Journal of Clinical Oncology (JCO) Podcast – Détails, épisodes et analyse

Host Dr. Davide Soldato and guests Dr. Kerin Adelson and Dr. Maureen Canavan discuss JCO article "Association Between Systemic Anticancer Therapy Administration Near the End of Life with Health Care and Hospice Utilization in Older Adults: A SEER Medicare Analysis of End-of-Life Care Quality," highlighting adverse outcomes for patients who receive any type of systemic anticancer therapy(SACT) at EOL (end of life) and the need for better communication between oncologists and patients regarding expected risk and benefits of such treatments to properly align goals-of-care.

TRANSCRIPT

Dr. Davide Soldato: Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, medical oncologist at Ospedale San Martino in Genoa, Italy.

Today, we are joined by JCO authors Dr. Maureen Canavan, epidemiologist and associate research scientist at Yale Cancer Outcomes, Public Policy and Effectiveness Research Center; and by Dr. Kerin Adelson, Chief Quality and Value Officer, medical oncologist, and clinical researcher on health services and clinical care delivery at MD Anderson Cancer Center.

In the manuscript "Association Between Systemic Anticancer Therapy Administration Near the End of Life With Health Care and Hospice Utilization in Older Adults: A SEER-Medicare Analysis of End-of-Life Care Quality." that you recently published in the JCO, you performed an analysis that included more than 30,000 older adults in the SEER-Medicare database, and you observed that 7.6% of these patients received any systemic anticancer medication within 30 days of death. So, I wanted you to explain why you thought that this was a priority right now, and whether there was any previous data that was published in the literature, and if you think that there was any significant gap in the literature that led you to the research you just published.

Dr. Kerin Adelson: We have published a series of articles looking at real-world trends  in patterns of care, particularly related to systemic anticancer therapy at the end of life. This has been gaining increasing focus in recent years because of the understanding that when patients stay on systemic anticancer therapy, that is often a surrogate for a lack of goal-concordant care.

So, patients who continue to receive systemic therapy have worse quality of life, are more likely generally to have a medicalized death, and less likely to use hospice. And what our prior work has shown is that more and more we are seeing patients using immunotherapies and targeted therapies towards the end of life. No prior work had really comprehensively examined whether these novel therapies were associated with those same patterns of care increases in acute care utilization and decreases in hospice.

Dr. Davide Soldato: So basically, the data that we had up until that point was mostly with cytotoxic chemotherapy, and the emergence of this new treatment, which frequently are thought to be less toxic and so less problematic also in the end of life, led to this research. Is that correct?

Dr. Kerin Adelson: Correct.

Dr. Maureen Canavan: I would also build on that. I think that as the landscape of cancer care changes, it is important to really understand the availability of treatments, but then also, as Kerin noted, it is important to focus on goal-concordant care. We have established literature, studies we have done and some other studies that have looked at cytotoxic chemotherapy, but with the emergence of these targeted therapies, we really did not know a few things. We did not know the rates of utilization in a large national population, and how that was associated with these elements of medicalized death like ED use, hospitalizations, acute care use.

So this was really a question that we had going into it. How can we expand the knowledge base so that both patients and providers can be more cognizant when thinking about goals of care conversations and ensuring that that is in place?

Dr. Kerin Adelson: And our work has kind of evolved to answer some critical questions. So, one of our early papers looked at different rates of systemic anticancer therapy at the end of life, and that is where we showed that we were seeing a lot more immunotherapy and targeted therapy. And then we asked the question, well, oncologists generally when they give these treatments, they are hoping that those treatments are going to work and help the patients live longer. So we did another paper where we actually looked at practices who were more aggressive near the end of life and whether they had better overall survival than practices that were less aggressive, accounting for the fact that there could be populations of patients who benefited.

And in fact, we showed there was no survival difference. So then this paper sort of answered the question: Well, if it is not having benefit, is this treatment actually doing harm? And this study gets at that question: What are the harms of continuing patients on therapy past the point of benefit?

Dr. Maureen Canavan: And I think building off of that, the use of the SEER-Medicare database is a quite robust database. So in this, we have very specific data we can track. We can track the exact type of treatment they had, you know, was it a targeted therapy? Was it immunotherapy? So looking at those subclasses of therapy. We were also able to directly link it within that time frame to the acute care utilization, a limitation that we had in some of our previous work that that data was not always available.

So it is more focused in the sense that we were looking at older adults, so patients 66 years of age and older, but we were able to get those individual metrics. So to Kerin's point, we did not see the survival benefit. What do we see then for these medicalized death elements? So the higher rates of all of them across the board.

Dr. Davide Soldato: So coming back to the cohort and to the data that you utilized, Dr. Canavan mentioned the use of the SEER system to analyze these data. You already mentioned that you included mostly older adults, so those aged 66 and more. And also there was a little bit of restriction regarding the fact that the patient needed to be covered by Medicare in the last year of death concerning Part A and Part B, and the last 30 days from death concerning Part D. So I just wanted to ask a little bit of a question regarding these findings and whether you think that we also need additional work, especially in the younger population because I think it is something that all of us who work in oncology have seen. The aggressiveness, and this is also something that you showed in your data, tends to increase as the age of the patient tends to decrease. So we tend to be more aggressive towards younger patients. So just a comment on that on the population and generalizability of the findings.

Dr. Maureen Canavan: Yeah, I will start with the data question element. Thank you. I think there are a few things to point out for that. So in terms of the restriction to ensure that they had continuous Part D coverage, that was necessary for us to track their oral medication use during that time. So kind of an easy response. The Part A, Part B requirement, it is actually pretty widely used in studies of SEER-Medicare data, and that is you want to establish the patient population, that they are not getting treated with another insurance provider in some way that you are not able to track.

So that ensures that we can track not only their systemic anticancer therapy use but also when we are trying to make sure that we are controlling for confounders like chronic conditions and stuff, we are able to track the presence of chronic conditions. So we wanted to make sure we were not biasing the data, so I think that was an important consideration.

You do point out very wisely that there are then limitations with the generalizability, and I think we would be lacking if we did not account for that. But I think it is important to establish this baseline relationship association, and then you can step out, we will say, to more diverse populations. So I think we could potentially maybe try to relax the timeline to see if people that might have influx in and out of the Medicare system are still seeing those same rates. I think it is likely they would.

But I think to the bigger point that you bring up is that establishing this within the older adults where, you know, we do see as they get older maybe less rates of systemic therapy, extending it to the younger population. There is a challenge with that in that just that data is not available to the robust level that SEER-Medicare is. Both Kerin and I have noted that there is the possibility to look within one specific insurance provider type. Again, recognizing the limitations of the generalizability, but always slowly pushing the needle, finding out more about younger adult populations.

And I think this is maybe in an ideal world, but setting the precedent that we really do need to track this on a national scale within younger adults because they do have the need. We do see these higher rates of utilization, and really making sure again with the mindset always of the best interest of patients and the most informative to providers in how we are looking at care.

So I think generalizability is definitely a goal. However, there are limitations of the availability of data for younger populations and I think that they are a necessary restraint that all researchers should acknowledge.

Dr. Kerin Adelson: Yeah, I think it is important for our audience to understand that health services research and large database research is really limited by what databases are available and what are the characteristics of those databases. So we have done a lot of work in an electronic health record database, and there you can get certain kinds of granularity that you may not be able to get in a payer or a claims-based database. But what you do not get is that comprehensive look at, say, what happens if a patient goes to another practice.

Claims-based databases offer you that, but research on US populations is limited by our payment system. So when you look at younger patients, there are so many different insurance companies that when you are trying to get that comprehensive view, it can be hard or very expensive actually. These commercial insurers will sell their data to different databases. So for us, the largest single payer in the United States is the US government, and that is for patients who are over age 65, and that is why you see lots of US-based studies done in the Medicare population.

Interestingly, a recent paper by a Canadian group showed very, very similar patterns. It was a significantly smaller study but, right, Canada is a single-payer system and so they were able to really look at all ages, and we did see the same patterns of care in a different payment system.

Dr. Davide Soldato: Going back a little bit to the type of treatments that were observed in your manuscript, so we start from a 7.6% of patients who received any type of systemic anticancer therapy within 30 days from death. And when we split the different categories that you analyzed, which I think is a very strong aspect of your manuscript, we see that more or less 50% of the patients received chemotherapy, 20% more or less received immunotherapy, more or less 20% targeted therapy, and then there is a combination of those agents. So just wanted to have a little bit of your opinion compared also to the data that you already published and that you mentioned before. Was this in line with previous data? Was there anything surprising about this? We saw a little bit of a raise in the use of immunotherapy and targeted therapy as you were saying, but still, there is a very high proportion of chemotherapy, 50%.

Dr. Kerin Adelson: So I think that really, really reflects the time period in which we studied where immunotherapies were gaining ground. There was tons of excitement and we were seeing this shift. I bet if we do the same study in five years that chemotherapy percent may even go down to half, and we are going to see more and more targeted and immunotherapies, and that is just reflecting the pattern of drug discovery that we are seeing.

Dr. Davide Soldato: Coming to the real question that you wanted to answer with this manuscript, so is systemic anticancer therapy associated with worse outcomes in terms of healthcare utilization and use of hospice resources? Was there any hint that for example immunotherapy was related to less of these adverse outcomes?

Dr. Kerin Adelson: So I will be honest, I was a little bit surprised that the combination of chemotherapy and immunotherapy was that much more strongly correlated with acute care use at the end of life. You know, I had really thought most likely that what we would see were similar rates. And we did. Each different type of systemic anticancer therapy was associated with significantly higher odds of ending up in the hospital, going to the ICU, dying in the hospital, going to the ED. But that group that got dual therapy was that much higher, you know, over three times the risk.

And that surprised me because what it suggested is that there is likely a component of treatment toxicity that is leading to some of the acute care use. It is not simply just a constellation of patients who have not yet transitioned towards hospice or palliative care or end-of-life care who are then more likely to end up in the hospital. But the fact that we see a difference between, say, single-agent immunotherapy and dual combination with chemotherapy does suggest that the treatments are actually contributing to some of what we are seeing.

Dr. Davide Soldato: But still, all of the treatments that you evaluated were still associated with higher healthcare utilization. Like there was no signal that, for example, giving immunotherapy at the end of life was not associated with these adverse outcomes. Correct?

Dr. Kerin Adelson: Correct. And you will find oncologists out there who will say, actually, these treatments are so good that they might actually lower rates of hospitalization because they keep patients healthy. And certainly, that may be true upstream or earlier in the course of disease, but at the end of life, any form of systemic anticancer therapy is really a surrogate marker for lack of transition towards what is likely appropriate end-of-life therapy.

And I just want to point out that time spent in the hospital, going back and forth to invasive procedures, going to the intensive care unit, even going back and forth to an infusion center, that is time that is not spent at home with loved ones for people who have very little time left to live.

Dr. Davide Soldato: Thank you very much. That was exactly the point that I wanted you to stress because I think it is really the most important message that we can get as oncologists from this manuscript. Like there is no treatment that is not associated with potentially harming our patient and, as you were saying, taking off time with loved ones in a critical period of the life of these individuals who have been diagnosed and treated for cancer.

So, basically what we saw in the paper was a 7.65% utilization of systemic anticancer therapy. And I might imagine that for some oncologists or for some hematologists that might not actually be that much. Like they could potentially say, "Okay, but it is like 7%, it is not that high. I would have expected something higher." So I just wanted a little bit of perspective regarding also quality metrics that we have available for these types of indicators at end-of-life care. What would be the appropriate percentage of people receiving any type of treatment within 30 days from death?

Dr. Maureen Canavan: A couple caveats, as a data person I always like to give those. This was among all cancer patients, so not necessarily patients that had been on active treatment. So I think that number was actually quite lower than when we looked in another study about patients that had chemo within the last year, so on, you know, active treatment. So I think that is an element to take into consideration is that those numbers will vary based on who your denominator population is. So that is important to consider.

Additionally, the National Quality Forum, they call for reducing rates of systemic therapy at end of life. But I think they, similar to how I would be, are cautious to point out this is the exact number, or it should be zero. Because there are cases where you have to go in line with patient preferences. And if a patient is very adamant that they want to continue treatment, that needs to be a decision that comes between them and their provider.

So, you know, the zero, though sounding ideal to us who want to encourage transitions and encourage goals of care conversation is a nice number, it is not a realistic. So, to evade your question completely, I do not think there is a set number. But the goal is to make sure that both patients, providers, everyone is informed and is making the best holistic decision. So there is this natural tendency, I think, to keep fighting both for the patient and the provider to try to beat something, but recognizing the point at which we are beyond a benefit of treatment and what would be most beneficial to the patient in terms of getting back to that idea of, you know, the time with their families and whatnot.

So is the number zero? No. Could it probably be lower than we have? I think yes, definitely.

Dr. Kerin Adelson: I completely agree with everything Dr. Canavan said. I think one of the other challenges is that this data isn't being tracked and publicly reported across the world. And so what that optimal rate is, is a little unclear. We see different rates also depending on the population included. So one of the things Dr. Canavan said is our database included patients who were likely treated long ago for cancer and cured of their cancer. So they were less likely to die on systemic therapy. But until everybody starts tracking and reporting, it is really hard to know where we are as a country or really as a global population, and then what are the bars that we want to achieve in driving down the rates.

I think some data shows that probably something in the range of 10% or below, you know, for patients who have more active cancer is probably where we should be going and driving towards. But until we have more public reporting of these metrics and consistency in how we measure them, it is really hard to come up with a single number.

Dr. Davide Soldato: I have the impression that sometimes there is also a little bit of difficulty for the oncologist or the hematologist to really understand who are the patients who are approaching end of life. So there has been some data and you also report some of them in the discussion of the manuscript regarding, for example, prompts inside of the electronic health records or the use of artificial intelligence to try to predict what is the disease course. So just wanted a little bit of perspective if you think that these tools could potentially be helpful and if you think that we will be able at a certain point to implement them in routine clinical care.

Dr. Kerin Adelson: I have been working on trying to do this actually at MD Anderson and coming up with a really reliable data tool that will tell us who are the patients who are going to die in short order after receiving systemic anticancer therapy. And it is not that easy, I will say. So, you know, I think we all want this amazing machine learning model that is incredibly reliable. But like any statistical test, there are problems, right? So a very sensitive test that is going to identify high, high risk of dying at the end of life is going to be compromised by false positives. And when an oncologist knows that the test might be a false positive, it becomes very hard for them to take action on it.

Similarly, you know, a very, very specific test is going to be compromised by false negatives. So in that case, you could end up having patients who are at risk for dying and still treating them with chemotherapy. And so, you know, I think in the end we need some tools. It will be great if machine learning becomes very reliable and we have the right structured data elements in our electronic health records to give these reliable prediction tools.

