mean, this is a major health shock that leads to potentially severe and long-term effects on people's financial health. Dr. Ramsey: And overall, the excess risk for any of these adverse financial outcomes was about 71% higher for the cancer patients compared to the non-cancer patients. Dr. Westin: Wow. That's an incredible number. I read your paper, but still hearing it just is incredible. So, what can we do? What recourse do we have here? How can we help support these patients? Dr. Shankaran: Well, I think you touched on this a little bit earlier, Shannon, which is that, how do we screen people for financial risk in the first place? How can we identify those who are most likely to develop these adverse events? I wouldn't say that screening everyone's credit score and credit status is really feasible at the clinic level, but our hope is to use these data along with other studies we've done to see if we can develop risk scores to try and predict those who would be most likely for these kinds of severe credit impacts. I think, in addition to screening, what we're really thinking about a lot, and I'll let Scott add to this in a second, but is what can we do at the clinic level to help avoid financial hardship. And we've been doing a lot of work on developing financial navigation interventions, which is essentially kind of like patient navigation, where you're trying to get people to their appointments and get them there on time, but really instead of navigating the logistics, navigating more of the financial aspects. So, hooking them up with resources for copay assistance or lodging, transportation, in the hopes that kind of comprehensively addressing all the financial aspects of care can help, ultimately, people stay on treatment and live better, have better outcomes. Dr. Ramsey: Yeah, and I'd add that I think the immediate things that we can do for patients—Veena outlined very well—screening people to find out people who are financially fragile, getting those folks to financial counseling services so that they can adjust their spending and saving so that they can withstand what could be months or years of excess costs due to cancer. It's worth noting that a lot of people don't choose to enter cancer, and they come with the financial situation they have, and some are well off, and some are very tenuous. And in order to prevent people getting into a disastrous situation, having someone look at their current situation is critical, and we've worked with a bankruptcy judge who says often it's the people that are kind of in the low or middle income that are at the biggest risk for falling because they have expenses that we all have, cable bills and car payments and everything else. And they don't think about adjusting those when they have cancer because they don't think this is going to be an issue, and pretty soon the added expense of paying for cancer care and the loss of work and the caregiving needs pile on to all the other expenses, and before they realize it, they're in serious trouble. It's much harder to get out of trouble at that point than to try to adjust your expenses to accommodate what's going to be a long journey for many people with cancer. Dr. Westin: What about more globally? I think that you addressed kind of at the clinic level. What about from an advocacy standpoint? Drug charges are the elephant in the room here, right? And I think one of you mentioned copays. I feel like we do quite a bit of targeted therapy in GYN oncology with PARP inhibitors and now lenvatinib and pembrolizumab, and it's just such a wide range. I have patients that have $0 copays and patients that it's going to be $2000 dollars a month or even more. So, how do we level that? And how can we advocate to our lawmakers to try to reduce the bonkers costs right now of targeted therapies and novel drugs in America? Dr. Ramsey: Well, I think it'd be easy to blame the pharma companies and the high price of drugs, but it really is a multifaceted problem. And I personally think we do need to have some policy discussions about what we can do to address this because it's so prevalent. I should add that it goes beyond cancer.  People with other chronic diseases surely suffer the same problem. But yes, the drugs are very expensive. But there’s also the insurance plans have copay and deductible structures that really are beyond the means of many Americans. I mean, as we mentioned, in the paper, a federal reserve study found that only 40% of US households could afford a $400 unexpected bill in their average life. And we know that's going to happen in probably the first week of a cancer diagnosis or more. So, I think the insurance needs to be restructured to address the fact that people can't afford the out-of-pocket costs that are part of the insurance system right now. I also think physicians need to have some role in this. Most of us don't prescribe thinking about the cost and its impact. In situations where there is an option between different regimens, one which would have a bigger out-of-pocket burden and one would have less, if we know the patient's financially fragile and the outcomes are similar, it's worth having that conversation to try to protect our patients. So, yes, the prices of drugs, we need to address that, but we also need to address insurance coverage. And as providers, we need to be mindful of what we're prescribing and how that impacts patients. Dr. Shankaran: I'll just add to what Scott said. I think one of the key things that we need in order to accomplish that goal of trying to be mindful about what we're prescribing is understanding what the costs are. So, there's very little cost transparency. You probably can't tell your patients that you treat how much the drug is going to cost them until you run it through the billing coordinator or people try and pick up the medication at the pharmacy or the bill comes to their house. So, we have not good strategies in place to be able to identify the cost in real-time and also the cost of alternatives. So, it's only helpful that we can adjust our decisions and include cost information in the shared decision-making process so long as we actually have that information. So, I think that's kind of part of the problem. I totally agree with everything Scott said, and will just add the way insurance works is that you pay more for things that are expensive for the most part, and you reach a cap at some point, which is one of the many good things that came out of the Affordable Care Act is that there are at least limits on how much you can spend over the course of a year for most insurance plans. But that limit is around $13,000 for a family over the course of a year. And given what Scott just said about how much liquid cash that most households have—it's $400 or less in most households in America—that's going to be really hard for most people to cope with. Dr. Westin: Well, thank you both. That went by so fast, and I really appreciate how in-depth you were able to get in a really accessible way, especially for somebody like me, who is just a novice at this and actually has been known to say, “I'm blissfully unaware of the cost of that,” which now I'm thoroughly chastened and will work very hard to expand my understanding so that my patients are in a better situation. So, thank you both for all of your hard work in this area. Really, really appreciate everything you've done and can't wait to see what comes next. And with that, I think we'll close this episode of JCO After Hours. Thanks to all our listeners, and we will see you next time.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
4/1/202219 minutes, 44 seconds
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JCO After Hours: A Discussion With Kirsten Beyer and Jennifer Griggs

