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."

If you enjoy our show, please leave us a rating and review and be sure to come back for another episode. You can f ind 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.

 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.

[MUSIC PLAYING]

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

[MUSIC PLAYING]

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

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

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

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

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

RESHMA JAGSI: Thanks for having me.

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

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

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

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

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

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

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

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

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

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

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

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

ABBY ROSENBERG: No, you go.

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

[LAUGHTER]

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

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

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

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

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

[LAUGHTER]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Also, I've heard this before, but when I was reading the paper about the children that 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.

[MUSIC PLAYING]

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

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

[MUSIC PLAYING]

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

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

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

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

JENNIFER GRIGGS: Thank you.

KIRSTEN BEYER: Thank you very much.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

JENNIFER GRIGGS: Thank you so much.

KIRSTEN BEYER: Yeah, thank you very much.

[MUSIC PLAYING]

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

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

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

TRANSCRIPT

[MUSIC PLAYING]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

This concludes this JCO podcast. Thank you for listening.

[MUSIC PLAYING]

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

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

TRANSCRIPT

[MUSIC PLAYING]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

This concludes this JCO podcast. Thank you for listening.

[MUSIC PLAYING]

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

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

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.

Dr. Lindsay Morton of the National Cancer Institute at the National Institutes of Health reflects on research findings by Øvlisen et al that leverage large-scale linked registries in Denmark to suggest that improvements in both chemotherapy treatments and assisted reproductive technologies have made it possible for more survivors of Hodgkin lymphoma to become parents.

TRANSCRIPT

This JCO podcast provides observations and commentary on the JCO article "Rates and Use of Assisted Reproduction Techniques in Younger Hodgkin Lymphoma Survivors: A Danish Population-Based Study of 793 Patients and 3965 Matched Comparators" by Øvlisen and colleagues. My name is Lindsay Morton, and I am a Senior Investigator and Deputy Chief of the Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, at the Intramural Research Program of the National Cancer Institute at the National Institutes of Health. I am trained in epidemiology, and my oncologic specialty is in hematologic malignancies and cancer survivorship research. I have no relevant conflicts to disclose.

The adverse effects of treatment among patients with Hodgkin lymphoma have long been at the forefront of oncology research. In the late 1960s, patients with Hodgkin lymphoma were some of the first to receive combination chemotherapy with a four-drug regimen called "MOPP," consisting of mechlorethamine, vincristine, procarbazine, and prednisone. MOPP resulted in dramatic improvements in patient outcomes following diagnosis with Hodgkin lymphoma. But in subsequent decades, the toxicities of MOPP came to be understood, including both acute toxicities – most notably myelosuppression – as well as longer-term toxicities such as second cancers and sterility, especially in males. Around the same timeframe, long-term toxicities of radiotherapy also were increasingly recognized, which set off a search for effective Hodgkin lymphoma treatment approaches with fewer short- and long-term toxicities. I often think of how research on adverse effects in patients with Hodgkin lymphoma has been at the vanguard in cancer survivorship: this focus has helped to drive development of new therapies and changes in clinical practice. This has occurred in part because Hodgkin lymphoma is frequently diagnosed in early adulthood and patients now have such a good prognosis; this means there is a longer window in which to experience any long-term effects of cancer treatments, and patients face unique issues, such as impacts on fertility, which aren't relevant for older cancer patients.

In the paper accompanying this podcast, Øvlisen and colleagues present novel data on parenthood rates and use of assisted reproduction techniques in Danish patients with Hodgkin lymphoma. Importantly, the results of this study are very relevant to current patients because all the patients in the study were treated between 2000 and 2015 using standard treatment approaches that are still frequently used today. About one-third of the study population received radiotherapy plus 2-4 cycles of the combination chemotherapy regimen called "ABVD," which consists of doxorubicin, bleomycin, vinblastine, and dacarbazine, and is the preferred front-line therapy approach for Hodgkin lymphoma patients in the United States. Another third of the study population received 6-8 cycles of ABVD, while in the remaining third, about half received either "BEACOPP" (a seven-drug regimen, which includes bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, and which is commonly used in Europe) or some other chemotherapy regimen.