But I think there are some basic things that we all know, and those are the markers of chronicity of cancer. So patients who have had multiple lines of therapy already, right? Past the point of clinical trial benefit. Patients who have lost significant amounts of weight. Patients who are not getting out of bed and have worse performance status. Patients who are increasingly confused, right? And not mentally engaging the way they did previously. Those markers have been shown in numerous publications by a colleague of mine, David Hui and others, to really be pretty strong predictors, and they resonate with clinicians more than a machine learning score might. You know, I think when clinicians do not understand what the elements in a machine learning tool are, they are less likely to trust it and more likely to say, "Oh, it is a false positive or a false negative." But very few clinicians can argue against the fact that the patient who hasn't gotten out of bed in two weeks is somebody who is less likely to benefit.

Dr. Davide Soldato: Dr. Adelson, I would like to close this podcast and I would like to thank you again for joining us today.

Dr. Maureen Canavan: Thank you so much.

Dr. Kerin Adelson: Thank you so much for having us.

Dr. Davide Soldato: Dr. Canavan, Dr. Adelson, we appreciate you sharing more on your JCO article titled "Association Between Systemic Anticancer Therapy Administration Near the End of Life With Health Care and Hospice Utilization in Older Adults: A SEER-Medicare Analysis of End-of-Life Care Quality."

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 Disclosures

Kerin Adelson
Stock and Other Ownership Interests: Carrum Health
Consulting or Advisory Role: Abbvie, Quantum Health, Gilead Sciences
Patents, Royalties, Other Intellectual Property: Genentech
Other Relationship: Genentech/Roche

Employment: Emilio Health/Brightline Health(An Immediate Family Member)
Stock and Other Ownership Interests: Emilio Health/Brightline Health, Lyra Health (An Immediate Family Member)

Guests Dr. Andrea Necchi, Dr. Ashish Kamat and host Dr. Davide Soldato discuss JCO article "End Points for the Next-Generation Bladder-Sparing Perioperative Trials for Patients With Muscle-Invasive Bladder Cancer," focusing on the evolving treatment landscape of MIBC (muscle-invasive bladder cancer) and the need to properly design novel trials investigating non-operative management while including the incorporation of biomarkers and patient perspectives in clinical trials.

TRANSCRIPT

The disclosures for guests on this podcast can be found in the show notes.

Dr. Davide Soldato: Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, medical oncologist at Ospedale San Martino in Genoa, Italy.

Today we are joined by JCO authors Andrea Necchi, Associate Professor of Medical Oncology at University San Raffaele and Medical Oncology at Ospedale San Raffaele in Milan, Italy, and Ashish Kamat, Professor of Urologic Oncology and Cancer Research at University of Texas MD Anderson Cancer Center. Both Professor Necchi and Professor Kamat are internationally recognized experts in the field of genitourinary malignancy and particularly in bladder cancer.

Today we will be discussing the article titled "Endpoints for the Next Generation Bladder-Sparing Perioperative Trials for Patients with Muscle-Invasive Bladder Cancer."

So thank you for speaking with us, Professor Necchi and Professor Kamat.

Dr. Andrea Necchi: Thank you, Davide, and thank you JCO for the opportunity.

Dr. Ashish Kamat: Yeah, absolutely. It is a great honor and privilege to be discussing this very important article with you. So thank you for the invitation.

Dr. Davide Soldato: The article that you just published in JCO reports the results of a consensus meeting that was held among experts in the field of genitourinary malignancy and particularly for bladder cancer. So the objective was really to define endpoints for a novel generation of trials among patients diagnosed with muscle-invasive bladder cancer. So my first question would be: what is the change in clinical practice and in clinical evidence that we have right now that prompted the start of such consensus in 2025?

Dr. Andrea Necchi: So, we are living so many changes in the treatment paradigm of patients with muscle-invasive bladder cancer. In general, patients diagnosed with bladder cancer or urothelial cancer today, thanks to the advent of immunotherapy or immunotherapy combinations, and today thanks to the advent of novel antibody-drug conjugates like enfortumab vedotin in combination with immunotherapy that are actually changing the landscape of treatment of patients with metastatic disease and also are entering quite fast into the treatment paradigm of patients with organ-confined disease with a lot of clinical trials testing these combination therapies, neoadjuvantly or adjuvantly, before or after radical cystectomy.

Having said that, by potentiating the efficacy of systemic therapy, an increasing number of patients that receive neoadjuvant therapy of any kind, at a certain point in time, result to have achieved a deep response to systemic therapy, evaluated radiologically with conventional imaging, CT scan or MRI, or with cystoscopy or with other urology-based techniques, urinary cytology, and so. And based on the fact that they achieve a complete response, so no residual viable disease after systemic therapy, they raise concern about the fact that they have to undergo surgery like radical cystectomy that is quite impactful for their quality of life and for the future of their lives after the surgery. So the point that the patients are raising, and the patients are raising this point, is primarily due to the efficacy of systemic therapy.

And we have seen so many cases fortunately achieving a deep response. So the question about what to do with the patient that at a certain point, at the start with the commitment to radical cystectomy, but at a certain point in time change their mind towards something else if possible, depending on the fact that they have achieved a deep response, is something that is a question and is a need to which we have to provide data, information, and guidance in general to the patients.

Dr. Davide Soldato: If we look at the population that the recommendations were formulated for, we are mainly speaking about patients who would be fit for cystectomy, and this is a very distinct population compared to those who are not fit for cystectomy, both from a medical oncology point of view but also from a urologic point of view in terms of surgery. So, can you explain a little bit to our listeners why you think that this distinction is critical and why you developed this recommendation especially for this population?

Dr. Ashish Kamat: That is a very important distinction that you made. To build upon what Professor Necchi mentioned earlier, this question that we get from patients after neoadjuvant therapy or systemic therapy is not a new question. It has been something that they have been asking us for the last 20 or 30 years. "Do I really need to have my bladder taken out?" And patients who are especially not fit for surgery will sometimes say, "Do I need to have my bladder taken out? And if I cannot have my bladder taken out, am I going to just not have anything done?" Because the eligibility for radical cystectomy is also a moving target.

Over the years with improvement in surgical technique, improvement in perioperative therapy, ERAS protocols, et cetera, it is really unusual for us to deny a patient the opportunity to have major surgery unless clearly they have very significant comorbid conditions. So I think this endeavor is more broadly encompassing of the patient population than what was evident in previous years.

And I really want to give a shout out to Professor Necchi because what we did was, as part of the International Bladder Cancer Group and Professor Necchi is an integral part of the scientific advisory board, we broached this topic broadly during one of our discussions. And of course, Andrea always does this, he picks on a topic and then he says, "Okay, we need to discuss this really in detail," put together a multinational, multicenter collaborative group, but the driving force was our patients. Because our patients are constantly asking, "Do I need to lose my organ? Do I need to have radiation therapy?" which again, also, has a lot of side effects.

So this was really to answer the question in today's day and age as to do we need to do local consolidation, and if so, in what way? It is not a new question, but we have newer therapies, newer technology, and better ways to answer this. So it is a much needed question that needs to be answered. And I think the distinction between non-surgical candidates and surgical candidates is a little bit blurred in today's day and age.

Dr. Davide Soldato: What about the eligibility, for example, for cisplatin-based chemotherapy? Because I think that that is a very fundamental part of this type of strategy that we apply to patients with muscle-invasive bladder cancer. So we know that there are some caveats for proposing such treatment. And also this population was specifically defined inside this recommendation.

Dr. Andrea Necchi: I think that the focus of our work is just to analyze what is happening after any type of systemic therapy the patient may get neoadjuvantly. So it is not actually a question of treatment eligibility or including cisplatin eligibility. This is an old question of today's practice and clinical trials. But regardless of what the patient received neoadjuvantly, the point that we have addressed in our consensus meeting was what to do next as a further step after systemic therapy or not.

So basically we are- the consensus guidance includes all-comers, so patients to get any type of systemic therapy. So really non-selected based on specific features that determine a special eligibility to a special or a particular therapy. But an all-comer approach is always the winning approach for the translation to be in practice, an all-comer approach just focusing on what has happened after treatment and that we are assessing by the use of conventional imaging, MRI or CT, cystoscopy, urinary cytology, and trying to merge all together this information, all these features in a unique, shared, reliable definition of clinical complete response that could be used as a biomarker for the selection of newer therapies instead of pathological response that has been historically used, and maybe surrogate for the outcome, the long-term outcome and survival of these patients.

Dr. Davide Soldato: A very specific point of the consensus was actually the definition of clinical complete response. As you were saying, this is actually a combination of several parameters including urinary cytology, the use of cross-sectional imaging, for example CT scan, but also the evaluation in cystoscopy of the bladder. Do you foresee any potential problems when applying this type of recommendation, not inside clinical trials, but in the context of routine clinical practice?

Dr. Ashish Kamat: Absolutely. And that was the whole reason we had this consensus meeting. What happens nowadays in daily practice, and we see this every day at our center, we see patients referred to us. This definition or this sort of attempt to define clinical complete response is an ongoing issue. And urologists, medical oncologists, radiation oncologists are always looking to see, does my patient have a complete response? That definition and those paradigms have changed and evolved over the years.

The FDA had a workshop many years ago looking at this very question. And it was to address the proposal that complete clinical response, which is a clinical definition, a clinical state, does this correlate with pathologic response? And with the technology and the systemic therapies we had then, the answer was 'no'. In fact, more patients got recurrent disease than did not get recurrent disease. And that is why, of course in the paper we mention the trials that looked at this question, the trials that evolved around this question.

And I think the distinction between a clinical trial and daily practice is extremely important when we are looking at this definition per se. Because essentially what happens with this issue is that if the patient is not appropriately counseled, and if the physician does not do the appropriate clinical complete response assessment as Professor Necchi mentioned, right, cystoscopy, cytology, imaging, use of markers that are still in evolvement, we risk doing harm to the patient. So we caution in the paper too that this definition is not ready for prime time use. It is something that needs to be studied. It is a rigorous definition and currently we are recommending it for clinical trials. I am sure eventually it will trickle down into clinical practice, but that guidance was not the purpose of this consensus meeting.

Dr. Davide Soldato: There are several parameters that are potentially evolving and could potentially enter inside of clinical practice. For example, you mentioned pelvic MRI and we have now very specific criteria, the VI-RADS criteria, we're able actually to diagnose and also to provide information. So along with these novel imaging techniques, we also know that there are novel biomarkers that could be explored, for example ctDNA and urinary DNA. So what I was wondering is, why were not these included inside the definition that you provide for clinical complete response? And do you think that, as we are designing these trials to potentially spare cystectomy for this patient, we should include these biomarkers very early so that we can actually provide better stratification for our patients and really propose this type of cystectomy-sparing strategy only to those where we are very confident that we have obtained a clinical complete response?

Dr. Andrea Necchi: I would say you have just to wait. So a follow-up is ongoing and hard work is ongoing. At the time we met, at the time we established the meeting in mid-December last year, we had no information on the ctDNA data from major trials, with only a few exceptions. So we were just at the beginning of a story that was more than likely to change but still without numbers and without data from clinical trials. Now in just nine months or 10 months time, we have accumulated important data and newer data will be presented during just a few weeks and a few days regarding the ctDNA, circulating tumor DNA in particular, as a prognostic marker assessed baseline or assessed after neoadjuvant therapy.

So the point is certainly well made and ctDNA is certainly well shaped to be incorporated in a future definition of clinical complete response. But you have to consider the fact that most of the data that we are accumulating related to ctDNA are about the post-cystectomy field or the metastatic field. So regarding neoadjuvant therapy, you know, we have neoadjuvant therapy in the context of bladder-sparing approach, basically we have no information.

And the point that is emerging in our daily practice when using these biomarkers or in clinical trials, and the impression in general, is that it is a very strong biomarker associated with survival, but we absolutely do not know what is the performance of the test in the prediction of superficial bladder relapses, high-grade pTa relapse in the bladder that is left untouched in the patient. We are considering, and maybe it will be just a matter of further discussion, not just what is happening within the immediate endpoint of clinical CR, but also what is happening later with other survival endpoints.

And for example, when looking at the type of events that we may see in this kind of bladder-sparing approaches, most of the events, also in the trials that have been published including the RETAIN study published in JCO, most of the events are related to superficial high-grade superficial non-muscle invasive relapses. So the ability to predict these types of events with ctDNA is completely unknown. Maybe, maybe other liquid biomarkers like urinary tumor DNA, utDNA, could be a bit better shaped in the prediction of this kind of events, you know. But we have still to build the story.

So the question is good. The answer is yes, we will likely, more than likely incorporate liquid biomarkers in the definition, but we have to wait at least more data and more robust data in order to translate this information in routine practice, you know. Another consensus meeting is organized by IBCG and the same folks for November. This meeting will be primarily focused on the liquid biomarkers, the interpretation and use and approval and so of liquid biomarkers including bladder cancer. And we will likely be able to address all these, most of these open issues, so most of these points in the next meetings.

Dr. Davide Soldato: In the consensus you say that probably clinical complete response is now ready to be included in early phase trials, so actually to test what is the efficacy of the regimens that is being evaluated inside of these trials. But you actually do very in-depth work of defining what are the most appropriate endpoints for later phase trials. So to be very specific, the phase three registrational trials that bring new regimens inside of this space. So I just wanted to hear a little bit about what was the definition for event-free survival, which you define as the most appropriate one for this type of trials. And as you were mentioning before, Professor Necchi, there is a very specific interest on the type of events that we observe, especially when we look at these superficial relapses inside of the bladder. So was this a very urgent matter of debate as we define which type of events should actually trigger event-free survival? And did you make a very thoughtful decision about why using this type of endpoint instead of others, for example metastasis-free survival?

Dr. Ashish Kamat: Yeah, this was a matter of intense debate as you might imagine. And again, this is a moving target. So as Professor Necchi mentioned, we tend to partner with each other, our organizations, on having definitions of clinical complete response, biomarker, retreats, and then using that as a marker, and you might imagine this definition of what is appropriate event-free survival, what events matter to the patient, is something we have been talking about for two years. It was not just something that came up at the retreat. But at the retreat there was intense discussion.

One of the things that we talked about was bladder-intact event-free survival because we are trying to spare the patient's bladder. And do we count bladder-intact event-free survival as something that is relevant? The patient advocates absolutely liked that, right? They wanted that. But then we also learned from some of the studies, for example from the RETAIN study, that the non-muscle invasive recurrences can actually lead to metastatic disease. It is not as benign when you have a patient with muscle-invasive bladder cancer that then develops a non-invasive tumor because maybe there is cancer growing underneath the surface that we don't detect when we look in the bladder.

So a lot of those discussions were held, debated. It was a consensus. I have to say it was not 100% agreement on that particular definition, but it was broad consensus. And Andrea, do you want to clarify a little bit as to how we came about that consensus? Because I think this is a very important point we need to make.