Dr. Shannon Westin, Dr. Kirsten Beyer and Dr. Jennifer Griggs discuss how mortgage lending bias and residential segregation intersect with cancer disparities and survival outcomes.   TRANSCRIPT [MUSIC PLAYING]   SHANNON WESTIN: Hello, everyone. My name is Shannon Westin, and I'm an Associate Professor at the University of Texas MD Anderson Cancer Center in the Department of Gynecologic Oncology and Reproductive Medicine. And I currently serve as the Social Media Editor for the Journal of Clinical Oncology. And we're starting a brand new podcast series to try to bring really exciting research that's being published in the JCO to you, and I'm so excited to kick off this series with a group of very accomplished women who are covering something that I don't think a lot of us don't know very much about. So I'm really excited to learn a ton over this next few minutes. So it's my pleasure to introduce Dr. Kirsten Beyer, who is an Associate Professor in the Division of Epidemiology in the Institute for Health and Equity as well as the Director of the PhD program in Public and Community Health at the Medical College of Wisconsin. We are also joined by Dr. Jennifer Griggs, who's a Professor the Department of Internal Medicine, Division of Hematology Oncology, as well as a member of the Institute of Health Care Policy and Innovation at the University of Michigan. She does predominantly practice taking care of women with breast cancer. Welcome, doctors. JENNIFER GRIGGS: Thank you. KIRSTEN BEYER: Thank you very much. SHANNON WESTIN: So we're talking today about the manuscript "Mortgage Lending Bias and Breast Cancer Survival Among Older Women in the United States" that Dr. Beyer published just this month in the JCO. In addition, Dr. Griggs and her colleague Dr. Pleasant were invited to participate in an editorial called "Contemporary Residential Segregation and Cancer Disparities." So let's get into to what was covered. So I think for me, the lowest hanging fruit here, Dr. Beyer, is understanding what exactly is redlining, because that was one of the critical exposure that you were assessing amongst these women with breast cancer. KIRSTEN BEYER: Thank you, Dr. Westin. Yes, redlining-- I think most people think about redlining as being a historical practice, where mortgage lenders would essentially draw red lines around particular neighborhoods and then not lend mortgages in those areas, regardless of whether or not the applicant for that mortgage was otherwise qualified. So it's generally thought of as a historical practice. But what we've done in this study is to look at some more contemporary data and create a new measure that we think represents contemporary redlining, maybe not in the legal sense in terms of housing discrimination. But this measure represents essentially the odds ratio of denial of a mortgage application for a property in a local neighborhood as compared to the metropolitan area as a whole. So we're really looking to see which areas of our US cities are systematically denied mortgage applications. By denying those mortgage applications, they are suffering from disinvestment, and I would argue structural racism is guiding a lot of that practice. SHANNON WESTIN: So can you explore that a little bit more with us? And how do you find that type of data? Where do you get this information about these denied mortgages? How do you get into the different covariates like race, ethnicity, things like that? KIRSTEN BEYER: Sure. So I think a little history lesson is important first. Between the historic practice of redlining and today, there have been a number of major laws that have been passed in the United States really to try to overcome housing discrimination. Some of the most important ones are-- in the Civil Rights Act of 1968, there was something called the Fair Housing Act, and that act prohibited discrimination in the sale, rental, and financing of housing based on race, religion, and national origin. And since then, they've added a few more protected categories. And then right after the Civil Rights Act of 1968, there was something passed called the Home Mortgage Disclosure Act. And this act was essentially to bring transparency to mortgage lending in this country. The idea was that we were requiring public disclosure of loan-level information about mortgages that were lent in the country. And the goal was to shed light on lending patterns, including those that could be discriminatory. And so the HMDA data-- it's commonly referred to as "hum-duh." That HMDA data has been collected then since 1975. And that database evolves over time, but we use that data for 2007 to '13 to really try to understand what are the mortgage lending patterns in our US cities in terms of their spatial distribution. And so there are a number of covariates that we were able to control for there. There are some things that we're not able to control for. I'm excited that the HMDA database has recently improved, and there are some new variables that are going to become available in the coming years. So what we did with the HMDA database was to calculate an index of redlining, so an odds ratio of denial of a mortgage application for a property in a specific neighborhood compared to all the properties across the metropolitan area. And so it's an area-level measure, a neighborhood-level measure. And then we put that measure into a statistical model to see what happens to women diagnosed with breast cancer if they live in redlined areas compared to if they live in other areas. And so we were able to control for a number of other factors, including race, including tumor characteristics, age, stage at diagnosis, and then to see what is the added effect of redlining over and above the things that we already know impact survival. So what we found was that women living in redlined areas in the