Journal of Clinical Oncology (JCO) Podcast

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Intensive Caring: Reminding Patients They Matter Apr 27, 2023

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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 muc…

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Barriers to Clinical Trial Participation for Transgender People Apr 13, 2023

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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.…

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JCO Article Insights: Trial Update on Development of Children After Maternal Cancer During Pregnancy Mar 27, 2023

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In this JCO Article Insights episode, Davide Soldato interviews Dr Frederic Amant from UZ Gasthuisberg - Katholieke University Leuven. Dr. Amant discusses his clinical trial update published in the March 10, 2023 JCO issue, "Cognitive and Behavioral Development of 9-Year-Old Children After Maternal Cancer During Pregnancy: A Prospective Multicenter Cohort Study", by Van Assche, et al. From the International Network on Cancer, Infertility and Pregnancy, the article reports the cognitive development of 9-year-old children after maternal cancer during pregnancy. TRANSCRIPT The disclosures for the guest on this podcast can be found in the show notes. Davide Soldato: Welcome to this JCO Article Insights episode for the March issue of JCO. This is Davide Soldato, and today I will have the pleasure of interviewing Dr. Frédéric Amant, corresponding author of the manuscript titled 'Cognitive and Behavioral Development of 9-Year-Old Children After Maternal Cancer During Pregnancy: A Prospective Multicenter Cohort Study' (10.1200/JCO.22.02005). Dr. Amant is a professor at the Ku Leuven in Belgium and at the University of Amsterdam, and he is the head of the Department of Gynecological Oncology of the Netherlands Cancer Institute and the Amsterdam University Medical Centers. Welcome, Dr. Amant. Dr. Frédéric Amant: Hello, good evening. Thank you for the introduction. Davide Soldato: So, Dr. Amant, you published this manuscript that reports the updated results of an ongoing prospective multicenter study. And this study is actually investigating cognitive and health outcomes in nine-year-old children that were born from women who were diagnosed and treated for cancer during pregnancy. So I wanted to ask if you could give us just a quick overview of the study design. What are the main outcomes that are investigated in the study, and also if you could give us some information about the results that you recently published in the JCO? Dr. Frédéric Amant: Well, the study is a follow-up study of children that are now nine-year-olds. A large part of these children, we have been following up since birth. So the first paper on this cohort basically was in 2015. And at that stage, children were 18 to 30 months old. Well, what we have to say is that all these children, or the majority of these children, in fact, the mothers, were exposed to chemotherapy during pregnancy. So the results actually in children at 18 or 30 months were, in fact, reassuring. And at that time, that was actually a big novelty because it was the first study where children were prospectively followed up and when they were compared to a control group. This study was actually changed a bit; the idea that chemotherapy during pregnancy was not possible. From there, we started to further follow up to some extent the children, but also it increased the awareness that we can treat cancer during pregnancy, including chemotherapy during pregnancy. This was followed up by a study two years ago in six-year-old children that was, in fact, also reassuring. Today, we discuss then the cognitive and the behavioral development of nine-year-old children when the mother was exposed to chemotherapy but also, in fact, cancer; all the diagnostic investigations, many women also received surgery, and actually, the children were controlled by researchers, by psychologists, by medical doctors to look into their general health. There were questionnaires to the parents, and then we assessed the IQ, we assessed memory tasks, and attention tasks. Overall, the results are, in fact, reassuring for the several subtypes of treatments, including several subtypes of cytotoxic drugs, and there were no differences when we looked into the intelligence quotient, so the IQ between exposed and non-exposed children. We did see some interesting analysis, however. To some extent, we did see that, for example, the IQ score increased by 1.6 points for each week's increase in gestational age. There was no difference in the full-scale IQ between the treatment types. Actually, in children prenatally exposed to chemotherapy, there was no association between full-scale IQ and the chemotherapy drugs, exposure levels, or the timing of the chemotherapy during pregnancy. So overall, the results are reassuring and indicate that during a critical maturation period of the child, when complex functions start to develop already and rely on the integrity of early brain development, this is actually reassuring. Especially, this critical maturation period means that when children are nine-years-old, we can test or do more complex tests when compared to children that are 18 months or 30 months, or even six years. So that is all reassuring news. Another finding, however, was if you look at the IQ, there are several components of the IQ, and there we see that the verbal IQ was, in fact, lower, and that was especially in children who lost their mother or for whom the mother was in a critical period. So the mother's health was not so good. So this could be correlated to the fact that the mother and the environment of a child at that stage actually had less attention to the child, resulting in effect that the verbal development of the child was suboptimal. That is one possibility. We need to say, however, that these children overall were also more preterm born. So that is also a confounding factor. So the lower verbal IQ is in children that were more likely to have a mother in a bad condition, but they were also more likely to be born preterm. So we don't exactly know if it's the preterm birth or the poor condition of the mother that actually contributes to this. Anyway, I think what it is in effect is a message that we need to or that we bring to the family that we need to pay attention to this verbal development of the child. So if we look into the overall data, I think there are some subtle differences. But overall, these children do, in fact, very well. They, apart from that, have normal behavior, they grow up very fine, there are no other problems. So this is important for physicians, for parents to be, where a decision nine years before needs to be taken, whether or not to treat cancer during pregnancy. I think that these data are then very reassuring that mothers can be treated and can receive chemotherapy during pregnancy since, also, after nine years, the children do, in fact, very well. And one can say children nine-years-old, but what about when they become older? So we don't have that answer yet, we hope to have that in the future. But what we can say is that if a child has a normal IQ and actually a normal development, that this is a very strong predictive factor that later on this will be normal as well. Of course, we don't know yet about fertility; we have no data on secondary cancers. Therefore, we need to follow up these children much longer, of course. But I think with this data, we can really reassure clinicians and parents to be that we don't have to interrupt the pregnancy or that we have to delay the maternal treatment, or that we have to deliver the baby very preterm, allowing doctors to treat after delivery. So it shows that we can treat the mother without delay and that the baby best stays with the mother as long as possible, and that maybe we can use these treatments to keep the baby as long as possible with the mother. So I think these are the main results and the main message that we actually bring to our patients. Davide Soldato: Yeah, exactly. I wanted to ask exactly that because from what you just told, so just to summarize for our listeners, we just heard that actually, exposure to cancer and treatment related to cancer during pregnancy actually is not associated with worse cognitive outcomes. And, probably, reading the paper, the strongest predictor of having a reduced IQ for these babies is more the fact of being born preterm compared to the fact that they are exposed either to cancer or to the treatments that are related. So I wanted to ask you exactly that if you feel that the main message that we can deliver to the oncologist community in general, but also to the parents and to the families that they are making a decision regarding the possibility of treatment, is that we can treat, we should treat. And probably the main objective, if you agree with me, is that we try to postpone the moment of the birth as long as possible, to allow for the development of these children. Dr. Frédéric Amant: That is completely correct. I think when we started with this research, the general idea, the general practice was actually, well, we cannot treat. So we deliver the baby preterm, and typically, that was around 32 weeks because 32 weeks of pregnancy, that means that the baby is viable but still very preterm. But the baby is viable, but it's two months early. But that was generally accepted in the absence of any data on the safety for children. With the knowledge we have now that we built up and for which the paper we discuss now is like the last update of this follow-up, it shows, indeed, that we should not fear too much, and that indeed of cancer treatment during pregnancy, including chemotherapy, and that this is to be preferred rather than interrupting the pregnancy or having a preterm baby. Or what was done also is that the mother was not treated, and then the pregnancy was continued, for example, until 32 weeks of gestational age, and then the mother was treated. But all these alternatives are either suboptimal for the mother or suboptimal for the baby, especially if there is a termination of pregnancy. But even when there is no termination and preterm delivery, that is also not particularly good for a baby. So the best solution for all parties there is to treat during pregnancy, including chemotherapy. And that is indeed the message that we need to bring, especially since the results confirm previous results and actually validate the previous results so, well, it adds to the solid results, actually, and that is really reassuring. And what we also need to say here, and although this is not really part of this paper, is that there are also not more congenital malformations because that is also a concern of many doctors, that actually these drugs are designed to kill rapidly dividing cells. We know they pass the placenta, they will go to the fetus, although in a bit lower dosages. But many people were scared about the increased chance for congenital malformations, and we know that this is not the case on condition that we give the chemotherapy after the first trimester. If you give chemotherapy during the first trimester, you will have an increased risk of congenital malformation. So that is a caveat that we need to take into consideration that it is possible, but mainly during the second and the third trimester. But of course, surgery, oncological surgery and even radiotherapy during the first trimester is possible. So it is only the chemotherapy, which is not possible during the first trimester. This is what doctors and patients need, that there is scientific data saying that this is possible, and that's why we are very happy that we could report on that and that the data validate the previous findings on this topic. Davide Soldato: And I think that one of the concerns that were also associated with the administration of chemotherapy, particularly with anthracyclines, was kind of the concern that there will be some effect on the cardiac function of the children born from these mothers. Well, it's not actually the object of this specific paper, but you previously also published data that were reassuring also regarding cardiac function. But one other thing that I wanted to ask you, you said before that there were lower verbal intelligence scores from babies that were born from mothers who then died, especially in the first part of the life of the baby. And also, there were some signals that some of these babies, especially those who were born preterm or that lost their mother very soon, were in need of remedial care. Although you say that once we arrive at the nine-year development, probably the development is going to be normal, but do you think that this kind of environment and social factors and difficulties in general in the family once we arrive to that stage of development could also lead to some differences for these babies? So more related to the social situation and loss of the mother than from the treatment that they received or that they were exposed to. And do you think it's important in general that we continue to follow up these now children also to kind of give an indication or somehow to raise attention on the fact that despite the cognitive outcomes, they are good, we still need to give social support or this type of help to these families? Dr. Frédéric Amant: Yeah, I think that's an excellent remark, excellent question because it's true. I wanted to say at the first session, the first part, but when I was talking about the predictive value of our results, they are very strong, and we can actually already now exclude that also, in the long term, chemotherapy on these cognitive factors will not have an effect. And that in the meantime, when the children grow up, the new external factors, in fact, become more important than the antenatal exposure. It is the social environment. Children will smoke, will use drugs, will drink alcohol, psychological traumas, and so on. So these are more likely to influence the further development of the children. And that's why I think, and the older the children are, of course, the more likely that it is that these external factors will play a role, so that will be more and more difficult to really disentangle all these external factors related to antenatal development. On the other hand, we also control for this, and we control for the maternal and the paternal education. We look at the education level of the parents. So this is all included when we analyze this, and it is actually interesting because now you refer to it. In fact, children do, well, or the intelligence outcome correlates to the maternal education. The paternal education is, in fact, less important in this. So just to underscore the fact that we look into this, so that will be maybe a bit more difficult to really explore in the future. But the future examinations, on the other hand, will give us more insight into, for example, fertility, the adolescence of the children, and their sexual secondary characteristics as maybe as a biomarker of fertility, which is not always the case. But at least it would be reassuring if we see that these sexual secondary characteristics develop normally and also, maybe later on, the increase on cancer development. Until now, these are theoretical concerns, but today we have no indication that this is actually true. So we think we definitely need to further explore that. But again, this is theoretical because some children now are 12, 15, 18 years old. They are not part of the analyses. But we have seen the children already. The results are in the data set, and we have no indication of more cancers. And we have no indication or the patterns at least, do not report to us that these biomarkers for fertility, let's say, the secondary sexual characteristics, are actually delayed or absent from the information we have from the children, older children. So the adolescents and their parents, we have no indication that there is a problem. So we have no mention that they are worried on these topics. So from that point of view, this is also reassuring. But of course, this is not hard science, but this will be part of the future analyses. The reason why we don't have these analyses now is that the children, of course, need the time, and they need to grow. So we have to follow them up. But what we tell in our clinic is exactly what I say now is that from the…