Dr. Andrea Necchi: We focused on a bit different definition of BI-EFS, Bladder-Intact Event-Free survival. Just stating EFS as an all-inclusive parameter including all type of high-grade relapse or progression or death that may happen to the patient. So that we were counting high-grade pTa, pT1, CIS relapses to the bladder and of course more deeper involvement in the muscle layer and so, and metastatic disease as a relapse. But the point is that as compared to the classical bladder-intact EFS definition of chemoradiation bladder-sparing approaches that is including muscle-invasive relapses only or death as events, we tried to be as inclusive as possible in order to be as much conservative as possible and to raise as higher the bar as possible for the success.

And this is actually what the patients are asking us. So they are asking, "Okay, I can save my bladder, sparing radical cystectomy, but at which cost?" So in order to provide an answer, we have to be very, very cautious and be on the right shape, on the right position to say, "Okay, we have accomplished the most, the safest points, you know, by which you can proceed with the bladder-sparing." This is the first point.

The other point is related to the MFS, metastasis-free survival that you have mentioned. For sure, it was recognized as a very important point for sure. But in the discussion was clear that our focus was in saving patients, curing the patient, and saving the bladder. Any single event, superficial event that may occur in the bladder-saving approaches of this kind may expose the patient to an extra risk of developing distant metastases, as it happened for example in the RETAIN study. So EFS defined as we have agreed and published, is actually a way of including or anticipating in a safest position the MFS. Because most or if not the entirety of the events of metastasis development in patients undergoing bladder-sparing after neoadjuvant systemic therapy were preceded by a superficial phase of disease relapse, you know.

So I remember very, very few, or we can count just on the finger of one hand, the cases that have been reported in the literature developing de novo metastatic disease in the similar bladder-sparing approaches, in particular when using a maintenance immunotherapy strategy, you know, after they reach TURBT. So this is the reason why with all the limitation that Ashish has mentioned, with all the uncertainties that are still there, the nervousness that is still there, EFS, as defined in the protocol, as put in the paper, is to us at the moment is the safest way to use a primary endpoint in potentially registration trials of this kind with perioperative systemic therapy and response-adapted surgery.

Dr. Ashish Kamat: And David, just to be absolutely clear for our listeners, right, so what was the event-free survival that we defined? Essentially it was a very inclusive definition. Event was defined as high-grade tumor persistence, recurrence, or progression during or after perioperative therapy, and receipt of any additional standard of care treatment including radical cystectomy, radiotherapy or even intravesical therapy. So this was done at the behest of our patient advocates because we really wanted to make a very robust definition that could be utilized appropriately as an adequate primary endpoint for both early and late phase bladder preservation trials.

Dr. Davide Soldato: I think that it really highlights one of the points that I liked the most about this consensus is that it really incorporated the patient vision and a sort of shared decision making process when we are deciding how we want to design these trials that will explore this bladder-sparing surgery.

And Professor Necchi mentioned something that I think will be also a very interesting question for trials that will be developed considering the activity of this combination that we are seeing right now, which is maintenance. Because right now our approach in the few cases where patients do not do any type of treatments after an induction with neoadjuvant treatments is basically represented by observation. So I was wondering if you think that the field will actually evolve to a sort of maintenance strategy even in patients that will achieve a complete clinical response?

Dr. Andrea Necchi: We just mentioned briefly in the paper, this is a very important point that was touched during the discussion, and in particular was raised and discussed by FDA people participating in the meeting. And when looking at the data from the trials that were available and are still available thus far, we could provide a suggestion that maintenance immune therapy is the preferred approach in this kind of approach as it currently stands, as the data currently stand. Because the cleanest data towards the successful part of this journey is related to the studies that provided a kind of maintenance therapy, like the study with nivolumab or the RETAIN-2 study with maintenance immune therapy instead of RETAIN study that was just stopping treatment until surgery with MVAC chemotherapy.

So in general the impression is that maintenance therapy may help in reducing the type of events, including the events that we incorporate in the EFS definition that we mentioned in the paper. The point that you mentioned is very important because on the other side we have a problem, a big problem of affordability and cost of the treatment. The de-escalation trials are an urgent need and represent a call for the studies. Unfortunately, as you mentioned, this is something that moves beyond the possibilities of this type of consensus because we don't have data and we have to accumulate data from clinical trials prior to saying, "Okay, certain patients could de-escalate therapy and stop therapy and some other not." So we are still at the very beginning. So we can do- we can discuss about this in the radical cystectomy paradigm but not in the bladder-sparing paradigm, you know. But this is for sure a point, a discussion point that will be taken, pretty well taken in one year or two year projection.

Dr. Davide Soldato: I was wondering if in the consensus, considering that patient advocates and patient associations were also involved, did you decide to actually suggest the inclusion of patient-reported outcomes or the evaluation of shared decision-making in the development of this trial really as endpoints that should matter as much or as much as possible as event-free survival and clinical complete response?

Dr. Ashish Kamat: Oh yeah, absolutely. We had patient advocates, we had the World Bladder Cancer Patient Coalition, Bladder Cancer Advocacy Network, patient representatives. And we always consider this. Shared decision-making is actually the impetus behind why these efforts have been launched, right? So it is the shared decision-making that is very, very important. It is the driving force behind what we do. And it is worth noting, for example, for the design of such studies, regulatory agencies consider response-based endpoints or overall survival as primary endpoints. But the patient advocates consider quality of life to be just as important, if not more important sometimes than overall survival numbers. Because patient advocates will say, "Well if I live longer but I'm miserable living longer, yes that works for regulatory agencies but doesn't work for us." So PROs clearly are very, very important. And, in fact, we just literally had a meeting in Houston, the IBCG meeting where PROs were a main point of what we discussed. So incorporating PROs in everything we do, not just this but everything we do, Dr. Necchi, myself, everybody involved in these fields realizes it is very, very important. So absolutely.

Dr. Davide Soldato: I want to thank again Professor Necchi and Professor Kamat for joining us today.

Dr. Andrea Necchi: Thank you.

Dr. Ashish Kamat: It is our pleasure.

Dr. Davide Soldato: Thanks again and we appreciate you sharing more on your JCO article titled "Endpoints for the Next Generation Bladder-Sparing Perioperative Trials for Patients with Muscle-Invasive Bladder Cancer."

If you enjoy our show, please leave us a rating and review and be sure to come back for another episode. You can find all ASCO shows at asco.org/podcast.

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

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

Host Dr. Shannon Westin and guest Dr. Hani Babiker discuss the JCO article "Tumor Treating Fields With Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma: Randomized, Open-Label, Pivotal Phase III PANOVA-3 Study."

TRANSCRIPT

TTFields in Locally Advanced Pancreatic Adenocarcinoma

Dr. Shannon Westin: Hello everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth with manuscripts that have been published in the Journal of Clinical Oncology. I am your host, gynecologic oncologist Shannon Westin, social media editor at the JCO, and just excited to be here to learn today about pancreatic cancer.

None of our participants have conflicts of interest related to this podcast, and it is my honor to introduce Dr. Hani Babiker. He is an associate professor of medicine, consultant in oncology at the Mayo Clinic in Jacksonville, Florida.

Welcome, Dr. Babiker.

Dr. Hani Babiker: Hi, Dr. Westin. Thank you for the great opportunity to discuss our trial, and thank you for having me here. I really appreciate it, and I am excited.

Dr. Shannon Westin: All right, so are we. So we are going to be talking about "Tumor Treating Fields with Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma: A Randomized, Open-Label, Pivotal Phase III PANOVA-3 Study." This was simultaneously published and presented in the JCO and at the annual meeting of ASCO on 5/31/2025.

So, let's level set. Can you speak to us just a little bit about pancreatic cancer? What is the survival, and what is the typical treatment for locally advanced disease? This gynecologic oncologist has not kept up in this field.

Dr. Hani Babiker: Absolutely, Dr. Westin, and thank you for that question. Pancreatic adenocarcinoma is a lethal cancer. When I first started my career, the 5-year survival, per the Surveillance, Epidemiology, and End Results, was at 4.5%. I always, whenever I was giving talks, say that I really hope that I will see it in the double digit. Now, the 5-year survival for all pancreatic adenocarcinoma is 13.3%. And the 5-year survival, and although it is a double digit, I still hope that I will see it in a higher double digit in the future. It is even worse in patients with metastatic cancer, about 3% 5-year survival for metastatic pancreatic cancer. It is a dismal diagnosis. I really hope in the future we will find a better therapeutic approach to this lethal cancer.

Dr. Shannon Westin: Yes, I just lost a very dear friend and colleague to this disease, so I completely agree with you.

Well, now that we are settled kind of with the basics here, I would love to talk a little bit about kind of the primary piece of this intervention, the Tumor Treating Fields. So, how does this work? And what diseases has it gotten indications in as yet?

Dr. Hani Babiker: Absolutely. So, Tumor Treating Fields is alternating frequency electrical fields that have been studied preclinically and shown that it abrogates cancer cell proliferation. Earlier on, we knew that it inhibits polymerization of tubulin, and hence, it affects cancer cells from proliferating. Later, we are learning that there are multiple mechanisms of action. It affects permeability, allowing for better drug delivery. It also inhibits cancer cell proliferation through affecting autophagy mechanisms that pancreatic cancer cells will use for proliferating and becoming more aggressive. There is also some early data preclinically in colorectal cancer cell lines and lung cancer cell lines and in vivo models showing that it potentially could activate the microenvironment to make it more pro-immunogenic. We recently published papers showing that it could also affect the nanomechanical properties of the tumor microenvironment within pancreatic cancer, hinting towards affecting, potentially, the stroma.

So, there are multiple mechanisms to Tumor Treating Electric Fields. It is a new, novel therapeutic approach. Sometimes when I speak with my trainees, I say, "Well, we have surgery, we have radiation and chemotherapy, and this is something new." Tumor Treating Fields initially was studied in refractory GBM and got an indication there. Subsequently, frontline treatment of GBM in a randomized clinical trial, and then malignant pleural mesothelioma and non-small cell lung cancer. We have studied it in pancreatic cancer.

Dr. Shannon Westin: I don't think I have ever heard it described so perfectly. That was brilliant. So thank you, and I hope everyone listening knows that you just got a masterclass on this mechanism. You know, they dabbled in it a little bit in ovarian cancer and it didn't quite make the grade, so I was a little definitely disappointed. But very excited about the data we're going to talk about today.

So let's get into the PANOVA-3 study. Can you highlight the overall design and also the key eligibility criteria that would be helpful for our listeners?

Dr. Hani Babiker: Absolutely. So, it started off with preclinical work in pancreatic cancer showing Tumor Treating Fields with chemo abrogate cancer cell perforation. It led to a trial, the PANOVA-2 trial, that was run in Europe that showed efficacy for OS and PFS in patients with locally advanced pancreatic cancer, which included metastatic and locally advanced pancreatic cancer, more so in locally advanced that led to the PANOVA-3 trial, which was an international, global study. This was in more than 190 centers, 20 countries in Latin America, North America, Europe, and Asia. It was a randomized trial. Patients were randomized 1 to 1 to either chemotherapy with gemcitabine plus nab-paclitaxel per drug label. The other arm was with Tumor Treating Fields at 150 kHz for a recommendation for patients to wear it 18 hours per day.

The primary end point of the trial was OS, overall survival. The secondary end point included other efficacy landmarks such as local PFS, pain control, quality of life, and safety. And there was a post hoc that looked at distant PFS.

Dr. Shannon Westin: That's a pretty common secondary end point in pancreatic studies of looking at the pain-free interval. I thought that was really brilliant because, you know, I think in gyn cancers, we see resolution of symptoms as being a really big deal, but it's not necessarily something that we always look at. So I thought that was really nice that you included that.

Okay, talk to us a little bit about the population. So, the population that actually got treated in PANOVA-3 is pretty generalizable to what people are treating in the clinic.

Dr. Hani Babiker: So, in pancreatic cancer, unfortunately, most of our patients present, approximately 80%, with metastatic disease. Local is divided to resectable, borderline, and locally advanced. We studied this trial, a randomized trial, in locally advanced and unresectable, which is really an unmet need. Most of our patients with locally advanced and unresectable are grouped up with other trials in the metastatic setting without a focus on locally advanced and unresectable, save for a few trials. This year, a trial that we were looking for for a long time, the LAPLACE trial, unfortunately, that we were very excited about, this is a molecule that targeted connective tissue growth factor, that showed earlier efficacy in a randomized trial, did not meet up the median OS end point. And hence, PANOVA-3 is the first trial in locally advanced and unresectable that did meet its primary end point.

So, it's a very unmet need in locally advanced and unresectable. A lot of the times, our patients in clinic are treated with frontline chemotherapy that was studied in metastatic disease and locally advanced and unresectable, which include either FOLFIRINOX, NALIRIFOX, or gemcitabine/abraxane. I do have in my clinic multiple patients that would stay on the regimen for such a long time, and then we would have to devise a mechanism of maintenance, although this is not studied really in details, either with capecitabine or dropping the oxaliplatin to continue FOLFIRI. And then we also approach chemoradiotherapy. So the trial was in a disease in pancreatic cancer that really is an unmet need.

So the inclusion criteria included a patient with locally advanced and unresectable. These were done at multiple centers. Most of them academic centers were discussed at the tumor board, and if it's unresectable, they will be meeting specific metrics of appropriate liver function tests, kidney function tests, and blood counts. We excluded patients that obviously had, given that these are electric fields, patients that have, for example, stimulators or pacemakers, knowing that this could potentially affect some of these devices. But for the most part, it was locally advanced and unresectable patients with a very good performance status and good counts.

Dr. Shannon Westin: That's great. I think everyone's excited to hear about the primary outcome of overall survival. What did you find, and how does it compare to some of the recent trials?

Dr. Hani Babiker: We're very excited that it did meet its primary end point of median overall survival. It was very exciting knowing that a lot of us were disappointed a little bit of some of the trials that were presented at ASCO GI, such as the LAPLACE trial that I alluded to. Just before the presentation, the PRODIGE 29 trial that is in locally advanced and unresectable that randomized patients with locally advanced disease to either FOLFIRINOX or single-agent gemcitabine, allowing for a crossover, although it did meet its primary end point of PFS, there was no overall survival benefit. So that kind of got us a little bit disappointed, but having the PANOVA-3 trial being positive in median OS got us all excited.

In addition, the 12-year overall survival rate was increased in both the intention-to-treat and modified intention-to-treat. The modified intention-to-treat were patients that have had at least one cycle of therapy with TTFields daily and/or one cycle with chemotherapy, which was gemcitabine plus nab-paclitaxel. There was a trend to improvement in PFS and local PFS, although that did not have statistical significance, but the 12-year PFS rate in both the intention-to-treat and modified intention-to-treat was significant. For me, as one of the investigators, that told me that there might be a specific biomarker that would tell me that patients could respond greater than others, more exceptional than others, given that 12-month PFS rate was improved. On a post hoc analysis, the distant PFS was improved with the intervention of Tumor Treating Fields with gemcitabine plus nab-paclitaxel. In addition, there was an improvement in global health status and quality of life in addition to pain-free survival, which is a strong hurdle in our patients with pancreatic adenocarcinoma that most present with significant abdominal pain.