In this study, the authors compared the rates of parenthood in patients with Hodgkin lymphoma to individuals in the general population who were matched to the patients by age, sex, and parenthood status. Overall, the news was good: both male and female survivors of Hodgkin lymphoma had similar parenthood rates as the matched individuals from the general population. But the details of this bigger picture finding are really worth understanding because of their important impact on patients. In particular, a larger number of patients with Hodgkin lymphoma than the comparison individuals from the general population used assisted reproductive technology in order to become parents. Specifically, nearly 22% of male and 14% of female survivors of Hodgkin lymphoma used assisted reproductive technology compared with only about 6% of those in the general population. When the authors looked at various predictors of parenthood in subgroup analyses, one other finding stood out: male survivors of Hodgkin lymphoma who had received BEACOPP therapy had about half the rate of parenthood compared with other Hodgkin lymphoma survivors and the general population. In contrast, for female survivors, parenthood rates were similar among the different treatment groups, but the numbers of female survivors treated with BEACOPP was small, so we should be cautious about drawing conclusions for females.

The results from Øvlisen and colleagues seem to reflect two important changes from previous studies, most of which included patients who were treated with older chemotherapy regimens, like MOPP. First, Hodgkin lymphoma treatments have continued to evolve, and adverse effects on fertility seem to be declining for the newer regimens. Second, of course, there also have been important advances in assisted reproductive technology, so that individuals who have trouble with conception initially can be helped by these technological advances.

In addition to hearing this good news for patients with Hodgkin lymphoma, the way the authors collected the information for this study was also exciting because it was large-scale, long-term, and systematic. Most of the data on fertility in patients with Hodgkin lymphoma previously has come from clinical trials. Those data have been invaluable, and in fact, provided some of the first signs several decades ago that patients with Hodgkin lymphoma treated with MOPP could face fertility issues. But we also know that clinical trials often have incomplete information on outcomes that occur more than a few years out, which raises some questions about the validity or generalizability of the study results for those outcomes.

In this report, the authors collected information on patients with Hodgkin lymphoma and the matched individuals from the general population from nationwide birth and patient registries. In countries like the United States, this study design would be virtually impossible because our healthcare system is fragmented – patients receive different types of care, like their cancer treatment and fertility treatments, in different places, and there is no easy way to link information on these different types of care for a specific individual. In this Danish study, the authors were able to leverage the centralized nature of the healthcare system in Denmark to capture not only all the information on the Hodgkin lymphoma treatments but also the birth registries and use of assisted reproductive techniques – connecting this information from different sources for all the individuals in the study. Because of the linkages that are possible among all these different sources of data, we are confident that the study provides complete, unbiased information even on longer-term outcomes.

While this study demonstrates both the importance of long-term patient follow-up and the power of registries, it also highlights the need to continue efforts to reduce toxicities and improve outcomes in patients with Hodgkin lymphoma, particularly those diagnosed in childhood, adolescence, or young adulthood. Fertility is just one aspect of quality of life that may be impacted by cancer treatment, and the more high-quality data we bring to bear on cancer survivorship, the better we will be at not just treating cancer but also taking care of the whole patient for the many years they have ahead of them.

This concludes this JCO Podcast. Thank you for listening.

This podcast describes the findings from a population-based retrospective decedent cohort study which suggest that palliative care involvement may be associated with a decreased need for high intensity of care during the final weeks of life in adolescents and young adults with cancer.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "Impact of Palliative Care Involvement on End-of-Life Care Patterns Among Adolescents and Young Adults with Cancer: A Population-Based Cohort Study" by Kassam et al. My name is Erica Kaye, and I am Director of the Quality of Life and Palliative Care Research Division at St. Jude Children's Research Hospital in Memphis, Tennessee, USA. My oncologic specialty is pediatric palliative oncology.