Full show notes at the publisher

Cancer Screening During the 2nd Year of the COVID-19 Pandemic Mar 23, 2023

Show notes

Dr. Shannon Westin and her guests, Jessica Star and Dr. Ahmedin Jemal, discuss how the COVID-19 pandemic affected cancer screening in the US in 2021.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours. I am your host, Shannon Westin, the social media editor for the JCO and Gynecological Oncologist at MD Anderson. And it's my pleasure to welcome you to our next episode, which is "Cancer Screening in the United States During the Second Year of the COVID-19 Pandemic." And please note the authors have no conflict of interest.

I'm joined by two of the authors on this important work. First is Jessica Star, who has an MA and an MPH and is Associate Scientist II for Cancer Risk Factors and Screening Surveillance Research at the American Cancer Society. Welcome.

Jessica Star: Thank you for having me.

Dr. Shannon Westin: Of course. And we're also joined by Dr. Ahmedin Jemal, the Senior Vice President for Surveillance and Health Equity Science at the American Cancer Society. Welcome.

We're so excited that you both are here, and I'm hoping that we'll have a really lively discussion about your important work. This paper was published online on February 23, 2023, in the Journal of Clinical Oncology. So let's level set. We'll start—Jessica, can you talk a little bit about how the COVID-19 pandemic initially impacted cancer screening in the United States?

Jessica Star: So the COVID-19 pandemic disrupted the delivery and receipt of routine preventative services, and that included cancer screening. What we've seen from a lot of 2020 data that has been published is that cancer screening declined during that first year of the COVID-19 pandemic. One of those papers includes a paper by the American Cancer Society led by Stacey Fedewa. And many other studies also reported similar declines, including for breast, cervical, prostate, and colorectal cancer screening. However, some of these papers, by the end of 2020, it appeared that screening rates were starting to rebound back to pre-pandemic rates. And so that was sort of the interest in looking at that 2021 data now.

Dr. Shannon Westin: And what did you hypothesize? Did you think that these data were correct? Like, did you think that we were going to start seeing an increase in screening in the second year of the COVID-19 pandemic, or what were your suppositions?

Jessica Star: Yes, I think we kind of hypothesized or hoped, based off of what we were seeing from the 2020 data, that we would start seeing more substantial increases as we were getting into 2021. Based off of those declines during the first part of the pandemic, we were really wanting to see individuals coming back into screening now that stay-at-home orders had sort of been reduced and now that individuals were going back to screening more frequently.

Dr. Ahmedin Jemal: I might add that the motivation for this screening, in addition to what Jessica said, is that the previous studies were based on representative US populations, either based on claims data or state-specific population-based studies. They were not based on nationwide population-based study. That's why we used the NHIS, National Health Interview Survey, which is a US population-based study, to look at whether screening in 2022 has returned to the pre-pandemic level.

Dr. Shannon Westin: Yeah, why don't we get into a little bit more detail here? I would love—Jessica, can you talk a little bit more about the National Health Interview Survey? I get the idea of why you all used it, but can you tell our listeners just a little bit more about that database?

Jessica Star: To go off of what Ahmedin mentioned, The National Health Interview Survey is a nationally representative cross-sectional household survey of the United States population that is generalizable. And that survey is housed by the National Center for Health Statistics in the Centers for Disease Control, and they report on cancer screening biyearly. So we have data from 2019, and we have data from 2021. And the next increment of the National Health Interview Survey that we'll have for cancer screening is in 2023.

Dr. Shannon Westin: And then talk a little bit about which cancer types you all focused on when you're looking into this hypothesis, that potentially screening was being increased.

Jessica Star: So we focused primarily on breast, cervical, colorectal, and prostate cancer screening. And some of the reason behind this was because of data availability. The NHIS only provided those four—receipt of those four screening types, as well as when we were looking at the data previously from that 2020 data, we were seeing a lot that were focusing on some combination of breast, cervical, colorectal, and prostate cancer screening. So we wanted to continue that work into the second year.

Dr. Shannon Westin: And then let's cut to the chase. What did you find? Did you prove or disprove your hypothesis?

Jessica Star: We mostly disproved our hypothesis. Our team found that past-year screening for breast, cervical, and prostate cancer screening decreased in 2021 compared to that 2019 level, with decreases largest primarily among non-Hispanic Asian persons. And this translated to a population-weighted estimate of approximately 1.1 million, 4.4 million, and 700,000 fewer eligible individuals receiving breast, cervical, and prostate cancer screening, respectively. However, we did find that colorectal cancer screening actually remained stable between 2019 and 2021, and part of this can be attributed to an increase in stool testing that offset a decline in colonoscopy testing.

Dr. Shannon Westin: Interesting. So people doing things from home allowed them—and I think we all got really good at that during the COVID-19 pandemic, is what actually can we do at home and be functional? That makes sense. Were you surprised at this? I know, as a gynecological oncologist, I was a bit disappointed to see the lack of cervical cancer screening and a bit surprised at the rest. What were your thoughts?

Jessica Star: I guess, upon more reflection and seeing that colorectal cancer screening had remained stable and sort of the reason why colorectal cancer screening rates had remained stable, it wasn't entirely surprising. It seems that many people were still hesitant to get screening done in the office or in hospital. And also, considering that many individuals had lost their jobs during the COVID-19 pandemic, many might not have been insured in the same method that they were previously, and so they might have hesitated to be screened as well.