Dr. Shannon Westin: One of the other questions that I think has come up is around central review. So did you all use central review in this study?

Dr. Hani Babiker: Most of the centers were academic centers. These were discussed in tumor boards, which included radiation oncologists and surgeons. I wanted to point out that it's very important to note that the primary end point was overall survival. So the primary end point was not PFS. Hence, the central review would help us, for example, with elaborating and making sure patients were actually locally advanced disease, but in a setting where the primary end point is overall survival, that was the key point of the clinical trial. This trial was discussed at academic centers, and all included tumor boards to decide if patients were locally advanced or not. In the trial, there was a good proportion of patients, or percentage, that had a CA 19-9 more than 1000. That could indicate that potentially there are a fraction of patients that actually had metastatic disease, micrometastatic disease. So that could hint towards why the median OS was slightly lower then in both arms when compared to, for example, the trial that was presented at ASCO GI, the LAPLACE trial. However, having said that, we were very excited about the trial. It was the first positive trial in locally advanced and unresectable to meet median OS survival.

Dr. Shannon Westin: It's so awesome. So congratulations. Okay, so let's talk a little bit about your very detailed secondary end points because you had a lot of really prudent choices there. So anything that was interesting or informative in those end points?

Dr. Hani Babiker: One major hurdle back we have for most of our patients with pancreatic adenocarcinoma, like I mentioned earlier, is pain. We try to approach it, obviously, with narcotics. If it doesn't work, we try to do celiac axis block interventionally, and that sometimes is successful and sometimes is not. So actually, to see the pain-free survival end point to be met was very exciting for us. And as for me, as a scientist that studies TTFields in clinic and lab as also to develop a mechanism and understanding really how that works. That was very important for us that in addition to chemotherapy, it improved pain-free survival or deterioration of pain. And most importantly, our patients with pancreatic cancer, this disease is very aggressive. It affects quality of life of patients. Patients feel fatigued, tired. It's a procoagulant tumor that causes clots and strokes, etcetera, marantic endocarditis. And one big problem we deal with when we're seeing patients in clinic is obviously that quality of life. Although data have shown with treatment, with frontline regimens, that quality of life improves with treatment and chemotherapy, it's actually great to see that that improvement happens early in addition to Tumor Treating Fields.

The other interesting point was that it was not only pain and quality of life, but also digestive symptoms that are improved with this intervention, knowing that a lot of our patients do have pancreatic cancer, pancreatic exocrine insufficiency that affect also with digestion, and a lot of our patients have abdominal pain after eating and diarrhea. So it was interesting to see that also improved with the intervention.

Dr. Shannon Westin: You have touched a little bit on some of the adverse events, kind of with the TT mechanisms, but I'd love to hear a little bit more detail around adverse events in general in this study, as well as specific AEs related to the Tumor Treating Fields.

Dr. Hani Babiker: Absolutely. So when we compared both arms, there was a similar toxicity related to the regimen, mostly with chemotherapy, but in specifically to Tumor Treating Fields, there was a rash, and that included dermatitis and rash. Most of the side effects were grade 1 and grade 2. Grade 3 toxicities related to skin was less than 10%, approximately 7% to 8%, and hence did not affect many patients. But it was something to note, and it's something that in the future, when we develop a mechanism of treating patients to note early. We in our clinic have learned to treat patients in the clinical trial early with topical steroids to each patient, of shifting the arrays to mitigate some toxicity and rash. We do advise our patients in hot areas, we keep them aware that sweating, for example, can lead to higher conductivity of electrical fields with a predisposition for rash. So if there's an opportunity to stay in a little bit of a cold area, make sure that the arrays are shifted, use topical steroids early. If it's a significant rash, to hold treatment for at least 48 hours and speak to the investigators. And through these mechanisms, we have learned that we were able to mitigate the rash quite a bit.

Dr. Shannon Westin: That's awesome. Thank you so much. Yeah, I'm, it's summer right now, and I think- I'm in Texas, you're in Florida, like we know.

Okay, so I guess, again, you have been kind of touching on this, but I would love to know, like if in the quality-of-life assessments or if just in your discussions with patients, like how easy is this to use? How easy is the Tumor Treating Fields device to use, and what do patients really think?

Dr. Hani Babiker: Absolutely. We have learned that whenever we speak with patients, it's always good to discuss with them briefly the science of it. A lot of patients would want to know if it's interventional, is that something that goes, is delivered percutaneously or not, and we explain that these are delivered through arrays that are through the skin. We always touch base with them about a lot of question I get about mechanism of action and then about compliance. So I think one important thing to note is that compliance with the use of the device is a lot of the question we'll get quite a bit. Patients know there's going to take an effort from them, and some of my patients enjoyed it because they felt like they also are fighting the disease by wearing the device. I have learned very quickly that having a team, surrounded by a team that knew how to mitigate some of the side effects and knew how to explain how to use the device helped quite a bit. And this included some of our nurses and our nurse practitioners and our clinical research coordinators who've done a wonderful job of showing these arrays actually to patients before they start on the trial, look at it, know how it works.

The other point to know is that the sponsor provided Device Support Specialist, we call them DSS, they have been instrumental in helping us, helping the patients know how to use the device, how to use the generator, how to change the batteries, and that helped us conduct the trials and enroll very well. I would envision in the future with education and relying on the Device Support Specialist and having a team that knows how to use the device and mitigate some of the side effects will go a long way for patients to learn about this treatment. Many of the times our patients said while they are on the clinical trial felt like they are also being part of this team in applying the device and fighting the cancer.

Dr. Shannon Westin: That's awesome.

Well, I guess the bottom line. Is it ready for prime time? Is this something you are going to use for your patients in the clinic?

Dr. Hani Babiker: Absolutely. In a disease that has poor prognosis, and we are trying our best to find new treatments to fight this cancer and treatment modalities, presenting patients with all the treatment options that are out there would be recommended. It's what I would do it for in my clinic. And you know, it's funny that I am mentioning that right now. I had a patient who was seen internationally asking about the trial and the device and had locally advanced and unresectable before they start frontline treatment. I do think that there is going to be an educational piece. Obviously, this is not a pill, it's not an intravenous chemotherapy that we're very well and accustomed to. And some of us in academic centers know it very well. I usually joke that whenever I am talking about it in pancreatic cancer, if there is a radiation oncologist in the room, they will be like, "Yeah, we know all about it. We have been treating patients with GBM over there." So a lot of the times, when we first went to trial, if I had any questions, I would call them and ask them. So from their perspective, they, because they use it as a standard of care in treatment of GBM, they develop significant expertise in it. I think in the GI world, specifically and with oncologists that treat pancreatic cancer and specifically oncologists in the community, learning about the device and how to use it, how to recommend it, how to mitigate side effects, will be hopefully for prime time in the future.

Dr. Shannon Westin: That's great. Sounds like some real educational opportunities there.

Well, this has been awesome. Thank you so much, Dr. Babiker. I mean, I learned a ton, and I wish that we could find a way to use this in gynecologic cancers, but really, really just want to commend you on the design of the trial and the success in this really devastating disease.

So again, this was "Tumor Treating Fields with Gemcitabine and Nab-Paclitaxel for Locally Advanced Pancreatic Adenocarcinoma: A Randomized, Open-Label, Pivotal Phase III PANOVA-3 Study."

And as always, I am your host, Shannon Westin. Please go check out our other offerings wherever you get your podcasts and have an awesome day.

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

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

Dr. Babiker Disclosures

Consulting or Advisory Role: Endocyte, Celgene, Idera, Myovant Sciences, Novocure, Ipsen, Caris MPI, Incyte, Guardant Health

Speakers' Bureau: Guardant Health

Research Funding:  Spirita Oncology, Novocure, AstraZeneca, JSI, Incyte, Qurient, HiFiBiO Therapeutics, Revolution Health Care, Elevation Oncology, Dragonfly Therapeutics, Zelbio, BMS, Mirati Therapeutics, Strategia

Dr. Shannon Westin and Dr. Antonio Di Meglio discuss the issue of fatigue among cancer survivors.

Transcript

[MUSIC PLAYING]

Speaker 1: The guest on this podcast episode has no disclosures to declare.

Shannon Westin (Dr. Westin): Hello, everyone. And welcome to another episode of JCO After Hours. This is our podcast where we get in depth with different authors and experts about wonderful manuscripts that are being published in the Journal of Clinical Oncology. And today it is my great pleasure to be accompanied by Dr. Antonio Di Meglio, who is a Medical Oncologist and a Physician Scientist at the Breast Cancer Survivorship Research Program in Gustave Roussy in France. So welcome, Dr. Di Meglio.

Dr. Antonio Di Meglio (Dr. Di Meglio): Thank you so much for having me here today.

Dr. Westin: We're so excited to have you. We're going to be talking about your article, which is due to be published January 21, 2022, in the Journal of Clinical Oncology titled "The Development and Validation of a Predictive Model of Severe Fatigue After Breast Cancer Diagnosis: Toward a Personalized Framework in Survivorship Care." And before we get started, I would just note that none of the guests have any relevant conflicts to disclose.

With that, let's get into it. I was so excited to read this paper because this such a critical problem for our patients. And I'm a gynecologic oncologist, but this goes across all—surgical, medical, any field that we could even think of. So why don't you start off by telling us what led you to explore the problem of cancer-related fatigue?

Dr. Di Meglio: Cancer related fatigue is one of the most troublesome and prevalent symptoms among cancer survivors and including breast cancer survivors. So several reports reported on the prevalence of cancer-related fatigue reporting up to 50% of patients in some studies with fatigue after cancer and the end of treatment. But what we know is that at least one in three cancer survivors experience fatigue symptoms at some point over time. In addition, we do know that fatigue is particularly distressing and impactful as it can impact on daily living and functioning and overall quality of life.

Also, there's an important impact on social function and return to work after cancer and adherence to oral therapies, especially in the age event setting in breast cancer survivors. Finally, we also know that fatigue is often inadequately addressed and often neglected because of lack of time, lack of resources. Definitely, we should do more in the clinic for our patients struggling with fatigue.

Dr. Westin: This is such an important issue. I think the elephant in the room here is how do we grade this and how do you advocate for a busy clinician in the clinic seeing 30, 40, 50 patients in a day. How do we really assess this? What's the best way to determine if somebody has cancer-related fatigue or is at risk?

Dr. Di Meglio: Thank you for this important point. In clinical research, we do have a number of instruments that we can use to grade fatigue, including the European Organization For Research and Treatment of Cancer, Quality of Life Questionnaires that are the questionnaires that we used in our study. These are instruments that our patient reported. So we really can hear patient voices and patient perspectives in terms of their own symptoms.

And some of the items that we use, for example, for cancer-related peak do not take much time to be asked also in a basic clinic. For example, we did use the EORTC QLQ Questionnaire C30 to score global fatigue. So we basically asked patient three questions: whether they needed to rest, they felt weak, or they felt tired, typical week. And these gave us the score of what we called global fatigue. There's also other instruments and companion models that we can use to assess more specifically dimensions of fatigue, including the physical, emotional, and cognitive dimension of fatigue.

It is true that in our busy day in clinics, this may not be easily implementable. But what I believe is that if we never ask patients the right questions, patients will never tell us the right answers that we can proactively use to address the symptoms. So even just assessing fatigue in a general way, asking whether their energy levels changed over the past weeks, if they know that any change that was related to the treatment or any tiredness that was not really related to their usual activities or that was impactful on daily activities, this should trigger clinicians to ask more and more and to find solutions for the problem. So just ask the questions, even though the assessment may not be comprehensive and extensive, but this can be very important and meaningful for the patients.

Dr. Westin: I think that's a really critical point because using validated instruments is obviously our aspirational goal and our attempted standard of care, but on a day in and day out clinic, it can be hard to have patients filling out a survey or something that may take a longer time. So I think that's a critical point is pull out these critical questions so that you can identify these issues and address them for your patient.

When we're talking about grading fatigue, say in the clinic, would you recommend maybe choosing one? How long do these types of assessments take? Is this something feasible for a busy oncologist in clinic?

Dr. Di Meglio: So definitely our study calls a little bit for the implementation of these instruments that are being used in mostly in clinical research over the past decades, also in the clinical practice. These are patient reported instruments that really can give us a sense of how impactful fatigue is in daily living and functionality. And when we grade fatigue using this instruments such as the EORTC scores, we can really capture fatigue that is defined as severe, meaning fatigue that really impacts on quality of life and needs to be absolutely addressed by clinicians and needs interventions urgently.

Dr. Westin: That makes a lot of sense. Why don't we get into a little bit more around your study using these specific instruments? Like what was the patient population? Run us through that.

Dr. Di Meglio: So this study was performed using CANTO data. CANTO is a longitudinal cohort of breast cancer survivors. Patients that were initially diagnosed with Stage 1, 2, and 3 breast cancer. It's a French cohort that enrolled patients across 26 centers in France starting in 2012. And at this point, the cohorts included over 10,000 patients, and this study was performed using a first split of the cohort for the development models that included around 6,000 patients overall, and then 3000 patients for the validation of these models.

So the availability of data of fatigue was really the driver of the patient population that we used for this study. So we used all available questionnaires of EORTC QLQ-C30 therapy, to which we assessed our primary outcome of interest, which was global fatigue. CANTO has a first assessment at baseline, that is a breast cancer diagnosis, meaning before the initiation of any cancer treatment. Meaning surgery, chemotherapy, radiation therapy, therapy of any type.

Then we perform longitudinal assessment at one year, two years, four years after diagnosis. There is a fifth assessment at five years after diagnosis for which data are not mature yet, but for the present study, we use data until four years after diagnosis. So our interest was to understand which are the risk factors for severe fatigue, primarily at two years after diagnosis. Then we also developed and validated models for severe fatigue at four years after diagnosis.

So our interest was to identify a population of patients that since diagnosis can be flagged as being at high risk of developing severe fatigue after diagnosis and of course after treatment for breast cancer. This is a population of early-stage breast cancer survivors. So I really want to highlight that these models were developed and validated for survivors that are free of cancer at the time of fatigue assessment. So whether they experience cancer recurrence, metastasis, second cancers, they exit cohort. So this is purely early stage survivors of breast cancer.

Dr. Westin: Thank you for that clarification. And I think it is important to really focus in on these populations because we are going to see differences in the occurrence of fatigue across patients that are actively receiving treatment in the continuum of recurrence or later in survivorship. So thank you for that clarification. I think that that really makes a lot of sense. And this is a population that's extremely large and very critical to our management. So why don't you tell us a little bit about what were some of the factors that you found to be associated with severe fatigue in your cohort?