In this paper, the authors aim to evaluate the prevalence and predictors of high-intensity end-of-life care in adolescents and young adults with cancer in Ontario, Canada, as well as assess the impact of palliative care involvement on intensity of care received at end of life. This topic is timely and important. Growing evidence demonstrates that adolescents and young adults with cancer, defined by the National Cancer Institute as patients diagnosed between the ages of 15 and 39, face a unique set of circumstances that may adversely impact their end-of-life experiences. Several single-institution studies in the U.S. have suggested that adolescents and young adults with advanced cancer disproportionately receive high intensity medical care in their final month of life compared to children or older adults, and these findings recently have been replicated in population-level studies in California and New York. These observations raise concerns about exposure of a vulnerable population to toxicity from high intensity care at a time when such interventions are less likely to offer meaningful benefit. However, these studies had several notable limitations: some involved only insured patients; others presented data only from inpatient end-of-life care; and none evaluated the impact of palliative care provision on the intensity of end-of-life care for adolescents and young adults with cancer. Moreover, findings from U.S.-centric data sets may not be generalizable to other countries.

In this study, the authors assembled a retrospective decedent cohort of adolescents and young adults with cancer who died between 2000 and 2017 in Ontario, Canada using a provincial registry linked to population-based health-care data. Predicated on previously published validated metrics, they used a primary composite measure for high-intensity end-of-life care that included receipt of intravenous chemotherapy less than 14 days from death; more than one emergency department visit; and more than one hospitalization or intensive care unit admission less than 30 days from death. Secondary outcomes included measures of the most intensive end-of-life care, such as intensive care unit admission within 30 days of death, mechanical ventilation within 14 days of death, and death in the ICU, as well as palliative care physician involvement. Predictors of outcomes were determined using regression models.

In a cohort of more than 7,000 adolescents and young adults with cancer across Ontario, authors found that approximately 44% experienced high-intensity end-of-life care – double the rate for adults and slightly higher than the rate for children in the region. This percentage is lower than that seen in single-site and population-level studies in the U.S., however lack of consistently defined high-intensity end-of-life indicators for adolescents and young adults with cancer make it challenging to compare findings across studies.

Importantly, adolescents and young adults with hematologic malignancies were at highest risk for receipt of high-intensity care at the end of life in Ontario, affirming findings seen across pediatric and adult populations in different countries. Some hypothesize that unique pathologies specific to hematologic malignancies may increase the risk of experiencing higher intensity end-of-life care. For example, a patient with refractory leukemia often requires frequent blood transfusions to prolong life and optimize quality time; this can be challenging to coordinate in the outpatient setting and may necessitate inpatient hospitalizations at the end of life. In both the U.S. and Canada, continuation of transfusion support often precludes hospice enrollment, further preventing patients from receipt of subspecialty palliative care in the home. In this context, legislation to support concurrent provision of palliative and hospice care with cancer-directed therapy may have the potential to mitigate high-intensity end-of-life experiences for this vulnerable patient population.

This study also found that palliative care physician involvement substantially reduced the odds of adolescents and young adults with cancer receiving high-intensity end-of-life care, including the most intensive experiences such as mechanical ventilation and dying in the intensive care unit. Palliative care physicians may lessen intensity of end-of-life care by promoting conversations about goals of care and advance care planning, coordinating complex medical care in the community, and providing real-time symptom management to decrease emergency visits or hospitalizations. However, further research is needed to explore these hypotheses. Ultimately, this study provides compelling evidence that palliative care involvement may lessen the risk of high-intensity end-of-life care in adolescents and adults with cancer. Unfortunately, universal access to subspecialty palliative care remains challenging, particularly in rural regions. Disparities in access to hospice and palliative care services for racialized communities remain deeply problematic as well. This study supports the need for institutional and regional programs and policies to provide equitable access to palliative care for adolescents and adults with cancer.

Strengths of this study include its population-level design, large health services dataset, and use of relatively standardized indicators for defining high-intensity end-of-life care. Study limitations include its retrospective design, which inherently precludes causal inference. Additionally, involvement of a palliative care physician was used as a proxy for integration of subspecialty palliative care; however, subspecialty palliative care is an interdisciplinary field in which care may be provided by non-physicians, and the study did not account for this phenomenon.