Dr. Shannon Westin: That's a great point. Medical coverage is so tightly linked to the work that we're doing. I hadn't even thought about that. That is a great point.

Now, you mentioned briefly about the largest decrease in the non-Hispanic Asian population. Did you see any other kind of associations based on race, ethnicity?

Jessica Star: We did. We also saw some declines for both Hispanic and non-Hispanic Black persons. But we particularly pointed out the decline for non-Hispanic Asian persons because it occurred for all three of the cancer screening types that we saw decline, so for breast, cervical, and prostate cancer screening, whereas for Hispanic and non-Hispanic black persons, they might have had a decrease in one or two screenings but not all three.

Dr. Shannon Westin: That's interesting. I bet there's a lot to explore there to try to understand why we would see such discrepancies across the different race ethnicities.

Now, we talked a little bit about how screening might have been improved for colorectal cancer having at home. So what's the lesson here that we can maybe utilize to direct guidance to other screening programs?

Jessica Star: The lesson here, which will also have a bit of a caveat to it, is that home-based screening is effective at least getting in that initial screening for when there are healthcare disruptions, whether it's because of the COVID-19 pandemic or even thinking about environmental disasters or all of those different things. But the important thing to note is that once you are screened for colorectal cancer using, for example, like, a home-based stool testing, if you have a positive test, you would need to go in for that follow-up colonoscopy, so you still would need that in-office visit. It does allow a lot of people to get screened, figure out that they're negative, and then not have to proceed any further for those individuals.

Dr. Shannon Westin: Yeah. I wonder, do you have the opportunity to look at data to see how many of those people, if they found something, if they had a positive test then went on to get that next step? I'm sure not from this type of survey.

Jessica Star: Not from this study. From other literature that is already out there, it seems that the estimates are quite low for follow-up colonoscopy. So that's kind of the caveat there is that there would still need to be follow-up to be fully screened if you have an abnormal test.

Dr. Shannon Westin: There are some really interesting opportunities to potentially do at-home cervical cancer screening. One of my colleagues is working very hard to try to get that out. And I think you're bringing up a really big elephant in the room of what will need to be addressed, because it's going to be something similar where, if you have a positive screening test and then you don't go to that next step, then you've lost the opportunity there.

Jessica Star: Yeah. And that's one of the things we did touch on a little bit in the paper, was about cervical cancer screening, since that is an area where there is a home-based option. But since it hasn't yet been approved by the FDA, it hasn't been able to be approved as an appropriate screening method moving forward. But that is definitely an area where we suggest further research sort of comes in to see about allowing cervical cancer screening to also have that home-based option.

Dr. Shannon Westin: So not what we were hoping to see, with the decrease in the screening across three of the major cancer types. What do we do? How do we address these findings? How can we make an impact?

Jessica Star: So I think there's many different areas that can allow for an impact. Clinicians and healthcare professionals should be playing a major role in the return to screening campaigns by recommending screening to each of their eligible patients according to screening guidelines, with that special emphasis on non-Hispanic Asian persons and other historically underserved groups. And I think another area is just continuing to put out research on this topic and continuing to follow up to see about how cancer screenings are continuing to progress as time goes on. This is looking at the second year of the pandemic, and we have data from the first year of the pandemic that's already been published by other people. And we need to sort of keep following it because, in the short term, this problem of delayed cancer screening might lead to late-stage diagnosis, but in the longer term, that can correlate to poor survival and increase mortality as well.

Dr. Ahmedin Jemal: Yeah. I might add one point to what can be done to what already Jessica said. Insurance is a major determinant of access to care, which includes the screening. But we have about 27.5 million, close to 30 million elderly adults who are uninsured. Especially if you look at the expansion of Medicaid, there are 11 states that haven't yet expanded Medicaid. So I think lawmakers can work to expand Medicaid to all populations—to income populations—low-income populations, not all populations.

Dr. Shannon Westin: I think you bring up a good point. Policy is really important here, and we've seen this across cancer outcomes. And there's been a lot of really nice data in those states that expand Medicaid that we see improvement in mortality and surgical morbidity and so many things. And so it's a great point. I don't think I've ever heard it referenced towards cancer screening, but there's an opportunity there with policy to improve those numbers as well.

Well, great. I'm so grateful to the two of you. This was—it's such an important work, and really disproving hypotheses is a good thing, because if we just assumed everything was getting better and didn't act accordingly, then we would be really negatively impacting our patients and potentially with our heads in the sand. So this work was so important, and I'm really grateful for you all to take the time today to have a chat with our listeners.

So listeners, thank you for being here. Again, this was "Cancer Screening in the United States During the Second Year of the COVID-19 Pandemic," published online February 23, 2023. Thank you for listening to JCO After Hours, and please do check out our other episodes. And we'll see you next time.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Sequencing Matters – Combination Dabrafenib/Trametinib Versus Nivolumab/Ipilimumab for Advanced BRAF-Mutant Melanoma: The DREAMseq Trial Mar 09, 2023