Dr. Di Meglio: So our models allowed us to identify a number of factors that are risk factors for severe fatigue after breast cancer diagnosis. So first of all, the most consistent and the strongest factors that was identified as associated with post-treatment fatigue was pre-treatment fatigue. So patients that are already severely fatigued at diagnosis have much higher likelihood of reporting severe fatigue also years after diagnosis. This was identified as a risk factors also in previous literature as it may set stage for post-treatment fatigue because maybe there are biological disruptions or bio-behavioral disruptions that are already present at the moment of diagnosis.

So they keeping there and they put patients at higher risk of post-treatment fatigue. In addition to this, we found that clinical factors such as younger age was associated with high risk of fatigue after treatment. And there are also behavioral risk factors.  Patients that are current smokers at the time, active smokers at the time of the diagnosis, as well as patients with a higher body mass index. They are all at higher risk of persistent, severe fatigue after diagnosis.

Finally, we also identify concomitant symptom clusters that are associated with a higher risk of severe fatigue. And these include emotional distress and particularly anxiety, insomnia. So sleep disturbances and pain at the moment of diagnosis. These are the risk factors that emerged for the models of severe fatigue at year two after diagnosis. But when we look further in to the risk factors of fatigue at year four after diagnosis, we consistently identified premenopausal status that is very consistent with younger age and also received of hormonal therapy. So our assumption was that longer these patients are into hormonal therapy, the higher the risk of severe fatigue becomes. So even though our models at Tier 4 are to be considered exploratory, we believe that they give us an additional insight into which treatment related factors would be associated with higher risk of fatigue.

Dr. Westin: You'll have to forgive me because my knowledge of early breast cancer is very minimal. So for these patients, did any of them receive chemotherapy and was that at all relevant or is this a population that generally got maybe surgery and hormonal therapy?

Dr. Di Meglio: So in the population that we study and consistent with the stage distribution, over 50% of the patients received chemotherapy. Almost 80% and more received hormonal therapy. So we really investigated the impact of all treatment types on the risk of fatigue. And we did find a differential impact of different treat modalities on the risk of fatigue.  I liked this in the paper because this is Year 1 model while our main interest was Year 2 after diagnosis models. But we did find an impact of chemotherapy on the risk of fatigue at one year after diagnosis, meaning the closest time point that we have to the end of primary treatment, including chemotherapy. And this effect seems to produce over time, and we don't find it in models at Year 2 and Year 4 anymore. So it's less consistent and it's not confirmed invalidation models.

In contrast, the impact of hormonal therapy was much stronger at Tier 2 was confirmed at Tier 4. So this gives us the sense that the longer patients are on hormonal therapy, the higher risk of severe fatigue becomes for them. And this is also consistent with previous data from other literature. For example, Pat. A Ganz in The Mind-Body Study had demonstrated that hormonal therapy can delay the recovery from treatment-related symptoms that are usually associated with chemotherapy. And in a previous study using the CANTA cohort, we also had found an impact of hormonal therapy on the recovery of symptoms and functions that usually get better over time, for example, emotional function or future perspectives whose recovery seems to be delayed among patients that receive hormonal therapy.

Dr. Westin: Well, this is great, understanding who might be at risk and trying to identify these patients. I guess the natural question is next. Like what do we do? What are our available options to treat cancer-related fatigue or even prevent it?

Dr. Di Meglio: I think this is a great point and that definitely leads me to trying to understand and to explain what is the implementation of our models in clinic. So what we envision would be a clinical care setting where our models would aid clinicians to be more aware about the problem of fatigue and about ways that we have to better describe fatigue among our patients and better identify its risk factors. So let's imagine that we have an incoming new patient in our clinic and we assess the risk of severe fatigue in this patient after treatment. By assessing risk factors, we also assess fatigue at the moment of diagnosis. And we do know that in this analysis, we found that almost 25% of patients present already with severe fatigue diagnosis, and a patient like this needs to be already treated for the symptoms that he or she is reporting.

So we do have now available interventions to treat fatigue when it's already present. So first of all, increasing physical activity. We also have psychosocial interventions, including cognitive behavioral therapy and psychoeducational therapies that we know that work for cancer-related fatigue and some mind-body interventions, such as yoga demonstrated some activity for cancer-related fatigue.

Other approaches include mindfulness based approaches or acupuncture that can be offered to patients that already present with severe fatigue and diagnosis, particularly also the assessment of all concomitant conditions, such as nutritional imbalances should be performed in detail at the moment of diagnosis. In contrast, we might find a patient that doesn't have symptoms of severe fatigue at the moment of diagnosis, but definitely our models can increase the awareness of the risk factors and highlight a way to recognize symptoms that can hurl out the onset of fatigue and facilitate the management of risk factors and the referral to dedicated consultations or to dedicated specialists that can take care of such risk factors.

In fact, the majority of risk factors that we identified are modifiable, such as we can address as tobacco use. We can address overweight and obesity as well as we can address specific symptom clusters that usually come in conjunction with fatigue, sleep problems, pain, emotional distress. We do have interventions available for all these symptoms.

Of course, there is an important question there arises here, that is by addressing all three factors, is fatigue preventable at this point. I am not sure that we have the answer yet for this question at this point, but definitely by addressing risk factors, by addressing behavioral problems, we are addressing survivorship problems in a more comprehensive way. That is the direction in which survivorship care should probably go today. So as next steps, definitely we should look towards the implementation of risk models in clinical practice towards planning more meaningful prevention trials for problems such as cancer-related fatigue.

And in addition, I believe that cancer-related fatigue is just an example of very common and prevalent and distressing symptoms that are not often taken care of or sufficiently taken care of in the clinic. So this can serve as a case study, as a model to expand our no also of other symptoms and of other survivorship issues that our patients and survivors may face.

Dr. Westin: Well, I just want to commend you. These are really such exciting work, and I know it's something that will be implemented in the breast cancer community but also beyond. And I'm hoping that some of our other cancer-type survivorship experts are listening right now and getting inspired by your work. So we can look at this in other tumor types and really help implement this across the world. So thank you so much again for your amazing work. Thank you so much for taking the time to meet with me today, and best of luck in moving this forward.

Dr. Di Meglio: Thank you so much, Dr. Westin. It was great to be here with you today.

Dr. Westin: Thank you so much to all our listeners. We are always so grateful that you tune in and we can't wait to bring you discussion of our next manuscript. Have a great one.

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Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Shannon Westin, Dr. Abby Rosenberg, and Dr. Reshma Jagsi discuss the timely issue of diversity, equity, and inclusion in the field of oncology.

TRANSCRIPT

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SHANNON WESTIN: Hey, everyone and welcome to JCO After Hours, the podcast that gets a little bit more in-depth about some of the articles and amazing research that have been published in the Journal of Clinical Oncology. I'm so excited to be with you today. And more importantly, I'm very excited to talk about this amazing manuscript, which is called "Picture a Professional-- Rethinking Expectations of Medical Professionalism Through the Lens of Diversity, Equity, and Inclusion."

And this was a Comments and Controversies article that was just published in October of 2021. And I am beyond thrilled to be joined by Dr. Abby Rosenberg, who was the lead author on this manuscript. And she is currently an associate professor in the Division of Hematology-Oncology, as well as in the Division of Bioethics and Palliative Care at the University of Washington School of Medicine.

She has a number of different amazing accomplishments, including being the director of Palliative Care and Resilience Lab at the Seattle Children's Research Institute, the director of Pediatrics at the UW Cambia Palliative Care Center of Excellence, and the director of Survivorship and Outcomes Research in Pediatric Oncology at the University of Washington. In addition, she is our ASCO chair of our Ethics Committee. Welcome, Dr. Rosenberg. So excited to have you.

ABBY ROSENBERG: Thanks for having me. Happy to be here.

SHANNON WESTIN: And in addition to Dr. Rosenberg, we're also joined by one of her co-authors, Dr. Reshma Jagsi, who is the deputy chair of radiation oncology, the Newman Family Professor of Radiation Oncology, and the residency program director and the director of the Center for Bioethics and Social Sciences at the University of Michigan. You guys, we're going to spend this whole podcast just talking about how amazing the two of you are. Thank you so much for being here.

RESHMA JAGSI: Thanks for having me.

SHANNON WESTIN: So let's get into it. I'm really excited about this paper. I think it's super timely and certainly something that we've all been, I think, dealing with on a day-to-day basis and also reading about and really trying to get better at. So can you tell us a little bit-- and we'll start with you, Dr. Rosenberg-- about what first drew you to this work, how you got involved and, really, how you became passionate about it?

ABBY ROSENBERG: Yeah, happy to. I think just, as you said, Dr. Westin, there is this ubiquity in the experiences, in particular of women and folks of color in medicine, where we feel discriminated against, and we feel like we don't belong. And we know from some really great data from the National Academies of Sciences that 50% of women in med school, for example, experience discrimination before they graduate. And when we educate them about what microaggressive and sexist behaviors can actually look like, that number goes way up.

And most women, in particular, say that they're willing to, quote, "pay this price" for being in medicine because they believe in the work, and they believe in the mission. And for me, this was really personal. Because I was one of those people, too, until I got to the point in my career where I noticed how my mentees and people who reported to me were being held back. And that, to me, made me feel like there was something I really needed to do now as an advocate and mentor to try to change the system so that more women and people of color could be successful in our field.

SHANNON WESTIN: That's great. And then how did you get involved Dr. Jagsi? I'd love to know how the collaboration came about and also about your passion for this work.

RESHMA JAGSI: Thank you. Yes, so both Dr. Rosenberg and I have had the privilege of chairing ASCO's Ethics Committee. And I think, to both of us, this is a fundamental matter of professional ethics. And there's really two reasons that this is so centrally and fundamentally an ethical issue.

And so one of them is that human beings have a duty to resect the dignity of other human beings. And this is a situation in which we are not treating one another with due dignity. And then, of course, there's also really important consequences when we do fail in that duty.

And so it's important because we share a professional mission here to promote the highest quality of patient care, to educate those who are following in our field, and to do the scholarly research to discover advances that will ultimately benefit patients and society in the future. And all of those missions are enriched when we have a diverse workforce. So this is really squarely in the lane of ethics. And so when Dr. Rosenberg proposed this article, I was just more than delighted to be included in this work.

SHANNON WESTIN: And it's so important for us, as women. And I am not a woman of color, but especially as we cross all of these different groups to really elevate each other and to move the message and put it out there and make sure that people feel OK bringing these things up and understand that they're not alone, I think that's, to me, that resonated so much, with both of you saying this.

Like, we've all experienced this and some of us don't even know we're experiencing it, right? Because it's just, oh, this is the way it's always been. This is the price you pay. It's the price of doing business. And I'm so grateful for people like you all that are kind of not afraid to step up and step out so that our trainees, and even pre-trainees-- people that are considering coming into the practice of medicine-- will know that this is a safe space. Because I think that's the issue, right?

So I'm so grateful to you. I think, for me, it's been very interesting across these last few years, especially in the idea around #MeToo, which I know was not a new idea but certainly became very much a focus over the last three or four years. This focus on diversity, equity, and inclusion has really become, I think, a welcome change amongst a number of professions.

Can you speak a little bit-- and I'd be interested on both your takes, and feel free to interact-- but can you guys speak on why we've been slow to take this on in medicine? Is it just that kind of-- gosh, I'm going to offend some people-- old, white male kind of leading the way and keeping us from doing this? Or what's been the hold-up here? Nobody wants to-- they're like, whoa, Shannon. Whoa, Shannon.

RESHMA JAGSI: I have some thoughts if you want me to go. I'm yielding to you because this is really your thing.

ABBY ROSENBERG: No, you go.

RESHMA JAGSI: This might be a landmine, so let me go first.

[LAUGHTER]

No, it's totally fine. Because I think that there are very good reasons that medicine has been a conservative profession, that we've had strict hierarchies. It makes sense. You're in the operating room, you really want one person to be in charge. You need a captain of the ship. There's a lot of reasons that many of our traditions sprang up the way that they did.

But they have made us a field within which individuals rise to positions of leadership. There's relatively little turnover. We've not embraced, for example, term limits in the way that many other academic fields have.

And so there has been this tendency for people who have certain shared lived experiences to be able to react to the things that they've experienced but perhaps not to have as much familiarity with those things that they haven't experienced. And so I think that's one of the challenges that we have.

SHANNON WESTIN: Dr. Rosenberg, do you have anything to touch on or add there?

ABBY ROSENBERG: I totally agree. And thanks for launching that grenade for us. [INAUDIBLE].

[LAUGHTER]

I think that change is hard, and change takes a lot of time. I'll share sort of a minor anecdote, but bear with me. When I started to really try to speak about this publicly and move the needle, my father was very ill. And he actually died during the year that I started this own crusade at my workplace. And my father had been this big civil rights activist back in his day.

And I was talking to a colleague who said, oh, your dad would be so proud of you. And he said, what do you think your dad would say? And I said, you know what my dad would say is how silly it is that I thought I could make this dramatic change within a matter of months. Because it takes years and years and years to really do that.

And I think where we are in academic medicine is years behind everybody else. And we're watching this change happen and this culture change happen in other industries, and we're trying to catch up. But within our own culture, it just takes a lot of time. Because there is this real institutionalized history, as Dr. Jagsi was describing, of the way we've always done it.

I will also name, to just be even more provocative, that the people who have the power of influence, the people who have the power to really make those changes, are the very people who I think wrongly perceive it as a loss of their power to diversify and change the way we do it. And that's really threatening to people who can make those changes with us. And so the additional barriers we have as a grassroots community that's trying to make change becomes really hard when it's not ubiquitous from the bottom up and the top down that people are trying to be change makers themselves.

SHANNON WESTIN: I think that's a great point. And I guess that kind of leads to my next question. How do we overcome this? How do we help those people in power understand what the benefits are to focusing on diversity, equity, and inclusion?

And also, how do we overcome that existing bias in medicine that is affecting not only our professionalism standards but also, frankly, the care of our patients? We know that this is a clear indicator of poor outcomes for our patients, not only in oncology, which, obviously, is where we all sit, but across a number of different fields. I'm just asking you to solve all the world's problems in this podcast.

ABBY ROSENBERG: Yeah. Well, Dr. Jagsi mentioned some of this. I think if you go back to it needs to be top-down and bottom-up. The top-down piece is we need leaders who look like the workforce. People cannot aspire to belong if they don't see that they belong. And so things like term limits, our abilities to promote and ensure that the tippy-top levels, and every level in addition, is really representative of the diversity of the workforce we want. That's really important.

But then, from the bottom up, we need to be bringing people in. We need to be working extra hard to make sure that folks who have been historically marginalized with fewer opportunities are given the additional opportunity and resources they need to succeed in medicine.

And so the system, to go back to our previous question, why it's so hard, it's not easy. I mean, all of us know going through our medical training and getting to where we are is really, really difficult. And every step along the way, there are so many obstacles. And what we need to be doing is supporting those who are bringing diversity in to ensure that they continue to succeed.