Lastly, the study is predicated on certain assumptions about the negative ramifications of high-intensity end-of-life care. Notably, certain experiences categorized as high-intensity care, such as more than one hospitalization during the final month of life, may not be experienced as high-intensity or burdensome by patients or families. An adolescent patient may wish to be hospitalized on multiple occasions to optimize comfort at the end of life. Or a family may request hospitalization for respite, or to protect siblings from seeing suffering at end of life. Although technically high-intensity, these interventions also may represent goal-concordant comfort care, and further research is needed to determine best practices for optimizing care that aligns with the goals of adolescents and young adults at end of life.

This concludes this JCO Podcast. Thank you for listening.

Minimal residual disease positivity is predictive of disease progression in patients with large B-cell lymphoma treated with anti-CD19 CAR T-cells.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article 'Monitoring of Circulating Tumor DNA Improves Early Relapse Detection After Axicabtagene Ciloleucel in Large B-Cell Lymphoma: Results of a Prospective Multi-Institutional Trial' by Frank et al. My name is Patrick Reagan, and I am an Assistant Professor of Medicine at the Wilmot Cancer Institute, University of Rochester in Rochester, NY. My oncologic specialties are lymphoma and cellular therapy. I would like to disclose consultancy for Kite Pharma.

Frank and colleagues present data from a prospective, multicenter trial examining serial testing of circulating tumor DNA in 72 patients with large B-cell lymphoma who received treatment with the anti-CD19 CAR T-cell, axicabtagene ciloleucel, abbreviated as axi-cel. These patients had circulating tumor DNA monitored in plasma prior to lymphodepletion chemotherapy, as well as at multiple times following axi-cel infusion. Ninety-six percent of patients had adequate DNA to identify a clonotype to track over time at study enrollment, and 60 patients had an adequate sample for analysis at day 28 after axi-cel infusion.

There are several key findings in this study. The first key finding is that circulating tumor DNA may serve as a surrogate for tumor burden. A lower level of circulating tumor DNA was associated with both improved disease and toxicity outcomes. Patients who had a lower baseline circulating tumor DNA had improved progression-free and overall survival, as well as less severe cytokine release syndrome and immune effector cell associated neurotoxicity syndrome. 

A second key finding of this study is that circulating tumor DNA can serve as a marker for minimal residual disease in large B-cell lymphoma patients treated with CAR T-cells, and can be predictive of disease relapse. Seventy percent of patients who had durable response were negative for circulating tumor DNA one week following CAR T infusion. All patients with disease progression had at least one sample that was positive for minimal residual disease, and all but one were positive for minimal residual disease concurrently with radiographic progression. At day 28-post CAR T-cell treatment, negativity for minimal residual disease by circulating tumor DNA was strongly associated with improved progression-free and overall survival.  

A third key finding in this study was that positivity for minimal residual disease was highly predictive in patients who have a partial response or stable disease at day 28-post CAR T-cell treatment. Deepening of response over time has been reported with various CAR T-cell treatments suggesting that there are limitations of PET CT to assess response, particularly at early time points. In the patients who had stable disease or partial response who were positive for minimal residual disease at day 28 following axi-cel, 15 of 17 patients had a progression-free survival event, while only two of ten who were negative for minimal residual disease had a progression-free survival event.

This study has multiple implications for future clinical research, which may influence routine clinical care over time. High tumor burden defined by the sum of product diameters or metabolic tumor volume has been associated with both treatment failure and excess toxicity with axi-cel, as well as tisagenlecleucel. As a potential surrogate for tumor burden, baseline circulating tumor DNA could be useful in determining high-risk groups to target for clinical trial participation. Additionally, this could be a stratification factor for randomized studies involving CAR T-cells. Additional studies with axi-cel as well as tisagenlecleucel and lisocabtagene maraleucel, which are also commercially available for large B-cell lymphoma, are important to confirm this observation.