Show notes

Dr. Shannon Westin and her guests, Dr. Michael Atkins, Dr. Adil Daud, and Dr. Gary Schwartz, discuss a definitive work: The DREAMseq Trial. TRANSCRIPT The guests on this podcast episode have no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast that gets in-depth on articles that have been published in the Journal of Clinical Oncology. And it is my great pleasure to be your host. I'm Shannon Westin, GYN oncology, and I serve as the social media editor for the Journal of Clinical Oncology. Today, we're going to be discussing a very exciting article describing "The DREAMseq Trial—ECOG-ACRIN EA6134, Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients With Advanced BRAF-Mutant Melanoma." This article was published in the JCO on January 10th, 2023. And I am joined today by the lead author, Dr. Michael Atkins, who is Deputy Director, Georgetown Lombardi University Hospital, and Scholl Professor and Vice Chair of Oncology at Georgetown University Medical Center. Welcome. Dr. Michael Atkins: Thank you. Nice to be here. Dr. Shannon Westin: In addition, we are also accompanied by two experts in the field, Dr. Adil Daud, Professor in the Department of Medicine at the University of California San Francisco, and Director of Melanoma Clinical Research at UCSF Helen Diller Family Comprehensive Cancer Center. Welcome, Dr. Daud. Dr. Adil Daud: Hi, great to be here. Dr. Shannon Westin: And with Dr. Daud is Dr. Gary Schwartz, the Division Chief of Hematology Oncology and Deputy Director of the Herbert Irving Comprehensive Cancer Center in Columbia, New York. Thank you for being here. Dr. Gary Schwartz: Delighted to be here. Dr. Shannon Westin: So I'm surrounded by experts, and I'm very excited as a GYN oncologist to hear all of what you all have learned in melanoma because we're always excited to take that back into our field. So I think first, though, for those of us that aren't melanoma experts, Dr. Atkins, can you just level set for us and tell us what was the standard of care for melanoma when you began this study? Dr. Michael Atkins: Sure. Well, first of all, this was a study for patients with BRAF V600 driver mutations in their melanoma, which represents about 50% of the patients with metastatic melanoma. And at the time the study was launched in 2015, two BRAF/MEK inhibitor combinations were FDA approved and shown to produce significant progression-free survival and overall survival benefits relative to BRAF inhibitor monotherapy. In addition, combination checkpoint inhibitor therapy with nivolumab and ipilimumab was shown to be superior to ipilimumab and, in particular in patients with BRAF-mutant melanoma, also to nivolumab monotherapy based on the results of the CheckMate 067 study, leading to its FDA approval. So we had these two regimens there that were approved. Of note, despite the many debates and attempts to garner real-world evidence at the time—the study actually reported out in 2021—marketing data showed that half of all patients in the US with metastatic BRAF-mutant melanoma were receiving BRAF/MEK inhibitors, and only one-quarter received nivo-ipi as initial therapy. So there remained a confusion throughout the course of the study as to which regimen was best in the US and around the world. Dr. Shannon Westin: Tell me, what led to the current study? Was it really trying to drive at that very question? Dr. Michael Atkins: These were the best treatment available at the time. And they really had changed melanoma patient outcomes in ways that we could have only dreamed about just five to 10 years prior, when median survival for patients with metastatic melanoma was six to nine months. Hence, the DREAMseq trial, this doublet, randomized evaluation of advanced melanoma sequencing, was really an apt acronym for the trial. But we had these two regimens of BRAF/MEK inhibitors tending to display the overall survival curve, while immunotherapy tended to raise the tail. And at the time the study was launched, it was really unclear which treatment was preferred in general or for particular subsets of patients. And given that patients would likely have the option to receive both approaches, was there a preferred sequence? So the DREAMseq trial was a launch to address these questions. Dr. Gary Schwartz: I can echo Michael's statement about that. There was also—having been at the beginning of immunotherapy and targeted drug therapy, the transformation of cancer medicine in melanoma was extraordinary. Over a very short amount of time, we transformed a disease that's incurable to curable. And I don't think anybody, at least not in my lifetime, that ever think we'd ever see—or I'd see that type of transformation. But the debate in the community was what should be the first therapy. Should it be a targeted drug combination targeting RAF and MEK for BRAF-mutant melanoma, or should it be immunotherapy? And actually, there was a trend favoring immunotherapy, I think, at the time of the start of the study. It was actually an unresolved issue that many of us were continuing to debate up to the publication of this data, which certainly has now solidified the role of immunotherapy as a starting point for patients with BRAF-mutant melanoma. Dr. Michael Atkins: Thanks, Gary. Dr. Shannon Westin: I would love for you—because it is a complex design, and I feel like a lot of times, as drug developers, we're often discouraged to do too many lines in a row. And I was just so intrigued at how well this was laid out to really understand those very questions of superiority as well as sequence, which we don't often assess. Dr. Atkins, will you just summarize the design so that all of the very smart researchers on the line can utilize that for their own cancer types? Dr. Michael Atkins: Yeah, it was complicated to execute, but the design was pretty simple. Patients with treatment-naive BRAF-mutant metastatic melanoma were stratified according to ECOG performance status and LDH normal and high and randomized in step 1 to receive either combination nivo-ipi induction for 12 weeks, followed by nivo monotherapy maintenance for up to 72 weeks—that was arm A, and that was standard of care for that regimen—or dabrafenib-trametinib continuously, and that was arm B. And if patients experienced disease progression and met the step 2 eligibility criteria, they were able to cross over to the alternative sequence: arm C, dabrafenib-trametinib, or arm D, nivo-ipi. And we followed the patients and chose two-year overall survival as the primary endpoint. Dr. Shannon Westin: And we kind of got a little hint. So what was the primary finding? Dr. Michael Atkins: Yes, because of the anticipated distinct shapes of the overall survival curves, with the BRAF/MEK inhibitors tending to have their benefit early and the immunotherapies tending to raise the tail of the curve, we thought there'd be non-proportional hazards and that the overall survival curves might cross. And therefore, we chose as a primary endpoint two-year landmark overall survival, with an estimate that the nivo-ipi first sequence would have a 70% overall survival rate compared to 50% for the dab-tram first sequence. And with 300 patients enrolled and 270 evaluable, there was about a 90% power to show this difference in two-year overall survival rate, with a two-sided type one error rate of 0.05. Dr. Shannon Westin: And it met its primary endpoint? Dr. Shannon Westin: Yes, the study was opened in July of 2015, and it was set up that there would be Data Safety Monitoring Committee meetings after the first 100 patients were accrued every six months and that the data cutoff used for the fourth interim Data Safety Monitoring Committee meeting, which was a median follow-up of a little over two years, 265 patients had enrolled in step 1—those were evenly split between the two arms—and 73 had enrolled in step 2, with nearly two-thirds of those being on arm D, second-line nivo/ipi. And the two initial arms were