RESHMA JAGSI: Yeah, I love the way that you've approached this with the top-down and the ground-up for culture change. And just to add to some of the things that we can do from the top down, in addition, we can provide sponsorship. We can be intentional about that, not exhibit homophily and simply think of the person that reminds of us of ourselves when we were younger when we have the opportunity to give someone a chance to shine.

We can be absolutely intentional about developing mentor networks for individuals, recognizing that simple hierarchical dyads tend both not to be effective and not to be safe. We should be thoughtful about implementing unconscious bias training.

Certainly, there are some that don't work. But Molly Carnes at the University of Wisconsin has actually developed some within medicine that can be very effective. And again, I'm saying this all from the top down because this is not about fixing the individuals.

The top-down bit is that we have to change the structures, right? We're not fixing individual human beings. We're fixing systems. We need to develop transparent, consistent, criterion-based hiring, promotion, compensation processes.

And then, from the ground up, we need to develop our allyship behaviors. I had a very smart trainer come to our department about a year ago who talked about how we should approach allyship development in the same way we approach behavior changes in other areas.

There's people that are pre-contemplation. They're not really sure they want to be an ally yet or don't even know that allyship is a thing or necessary. There's people who are in contemplation who'd like to be allies. They're not sure exactly how to do it.

There's people who are actively trying to be allies and even become advocates for change but need more support. And we need to meet people where they are in that behavior change wheel so that we get that ground-up cultural transformation at the same time that we're changing the system.

ABBY ROSENBERG: As we're talking, I'm sitting here, realizing that we're talking about the larger problem of diversity in medicine. And I did want to get back to this idea of what professionalism in medicine is and how the two are related. Because that's sort of what we endeavor to do with this project.

And it gets more granular and more opaque at the same time. So the granularity is part of that progression of success is this thing that we call professionalism, which is hard to measure. Sometimes it's like are you accountable, are you honest, do you communicate well? But they're these super-nebulous things-- are you a good person, essentially? And I think we all want to be those people.

The folks who are judging professionalism, the folks who are grading it, so to speak, especially as we're trainees, are not necessarily consistent with how they assign good or bad professionalism merit. And what we want to do with this project, we wanted to focus on this particular aspect of how to improve the diversity of our workforce and the success of a diverse workforce by sort of naming this problem.

And what Dr. Jagsi is saying is, I think, the accountability of how we record professionalism, the accountability of how we say, no, no, no, that wasn't actually professional behavior and therefore, you are not necessarily representing what we want as the best of our field, those kinds of behaviors and those kinds of metrics have not really been established in medicine. And I think that's the particular needle we were trying to move with this paper.

RESHMA JAGSI: And that's where the brilliance is in the title that Dr. Rosenberg developed for this piece-- "Picture a Professional." Because when we're trying to assess, are you a good person, really, what we end up doing is deciding, do you look like a good person? I mean, we literally look at appearances rather than behaviors. And I think that she just so hit upon such an important point there.

SHANNON WESTIN: Yeah. And you all mentioned that those biases are, again, the way medicine was originally-- what was the face of medicine-- the white male. And now that the face has changed, how can we also adjust what we picture?

Also, I've heard this before, but when I was reading the paper about the children that were asked to draw a professional or draw a physician or a scientist and what that was back in the '60s and what might it be now? I know in the 2010s, it was still overwhelmingly male. And I think that speaks to a bigger problem. That speaks to a larger issue.

So now the question is, how do we change that picture in the minds of people that are hiring and promoting physicians and medical professionals? I think that's what I took away. And I felt this table was so-- I was like, wow, how did they even figure this out? Because it's so granular and so specific.

And I feel like that is really the marching orders that I got from this paper is how do you take these types of descriptions and apply them when you're looking at candidates and when you're looking at promoting within your institution. And I'd just be interested to hear your thoughts. I know that really wasn't a question. I'm just so inspired by kind of what you were able to do in this short piece.

ABBY ROSENBERG: Oh, yeah. No, thanks, Dr. Westin. I'll start because when we were developing this, we were actually looking up, how does professionalism get defined in different places? And it is super vague. It's super different in different places.

There are some really outrageous, frankly confined, if not racist and sexist, things out there that say, you should dress like this. And it's very white patriarchal standards. But most places have these nebulous things, like the American Medical Association, which is what we pulled down. And I actually have the paper in front of me. Because it's sort of like, "Refrain from supporting or committing crimes against humanity." I mean, really? Is our benchmark that you didn't commit a crime against humanity?

[LAUGHTER]

SHANNON WESTIN: It's a pretty low bar.

ABBY ROSENBERG: That is so bizarre to me. But OK, fine. So let's say we all endorse that we are not going to commit a crime against humanity. How do you actually measure that? And so what we wanted to say is, actually, what we should be doing is holding ourselves accountable, being responsible for what we think represents our field in medicine.

And in this new era, as we are becoming more and more aware of the importance and the value of diversity, equity, and inclusion within any workplace, we need to really come up with ways to translate "refrain from this badness" to "do good." And so we thought, what if we instead said, we're going to demonstrate an intolerance of bias. You have to actually show that you are willing to speak up, that you're willing to interrupt it when it happens, that you are investing in the skills development to be that kind of inclusive leader or workforce member.

And those are actually measurable things that we can say, as far as folks are going along in their training and their career development, are you meeting these particular benchmarks? Do we see that you are demonstrating these particular values that we all hold so dear?

RESHMA JAGSI: It's that type of specification that makes it so useful. And I'm just so grateful, Dr. Rosenberg, for you taking this on. Because I really do think that this document is, as you said, Dr. Westin, something that is concrete and can be useful to people who are in the position of assessing professionalism as a competency, for example, as I do, as a residency program director.

SHANNON WESTIN: I think that's what we're lacking, right? Because it has been this idea that's so nebulous. And I think we've all had experiences where your hair is too big or your skirt is too short or you're whatever-- you're too quiet, or you're too loud, or you're too pushy. I mean this is what we get judged based on.

And I think I just was so pleased with how clear and how measurable each one of those things were. And some of them weren't even related to diversity or equity, like applying evidence-based best clinical practices, acknowledging medical errors, that type of thing-- conducting rigorous research and disseminating your results.

This spans well beyond DEI. But it's rooted in overcoming those issues of bias. So I really just was so impressed with this paper. And I think that it really does bear getting this out here. Obviously, everyone listening right now loves the Journal of Clinical Oncology and is thrilled to hear the novel research that's presented there on a weekly basis.

But I really do think we should be thoughtful about how else we can get this information out here. And I'm just interested to see, are the invitations just flooding in now? Are you preparing a dog and pony show to go out to disseminate these practices and these ideas to the world?

ABBY ROSENBERG: So Dr. Jagsi has been so kind and effusive, I'll just put that back on her. She is really a hero to so many of us as an advocate for women in medicine and has been such a role model for how do you do this work, how do you do this advocacy, how do you get this message out there, and how do you persevere, to be totally honest.

Because I think what happens is folks will have a story. They'll have an experience. They might share it. They might not. And then we get kind of smushed back under the rest of the burdens of our work and the hardness of change-making so that folks just stop trying and they stop talking about it. And then the cycle repeats itself.

And so what I have learned from working with Dr. Jagsi is that you can't stop talking about it. You do have to continue to get back up on that soapbox, share this message. And every single time that I do, the number of people who reaches out to me to say thank you is overwhelming.

And that tells me two things. Number one, we still have a lot of work to do. And number two, we are doing real good by continuing to distribute this message and remind people that, no, they're not crazy. This is actually real and that together, we can make a really meaningful change.

RESHMA JAGSI: Thank you. I really can't say more than that, other than blush. But I am so grateful that I've seen, over the years that I've been studying these issues and speaking about these issues, the number of people who are doing thoughtful, rigorous research into these issues and taking the platform and having the courage to speak up about experiences they've had, to provide that vivid detail, that personal stories can provide that dry data simply cannot.

That's the power of the #MeToo movement. It's showing people that they're not alone. It's encouraging people who haven't had these experiences to understand what it is like. And it really does, then, motivate us to change. And I think it's a great time right now for us to be doing this kind of work. I really do see change.

And so we may have been a little slow in coming to it. And we may be the field that, in the National Academies Report on the Sexual Harassment of Women in science, technology, engineering, mathematics and medicine, we may have been the worst field of everyone they studied. But I have faith that we can actually have the fastest trajectory towards positive change, as well, and we can become exemplars.

SHANNON WESTIN: That's great. Super inspiring. And I hope that our ASCO leadership are listening to set this up as a educational session at the next ASCO and really also figure out how we can get these very granular and very specific ways to improve our inclusivity in medicine over the next few years. So I am so grateful to both of you, Dr. Rosenberg and Dr. Jagsi, for spending the time with me.

And I hope that we can have a podcast, maybe, in a year or two, talking about all that we've accomplished and a celebratory podcast, perhaps. So with that, thank you all so much for listening to JCO After Hours. And see you next time.

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SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. For more original research, editorials, and review articles, please visit us online at jco.org. This production is copyrighted to the American Society of Clinical Oncology. Thank you for listening.

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

Dr. Shannon Westin, Dr. Kirsten Beyer and Dr. Jennifer Griggs discuss how mortgage lending bias and residential segregation intersect with cancer disparities and survival outcomes.

TRANSCRIPT

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SHANNON WESTIN: Hello, everyone. My name is Shannon Westin, and I'm an Associate Professor at the University of Texas MD Anderson Cancer Center in the Department of Gynecologic Oncology and Reproductive Medicine. And I currently serve as the Social Media Editor for the Journal of Clinical Oncology.

And we're starting a brand new podcast series to try to bring really exciting research that's being published in the JCO to you, and I'm so excited to kick off this series with a group of very accomplished women who are covering something that I don't think a lot of us don't know very much about. So I'm really excited to learn a ton over this next few minutes.

So it's my pleasure to introduce Dr. Kirsten Beyer, who is an Associate Professor in the Division of Epidemiology in the Institute for Health and Equity as well as the Director of the PhD program in Public and Community Health at the Medical College of Wisconsin.

We are also joined by Dr. Jennifer Griggs, who's a Professor the Department of Internal Medicine, Division of Hematology Oncology, as well as a member of the Institute of Health Care Policy and Innovation at the University of Michigan. She does predominantly practice taking care of women with breast cancer. Welcome, doctors.

JENNIFER GRIGGS: Thank you.

KIRSTEN BEYER: Thank you very much.

SHANNON WESTIN: So we're talking today about the manuscript "Mortgage Lending Bias and Breast Cancer Survival Among Older Women in the United States" that Dr. Beyer published just this month in the JCO. In addition, Dr. Griggs and her colleague Dr. Pleasant were invited to participate in an editorial called "Contemporary Residential Segregation and Cancer Disparities."

So let's get into to what was covered. So I think for me, the lowest hanging fruit here, Dr. Beyer, is understanding what exactly is redlining, because that was one of the critical exposure that you were assessing amongst these women with breast cancer.

KIRSTEN BEYER: Thank you, Dr. Westin. Yes, redlining-- I think most people think about redlining as being a historical practice, where mortgage lenders would essentially draw red lines around particular neighborhoods and then not lend mortgages in those areas, regardless of whether or not the applicant for that mortgage was otherwise qualified. So it's generally thought of as a historical practice.

But what we've done in this study is to look at some more contemporary data and create a new measure that we think represents contemporary redlining, maybe not in the legal sense in terms of housing discrimination. But this measure represents essentially the odds ratio of denial of a mortgage application for a property in a local neighborhood as compared to the metropolitan area as a whole. So we're really looking to see which areas of our US cities are systematically denied mortgage applications. By denying those mortgage applications, they are suffering from disinvestment, and I would argue structural racism is guiding a lot of that practice.

SHANNON WESTIN: So can you explore that a little bit more with us? And how do you find that type of data? Where do you get this information about these denied mortgages? How do you get into the different covariates like race, ethnicity, things like that?

KIRSTEN BEYER: Sure. So I think a little history lesson is important first. Between the historic practice of redlining and today, there have been a number of major laws that have been passed in the United States really to try to overcome housing discrimination. Some of the most important ones are-- in the Civil Rights Act of 1968, there was something called the Fair Housing Act, and that act prohibited discrimination in the sale, rental, and financing of housing based on race, religion, and national origin. And since then, they've added a few more protected categories.

And then right after the Civil Rights Act of 1968, there was something passed called the Home Mortgage Disclosure Act. And this act was essentially to bring transparency to mortgage lending in this country. The idea was that we were requiring public disclosure of loan-level information about mortgages that were lent in the country. And the goal was to shed light on lending patterns, including those that could be discriminatory.

And so the HMDA data-- it's commonly referred to as "hum-duh." That HMDA data has been collected then since 1975. And that database evolves over time, but we use that data for 2007 to '13 to really try to understand what are the mortgage lending patterns in our US cities in terms of their spatial distribution.

And so there are a number of covariates that we were able to control for there. There are some things that we're not able to control for. I'm excited that the HMDA database has recently improved, and there are some new variables that are going to become available in the coming years.

So what we did with the HMDA database was to calculate an index of redlining, so an odds ratio of denial of a mortgage application for a property in a specific neighborhood compared to all the properties across the metropolitan area. And so it's an area-level measure, a neighborhood-level measure.

And then we put that measure into a statistical model to see what happens to women diagnosed with breast cancer if they live in redlined areas compared to if they live in other areas. And so we were able to control for a number of other factors, including race, including tumor characteristics, age, stage at diagnosis, and then to see what is the added effect of redlining over and above the things that we already know impact survival.

So what we found was that women living in redlined areas in the United States were more likely to die faster after breast cancer diagnosis than women living in other areas. We also found that among people living in redlined areas, there was a discrepancy in terms of the race and ethnicity of those women. So 79% of Black women, 57% of Hispanic women, and 34% of white women lived in redlined areas in our sample.

SHANNON WESTIN: That's so interesting, because I think we've all read and seen across a number of different cancer types how race and ethnicity can be associated with worse outcomes. So I think you're starting to scratch the surface of why that might be. Now, do we think that is there an association with other factors like socioeconomic status or insurance or anything like that?

KIRSTEN BEYER: Yes, I think those are really good questions. Not all databases contain all of the information we would like. But in SEER-Medicare, which is the database we use, we know that all of the women have health insurance because it's a linked database with cancer registry data and then Medicare claims data. So health insurance wasn't a factor here, but we certainly know that it could be a factor in a larger sample of women across the age spectrum.

And I think when you get into questions of socioeconomic status, you also have to think about, as opposed to statistically controlling away the effect of socioeconomic status, what is the mediating effect? Or what is the explanation? What factors explain the relationship between redlining and breast cancer survival? So I think that's where we'll see a lot of the important explanations for how does redlining contribute to survival.

SHANNON WESTIN: Thank you. I think you nailed it right there, because finding a problem is, of course, important, but then what do we do next?

Dr. Griggs, I thought your editorial was just so great at providing context for this issue, and I was wondering if you could expand a little bit more on this idea around residential segregation and how it impacts outcomes for these patients.