Management of patients who initially achieve a partial response or have stable disease at the first disease assessment is a common clinical problem in patients with large B-cell lymphoma treated with CAR T-cells. A proportion of patients with large B-cell lymphoma who initially have partial response or stable disease will go on to develop a complete response over time. This has been reported in all of the commercially available anti-CD19 CAR T-cell products. In the ZUMA-1, JULIET and TRANSCEND trials, approximately one third to one half of patients who initially had partial response or stable disease went on to achieve a complete response. Patients who ultimately have progressive disease have poor outcomes with a median overall survival of 180 days. Those who have stable or progressive disease as best response have a medial overall survival of only approximately 50 days. Predicting which patients are at risk to relapse is important given the small window of time to intervene. It would also potentially spare low risk patients from additional therapy, which may be difficult to tolerate given the acute toxicity of CAR T-cell therapy, as well as the prolonged hematologic toxicity seen in some patients.

Disease progression following anti-CD19 CAR T-cell therapy is a pressing clinical problem in patients with large B-cell lymphoma and there is a need for clinical trials. Clinical trials should be considered in all patients who relapse following CAR T cell therapy. Early detection of relapse can help to facilitate enrollment prior to the development of complications related to progressive disease that may preclude their enrollment. There are now multiple clinically active, targeted therapeutics in large B-cell lymphoma, and a trial of maintenance or consolidative therapy could be considered in this population. This could target only the highest risk patients by using positivity for minimal residual disease as assessed by circulating tumor DNA as a criterion for inclusion. Alternatively, this could focus more broadly on the patients with stable disease or partial response, but given these results, outcomes by circulating tumor DNA status would be important secondary endpoints. Either way, circulating tumor DNA would be critical to the study design and interpretation of results.

This concludes this JCO Podcast. Thank you for listening. 

JCO fellow Dr. Ece Cali speaks with JCO Associate Editor Dr. Thomas E. Stinchcombe to discuss the JCO article "Phase 2 Dose-Randomized Study of Sunvozertinib in Platinum-Pretreated Non-Small-Cell Lung Cancer with Epidermal Growth Factor Receptor Exon 20 Insertion Mutations (WU-KONG1B)", that was simultaneously released at the IASLC 2025 World Conference on Lung Cancer.

TRANSCRIPT

Dr. Ece Cali: Hello, and welcome to our series where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's most important oncology meetings. I am your host, Dr. Ece Cali, JCO editorial fellow, and I am joined by Dr. Tom Stinchcombe, JCO associate editor, to discuss the Journal of Clinical Oncology article and 2025 World Conference on Lung Cancer abstract presentation, "Phase II Dose-Randomized Study of Sunvozertinib in Platinum-Pretreated Non–Small Cell Lung Cancer With EGFR Exon 20 Insertion Mutations."

The WU-KONG1B trial is a multinational, phase II study that investigated the efficacy and safety of different doses of sunvozertinib in patients with metastatic non-small cell lung cancer and EGFR exon 20 insertion mutations after progression on platinum based chemotherapy. Tom, before we dive into the results, could you walk us through the rationale for this study, and how does it fit into the current treatment options for patients with EGFR exon 20 insertion?

Dr. Tom Stinchcombe: Thank you, Dr. Cali. I think the clinical context is always important. We have known that EGFR exon 20 insertions exist and that they are resistant to our currently available EGFR tyrosine kinase inhibitors, and I think there have been attempts in the past to develop a tyrosine kinase inhibitor, but there is a very narrow therapeutic window between the dose you need to inhibit the EGFR mutation in the cancer and the EGFR receptor on normal tissues, most notably the mucosa, the gut, and the skin. And so, our previous attempts have failed largely because the dose required was not tolerable for patients and they could not really stay on the drug for a long time or they were not very active.

And so, I think there was a real desire to develop an EGFR tyrosine kinase inhibitor, and then, historically, the standard had been a platinum based doublet as the standard of care. And more recently, platinum based doublet with amivantamab has proven to be superior to platinum based chemotherapy alone. I think the context is also important that amivantamab is not necessarily available in all the countries, and so, there are patients who do not have access to amivantamab. Going to the rationale, I think that this drug had shown preliminary promise of having activity but without that being encumbered by those EGFR wild type toxicities, and, therefore, it was really explored in this larger study.