balanced for most of the characteristics and was randomized for the important characteristics. And from an efficacy standpoint, once again, we chose landmark two-year overall survival as a primary endpoint. And the overall survival curves for the combined sequences showed the anticipated biphasic pattern; they actually crossed around 10 months, and 100 patients had died, with 62 of them on the sequence beginning with dab-tram. And the two-year overall survival rate was 72% for patients who started on nivo/ipi and 52% for those who started on dab-tram. And that was a pretty significant difference; P equals about 0.01 by log-rank test. And so this 95% repeated confidence intervals, along with the 20% difference in overall survival, ranged from 3% to 38%, and the O'Brien-Fleming boundary had been crossed based on this estimate. Interesting, as we published, the three-year overall survival difference was even greater, approaching 24%. So that was the main study endpoint. And because the Data Safety Monitoring Committee felt that that difference was clinically significant even though we had only had about 59% information, they recommended at that point that the study be closed early and that patients who were on arm B, dabrafenib-trametinib, be given the option to cross over to immunotherapy before disease progression. So that was the primary endpoint. I'm going to pause there. There were some secondary endpoints that I think were interesting, but maybe Gary or Adil have comments about this. Dr. Shannon Westin: I hope they do, yeah. I'm going to give over my podcast hosting to you. Dr. Adil Daud: Mike, congratulations on that study. I mean, that's transformative. I mean, I think there was a feeling, like Gary was saying, that immunotherapy might be better in the long term. But I remember a lot of discussions, and I think you answered them in 2015 or 2014 and 2013 because you've been working on this design for a while, that the people who were treated with BRAF inhibitor therapy were just different. And a lot of people would say that when somebody walks into the clinic, the folks who are BRAF-mutant, they just have rapidly progressive disease, like something really bad is going on. And that's why the results on BRAF/MEK inhibitor therapy just looked different than immunotherapy. Immunotherapy was for slower-growing tumors, and I think your study kind of puts maybe a different spin on that, basically suggesting differently. Would you comment on that? Dr. Michael Atkins: Yeah. So, Adil, I think early on, people thought that the BRAF/MEK inhibitor was for patients who had rapidly progressive disease, and you needed to get a response to get the disease under control. But over time, as those studies were followed out, it appeared that the BRAF/MEK inhibitors tended to work best in patients who had less aggressive disease—performance status 0, M1a or b disease, and normal LDH. And so it was still confusing as to who should get which therapies. And when you compared the results using retrospective data between those who got immunotherapy and those who got targeted therapy, it was really difficult to be sure that these were the same patient population. So the only way you could really know whether immunotherapy was truly better was to do prospectively randomized studies where the two arms were balanced, which is what we set out to do in DREAMseq. Dr. Adil Daud: Yeah, I think there's a lot of areas in oncology where people think whether you should give somebody a CAR T-cell or whether you should give somebody myeloma therapy or—people think, well, these are just totally different. Or in melanoma, I think, the TIL therapy, there's this question about, can you really compare that to anything else? And I think your study, which perhaps wouldn't be done by a pharmaceutical company and perhaps wouldn't be— outside of the cooperative groups, I feel that it's hard to really do a study of that type. Dr. Michael Atkins: I agree. Dr. Gary Schwartz: Yeah. First, I want to say congratulations on really an extraordinary study, Michael. I think it really answers some critical clinical and biological questions that have been subject to debate in the melanoma and the medical oncology community for the last five or more years. There were a couple of things that surprised me. One was the fact that patients that started on dab-trame, when crossed over to immunotherapy, the outcomes were pretty poor. And that was a biological outcome, I guess, we kind of thought about. But this study certainly suggests that there's something about prior targeted drug therapy that may affect outcome and immunotherapy. And also, the other thing that was surprising was the number of dropouts that developed and couldn't cross over because of the rapid progression on the first-line study. Do you want to comment on both of those points and maybe share some thoughts about what that means for the medical care of patients who get this type of treatment? Dr. Michael Atkins: Sure. First of all, response rates were similar between the step 1 regimen and for dab-tram, whether used in step 1 or step 2. In contrast, as you said, nivo-ipi appeared to be less effective after progression on dab-tram than in the first line. It was like a 46% response rate in the first line, and about 30% in the second line. The median PFS in the first line was about 11+ months, and in the second line, was only about three months. And I think there was some feeling in the community—probably wishful thinking and also based on what I think are some flawed preclinical and translational studies—that BRAF/MEK inhibitors might cause some immunogenic cell death and cause new antigens to be expressed and activate the immune system, be synergistic with immunotherapy given afterwards, while I think other data suggested that the resistance mechanism to the dabrafenib-trametinib was immunosuppressive, leading to upregulation of VEGF and things like that. So this result suggested that immunotherapy didn't work as well in the second line. There are probably several reasons for that. It could be biologic changes, which I think we don't pay enough attention to when we think about what we're doing in the first and the second line. But also the type of patients who progressed on BRAF/MEK inhibitors. when you stop those drugs, the disease tends to accelerate. Many of them probably had subclinical CNS disease, and it was just not a good time for them to be going on immunotherapy, while in the front line, you didn't have to deal with those type of issues. And with regard to crossover, one of the things that we looked at as a secondary endpoint in this study was feasibility of doing the crossover. Because in clinical practice, we found that if you waited until disease progression on BRAF/MEK inhibitors and then tried to cross them over, oftentimes, patients progressed really rapidly, and you weren't able to get the immunotherapy in to large degree, while in patients who got immunotherapy, they had a lot of toxicity often, which caused them to stop therapy. And if they had toxicity at the time they were progressing, it might be complicated to add new drugs in. And so I think the community was a bit surprised that only about half the patients were able to successfully cross over. But I think that's reality, that if you use these drugs to progression and then have eligibility criteria, which you have to have in a clinical trial for patients to go on the second-line treatment, you're going to have a lot of dropouts. One of the major reasons for dropouts on dab-tram was progression in the CNS, and dabrafenib-trametinib doesn't work as well in the CNS as it does systemically, while immune therapy actually a…

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JCO Article Insights: Phase III POSEIDON Clinical Trial Results Feb 27, 2023

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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.