United States were more likely to die faster after breast cancer diagnosis than women living in other areas. We also found that among people living in redlined areas, there was a discrepancy in terms of the race and ethnicity of those women. So 79% of Black women, 57% of Hispanic women, and 34% of white women lived in redlined areas in our sample. SHANNON WESTIN: That's so interesting, because I think we've all read and seen across a number of different cancer types how race and ethnicity can be associated with worse outcomes. So I think you're starting to scratch the surface of why that might be. Now, do we think that is there an association with other factors like socioeconomic status or insurance or anything like that? KIRSTEN BEYER: Yes, I think those are really good questions. Not all databases contain all of the information we would like. But in SEER-Medicare, which is the database we use, we know that all of the women have health insurance because it's a linked database with cancer registry data and then Medicare claims data. So health insurance wasn't a factor here, but we certainly know that it could be a factor in a larger sample of women across the age spectrum. And I think when you get into questions of socioeconomic status, you also have to think about, as opposed to statistically controlling away the effect of socioeconomic status, what is the mediating effect? Or what is the explanation? What factors explain the relationship between redlining and breast cancer survival? So I think that's where we'll see a lot of the important explanations for how does redlining contribute to survival. SHANNON WESTIN: Thank you. I think you nailed it right there, because finding a problem is, of course, important, but then what do we do next? Dr. Griggs, I thought your editorial was just so great at providing context for this issue, and I was wondering if you could expand a little bit more on this idea around residential segregation and how it impacts outcomes for these patients. JENNIFER GRIGGS: Thank you very much, and thanks for including me on this great podcast. It's so important to understand that place matters more than race, and we've known this for quite a while. So that area-level factors are associated with environment-- for example, pollutants, safe water, safe places to play, safe places to exercise, transportation fragility, for example, a robust public transport system. We know that neighborhoods that are in redlined areas are more likely to be policed in different ways, which takes children from school being suspended at higher rates. There's less educational investment, but Dr. Beyer mentioned this disinvestment in neighborhoods basically has shutters all the way down. It shutters from childhood all the way to how we age and access to healthy food. We know redlined areas are associated with poor markers of diabetes control, and if you take somebody from an area that's a poor neighborhood that's segregated and give them a voucher to live in a more affluent area, that markers of diabetes improve and weight goes down. So just to think about this, that the impact of where we live affects things that we think of as personal behavior-- like, what we eat or how we control our diabetes. There are, of course, implications for access to high-quality health centers when we think about people sort of locked into certain neighborhoods, all that goes along with that, including wealth. Wealth is probably one of the biggest predictors of health and not being able to have the wealth associated with home ownership decreases economic stability. And we know these things like allostatic load or stress, sometimes called wear-and-tear effects, are associated with things like tumor biology and breast cancer. We see more triple-negative breast cancers in areas where there's more allostatic load. So imagine, we think about race as this fixed-- sometimes people even construe race as a biologic construct, when really, of course, it's a social construct that has systematically-- our systems have been put in place so that even the legislation, Fair Housing Act, can't be overcome, as shown in Doctor Beyer and colleague's paper. In other words, despite legislation, we continue to see mortgage lending bias, which we've termed contemporary redlining. Yet, we think of race as this fixed, deterministic way of describing people and explaining differences and outcome. So this kind of work is really important when we can show the effect of place independent of race and if we can show that there has been systematic construction of something so important as residential segregation. What this does is it drives us to really a call to action. A lot of ideas in there, but basically, showing where people live being associated with their outcome in breast cancer-- and this has been shown in other cancers, as well-- through pathways like economic stability and wealth, wear and tear on the body, and then to acknowledge the sad truth that things have been intentionally constructed structures. SHANNON WESTIN: I mean, I think this is really in line with a lot of what we're learning about our society and our country, the way we were educated when we were younger was that we did not always hear the truth about what really went down as this country was built. I think that you really touched on a lot of very critical points. And I think for me, a lot of times when we read about these racial and ethnic disparities, I feel like it often comes down to where people are like, oh well, it's just access to care, or lack of insurance, or they're just not focusing on these things. They're not educated. They don't know that these things are important. But what I hear the two of you saying is, it goes much deeper than that. So Dr. Beyer, I'd be interested to hear your thoughts on that with these areas. Should we be