JENNIFER GRIGGS: Thank you very much, and thanks for including me on this great podcast. It's so important to understand that place matters more than race, and we've known this for quite a while. So that area-level factors are associated with environment-- for example, pollutants, safe water, safe places to play, safe places to exercise, transportation fragility, for example, a robust public transport system.

We know that neighborhoods that are in redlined areas are more likely to be policed in different ways, which takes children from school being suspended at higher rates. There's less educational investment, but Dr. Beyer mentioned this disinvestment in neighborhoods basically has shutters all the way down. It shutters from childhood all the way to how we age and access to healthy food.

We know redlined areas are associated with poor markers of diabetes control, and if you take somebody from an area that's a poor neighborhood that's segregated and give them a voucher to live in a more affluent area, that markers of diabetes improve and weight goes down.

So just to think about this, that the impact of where we live affects things that we think of as personal behavior-- like, what we eat or how we control our diabetes. There are, of course, implications for access to high-quality health centers when we think about people sort of locked into certain neighborhoods, all that goes along with that, including wealth.

Wealth is probably one of the biggest predictors of health and not being able to have the wealth associated with home ownership decreases economic stability. And we know these things like allostatic load or stress, sometimes called wear-and-tear effects, are associated with things like tumor biology and breast cancer. We see more triple-negative breast cancers in areas where there's more allostatic load.

So imagine, we think about race as this fixed-- sometimes people even construe race as a biologic construct, when really, of course, it's a social construct that has systematically-- our systems have been put in place so that even the legislation, Fair Housing Act, can't be overcome, as shown in Doctor Beyer and colleague's paper. In other words, despite legislation, we continue to see mortgage lending bias, which we've termed contemporary redlining. Yet, we think of race as this fixed, deterministic way of describing people and explaining differences and outcome.

So this kind of work is really important when we can show the effect of place independent of race and if we can show that there has been systematic construction of something so important as residential segregation. What this does is it drives us to really a call to action.

A lot of ideas in there, but basically, showing where people live being associated with their outcome in breast cancer-- and this has been shown in other cancers, as well-- through pathways like economic stability and wealth, wear and tear on the body, and then to acknowledge the sad truth that things have been intentionally constructed structures.

SHANNON WESTIN: I mean, I think this is really in line with a lot of what we're learning about our society and our country, the way we were educated when we were younger was that we did not always hear the truth about what really went down as this country was built. I think that you really touched on a lot of very critical points.

And I think for me, a lot of times when we read about these racial and ethnic disparities, I feel like it often comes down to where people are like, oh well, it's just access to care, or lack of insurance, or they're just not focusing on these things. They're not educated. They don't know that these things are important.

But what I hear the two of you saying is, it goes much deeper than that. So Dr. Beyer, I'd be interested to hear your thoughts on that with these areas. Should we be working on improving what is available to people in these areas? Or should we work on breaking down or both?

KIRSTEN BEYER: Yeah, thanks, Dr. Westin. That's a great question, and it's a complicated one. I think Dr. Griggs mentioned housing vouchers. And so for example, when we are giving someone a housing voucher to move from a more vulnerable neighborhood, let's call it, to a less vulnerable neighborhood, that can improve health outcomes for sure.

But we also know that there's a downside to that. Sometimes there are impacts on social support or mental health. And then on the flip side, if we are trying to improve neighborhoods themselves so that the people living in them can benefit from those enhancements, we often see that what happens is gentrification, when people who are living in those neighborhoods get displaced, and newer people, wealthier people, move in and take those amenities. So I think it's something that really requires close management with housing policy.

And then I think another thing that I would add is that, as you mentioned, we're really scratching the surface. I think that's an important thing to emphasize. This is one aspect of housing. There are other aspects that are very important, like quality of housing and stability of housing, which is what Dr. Griggs mentioned.

And I think it's also important to note that even if a person is denied a mortgage application because of a credit score, that credit scores, wealth, income, and many other things that are considered in the mortgage lending process are also affected by structural racism, as are things like home appraisals, mentorship, and eviction, something that we've certainly seen during the COVID-19 pandemic.

SHANNON WESTIN: Wow, so thoughtful. I feel like I'm trying to take notes as fast as I can because I'm learning so much. I think we didn't hear about anything like this in our medical school and your PhD training. I don't know if you all got any type of background in this. Dr. Griggs, did you-- I mean, we never even scratched the surface with the impact of structural racism. And in fact, I think a lot of our medical education was founded in that structural racism.

JENNIFER GRIGGS: I couldn't agree more, and I couldn't agree more with what Dr. Beyer said about things like housing vouchers, so I just want to acknowledge that it's not as simple as giving people a voucher, obviously. No, we are calling for structural competence. There are multiple calls that we teach medical students and current practicing clinicians and scientists the structures that have been put into place and that persist.

So again, that intentionality that these systems were put in place through deliberate efforts, and it's only going to be through deliberate efforts that they're dismantled. And teaching people that individual behaviors are not predetermined or, frankly, learned. They cross multiple generations, and they reside within a place and the way not just a person, but an entire people, have been treated.

And I do just want to say, although this may be new to a lot of us, that the lived experience of people who live in vulnerable neighborhoods and their life experience and their family's experience going back many generations make this not new news, right? This is old news. This is stuff people have known for generations that they're being systematically cut out of opportunities for advancement and for accumulation of wealth.

So I think we just want to be-- I just want to be careful when I'm talking with my colleagues, my team, my research colleagues that this is not new knowledge. And we want to also be careful not to be parasites in a way on other people's suffering, that we want to be careful not to glorify our own ideas because number one, they're not our ideas. And number two, this type of work is the lived experience of people for many, many years, not just our neighbors and friends and colleagues.

So there's so much harm that's been done, and we can celebrate advances and new knowledge, but I also think we want to focus on cultural humility and do a lot of deep listening and less talking and build trusting relationships with communities that are not about our career advancement but are really about fairness and justice.

SHANNON WESTIN: I think that needs to be shouted from the rooftops, and I think it is a very careful balance, because we want this research to get out. We want to make sure people understand this. You're right. It's not new knowledge, but I think it's something that hasn't necessarily been highlighted in academic fields up until, like, the last few years, where I feel like we've started to see this.

But you're exactly right. We can't just do the research and find the association. Now it's time for the next steps. And I'd be interested to hear from both of you, because, to me, there are several levels of steps that we can take. There's the local level, right? So what can we do for the patients in front of us?

And then I'd be interested to hear what you all think about what do we do on the more institutional-- and by institutional, I mean, our entire country. Like, what can we do? How do we advocate for policies that will help to reverse these practices? I don't know Dr. Beyer, if you want to start. I know that was a really big question. What can we do when we're seeing patients in the clinic? Are there ways, or are there things we can offer or things that we can do on the local level that could help to address some of these disparities?

KIRSTEN BEYER: Yeah, thank you, Dr. Westin. I'm not a medical doctor, but I work a lot with medical students. We have some pathways at the Medical College of Wisconsin, one on urban and community health and one on global health. And in those pathways, we do try to put forth a lot of this type of content and learning. But again, that's just a select number of students who end up getting that training.

I think that structural racism is a fundamental force in our society, and therefore, it justifies a position in the core medical curriculum. I think since the murder of George Floyd, there has been a national consciousness that's been raised around this issue, that we should take advantage of that and try to push forward some core learning on structural racism for medical students.

And then beyond that, I think as a patient, I can use the patient perspective. As a patient, I would want my physician to take into account my life context when providing clinical care. How hard is it for me to get to my appointment and to get there on time? How hard is it for me to find child care? How hard is it for me to obtain the prescriptions I need and maintain them with any significant cost at hand? So I think that awareness for physicians is really a first step.

And then the last thing I would say is that doctors have power, and so I think it's the responsibility of those with power who are in the know about structural racism to leverage and use that power to make social change.

JENNIFER GRIGGS: I really appreciate what you said from education to practice. I would add that an integrated health system would be able to think from prevention all the way up to health care. I feel like by the time people are accessing health care, a lot of other things have gotten in the way of their health, right? That's why we talk about social determinants of health.

So I think we need to think about elevating the role of other people in the health care system. So even if you're in an individual practice, do you have access to a social worker? Are you including patient and family voices when you build your new office? We have transportation initiatives being made all over this country, and I know in Europe as well. So cities are being designed to undo transportation fragility and vulnerable neighborhoods.

I can't emphasize enough the importance of asking communities what they need. It strikes me that the ivory tower is just that, right? It's very rarefied where we work. And to go into a community and say, this is what you need, feels-- which is not what you were suggesting, Dr. Beyer or Dr. Westin, but to start by listening and ask the communities what they need and then to provide it and to listen and not leave once the, quote, "problem is fixed."

And I think the same is true nationally. We need to make sure that the administration's priorities actually bear fruit and soon, that we not kick things down the road and make compromises at the level of national policy. And as physician clinicians, those physicians who are listening, we should be going to the city council meetings when a new building is being erected. Is there going to be a consequence for neighborhoods in terms of things like gentrification?

Cities have been constructed intentionally to isolate people, and we need to start undoing that, and cities are doing that. They're taking down freeways that divide the rich from the poor. I think we need to make sure as clinicians that we are speaking up about equitable and high-quality education for young people because we know your early life experiences and education are associated with health.

Publishing work like Dr. Beyer's work, ASCO has a heavy advocacy arm. And as Dr. Beyer said, we have power. Inequities in power is what got us to where we are. So really, the burden is on those with power to speak on Capitol Hill and other places, local level, statewide level, to make change and to insist on it for the health of our patients and our communities.

SHANNON WESTIN: That is so thoughtful and such a great call to action. And I do think there's a huge opportunity for members of ASCO to get involved. The advocacy is extremely strong. There are Capitol Hill days and committees, and now we even have their own political action committee, where we can work to lobby for patients and their health care.

So I think that is a perfect place for us to end this conversation. I would like to give Dr. Beyer last opportunity to one-liner to sum up where we are and what we need to do next for those people that tend to fade in and out of these types of things.

KIRSTEN BEYER: Sure. Thank you, Dr. Westin. I would say, to summarize, that the housing sector is actively revealing structural racism. This isn't a historic practice only. We are seeing structural racism in housing right now, and it's actively revealing both structural racism and economic disinvestment. And it's a very actionable policy target, so that we can mitigate those upstream determinants of health for the benefit of patients with cancer and with other diseases.

And then I think as a final, I would say that there's a great quote from Matthew Desmond, who's a housing equity writer and scholar and activist. And he says, "A stable home functions as a secure foundation on which to build holistic and cost-effective health care." And so I think that's a great way of thinking about it from a practical standpoint. Housing is primary. It's an important foundation on which we build all the other things that we can do to improve people's health.

SHANNON WESTIN: Perfect. Thank you both so much. Thank you, Dr. Beyer. Thank you, Dr. Griggs. And thank you, all of the listeners. We'll be back soon with a new podcast coming to a ear near you.

JENNIFER GRIGGS: Thank you so much.

KIRSTEN BEYER: Yeah, thank you very much.

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SPEAKER 1: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

For more original research, editorials, and review articles, please visit us online at jco.org. This production is copyrighted to the American Society of Clinical Oncology. Thank you for listening.

This podcast will discuss data from a phase II trial evaluating the dose-adjusted EOPCH-R chemo-immunotherapy regimen for the treatment of primary mediastinal B-cell lymphoma in children.

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LISA GIULINO-ROTH: This JCO podcast provides observations and commentary on the JCO article "Dose-Adjusted Rituximab Therapy in Children and Adolescents with Primary Mediastinal B-cell Lymphoma, a Multicenter Phase II Trial" by Burke et al. My name is Lisa Giulino-Roth, and I am a pediatric oncologist at Weill Cornell Medical College in New York. My oncology specialty is lymphoma in children, adolescents, and young adults. I have no relevant disclosures.

Primary mediastinal B-cell lymphoma, or PMBCL, is an aggressive non-Hodgkin lymphoma derived from thymic B-cells. While previously classified as a subtype of diffuse large B-cell lymphoma, PMBCL is now recognized as a distinct clinical and pathologic entity. Unlike diffuse large B-cell lymphoma, PMBCL has a peak incidence among adolescents and young adults and is more common in females.

PMBCL also shares many molecular characteristics with Hodgkin lymphoma, including alterations in JAK-STAT pathway signaling and amplification of the 9p24.1 locus, leading to upregulation of PD-L1. Adults with PMBCL have historically been treated on regimens designed for diffuse large B-cell lymphoma, which in the US was most commonly R-CHOP and radiation therapy. More recently, adult patients have been treated with a dose-adjusted EPOCH-R regimen, which is composed of dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab.

This radiation-free approach is of interest, given this young and predominantly female population who are at risk for significant long-term toxicity from chest radiation. In a single center NCI-led study by Dunleavy and colleagues, dose-adjusted EPOCH-R was administered for six to eight cycles without radiation therapy and resulted in excellent outcomes with a five-year event free survival of 93% and overall survival of 97% among 51 adult patients.

Pediatric patients with PMBCL have historically been treated on regimens designed for mature B non-Hodgkin lymphoma, which in pediatrics is most commonly Burkitt lymphoma or diffuse large B-cell lymphoma. These dose intensive multi-agent regimens include doxorubicin, high dose methotrexate, and intrathecal chemotherapy without radiation.

Outcomes for children with PMBCL treated on these regimens are inferior to pediatric patients with diffuse large B-cell lymphoma treated on the same protocol. Children with PMBCL have a five-year event-free survival ranging from 65% to 75% in different international series. Given the excellent outcomes observed with dose-adjusted EPOCH-R in the adult NCI trial, an international phase II trial of this approach was conducted by two cooperative groups, The European Intergroup for Childhood Non-Hodgkin Lymphoma and the Children's Oncology Group.

This single arm trial enrolled patients age 18 and under with primary mediastinal B-cell lymphoma. All patients were treated with six cycles of dose-adjusted EPOCH-R without radiation. The primary endpoint was event-free survival with events defined as any of the following-- viable cells in any residual mass after six cycles of treatment, relapse, progressive disease, secondary malignancy, or death from any cause. The four-year event-free survival from this trial would be compared with the event-free survival from historic controls, which was estimated at 67%.

A total of 46 pediatric patients were enrolled between 2012 and 2016. All patients received six cycles of dose-adjusted EPOCH-R without RT. At a median follow-up of 59 months, there were 14 events, including four patients with viable cells in the residual mass at the completion of therapy, eight progressions or relapses, and two secondary malignancies, including one case of Hodgkin lymphoma and one case of acute promyelocytic leukemia.

The event-free survival of the entire cohort at four years was disappointing at 69.6% with a 95% confidence interval of 55.2% to 80.9%. This was not statistically different than historic controls treated on pediatric mature B and HL regimens. Overall survival at four years was 84.8% with a 95% confidence interval of 71.8% to 92.4%.