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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.

One-Stop-Shop Comprehensive Cancer Screening Center Focused on Asymptomatic Screening Feb 23, 2023

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Dr. Shannon Westin, Dr. Ezra Bernstein, and Dr. Nadir Arber discuss increasing cancer prevention and early detection with a one-stop-shop comprehensive cancer screening center. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, our podcast where we get in-depth on manuscripts that have been published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN oncologist and social media editor of the JCO. And I am thrilled to be discussing this very interesting paper entitled "Data From a One-Stop-Shop Comprehensive Cancer Screening Center," focused on asymptomatic screening. And this very important work was published by these two authors who are joining me today. We have Dr. Nadir Arber, professor of Medicine and Gastroenterology, head of the Integrated Cancer Prevention Center, head of the Cancer Prevention section of the European Society of Medical Oncology at Tel Aviv Sourasky Medical Center in Tel Aviv, Israel. And we're also joined by Dr. Ezra Bernstein, Fulbright fellow and researcher at the Integrated Cancer Prevention Center that we're going to be discussing today at Tel Aviv Sourasky Medical Center in Tel Aviv, Israel. And he's also, impressively, a resident in internal medicine at the New York University, so he's a gentleman of many talents and quite busy. Welcome. Dr. Ezra Bernstein: It's great to be here. I had a slow clinic day. Dr. Shannon Westin: Oh, I was going to say I'm impressed you, as a resident, could find the time. So we're really excited to have you, and you certainly have a bright future ahead of you as an oncology practitioner. So let's get started. I think certainly most of our listeners are quite familiar with the benefits of cancer screening. But I think it would be great if you all could level set and review the benefits at the patient level as well as at the healthcare system level. Dr. Ezra Bernstein: Sure. So I think, kind of breaking it down, on the patient level, the scientific community has made incredible progress over the last several decades in not only the understanding of the biology of cancer, but also that's translated into the treatment of cancers, from genomic sequencing to targeted therapy, which you now have specific small molecule inhibitors for specific mutations in each cancer. But despite all these incredible improvements and advances and the ability to treat many cancers, the greatest prognostic factor is still often the stage of diagnosis because the chances of survival and the chances of complete cure increase dramatically if the disease is detected in its earlier stages. So earlier detection and diagnosis can greatly reduce mortality, it can increase treatment effectiveness, and ultimately improve the quality of life for the cancer patients. On a healthcare system level, often when you're doing screening, you're discussing cost-effectiveness. And so the thing about the healthcare system, which we didn't really address in our paper–we initially were going to, but we think we're going to do a follow-up paper on this–the cost of cancer care is very high. In Europe, the total cost of cancer care in 2018 was $199 billion. And then I think the last data I saw was the US, in 2015, the total cost of cancer care was $183 billion. So, on a healthcare system level—and those are just the costs of cancer care; there's tons of other costs that go into when patients have cancer: lost wages… So I think that it's crucial not only for the patient but also for the healthcare system to help catch these cancers earlier. Dr. Shannon Westin: Yeah, I completely agree. I think we have such great guidelines on how we should be screening our patients. I think there's a number of different areas where providers can look to understand what they should be doing with the patient in front of them. What do you think are some of the barriers of implementation of this guideline-based cancer screening? Dr. Ezra Bernstein: That's a crucial question. We have the guidelines, especially in the US; we have our grade A recommendations: colon cancer, cervical cancer. We have our grade B recommendations: mammography. And lung cancer. So a big hurdle, especially in the US now with the recommended screenings at this point, is just getting people to do it. You look at the US, and for Pap smears, it's pretty good; 80% of the population is up to date with PAP smears. Mammography, a little bit less, low 70s. And then colon cancer screening, a little bit less. So how do we get these up, and what's the barriers? And that's kind of the idea behind the Integrated Cancer Prevention Center is it's cost, it's time, and it's also awareness. And this kind of gets into a little bit of the theory for what kind of created the Integrated Cancer Prevention Center is the idea that if you do a one-stop-shop approach where patients come in in a single visit and they get screened for all the recommended cancers, so they don't have to do multiple appointments, they don't have to take off work multiple times, and they can get it all done at once, that automatically leads to 100% compliance for those screenings that they do during that day. So that was kind of the theory behind it is you're able to remove a lot of the barriers to the implementation of the guideline-based cancer screening. The other thing is awareness and just making sure that patients are aware. I think it's actually great timing with this paper. They haven't done it so much lately, but the NFL, the National Football League, they were actually running a campaign for the first few games of the season where—you know, you have millions and millions of American viewers—it was called Intercepting Cancer, and they were highlighting the importance of screening and prevention. They gave a link, which is great, but it really just links you to your providers in your area to then go ahead and screen individually. That initiative was important in getting more awareness, but still, there's the cost and the time issues that are still barriers. Dr. Nadir Arber: Let me just emphasize what Ezra brilliantly says. He said that the best therapy of cancer is prevention, so increase early detections. I'm a gastroenterologist, so I'm fairly aware of preventions. I do colonoscopy, I found the polyp, I take it out, I prevent colon cancer. In other cancers, it's not that obvious, especially colon cancer. But then to detect it at an early stage, it means when the patients have no symptoms. When there are symptoms, mostly—not all, but mostly—it's too late. And then, when somebody feels good and well, it is not acceptable, it's not possible to go to all these different facilities and to have the referral. You want to go to screen for colon cancer, you go to your GP, who sends you to a gastroenterologist, you get the colonoscopy, then you come back, go to another GP, then you have to screen for prostate cancer. So you ask him, "Can you send me to a urologist?" They send you to a urologist. And they send him for a PSA and then free PSA and the rest of it. And then, if you do it on one stop, this is the only way that is feasible, for maybe the five major or six major cancer screening, there is no doubt and no questions. But then, with Ezra, we have learned that there is more than that. It's not only screening, but it's also case finding. Patients come to me for different reasons. They came to the center to be screened for skin cancer, breast cancer, colon cancer. So let's just tell him, "Can you open your mouth?" And then five minutes, not more than that, an oral surgeon checks your mouth. It is not cost effectiveness to call the patients to come to check, but he's coming for another reason. This is what you call case finding. People are not that aware about the difference between screening and case findings, and I would like to emphasize before I let the floor to you, so I'm not speaking about cost-effectiveness; I'm speaking about cost saving. It saves money. It does not cost; it saves. Actually, I was in Singapore when maybe I was invited to Singapore by the Singapore government. They heard about my concept and invited me to speak, and like we have just said, and that it's going to be published in the JCO, in the journal. And they told me—and they were very impressed—"We are going to do it because it's going to save money for us." And I said, "But how you are going to implement it?" They said, "We are a democracy; we cannot force the people to do it, but we are going to offer them free of charge. Free, because we understand that if they do, the government are going to save money." But if they offer it free of service, free of charge, and then somebody does not want to do it and he has cancer, it is his problem. It's like somebody has a car, buying a new car. He's not obliged to make insurance for the car, but if he doesn't do it and something happened to the car, he cannot come to the government or the insurance company or his spouse and complain. It's his problem. I think when you understand it, and we understand that it's cost-saving and it's a win-win situation, then we can make a big step ahead, and this is the way to go. Dr. Ezra Bernstein: I think Professor Arber brings up a very interesting point that I'm just going to make real quickly when he talks about kind of the case findings and the screening for something like oral cancer and skin cancer, which aren't currently grade A or grade B recommendations by the USPSTF, but in the context of a one-stop shop, it kind of changes the game a little bit. It's one thing to go to your dermatologist once a year in terms of screening for skin cancer, but if you're already at a one-stop-shop center screening for skin cancer, screening for thyroid cancer, and things which aren't currently—the thyroid is a little bit different, but screening for certain cancers aren't currently recommended for because they're not cost-effective, it changes the game a little bit in the concept of the unique setup that Professor Arber started. Dr. Nadir Arber: And at the same times, we also measure blood pressure, we measure sugar, hemoglobin, A1Cs, and other things that are known, but not only for cancer, but the patient is scanned when he's there. And also, if we found something—and we have the data, between 1% to 2%, we do find cancers—then we can help the patient to solve it on the spot because he's in the hospital, so we can arrange whatever he needs. So the patients like it. They appreciate. They know that they're in safe hands. And if you like, "I need to do ultrasound. I have some very suspicious legion," I can do it on the spot. Vaginal ultrasound, Pap smear, now we do it for HPV, DNA. So everything is on the spot, and we give solutions if something happens. People need—they found something or anything, so we can do everything. For this is the way of modern medicine. Ezra and myself have been working for many years. But eventually, it's going to catch up because this is the right things to do. The modern medicine, the way we see it in the future, is turning from sick care to health care. This is the way to go. This is one of these when we are advancing the technology and everyone is health conscious. Dr. Shannon Westin: I really appreciate you kind of giving that laundry list of all the things you're doing because I do think you're exactly right, that people are doing a better job around the kind of the most common screening tests. I'm a gynecologist by trade, so Pap smears are part of my daily activity. But I think mammograms, Pap smears, colon—I think that's more common. But this is a great way to kind of get screening for all of those other things. Like, I know a friend who just got diagnosed with an oral cancer, and it's like nobody's screening for those things. And you're right, Ezra, where they say that it's not cost-effective to have a visit just for that, but if you can encompass it all in one visit, it just makes so much sense. So I think that that takes us into the current study. Can you kind of just take us through briefly the design and your outcomes that you looked at? Dr. Ezra Bernstein: Yeah. So it was a retrospective analysis of over 17,000 patients that have visited the ICPC, the Integrated Cancer Prevention Center, between 2016 and 2019. And as Professor Arber was saying, patients come in, they're mailed a questionnaire beforehand, they ideally fill it out before, but they'll then meet with an internist or an oncologist. And they'll go over the questionnaire, they'll go over family history, risk factors, and then it will be really a tailored screening exam for that. They'll get the classic recommended screenings based on if they're due for a mammogram, if they're due for a Pap smear, and then from there– Do you want me to go through in detail or just kind of overall? Dr. Shannon Westin: I think overall is fine, yeah. Dr. Ezra Bernstein: Overall? Okay. So they do their screening test, they'll get some blood work done, and then if there's anything abnormal, then as Professor Arber was saying, the great thing is you get worked up right there. So they'll get TFTs, thyroid function tests. If those are abnormal, then they'll indicate a thyroid ultrasound needs to be done. They do all their screenings, all their testings. Most of it is done there. Professor Arber, do they do the biopsies there too if there needs to be a biopsy? Dr. Nadir Arber: Yes, obviously. But what is Ezra also referring, we are trying to do precision medicine. When somebody is coming to us, like you said, the woman, so we are measuring her Tyrer-Cuzick score and to see, if it is high, then we send her to do an MRI, if it is above 20%. Dr. Shannon Westin: So what were the outcomes that you measured in the study? Dr. Ezra Bernstein: So, after they did all the screening, our main outcomes were the number of malignant lesions detected and then also what stage were they detected. Basically, if the cancer was found within a year of a visit to the ICPC and it was found as a direct result of the screening done that day or if there were recommendations for follow-up that then led to a successful detection, we counted that as a malignant cancer that was successfully detected through the ICPC. Dr. Shannon Westin: What about the results? Were they as expected? How did your detection rates compare to kind of, say, the general population? Dr. Ezra Bernstein: A successful cancer screening program is always going to have a shift in detection of cancer to earlier stages, which is exactly what we saw, which was great. We then compared it to the Israeli general public over a similar time period, and the percentage of cancers found at a metastatic stage at the ICPC, that was lower for all cancers. Just going through: Colon was 20% versus 46.2% in the general populations. There was no metastatic, cervical, or uterine cancer found. Prostate was 5.6 versus 10.5, lungs 6.7 versus 11.4, as well as renal, which isn't recommended we screen for, but that was 7.7 versus 10.3. Dr. Shannon Westin: That's so incredible. I guess the other thing I thought was really nice that you did is looking at patient satisfaction and making sure—we're very much focused on patient experience and satisfaction right now in medicine. So what were your findings there? Were the patients satisfied with the process? Dr. Ezra Bernstein: Yeah, so this is something that we started doing towards the end of the study per…