working on improving what is available to people in these areas? Or should we work on breaking down or both? KIRSTEN BEYER: Yeah, thanks, Dr. Westin. That's a great question, and it's a complicated one. I think Dr. Griggs mentioned housing vouchers. And so for example, when we are giving someone a housing voucher to move from a more vulnerable neighborhood, let's call it, to a less vulnerable neighborhood, that can improve health outcomes for sure. But we also know that there's a downside to that. Sometimes there are impacts on social support or mental health. And then on the flip side, if we are trying to improve neighborhoods themselves so that the people living in them can benefit from those enhancements, we often see that what happens is gentrification, when people who are living in those neighborhoods get displaced, and newer people, wealthier people, move in and take those amenities. So I think it's something that really requires close management with housing policy. And then I think another thing that I would add is that, as you mentioned, we're really scratching the surface. I think that's an important thing to emphasize. This is one aspect of housing. There are other aspects that are very important, like quality of housing and stability of housing, which is what Dr. Griggs mentioned. And I think it's also important to note that even if a person is denied a mortgage application because of a credit score, that credit scores, wealth, income, and many other things that are considered in the mortgage lending process are also affected by structural racism, as are things like home appraisals, mentorship, and eviction, something that we've certainly seen during the COVID-19 pandemic. SHANNON WESTIN: Wow, so thoughtful. I feel like I'm trying to take notes as fast as I can because I'm learning so much. I think we didn't hear about anything like this in our medical school and your PhD training. I don't know if you all got any type of background in this. Dr. Griggs, did you-- I mean, we never even scratched the surface with the impact of structural racism. And in fact, I think a lot of our medical education was founded in that structural racism. JENNIFER GRIGGS: I couldn't agree more, and I couldn't agree more with what Dr. Beyer said about things like housing vouchers, so I just want to acknowledge that it's not as simple as giving people a voucher, obviously. No, we are calling for structural competence. There are multiple calls that we teach medical students and current practicing clinicians and scientists the structures that have been put into place and that persist. So again, that intentionality that these systems were put in place through deliberate efforts, and it's only going to be through deliberate efforts that they're dismantled. And teaching people that individual behaviors are not predetermined or, frankly, learned. They cross multiple generations, and they reside within a place and the way not just a person, but an entire people, have been treated. And I do just want to say, although this may be new to a lot of us, that the lived experience of people who live in vulnerable neighborhoods and their life experience and their family's experience going back many generations make this not new news, right? This is old news. This is stuff people have known for generations that they're being systematically cut out of opportunities for advancement and for accumulation of wealth. So I think we just want to be-- I just want to be careful when I'm talking with my colleagues, my team, my research colleagues that this is not new knowledge. And we want to also be careful not to be parasites in a way on other people's suffering, that we want to be careful not to glorify our own ideas because number one, they're not our ideas. And number two, this type of work is the lived experience of people for many, many years, not just our neighbors and friends and colleagues. So there's so much harm that's been done, and we can celebrate advances and new knowledge, but I also think we want to focus on cultural humility and do a lot of deep listening and less talking and build trusting relationships with communities that are not about our career advancement but are really about fairness and justice. SHANNON WESTIN: I think that needs to be shouted from the rooftops, and I think it is a very careful balance, because we want this research to get out. We want to make sure people understand this. You're right. It's not new knowledge, but I think it's something that hasn't necessarily been highlighted in academic fields up until, like, the last few years, where I feel like we've started to see this. But you're exactly right. We can't just do the research and find the association. Now it's time for the next steps. And I'd be interested to hear from both of you, because, to me, there are several levels of steps that we can take. There's the local level, right? So what can we do for the patients in front of us? And then I'd be interested to hear what you all think about what do we do on the more institutional-- and by institutional, I mean, our entire country. Like, what can we do? How do we advocate for policies that will help to reverse these practices? I don't know Dr. Beyer, if you want to start. I know that was a really big question. What can we do when we're seeing patients in the clinic? Are there ways, or are there things we can offer or things that we can do on the local level that could help to address some of these disparities? KIRSTEN BEYER: Yeah, thank you, Dr. Westin. I'm not a medical doctor, but I work a lot with medical students. We have some pathways at the Medical College of Wisconsin, one on urban and community health and one on global health. And in those pathways, we do try to put forth a lot of this type of content and learning. But again, that's just a select number of