Dr. Ece Cali: And what are some key findings from this trial?

Dr. Tom Stinchcombe: So, I think that we should look at the study design. It is a little quirky, for lack of a better term, in that there is a randomization to 200 versus 300 mg, and then, there was a nonrandomized cohort of 300 mg. So, when you look at the study, if you are a purist, you will just look at the randomized patients. If you are sort of an aggregator, you look at all patients. So, it shows reporting on three cohorts, but I think the key findings are that the 200 mg and the 300 mg treatments had similar toxicities in terms of response rate, duration of response, and progression free survival. And as you know going through the review, there was a lot of queries from the reviewers as to which would be the preferred dose, and to me, I think this really illustrates a dose finding component to a trial design because there is a lot of debate about what the minimal effective dose is or the optimal dose. And in this case, having the two dose cohorts did provide us some valuable efficacy and toxicity information. And then, when I look at the study, I want to make sure it reflects my patient population, and about a quarter of patients had brain metastases, and about 15% had previous amivantamab, and about 5% to 10% had another EGFR tyrosine kinase inhibitor.

Dr. Ece Cali: And what is the objective response rate and the duration of response? These are pretty good numbers for this patient population.

Dr. Tom Stinchcombe: In the 200 mg cohort, it was about 46%. The duration of response was around 11 months, and the PFS was around 8 months. The 300 mg cohort was 46%, duration of response 9.8, and the median PFS is 6.9 months, and I think that this is greater activity than we have seen with our previous attempts at EGFR tyrosine kinase inhibitors.

Dr. Ece Cali: And based on these data, FDA granted accelerated approval for sunvozertinib very recently at 200 mg once daily dosing in this setting. So, that is a major step forward for our patients. Dr. Stinchcombe, how does this impact your clinical practice, and what side effects should oncologists be watching for if they prescribe this medication?

Dr. Tom Stinchcombe: So, I think it was very interesting that they chose the 200 mg dose, which I think was more tolerable, and when we kind of look at this, there still was a rate of diarrhea, all grade, rash, paronychia, which are the EGFR related toxicities. There can be some decreased appetite, stomatitis, and then, it can lead to some lab abnormalities, like increased CPK and creatinine that physicians have to be aware of.

You know, how it will affect my practice is that all these patients had received a platinum based chemotherapy as the first line therapy. I think that this would become my preferred second line therapy for patients outside the context of a trial because of the activity and the tolerability.

Dr. Ece Cali: And lastly, several other tyrosine kinase inhibitors are being evaluated for EGFR exon 20 insertion, including in the frontline setting. So, what are some of the outstanding questions in this space, and what data should our listeners keep an eye on moving forward?

Dr. Tom Stinchcombe: I think you are right that now, there is going to be another EGFR tyrosine kinase that may become available in the next year, and there is another drug, furmonertinib, that is being investigated.

I think, for the clinical question, is, well, can we move these into the first line setting? And actually, the development path has two ways of doing this. There is EGFR tyrosine kinase compared to platinum based chemotherapy, and then, platinum based chemotherapy with an EGFR tyrosine kinase versus platinum based chemotherapy, and both have their merits and strengths. And so, I think it is going to be very interesting as we see if those first line trials, one, can they be demonstrated to be superior to platinum based chemotherapy, and then by what magnitude and what the side effects are. But I think we are hoping that in the next couple of years, we will have an additional first line option for our patients.

Dr. Ece Cali: Yeah, it is always great to have more options for our patients.

Thank you, Dr. Stinchcombe, for speaking about the JCO article, "Phase II Dose-Randomized Study of Sunvozertinib in Platinum-Pretreated Non-Small Cell Lung Cancer With EGFR Exon 20 Insertion Mutations."

Join us again for the latest JCO simultaneous publications. Please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of World Lung Conference.

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.