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Improving Transparency in Phase 1 Clinical Trials Feb 09, 2023

Show notes

Dr. Shannon Westin and her guests, Dr. Paul Frankel, Dr. Judith Karp, and Dr. Robert Maki discuss how to better inform patients of the risks involved in phase 1 clinical trials. TRANSCRIPT Dr. Shannon Westin: Hello, everyone, and welcome to another episode of the Journal of Clinical Oncology After Hours podcast, where we do a deep dive on manuscripts that are published in the Journal of Clinical Oncology. We're so excited to have you all here today. I am your host, Shannon Westin, GYN Oncologist at MD Anderson Cancer Center, and it's my great pleasure to serve as the social media editor of the JCO and the host of this podcast. Today we are going to be discussing a very important manuscript titled "Ethics and Clinical Research: Improving Transparency and Informed Consent in Phase 1 Oncology Trials". And I'm joined today by several of the authors, as well as one of our editors that helped to review this paper. But before I start, I'll note that none of our authors have any conflicts of interest to disclose. And with that, I'd like to introduce our guests. First is Dr. Paul Frankel. He's a research professor at the Division of Biostatistics, Department of Computational and Quantitative Medicine, at the City of Hope National Medical Center. Welcome. Dr. Paul Frankel: Hello and thank you. It's a great honor to be here today. Dr. Shannon Westin: Also with Dr. Frankel is Dr. Judith Karp, who is Professor Emerita of Oncology and Medicine at the Johns Hopkins University School of Medicine in Baltimore, Maryland. Welcome. Dr. Judith Karp: Thank you. And I echo exactly what Paul said. Thank you for having me. Dr. Shannon Westin: And then finally, our esteemed Associate Editor of the JCO, Dr. Robert Maki. He's a professor of hematology and medical oncology, a physician leader in developmental therapeutics, clinical leader of the Sarcoma program at the University of Pennsylvania. Dr. Robert Maki: Hi, Shannon. Thanks for having me on the program. Dr. Shannon Westin: Well, it's awesome to have this star-studded group of guests. We are going to try to cover as much details about this important paper as we can in a short period of time. But I encourage you also to check out the JCO to read the paper in full. So first, let's level set. As we start this discussion around phase 1 trials and ethics, maybe, Dr. Mackie, can you start by giving the basics of just phase 1 trials just to make sure everyone's on the same page? Dr. Robert Maki: Sure, absolutely. Since we have people who are listening from different walks of life, that's for sure. Clinical trials in cancer run anywhere from phase 1, 2 to 3. There are also such things as phase 0 and phase 4 trials. But the primary ones we'll discuss today are phase 1 trials. These are the initial tests, be there a brand-new drug never tested before in people, or it might be testing a new combination of treatments, or it might be looking at an already approved drug or an experimental drug in a new population of patients. Let's say you wanted to take a look at a drug in an elderly population. There aren't any data about that in people who are, let's say, 80 or older, and that would constitute a phase 1 trial. The idea of the trial is to start with low doses of a medication and increase the doses in a systematic way, tracking the side-effects that occur with treatment, and then come to an answer as to how you should move forward with the medication in future trials to determine whether the drug is actually active or not and in which setting. The important point, I guess, in that sense is that a phase 1 trial isn't necessarily looking at whether a drug is useful or not, really just looking at the toxicity of the agent or new combination or new setting overall. Dr. Judith Karp: If I could add one thing to that, and I think this is something that has evolved—well, it's evolved over the last 30 years, but in terms of practicality and application, it's really over the last 10 years, roughly speaking. It's also, I think, the opportunity to identify potentially informative biomarkers through a series of pharmacodynamic studies. I'm an old leukemia doctor, and so I've had that capability, if you will, with our diseases because they're so accessible. But I think there's been a new emphasis on that over the last decade. And it's an important one because it becomes a tool for stratifying in phase 2 and ultimately for identifying, hopefully, in a prognostic fashion, who is potentially likely to respond versus not. And if it's a versus not, then you go in a different direction once you got a bunch of—or if you're lucky enough to have a bunch of different directions. Dr. Robert Maki: It's a really important point about looking at so called pharmacokinetic and pharmodynamic markers. How long is the drug staying in the body? What is the body doing to the drug? What is the drug doing to the body? Judith is right on the mark. You can get leukemia cells right out of the body, oftentimes take a look at them directly, whether you're actually hitting the target you think you're hitting. This is a really great place to—and it's often mandatory to get pre- and post-treatment biopsies, even in solid tumor patients, to know if you're actually hitting your target of interest. So, yeah, if you're not achieving that much, then you shouldn't really be moving the drug forward. Dr. Shannon Westin: I agree. And it's so critical because, as we've seen, you know, to your point, Dr. Maki, about the true goals of a phase 1 trial, I think we've done a lot better job of trying to ensure there is efficacy or trying to clarify for whom we are getting efficacy. And I think we all are aware of several drugs that have gotten approvals from an extended so-called phase 1, right? An appropriately selected population. And certainly that's something new over the last five, six, seven years that we've been able to do that. But things like PARP inhibitors in BRCA-mutant populations and TRK fusion inhibitors like Larotrectinib and others in those with NTRK fusions just come to mind kind of quickly. And even more so, we're seeing these focus drugs, right, that are focused on abnormalities in a specific—Exon, like the G12C inhibitors and things like that. So it is interesting to see how drug development is kind of changing in the phase 1 space where we're trying to move that efficacy potentially up earlier and earlier, just to Dr. Karp's point about that biomarker development. So I think it's a really exciting time. Okay, so the next piece I wanted to just make sure, again, to ensure that we're all on the same page, is these are very common trials, I'd say, and certainly the foundation of drug development. Do one of you want to give an estimate of approximately how many phase 1 trials are ongoing currently and maybe how that's changed over time? Are we seeing more phase 1? Less phase 1? About the same? Dr. Paul Frankel: Yeah, I can take a look at that. The number of phase 1 studies that are currently accruing patients today in oncology is around 4500, something like that. I think there's 4451 open clinical trials and phase 1 clinical trials in oncology today. If you look at, let's say, in May of this year, there was 4263. So you're seeing it's increasing. But if you want to look at really the increase, you can look at between 2000 and 2010. There were a little bit over 5000 phase 1 clinical trials that had started in that period, that 10-year period. If you look at the next 10-year period, 2010 to 2020, it's over 10,000 that started. So the number of phase 1 clinical trials is very large, and it's increasing at a rapid rate. And these do set, as you mentioned, the foundation for all the studies that subsequently follow. Dr. Judith Karp: It's very interesting to me that Paul has these numbers in his head. I am not as quantitative as Paul, but we have these increasing numbers of trials, and yet the percentage of patients who go on those trials has not increased at the same rate. There's still that gap where now for children with leukemia—actually, for children with cancers, it's 90%. 90% of those children go on clinical trials. But for adults, it's still around 8 or 10%. It's unfortunate. Dr. Robert Maki: It's a really good point. There really should be more adults being put on clinical trials. But by the same token, not every adult is appropriate for a clinical trial. Let's say you have—there are things you can do that are clinical trials that aren't treatment either. And if it's data collection or patient-reported outcomes, something that we really don't have a lot of information of in a broad manner, there certainly are clinical trials, even if you're getting standards of care in which patients can be enrolled. So you're certainly speaking to a group of people who espouse and promote clinical research wherever it can be done. Dr. Paul Frankel: These clinical trials, I think, are often the best opportunity that patients have. And even though we're going to be talking about issues with consent and other issues with regard to phase 1 clinical trials, they still remain the best option for patients in almost every situation, if you can get on them. Dr. Judith Karp: Yeah. I just think of them as… Dr. Shannon Westin: Yeah, and I think we could have a whole 'nother podcast of how to expand an exclusion criteria to allow for those patients, but maybe we'll bookmark that for another episode. Paul, you kind of started mentioning, I think, the last place to level set before we get into a little bit more detail from the paper that you all wrote is from regards to informed consent. Can one of you, or more than one, review the importance and challenges of this process for our listeners? Dr. Judith Karp: I'll take a stab at that one. I think the importance of informing a patient, however well we can do it, of what we expect to happen and what we know and what we know we don't know is a very important part of the contract between the physician and the patient. And it's really a partnership, especially for phase 1 trials, where we really know so little. And what we do know is that the patient—these are for treatment trials. We know that there is no therapy widely available for that patient that's going to do that patient any good. So we have to enter into a partnership with the patient to say, "We're going to try something. We know this little bit. We don't know this huge amount." And so I think that that's really the importance, just ethically, to have the patient be informed. In terms of the challenges, I think that—this is certainly not politically correct, but were I on the receiving end, on the patient end, and somebody gave me a 35-page document to read, I would not for many reasons. In some ways, it's too much information. Most patients are not, by definition, medically sophisticated. That's one. Two, they don't want to read 30 pages. They're either going to sign it, or they're not. And it's confusing. And, yes, you can say to a patient, "Look, take this home, read it, come back in a week, call me in a week," whatever. There are many instances, certainly in the leukemia field, where you can't do that. You don't have that luxury. So I think that that is a real challenge that we really haven't addressed. And in the good ol' days when all of us physicians really sat down and talked to the patient, then I think that the challenges were much less. And I think that that's key. Dr. Robert Maki: Yeah. I mean, Judith, AML over age 65. You're not going to get most people into remission, and you've got a captive audience because there they are with low counts. And what are you going to do next? We all, in our research, want to follow the Belmont report. We want to respect people. We're looking for studies that offer beneficence, that do no harm. We can't really do no harm a lot of the time, but we can at least minimize harm. And I think it's where the consent process kicks in. And justice, the third tenet of the Belmont report, being sure that we're using well-considered procedures as part of the research. All those are part of those beautiful words that you used, "partnership" and "contract," that I think are really important in developing that bond with the individual patient who you're going to treat is super critical. Dr. Judith Karp: Yeah, absolutely. And in some senses, the only real informed consent is if the patient has been through it before. Dr. Shannon Westin: Right. Dr. Paul Frankel: So one of the things making it even more challenging, all these challenges exist throughout. And one of the focuses of our paper is that there's been an increasing trend to use designs that specifically target toxicity rather than limit toxicity during the dose finding of the phase 1 study. And so that introduces a whole 'nother aspect to the consent process. So if you look at those studies, the most common toxicity target, as noted by others, is a 25% DLT rate. And if interpreted directly, that means that these risk-targeting designs, they claim to aim to find the dose where one in four patients are expected to experience a severe or a life-threatening adverse event in the first cycle of therapy, which is usually 28 days. And that's despite dose modifications. And further, most of these designs consider it a positive feature if a large percent of the enrolled patients are treated near the target. Now, whether this is really what the physicians want or not is separate. But one way or the other, what we have noted in our paper is that our collective experience that the actual toxicity target, the targeted risk, whether it's 20%, 25%, or even 33%, is not disclosed to the patient in the initially submitted consent forms that we see. That is a fundamental change in the way we've designed studies, but it requires that we adapt the consent process to this very challenging problem. Dr. Judith Karp: Along those lines, you're talking about toxicity. Any treatment that targets a non-itchy skin rash has got to be a lot less toxic than a drug that is targeting refractory ovarian cancer or leukemia or what have you. And the disease itself is toxic. So I think there has to be a way to approximate and weigh those toxicities, the toxicity of the treatment versus the toxicity of the disease, because the disease is not benign. Dr. Shannon Westin: One of my mentors, Dr. Razelle Kurzrock, used to always say, "The worst toxicity is progression of cancer." And I completely—that's a very wise woman. But I think it's a really good point. And I think, just to kind of summarize what you all were saying, if we're targeting a certain toxicity level, we just need to make sure that patients are aware of that. And many of them might be willing and would probably be willing to take that for that potential benefit and things they might get out of it, but we need to be more transparent on that kind of individual protocol level. Would you say that's…? Dr. Paul Frankel: That's the critical thing is to be transparent about these things. And certainly certain different treatments which have maybe more curative potential, certain types of diseases, they're going to be more amenable to a higher toxicity threshold. But it depends on the intent of the therapy, and these need to factor into the decision of what's being used, what kind of target and kind of design is being used. That's kind of part of the issue of transp…

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JCO Article Insights: Elderly Patients Receiving Chemotherapy for Early-Stage Breast Cancer Jan 30, 2023

Show notes

In this JCO Article Insights episode, Davide Soldato summarizes two articles from the January 10th, 2023 Journal of Clinical Oncology issue: "Low-Intensity Chemotherapy for Early Breast Cancer in Older Women: Results From the Prospective Multicenter HOPE Trial" and "Inflammation and Clinical Decline After Adjuvant Chemotherapy: Results From the Hurria Older Patients Prospective Study ." Both articles report on clinical outcomes of elderly patients treated with chemotherapy for early-stage breast cancer.