students who end up getting that training. I think that structural racism is a fundamental force in our society, and therefore, it justifies a position in the core medical curriculum. I think since the murder of George Floyd, there has been a national consciousness that's been raised around this issue, that we should take advantage of that and try to push forward some core learning on structural racism for medical students. And then beyond that, I think as a patient, I can use the patient perspective. As a patient, I would want my physician to take into account my life context when providing clinical care. How hard is it for me to get to my appointment and to get there on time? How hard is it for me to find child care? How hard is it for me to obtain the prescriptions I need and maintain them with any significant cost at hand? So I think that awareness for physicians is really a first step. And then the last thing I would say is that doctors have power, and so I think it's the responsibility of those with power who are in the know about structural racism to leverage and use that power to make social change. JENNIFER GRIGGS: I really appreciate what you said from education to practice. I would add that an integrated health system would be able to think from prevention all the way up to health care. I feel like by the time people are accessing health care, a lot of other things have gotten in the way of their health, right? That's why we talk about social determinants of health. So I think we need to think about elevating the role of other people in the health care system. So even if you're in an individual practice, do you have access to a social worker? Are you including patient and family voices when you build your new office? We have transportation initiatives being made all over this country, and I know in Europe as well. So cities are being designed to undo transportation fragility and vulnerable neighborhoods. I can't emphasize enough the importance of asking communities what they need. It strikes me that the ivory tower is just that, right? It's very rarefied where we work. And to go into a community and say, this is what you need, feels-- which is not what you were suggesting, Dr. Beyer or Dr. Westin, but to start by listening and ask the communities what they need and then to provide it and to listen and not leave once the, quote, "problem is fixed." And I think the same is true nationally. We need to make sure that the administration's priorities actually bear fruit and soon, that we not kick things down the road and make compromises at the level of national policy. And as physician clinicians, those physicians who are listening, we should be going to the city council meetings when a new building is being erected. Is there going to be a consequence for neighborhoods in terms of things like gentrification? Cities have been constructed intentionally to isolate people, and we need to start undoing that, and cities are doing that. They're taking down freeways that divide the rich from the poor. I think we need to make sure as clinicians that we are speaking up about equitable and high-quality education for young people because we know your early life experiences and education are associated with health. Publishing work like Dr. Beyer's work, ASCO has a heavy advocacy arm. And as Dr. Beyer said, we have power. Inequities in power is what got us to where we are. So really, the burden is on those with power to speak on Capitol Hill and other places, local level, statewide level, to make change and to insist on it for the health of our patients and our communities. SHANNON WESTIN: That is so thoughtful and such a great call to action. And I do think there's a huge opportunity for members of ASCO to get involved. The advocacy is extremely strong. There are Capitol Hill days and committees, and now we even have their own political action committee, where we can work to lobby for patients and their health care. So I think that is a perfect place for us to end this conversation. I would like to give Dr. Beyer last opportunity to one-liner to sum up where we are and what we need to do next for those people that tend to fade in and out of these types of things. KIRSTEN BEYER: Sure. Thank you, Dr. Westin. I would say, to summarize, that the housing sector is actively revealing structural racism. This isn't a historic practice only. We are seeing structural racism in housing right now, and it's actively revealing both structural racism and economic disinvestment. And it's a very actionable policy target, so that we can mitigate those upstream determinants of health for the benefit of patients with cancer and with other diseases. And then I think as a final, I would say that there's a great quote from Matthew Desmond, who's a housing equity writer and scholar and activist. And he says, "A stable home functions as a secure foundation on which to build holistic and cost-effective health care." And so I think that's a great way of thinking about it from a practical standpoint. Housing is primary. It's an important foundation on which we build all the other things that we can do to improve people's health. SHANNON WESTIN: Perfect. Thank you both so much. Thank you, Dr. Beyer. Thank you, Dr. Griggs. And thank you, all of the listeners. We'll be back soon with a new podcast coming to a ear near you. JENNIFER GRIGGS: Thank you so much. KIRSTEN BEYER: Yeah, thank you very much. [MUSIC PLAYING] SPEAKER 1: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. For more original research, editorials, and review articles, please visit us online at jco.org. This production is copyrighted to the American Society of Clinical Oncology. Thank you for listening.
11/19/202126 minutes, 9 seconds
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Anticipating the Future of Hodgkin Lymphoma