Venetoclax in combination with FLAG-IDA chemotherapy shows safety and promising efficacy in both untreated and relapsed/refractory AML in this phase 1b/2 study, providing a strong rationale for phase 3 trials incorporating this agent in patients fit for intensive therapy.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "Venetoclax Combined with FLAG-IDA Induction and Consolidation in Newly Diagnosed and Relapsed/Refractory Acute Myeloid Leukemia" by DiNardo et al. My name is Richard Dillon, and I am a Clinical Senior Lecturer in Cancer Genetics at King's College London and Consultant Hematologist at Guy's Hospital, London, UK. My oncologic specialty is Adult Acute Myeloid Leukaemia. I'd like to note that my institution receives research funding support from Abbvie.

The recently published VIALE-A and VIALE-C trials demonstrated significant efficacy of venetoclax when added to low dose chemotherapy in patients with newly diagnosed AML who cannot receive intensive chemotherapy due to their age or comorbidities. Venetoclax has now become the standard of care for these patients, and there is growing interest in investigating how the potent anti-leukemic efficacy of this agent can be exploited in younger patients, who are fit to receive intensive treatment with curative intent. To date, only a small number of studies have addressed this important question.

In the front-line setting, a phase 1b study performed in Australia by Chua and colleagues tested the addition of 14 days of venetoclax to a regimen consisting of 7 days of infusional cytarabine and two doses of idarubicin for patients aged over 65 with previously untreated AML. This was well tolerated, and the overall response rate was 72%: 97% in patients with de-novo and 43% in patients with secondary AML.

Karol and colleagues from St. Jude's Children's Hospital performed a phase 1 study testing the combination of 28 days of venetoclax with varying doses of cytarabine and idarubicin in children with relapsed or refractory AML. At the recommended phase 2 dose, which was 600mg of venetoclax and eight doses of 1000mg per square meter cytarabine, with or without idarubicin, the overall response rate was 70%. Importantly, for children who received a lower dose of cytarabine (20 doses of 100mg per meter square), the response rate was markedly lower at 33%.

In the study referred to in this podcast, DiNardo and colleagues combined venetoclax with the FLAG-IDA regimen. FLAG-IDA is an intensive chemotherapy schedule incorporating high-dose cytarabine, typically used for patients with refractory or relapsed AML. And in this setting, overall response rates between 50 and 60% have been reported. FLAG-IDA has also been used in patients with newly diagnosed AML—for example, in the UK NCRI AML15 study, where the overall response rate was 86% and 5-year overall survival was 44%.

The current study comprised a phase 1b dose escalation in patients with relapsed or refractory disease, followed by a phase 2 dose expansion in both newly diagnosed and relapsed or refractory patient cohorts. In total, 68 patients were treated with the venetoclax FLAG-IDA combination. As expected, this combination was severely myelosuppressive, and during the dose-escalation phase, a number of alterations were made to the schedule to mitigate this toxicity, including reductions in the cytarabine dose to 1.5g per meter square and the length of venetoclax treatment to two weeks in induction and one week in consolidation. With these modifications, hematological toxicity at the recommended phase 2 dose was manageable. The time to count recovery was 31 days for previously untreated patients and 37 days for patients with relapsed or refractory disease and was not prolonged in patients who had undergone previous allogeneic stem cell transplantation. Haematological toxicity was more severe in the second cycle of treatment with 59% of patients experiencing delayed count recovery beyond day 45. Nevertheless, day 60 mortality was low at 4.4%.

The response rates observed in this study were impressive. At the recommended phase 2 dose, 97% of newly diagnosed and 70% of relapsed or refractory patients had achieved a composite complete remission, which included CR, CRi and CR with partial hematological recovery, CRh. CR or CRi was achieved in 72% and 48%, and MRD negativity by flow cytometry was achieved in 89% and 48% of patients with newly diagnosed and relapsed or refractory disease, respectively.