TRANSCRIPT

Davide Soldato: Thank you for joining JCO Article Insights. I'm Davide Soldato. Today I will be providing summaries for two different articles focused on elderly patients treated for early-stage breast cancer. Both articles are reported from the Hurria Older Patients With Breast Cancer Study. This study is also known as the HOPE Study, and it was a multicenter, prospective, study of patients aged 65 years and older treated with current standard (Neo)adjuvant chemotherapy regimens for early-stage breast cancer. The study captured several detailed geriatric clinical and treatment data from 500 patients that were recruited between September 2011 and May 2017 in 16 sites across the United States.

The first article is titled 'Low-intensity Adjuvant Chemotherapy for Breast Cancer in Older Women'. In this article, Dr. Sedrak and colleagues used data from the HOPE Study to investigate the incidence of chemotherapy administration with low relative dose intensity, associated risk factors, and relationship with survival outcomes. Previous data already showed that the receipt of chemotherapy with a low relative dose intensity is associated with inferior survival outcomes, and the commonly used threshold to define a low relative dose intensity is 85%. And this same threshold was used inside of the study that I am reporting. Elderly patients that are treated with chemotherapy are at higher risk of receiving chemotherapy with low relative dose intensity because of toxicity. However, previous data on the topic was mainly retrospective in nature and reported heterogeneous rates of low relative dose intensity up to 75%. And also, little information was available on risk factors and on the impact on survival outcomes. So, considering the paucity and the quality of the previous data and the potential clinical implication for survival outcomes, results of the HOPE Study are extremely relevant to clinical practice as they provide novel insight on the topic from a prospective multicenter study.

In the analysis that was reported in the January issue of JCO, the authors excluded patients with HER-2 positive disease, those receiving nonstandard chemotherapy regimens, and those with upfront chemotherapy dose reduction. The final analytic cohort included 322 patients with a median age of 70 years, 44% with stage II, and 22% with stage III disease. Docetaxel and cyclophosphamide, and anthracycline-based chemotherapy, and this one, either alone or with subsequent paclitaxel, were the most commonly used chemotherapy regimens. Additionally, 85% of patients received a primary prophylaxis with G-CSF. Relative dose intensity was variable in the study. More than half of the patients received full course chemotherapy with 100% relative dose intensity. However, the incidence of low relative dose intensity in the HOPE study was still 21%, thus identifying a subset of patients who received chemotherapy with a suboptimal dose intensity. The rates of low relative dose intensity were higher for patients receiving either anthracycline-based chemotherapy and those with a planned treatment duration over 12 weeks.

The authors developed a multivariable logistic regression model with stepwise selection to identify risk factors associated with low relative dose intensity. The results of this analysis showed that an age higher than 76 years, administration of anthracycline and CMF-based regimens, and a physician-rated Karnofsky Performance Status under 90 were associated with higher risk of low relative dose intensity ranging from 3 to 5 times greater compared to reference categories. Then the authors realized another model where they used the previously mentioned three variables, but they also adjusted for relevant clinical characteristics, including age, stage, liver and renal function, and also previous cardiovascular disease. And in this model, the three variables that were observed previously— age, type of chemotherapy, and Karnofsky Performance Status—remained significantly associated with higher risk of receiving chemotherapy with a low relative dose intensity.

Finally, the Authors evaluated the association between a low relative dose intensity and survival outcomes, specifically breast cancer-specific mortality, non-breast cancer-specific mortality, and overall survival. Patients who received the chemotherapy with a low relative dose intensity had a significantly lower overall survival, and this association persisted even after excluding patients older than 76 years. A higher risk of both breast cancer and non-breast cancer mortality was observed in patients with low relative dose intensity chemotherapy. However, the number of cause-specific events was too low to obtain statistical significance for both these endpoints.

In conclusion, the study by Dr. Sedrak and colleagues provides several relevant information for clinical practice. First, the HOPE study demonstrates that the administration of chemotherapy to elderly patients while maintaining an appropriate relative dose intensity is feasible. However, 1 in 5 patients received chemotherapy with a low relative dose intensity. So the results of this study reinforced the need to identify upfront patients most likely to require dose reduction. And these patients should be proactively supported during the administration of chemotherapy to ensure that appropriate toxicity management can reduce the risk of low relative dose intensity.

Second, in the study, the authors observed a significant association between a low relative dose intensity and the CARG and CARG-BC scores. These scores were previously validated to predict chemotherapy toxicity. The presence of this association is important because it suggests that these validated scores can be used routinely in clinical practice to identify patients that might benefit from a comprehensive geriatric assessment to optimize comorbidities treatments and assure optimal delivery of chemotherapy.

Finally, longer follow-up will provide the opportunity to establish if the higher mortality that was observed in the HOPE study in patients receiving chemotherapy with a low relative dose intensity is consequent to the low chemotherapy efficacy or to a clinical decline that might be consequent to chemotherapy itself.

I will now move to the second article titled 'Inflammation and Clinical Decline After Adjuvant Chemotherapy in Older Adults With Breast Cancer'. This article was published by Dr. Ji and colleagues, and it describes a secondary analysis of the HOPE study. In this specific manuscript, the authors wanted to evaluate the potential predictive role of baseline inflammatory biomarkers on the risk of clinical decline after administration of chemotherapy. In the HOPE study, the authors collected information on frailty stages, pre and post-chemotherapy using the Deficit-Accumulation Index (DAI): this is a 50-item scale that evaluates deficits in physical activity of daily living, instrumental activities of daily living, psychosocial status, nutrition, frequency of falls, number of medications, comorbid conditions, social support, and laboratory values. The inflammatory biomarkers that were evaluated in the current study were CRP and IL-6, and their levels were determined on pre-chemotherapy blood specimens. Using the deficit accumulation index score, patients were categorized pre-chemotherapy as being robust, pre-frail, or frail; this is important because previous studies already demonstrated that there is a significant association between this categorization and morbidity and mortality outcomes in older adults.

The primary outcome of the study was a chemotherapy-induced clinical decline that was defined as a decline from a robust stage pre-chemotherapy to a pre-frail or frail status after chemotherapy. The overall analytic cohorts included 295 robust women. The median age was 69, 62% of patients had stage II or III disease, median number of comorbidities was 1.9, and mean BMI was 28.5. One in 4 older women included in the study experienced a chemotherapy-induced decline in frailty status, so this means that they transitioned from a robust status pre-chemotherapy to a pre-frail or frail status after chemotherapy. This decline in frailty status was more frequent among patients with a higher BMI, those with more comorbidities, and those with stage II and III disease.

Additionally, the patients who experienced chemotherapy-induced decline had higher baseline levels of both IL-6 and CRP. Univariate analysis also showed that patients with high IL-6 and CRP had a threefold higher risk of experiencing chemotherapy-induced decline in frailty stages. This association between higher inflammation and the decline in frailty status remained significant in a multivariable logistic regression analysis that was adjusted for relevant clinical and demographic characteristics, including age, stage, race, education, BMI, breast cancer surgery, anti-inflammatory medication, and number of comorbidities. Specifically, the results of these models showed that patients who had both high CRP and IL-6 at baseline had a threefold higher risk of experiencing a decline in frailty status.

So, in conclusion, this study shows a significant association between systemic inflammation and a decline in frailty status in elderly patients receiving chemotherapy for early-stage breast cancer. From a biological perspective, these higher levels of systemic inflammation might be a direct byproduct of a more advanced biological aging following the accumulation of senescent cells. There are several intriguing future perspectives that come from this study. First, if validated in additional cohorts, these findings might lead to higher treatment personalization thanks to the identification of patients at risk of clinical decline based on clinical characteristics but also on systemic inflammation. And these patients could be then proactively supported during chemotherapy to try and reduce the appearance of the clinical decline. Second, we know that inflammation is a potentially targetable pathway, and previous data obtained in breast cancer patients showed the potential of behavioral, exercise, and dietary interventions in modulating systemic inflammation. So, based on this new information, if validated in additional cohorts, future research should then evaluate if this interventions can be used to treat and eventually prevent the decline in frailty status in patients with high baseline systemic inflammation before receiving chemotherapy.

This is Davide Soldato in this episode of JCO Article Insights. We discussed two publications: 'Low-intensity Adjuvant Chemotherapy for Breast Cancer in Older Women: Results from the Prospective Multicenter HOPE Trial', and the second one, 'Inflammation and Clinical Decline After Adjuvant Chemotherapy in Older Adults with Breast cancer: Results from the Hurria Older Patients Prospective Study'.

Thank you for your attention, and stay tuned for the next episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

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Articles

Low-intensity Adjuvant Chemotherapy for Breast Cancer in Older Women

Inflammation and Clinical Decline After Adjuvant Chemotherapy in Older Adults With Breast Cancer

Find more articles from the January 10 issue.

Ensuring Employment After Cancer Diagnosis Jan 20, 2023

Show notes

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 careg…

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