This JCO Podcast provides observations and commentary on the JCO article “PET Score Has Greater Prognostic Significance Than Pre-Treatment Risk Stratification in Early-Stage Hodgkin Lymphoma in the UK NCRI RAPID Study” by Barrington et al. My name is Brue Cheson, and I am at Georgetown University Hospital, Lombardi Comprehensive Cancer Center. My Hematologic-oncologic specialty is Lymphoma.   Hodgkin lymphoma is clearly one of the most dramatic success stories in modern oncology. More than 90% of patients with limited disease and about 85% with advanced disease are cured using conventional chemotherapy regimens.  As a consequence, current clinical trials are focusing on augmenting or modifying treatment for those at higher risk and decreasing the intensity or duration of therapy for those at a lower risk of treatment failure.   One important question has been: how best to distinguish those disparate groups?  Over the years, various prognostic scoring systems have been devised.  The International Prognostic Scoring System (IPSS) differentiated patients into 6 groups using 7 clinical and laboratory factors.  However, only 7% of patients are in both the most and least favorable groups.  The German Hodgkin study Group (GHSG) and the EORTC each published criteria slightly different from each other for treatment selection.  Nevertheless, it is not clear that any of these schemas remains relevant in the context of current Hodgkin regimens.  More importantly, they do not reliably dictate how to treat patients, nor do they offer therapeutic targets.   FDG-PET scanning has revolutionized our management of patients with lymphoma.  In 2005 we first demonstrated that integration of PET into standard response assessment improved the ability to distinguish between residual tumor and fibrosis in patients with diffuse large B-cell lymphoma, leading to a revision of standardized response criteria. More recent studies have confirmed this observation in Hodgkin lymphoma and other histologies. Patients with advanced Hodgkin lymphoma can be distinguished into high and low risk groups based on PET scan results after 2 cycles of standard ABVD chemotherapy, regardless of their pretreatment IPSS score.  In a number of studies, reacting to the positive interim scan by intensifying therapy achieved outcomes markedly improved over expected.   In the paper that accompanies this podcast, Sally Barrington and her colleagues performed a secondary analysis of the RAPID trial to evaluate the role of pre-treatment risk factors and PET results in predicting outcome of patients with early stage Hodgkin lymphoma.  This study accrued 602 patients who were treated with standard ABVD and underwent PET scanning after the third cycle.  Those with a negative scan (a Deauville score of 1-2) were randomized to no further treatment vs involved field radiotherapy.  Despite a failure to demonstrate non-inferiority of progression-free survival in this cohort, the overall survival was the same, thus sparing 90% of patients unnecessary radiotherapy.  Those with a positive scan (defined as a Deauville score of 3-5), the primary focus of the current manuscript, received an additional cycle of ABVD plus radiotherapy.  Only the 21 patients with a Deauville score of 5, defined as an SUV at least 3 times greater than that of the liver, had an inferior time to progression or greater risk of Hodgkin-related death.  Importantly, this finding was independent of pretreatment prognostic factors using either the GHSG or EORTC scores.  Whether this observation can be extrapolated to patients with features not eligible for the RAPID study, such as those with bulky mediastinal disease or B-symptoms, is presently unknown.  Nonetheless, these data support the role of metabolic imaging over standard clinical and laboratory risk factors.   But we are clearly doing this all wrong.  Why do we treat all patients the same and then wait until the disease has demonstrated resistance before we alter therapy?  Several recent papers support the notion that anticipatory, biologically-based, risk-adapted approaches may be feasible. Pre-treatment total metabolic tumor volume (defined as the sum total of all metabolically active lesions) can predict outcome in Hodgkin lymphoma as well as follicular, diffuse large B-cell and primary mediastinal large B-cell lymphoma.  High heterogeneity of intratumoral FDG uptake distribution on PET-CT may be a marker of chemoresistance in solid tumors as well as various lymphoma histologies.  Unfortunately, those tests do not provide a target against which to direct a specific agent.  In contrast, a number of investigators have demonstrated a correlation between bcl-2, p53, FOXP3, CD68, STAT1, pattern of PD-1 expression, mutational patterns derived from next generation sequencing, and other factors in pre-treatment Hodgkin node biopsies and outcome.  Thus, if we are able to predict outcome prior to treatment, why do we expose patients to drugs to which we know they will not benefit? The goal of treatment should be anticipatory, risk-adapted strategies whereby patients with a high likelihood of benefit may receive standard of care, unless there is another clinical question being addressed.  On the other hand, those unlikely to benefit as determined prior to therapy should be spared the waste of time and toxicity and treated with novel regimens directed at specific targets.  Both groups should be monitored during treatment for the emergence of mutations, with treatment altered accordingly.  Yes, we may be a long way from having the appropriate tools for such an approach.  But, to quote the geneticist, molecular engineer and chemist George M. Church, “The best way to predict the future is to change it”.  Anticipatory, risk-adapted strategies could do just that.   This concludes this JCO Podcast. Thank you for listening.
5/21/20196 minutes, 56 seconds
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High Reward, High Toxicity: Combination Pembrolizumab and Lenvatinib in Advanced Endometrial Cancer