The authors acknowledge several limitations in the current study and challenges when comparing this study to the NCI trial. Not all patients adhered to the dose escalation rules, and 29% should have received a higher dose level in at least one course of treatment. Among the 10 cases of local relapse or primary refractory disease, five were noted to have a failure to dose escalate, including one patient with a clinical complication that precluded dose escalation.

Comparing this trial to the NCI trial is challenging due to several important differences. Adults in the NCI trial were treated with six or eight cycles of dose-adjusted EPOCH-R based on the response between cycles 4 and 6. In pediatrics, eight cycles was not deemed appropriate, given the potential for greater than 600 milligrams per meter squared of cumulative doxorubicin exposure and concern for significant long-term cardiac toxicity at this exposure level. In addition, the NCI trial did not consider residual viable cells or secondary malignancy as an event, both of which were defined as events in the current pediatric trial.

In a reanalysis of the pediatric data using the NCI event definitions, there was only a modest change in event-free survival with a four-year event-free survival of 73.9%. So where does this leave dose-adjusted EPOCH-R and the management of pediatric patients with PMBCL? In my opinion, there's no single superior regimen to treat pediatric PMBCL. Outcomes are similar across regimens. However, the toxicities are different. Dose-adjusted EPOCH-R offers significantly less short-term toxicity, but the potential for a higher cumulative doxorubicin dose compared to pediatric mature B and HL regimens.

Regardless of the chemotherapy backbone, it is clear that for children with PMBCL, outcomes remain suboptimal, and further studies are needed to advance treatment. Given the rare nature of PMBCL and the peak incidence in the AYA population, combined pediatric and adult trials may allow us to evaluate novel agents and advance outcomes.

Both children and adults with PMBCL may benefit from the incorporation of novel agents. Retrospective multicenter data from adults treated with dose-adjusted EPOCH-R have also failed to reproduce the excellent outcomes observed in the NCI trial. In two large retrospective series, adults with PMBCL treated with dose-adjusted EPOCH-R had a two- and three-year progression-free survival of 85% and 87% respectively.

To advance outcomes in PMBCL across age groups, our team at the Children's Oncology Group in collaboration with Alliance and the National Clinical Trials Network is conducting a randomized phase III trial of the checkpoint inhibitor nivolumab in combination with chemo immunotherapy for adult and pediatric patients with PMBCL. Checkpoint inhibitors, including pembrolizumab and nivolumab, have demonstrated efficacy and PMBCL in the relapsed setting. And pembrolizumab is FDA approved for children and adults with relapsed PMBCL after two or more lines of therapy. However, these agents have not been evaluated in the upfront setting.

In this trial, the treating physician will choose between R-CHOP and dose-adjusted EPOCH-R as the chemotherapy backbone. And patients will then be randomized to standard of care with six cycles of chemo immunotherapy alone or six cycles of nivolumab plus chemo immunotherapy. We are optimistic that this will define the role for checkpoint inhibition in the upfront management of PMBCL and work towards improved outcomes for both adult and pediatric patients.

This concludes this JCO podcast. Thank you for listening.

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SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care, and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. For more original research, editorials, and review articles, please visit us online at jco.org. This production is copyrighted to the American Society of Clinical Oncology. Thank you for listening.

This podcast discusses the study, steroid dose reduction, practice experience, and guidance changes.

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ROBIN ZON: This JCO podcast provides observations and commentary on the JCO article-- "Do Steroids Matter: A Retrospective Review of Pre-Medication for Taxane Chemotherapy and Hypersensitivity Reactions," by Lansinger et al.

My name is Dr. Robin Zon. And I am the quality oncology practice initiative lead physician for Michiana Hematology Oncology, an independent community oncology practice located in Mishawaka, Indiana. My oncologic specialty is general medical oncology. And I have a strong interest in breast cancer.

This article is based on the premise that there exists significant variation regarding the prescribing practices of steroids for pre-medication to minimize the known hypersensitivity reactions associated with the taxanes paclitaxel and docetaxel. In fact, the authors remind the reader that initial clinical development of paclitaxel was delayed due to the notable hypersensitivity rate of 25% to 30%, as patients did not receive pre-medication. Subsequent trials used a pre-medication strategy of dexamethasone, diphenhydramine, and H2 antagonist, with a reduction of the reaction occurrence to 2% to 3%. As a result of the improved reaction rates in clinical trials with the use of a pre-medication regimen, both paclitaxel and docetaxel, FDA approved package inserts recommend oral corticosteroid pre-medication, 20 milligrams, 12 and 6 hours prior to the taxane administration.

However, there has been no dose optimization to date. In fact, the authors note that lower dose regimens are routinely used in daily practice and may lead to increased risk of hypersensitivity reactions. Furthermore, steroids can cause multiple adverse effects if taken for extended periods of time, which can range from mild to moderate in their severity.

This study reviewed steroid prescribing patterns in patients receiving the first dose of paclitaxel or docetaxel at Stanford Cancer Institute between 2010 and 2020. A total of 3,181 patients met criteria for analysis, with an 8.3% rate of hypersensitivity reactions. And the adjusted multivariate analysis, the authors found no correlation between the hypersensitivity reaction rate or the severity among the variables evaluated, except for the gynecology/oncology clinic patients who had an increased risk for hypersensitivity reactions overall with a hazard ratio of 1.34 and high grade hypersensitivity reactions with a hazard ratio of 2.34, and female patients who had a higher rate of hypersensitivity reactions overall with a hazard ratio of 1.26, but not high grade hypersensitivity reactions.

The conclusion of the article is that neither dexamethasone dose nor route, IV or oral, correlated with subsequent hypersensitivity reactions. And that the recommended 40 milligrams dose of dexamethasone prior to taxane administration is no better than the 10 milligrams dose for protecting against hypersensitivity reactions. Therefore, the lower doses used in clinical practice is acceptable and even preferable to higher doses.

Although the study authors point out that the strength of the study is the large data set reviewed, they also point out that this study was a retrospective analysis completed on first dose dexamethasone use and not on subsequent taxane exposures Additionally, the authors also point out that since there was no external validity, the results may not be generalizable to other patient populations treated at other institutions. For the remainder of this podcast, the commentary represents my opinion only and may not represent the opinion of this journal or its editors.

First, I would like to commend the authors on this analysis, which addresses a very practical question-- do steroids matter. And is it possible to safely vary from the package insert? The work dedicated to collecting this data set does not go unnoticed.

As the authors acknowledge, the prescribing practice patterns for steroid pre-medication does vary considerably across and within practices. Furthermore, the common references that practices use for treatment guidance, including NCCN and UpToDate, describe differing options.

For example, the NCCN order template for weekly paclitaxel refers to using pre-medication of H2 blocker plus diphenhydramine and dexamethasone 10 milligrams IV with weekly doses, one to three, then may consider dose reduction of dexamethasone to 4 milligrams with weekly dose 4, and does not elaborate on further dose reduction. For Q2 or three-week paclitaxel dosing, the NCCN template follows the package insert. UpToDate also recommends 20 milligrams of dexamethasone orally 12 and 6 hours prior to drug administration with H1 and H2 receptor antagonists as a pre-medication regimen for Q2 or three-week treatment.

However, for weekly paclitaxel, UpToDate offers consideration of a dexamethasone dose of 10 milligrams IV with H1 and H2 blockers, then tapering the glucocorticoid by 2 milligrams decrements after weekly dose 3 or 4, and can even discontinue the dexamethasone in patients without infusion reactions.

For docetaxel, UpToDate suggests dexamethasone 8 milligrams orally BID for three days. To further confirm the practical world of dexamethasone pre-medication variability, in a straw poll within our practice and outside our practice, many providers do utilize the 10 milligrams dexamethasone dose for the first dose of Q2 or three-week taxanes, and reduce and then eliminate dexamethasone for weekly taxanes when feasible and have done so for many years, while other providers strictly follow FDA labeling.

Importantly the reason providers are willing to de-escalate the pre-treatment medications for taxanes is that patients have less side effects and are grateful to have this drug reduced or even eliminated from their treatment. So the question asked and the knowledge generated by the study becomes extremely relevant as providers consider ways to de-escalate interventions, especially if patient outcomes are not placed at risk and quality of life can be improved.

The next question relates to the authors' concern of lacking external validity and generalizability to other patient populations. In my opinion, it would not be feasible to conduct this labor-intensive data set collection and analysis at a multitude of independent community and academic sites. However, this could be an opportunity to query real world data platforms, such as ASCO's CancerLinQ, to look for steroid complications such as grade 3 and grade 4 events related to change in pre-medication strategies. But even real world databases may have limits based on the specificity of the query and the inadequate capture of adverse events, especially less severe toxicities, as this structure data may not be recorded in the electronic medical record.

Finally, the most relevant question is whether practice and guidelines should change as a result of this data. As I have discussed, many practices have already made this initial dose modification, and even safely dose reduced beyond the scope of this data set inquiry. Therefore, I do think that initial dosing as suggested by this study should be more widely guideline adopted and that consideration for further reduction with additional taxane doses be based on practice-specific experience and guidelines.

This concludes this JCO podcast. Thank you for listening.

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SPEAKER: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

For more original research, editorials, and review articles, please visit us online at jco.org. This production is copyrighted to the American Society of Clinical Oncology. Thank you for listening.

Improving care in vulvar cancer via the prospective Vulvar GROINSS VII study

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "Radiotherapy Versus Inguinofemoral Lymphadenectomy as Treatment for Vulvar Cancer Patients with Micrometastases in the Sentinel Node: Results of GROINSS-V II" by Oonk et al. My name is David Gaffney, and I am a professor and Vice Chair of Radiation Oncology at the University of Utah. I am also Senior Director for Clinical Research at the Huntsman Cancer Institute in Salt Lake City, Utah. My oncologic specialty is radiation oncology. I have no relevant disclosures to this study.

The GROINS VII study is the successor trial of the GROINS V I trial. In the GROINSS-V I study, the authors demonstrated that omission of an inguinal femoral lymphadenectomy was safe in patients with a negative sentinel lymph node with an isolated GROIN recurrence rate of 2.3%. It also showed that with long term follow up a significant proportion of patients will recur. At 10 years local recurrence occurred in 39.5% of all patients. Although local recurrences are treated with curative intent, the disease-specific survival of these patients decreases significantly. It is important to ask if there is a dose response to radiotherapy in vulvar cancer?  GOG 101 was published in 1998 and employed a split course of radiotherapy to a dose of 47.6 Gy with concurrent cisplatin and 5-FU. The complete response rate was 46.5%. The subsequent prospective phase II randomized trial, GOG 205, was published in 2012 and employed 10 Gy more of radiotherapy with weekly cisplatin to a total dose of 57.6 Gy. This study demonstrated a 78% pathologic complete response rate. Hence, by adding 10 Gy, the complete response rate increased by 30%, indicating a steep dose response. Also, by way of background, a retrospective study from MD Anderson by Stecklein et al. published in 2018 demonstrated a 3-year actuarial groin control rate of 83% with high dose conformal radiotherapy with a median dose of 66 Gy to grossly positive nodes. These data demonstrate that radiotherapy can sterilize gross disease in select circumstances.

The GROINSS-V II study was a phase II prospective study in a rare disease, and sought to answer whether radiotherapy to 50 Gy could be an effective and less morbid alternative to inguinofemoral lymphadenctomy   Patients were accrued from 59 hospitals in 11 countries. Eligibility for this study were patients with tumors less than 4 cm, with  negative groin nodes on preoperative CT, MRI, or ultrasound. The primary endpoint was a groin recurrence rate at 24 months. A combined technique was used to evaluate the sentinel lymph node of lymphoscintigram and blue dye. Bilateral sentinel lymph node procedures were required for midline lesions. The radiotherapy was 50 Gy in 25-28 fractions with the field size to extend to the bottom of the SI joints, including the distal external iliac lymph nodes. Greater than 1700 patients were registered. One hundred sixty patients were found to have micrometastases, that is disease less than 2 mm, whereas 162 patients were found to have macrometastases. The median size vulvar lesion for patients with negative sentinel lymph node was 18 mm, 23 mm for patients with micrometastases, and 25 mm for patients with macrometastases.

Results at 2 years demonstrated an isolated groin recurrence rate occurred in 1.6% of patients that were treated per protocol with micrometastases. Whereas patients with macrometastases had an isolated groin recurrence rate at 2 years of 12.2%. For patients with macrometastases treated with radiotherapy, the groin recurrence rate was 22%. Whereas groin failure was 6.9% for patients who had macrometastases treated with inguinal femoral lymphadenectomy and radiotherapy. For patients with macrometastases, no groin recurrences were observed in 7 patients treated with chemoradiotherapy. Among the 1213 patients with a negative sentinel lymph node, an isolated groin recurrence occurred in 31 patients for a rate of 2.7% at 2 years. For the 56 patients who suffered a groin recurrence, 31 of them died of vulvar cancer for an overall survival rate of 39% at 2 years.

This trial also looked at morbidity of patients treated with inguinal femoral lymphadenectomy versus sentinel lymph node procedure plus radiotherapy. The lower extremity edema rate was 32% at 6 months versus half of that for patients treated with the sentinel lymph node procedure plus radiotherapy. It should be noted that IMRT was utilized in 19% of cases, and chemotherapy was utilized in 12% of cases.

This trial clearly demonstrated that in patients with a macrometastasis or disease greater than 2 mm within a groin node, radiotherapy is not a safe alternative to inguinal femoral lymphadenectomy due to a higher rate of groin recurrence, albeit there was no difference in disease-specific survival.

Management of patients with vulvar cancer is complex. Clinicians need to control the ipsilateral and the contralateral groin. The GROINSS-V II study gives us data on contralateral groin failures also. Overall, there was a very low rate of contralateral groin failure.

The subsequent study GROINSS-V III will evaluate patients with macrometastases and compare inguinal femoral lymphadenectomy versus chemoradiotherapy with weekly cisplatin and an elevated dose of radiotherapy to the groin with 56 Gy utilizing a simultaneous integrated boost technique. It will be quite interesting in years to come to discern if IMRT with more precise daily imaging and dose escalation together with chemotherapy will improve local regional control. Additionally, there may be select populations of node positive patients where intensification of chemotherapy, radiotherapy, or more extensive surgery may be useful. McAlpine and colleagues have demonstrated that cases of HPV-negative vulvar cancers had a markedly inferior survival rate with a hazard ratio of 0.35. It is also hoped that advance radiotherapy techniques such as IMRT will decrease longstanding morbidity such as lymphedema. The GOG prospective study 244 demonstrated no increase in lymphedema in gynecologic cancer patients where radiotherapy was added compared to surgery alone.

The study by Oonk et al. is a remarkable effort in a rare disease demonstrating that patients with micromets can be safely treated with 50 Gy and patients with macromets should be treated with an inguinal femoral lymphadenectomy. It will be very interesting to see if chemoradiotherapy with increased dose can improve local-regional control and provide a high quality of life for patients with macro mets in the GROINS VIII trial.

 This concludes this JCO Podcast. Thank you for listening.