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