The combination of pembrolizumab and lenvatinib is a promising second line option for metastatic or recurrent MSS endometrial cancer, although there can be considerable toxicity and choosing appropriate patients is key.   TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Lenvatinib and Pembrolizumab in Patients With Advanced Endometrial Cancer” by Makker et al. My name is Meghan Shea, and I am an Instructor of Medicine at Harvard Medical School at Beth Israel Deaconess Medical Center in Boston, Massachusetts. My oncologic specialty is gynecologic oncology. Patients with advanced endometrial carcinoma have limited options after receiving the carboplatin and paclitaxel doublet for recurrent or metastatic disease. The study that accompanies this podcast evaluates the combination pembrolizumab and lenvatinib, providing a much needed second-line option for this patient population. The approval of single-agent pembrolizumab for tumors with microsatellite instability (from here on referred to as MSI high) does not have immediate relevance for the majority of patients with advanced endometrial carcinoma who have microsatellite stable disease (from here on referred to as MSS). Makker et al. now report the results of an ongoing phase 1b/2 study of pembrolizumab, an anti-PD1 antibody, and lenvatinib, an oral tyrosine kinase inhibitor that targets the VEGF-receptor, in patients with metastatic endometrial carcinoma. Eligibility criteria included patients with an ECOG 0 to 1 who had confirmed metastatic disease with less than or equal to 2 prior lines of systemic therapy. Notably the majority were not heavily pre-treated; 52.8% of patients in the study had only one prior line of systemic treatment. Patients received lenvatinib 20 mg once daily orally continuously and pembrolizumab 200 mg intravenously every 3 weeks – with a maximum duration of 2 years for pembrolizumab. All patients had imaging at baseline and then every 6 weeks for first 24 weeks and then every 9 weeks thereafter. The primary end point was objective response rate at 24 weeks. Forty-one of the 108 patients, 38%, had a response at 24 weeks with a median follow up of 18.7 months.  As expected, the MSI high tumors had a higher response rate of 63.6%, although this was a minority of the study population, only 11 patients. Most importantly, the patients with MSS tumors had a response rate of 37.2% with a median duration of response of 21.2 months. The histology did not appear to impact the response rate – the majority of patients had endometrioid (50.9%), although the study population also contained a reasonable proportion of serous and clear cell (38%) compared to the expected frequency in the general population of advanced uterine cancers. The PD-L1 status positive or negative did not correlate with response. One might question, before accepting a complicated regimen with both oral and IV chemotherapy as a new second-line standard option, whether anyone has studied the activity of either single agent lenvatinib or single agent pembolizumab in a similar population, especially for those with MSS disease. With the caveats of cross study comparisons, it appears that neither single agent is as active as the current combination. For instance, Vergote et al reported results of a phase 2 study of lenvatinib monotherapy for advanced endometrial cancer, where the response rate was only 14.3% with median progression free survival of 5.4 months. Likewise, Ott et al studied single agent pembrolizumab in endometrial cancer with 18 of 19 patients having MSS cancer, resulting in only a 13% response rate and progression free survival of 1.8 months.              So you may be wondering, what’s the catch? The issue is the potential toxicity of this doublet regimen, with 66.9% or 83 of 108 patients, having a grade 3 or 4 treatment-related adverse event. Overall 17.7% of the patients discontinued one or both drugs. Notably, pembrolizumab was never dose reduced - only dose held or discontinued. Most strikingly, 62.9%, roughly two thirds of patients, required a dose reduction of lenvatinib. Only 11 patients (that is 8.9%) stayed on full dose 20 mg of lenvatinib for greater than 6 months. The average dose for lenvatinib was 14.4 mg daily. The toxicity profile of lenvatinib may be related to the fact that it is a multi-targeted tyrosine kinase inhibitor that targets not only vascular endothelial growth factor receptors, but also fibroblast growth factor receptors, platelet-derived growth factor receptor alpha, RET and KIT. There were 51 deaths during this study; the majority occurred during follow up due to progression of disease. However, there were 16 deaths while on study, 4 considered treatment emergent adverse events and 2 judged to be treatment related.  The four deemed treatment emergent were due to gastrointestinal perforation, intestinal obstruction, general health deterioration and metabolic encephalopathy. The two deemed treatment related were from septic shock and intracranial hemorrhage. The National Comprehensive Cancer Network (NCCN) guidelines have added the combination of pembrolizumab and lenvatinib to their list of second line therapeutic options, and it also has been approved by the Food and Drug Administration (FDA). This recognizes the fact that this combination has the highest response rate of the available drugs listed, and thus should be a strong consideration for second line therapy for patients with MSS endometrial carcinoma. However, ensuring that this treatment is appropriate for a given patient is of the utmost importance.  First the patient must be a candidate for immunotherapy – ideally not on chronic prednisone and/or have an active autoimmune disease. In contrast to prescribing single agent anti-PD-1 or anti-PD-L1, a performance status of 0 to 1 is important with this combination. The most appropriate patient should have controlled blood pressure prior to initiating drug, be able to monitor their blood pressures, take their oral chemotherapy as prescribed, and readily report any new symptoms. I avoid prescribing this drug combination if the patient has a bleeding disorder, recent clotting, uncontrolled hypertension, or is at high risk of a fistula or bowel obstruction. Lenvatinib is a renally-cleared drug, and thus patients with a reduced glomerular filtration rate (GFR) require renal dosing. This is especially relevant for patients with recurrent uterine cancer, whose kidney function is dynamic, especially in the setting of hydronephrosis. In my practice, I consider starting patients with normal renal function at 14 mg lenvatinib daily, given that the vast majority of patients on study were eventually dose-reduced. Furthermore, I might start the lenvatinib dosing even lower for patients with dynamic renal function and for those who have a baseline GFR lower than 30. Overall this study provides a promising second line option for metastatic or recurrent MSS endometrial cancer, with responders having a durable response.  Patient selection and dose adjustments are key considerations to avoiding and managing toxicity. This concludes this JCO Podcast. Thank you for listening.
3/1/20207 minutes, 46 seconds
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An International Phase II Trial of Single-Agent Nivolumab for Hodgkin Lymphoma Relapsed or Refractory After Autologous Stem Cell Transplant

This podcast describes the extended follow-up of the large International phase II CheckMate 205 study of single-agent nivolumab for patients with relapsed/refractory classical Hodgkin lymphoma after failure from autologous stem cell transplant. Read the related article on JCO.org.
3/27/201810 minutes, 52 seconds
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Considerations in Predicting Neuropsychological Outcomes in Children Treated for ALL

Randomization to different methotrexate and steroid treatment strategies was not related to neuropsychological outcome in children treated for B-ALL, but age and insurance status were significant predictors. Read the associated article "Neurocognitive Functioning of Children Treated for High-Risk B-Acute Lymphoblastic Leukemia (HRALL) Randomized to Capizzi (CMTX) Versus High- Dose Methotrexate (HDMTX): A Report From the Children’s Oncology Group (COG)" on JCO.org.
7/3/201712 minutes, 21 seconds
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The True Costs of the 21-Gene Assay in a Cohort of 1,000 Patients

This podcast addresses the clinical implications of the high cost of the 21-gene assay in women with ER-positive, node-negative breast cancer. Related Article: Population-Based Study to Determine the Health System Costs of Using the 21-Gene Assay
12/1/20176 minutes, 41 seconds
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The Impact of Cigarette Smoking on Survival in Patients with Pancreatic Cancer

This podcast discusses the association between smoking and risk of death from pancreatic cancer.
3/30/20177 minutes, 32 seconds
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Prognostication Based on Site of Metastatic Disease in Castration Refractory Prostate Cancer: Implications for Patient Care and Clinical Trial Design

Impact of site of metastasis on overall survival in castration refractory prostate, and its implications on patient care and clinical trial design.
5/3/20167 minutes, 49 seconds
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Hepatocellular Carcinoma in Children and Adolescents: Time for a Strategy and a Trial

An update on clinical trials that have included children with hepatocellular carcinoma
1/25/20168 minutes
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Treatment Advances in Local-Regionally Advanced and Stage IVB/Recurrent Cervical Cancer: Can We Agree that More Isn’t Always Better?

The two recent papers by Kitagawa, et al and Rose, et al, give us treatment options and tools that help maximize not only the benefits of survival with treatment but minimization of non-beneficial treatment toxicity through identification of patients with advanced and recurrent cervical cancer that are most and least likely to benefit.
5/18/201511 minutes, 21 seconds
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Is It Biology or Brawn in Ovarian Cancer Surgery?

This podcasts provides perspective on a recent report evaluating disease volume and surgical complexity on post-operative tumor residuum and survival in ovarian cancer patients.
2/9/20159 minutes, 36 seconds
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Is There a Future for Cyclooxygenase-2 Inhibition in Non-Small Cell Lung Cancer?

This podcast reviews the available data from clinical trials using cyclooxygenase-2 inhibition with chemotherapy in non-small cell lung cancer and provides a perspective on patient selection and future directions.
12/1/20147 minutes, 50 seconds
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Intensified Frontline Chemoimmunotherapy with R-ACVBP May Improve Outcomes for Younger Patients with Non-Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma

A secondary analysis of a multicenter randomized trial suggests that the R-ACVBP regimen may improve outcomes in younger patients with the non-germinal center B-cell subtype of diffuse large B-cell lymphoma.
11/25/20147 minutes, 27 seconds
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Optimal Duration of MRD Monitoring During Therapy for Childhood ALL

Minimal residual disease monitoring has been very helpful in early response evaluation and risk stratification of children with acute lymphoblastic leukemia (ALL). This podcast discusses the pros and cons of extended MRD monitoring throughout the duration of therapy for childhood ALL.
11/25/20147 minutes, 40 seconds
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Functional Imaging as a Biomarker for Survival in Locoregionally Advanced Non-Small Cell Lung Cancer Patients

ACRIN 6668/RTOG 0235 demonstrates that a post chemoradiotherapy PET scan for locoregionally advanced non-small cell lung cancer can be used as an early indicator for long-term outcome.
9/16/201310 minutes, 34 seconds
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Evolution of Concurrent Chemoradiation Treatment Approaches in Head and Neck Cancer

This podcast provides commentary and observations on the long term results summary of RTOG 91-11 in which concurrent chemoradiation was shown to provide superior outcome over induction chemotherapy or radiation alone to achieve larynx preservation and locoregional tumor control.
3/5/20138 minutes, 56 seconds
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Caring For Patients With Transformed Follicular Lymphoma

If transplantation is selected as the treatment approach, the net effect is likely to be similar with allogeneic or autologous transplantation with the higher early mortality rate in the allogeneic patients offset by a higher relapse rate in the autologous patients.
2/12/20137 minutes, 23 seconds
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Outpatient Therapy for Fever and Neutropenia is Safe But Implementation is the Key

The fluoroquinolone class of antibiotics is a major target for antimicrobial stewardship programs, and the conservation of their effectiveness is important.
1/28/20135 minutes, 17 seconds
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Breast Brachytherapy in the United States: Increasing Use Despite Increased Complication Rates

This podcast will review a JCO article showing that the use of breast brachytherapy as a method of delivering partial breast radiation after breast conserving surgery was associated with higher rates of complications than the conventional approach of whole breast radiation.
11/1/20128 minutes, 3 seconds
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KRAS G13D Mutations in Metastatic Colorectal Cancer: Are They Different From Codon 12?

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