Although the number of patients was too small to reliably identify molecular and cytogenetic groups with a differential response, patients with relapsed or refractory AML with genotypes previously reported to be particularly sensitive to venetoclax containing regimens, which are NPM1, IDH1 and IDH2, appeared to have a particularly high rate of response with a composite CR rate of 100% and 12-month overall survival rate of 83%. In addition, the 7 patients with MLL rearrangements appeared to do particularly well, with a composite CR rate of 100% and 80% of patients testing negative for MLL fusion transcripts by PCR. One-year overall survival in this group was 80%, possibly highlighting MLL-rearranged leukemias as an additional group with particular sensitivity to BCL2 inhibition. This signal was not apparent in earlier trials using low doses of chemotherapy, perhaps because MLL rearrangements are much less frequent in older adults, or alternatively perhaps because this lesion requires higher doses of chemotherapy to synergise with BCL2 inhibition to overcome the apoptotic threshold.

On the other hand, there appeared to be some groups with less favorable responses. Patients with core-binding factor leukemias appeared to do less well than expected, with a median overall survival time of 7.6 months. Patients with these leukemias were excluded from the earlier phase 2 and 3 studies of venetoclax, so there is no prior clinical data regarding their sensitivity to BCL2 inhibition; however, this finding does concur with in vitro data suggesting a lack of sensitivity.

The outcomes for patients with TP53 mutations were disappointing with a median overall survival time of 9 months for newly diagnosed and 7 months for relapsed patients. Interestingly, even in the four TP53-mutated patients who tested MRD negative by flow cytometry, the TP53 mutation was still detectable by next-generation sequencing after treatment. The number of patients in these groups were small and will require confirmation in larger studies; however, alternative treatment strategies might be required for these patients.

Overall, these results appear extremely promising and suggest that venetoclax may have significant activity when used with intensive induction or salvage chemotherapy schedules in younger adults. This now needs to be confirmed in randomized trials comparing intensive chemotherapy with and without venetoclax in both the front-line and salvage settings. If these trials are positive, further comparative studies will be needed to define the best chemotherapy schedule to combine with venetoclax. While limited data indicate that standard doses of cytarabine are likely inadequate, the optimal dose of cytarabine, and the additional value of fludarabine and anthracyclines remains to be defined. Nevertheless, the study by DiNardo and colleagues represents a significant step forward in the deployment of venetoclax in young fit adults, with the hope that this will increase the rate of long-term cures from this aggressive and frequently fatal hematological malignancy.

This concludes this JCO Podcast. Thank you for listening.

This podcast comments on a large registry study evaluating the effect of ultra-high-resolution HLA typing on outcomes of unrelated donor transplantation.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article 'Impact of Previously Unrecognized HLA Mismatches Using Ultra-High-Resolution Typing in Unrelated Donor Hematopoietic Cell Transplantation" by Mayor et al. My name is Navneet Majhail, and I am the Director of the Blood and Marrow Transplant Program and the Vice-Chair for the Department of Hematology and Medical Oncology at the Taussig Cancer Institute, Cleveland Clinic. My oncologic specialty is transplantation and cellular therapy. 

For patients who are potential candidates for allogeneic hematopoietic cell transplantation, the first critical step is finding an HLA-matched donor. The HLA genes are located within one of the most gene rich regions of the human genome, are highly polymorphic, and encode proteins that critically modulate the body's immune responses against a variety of stimuli. When selecting an unrelated bone marrow or peripheral blood stem cell donor, we typically try to identify donors who are matched at HLA genes where polymorphism is predominantly present, namely, class I genes HLA-A, -B, -C, and class II genes HLA-DRB1, -DQB1 and –DPB1. Guidelines recommend using a donor who is matched at least at HLA-A, -B, -C, and –DRB1, and preferentially at -DPB1 and -DQB1 as well. 

Graft-versus-host disease or GVHD is an immune-mediated complication that continues to be a major threat to successful patient outcomes after hematopoietic cell transplantation. Better matching between the donor and the recipient lowers risk of GVHD, and guidelines recommend use of an HLA 8/8 matched unrelated donor, though in clinical practice we prefer an HLA 10/10 and even a 12/12 matched donor if one is available. In the past, HLA typing methods used 'antigen-level' serological testing. However, with advances in technology, the field has moved on to 'allele-level' or high-resolution typing which can discriminate among HLA genes that encode cell-surface proteins that ultimately constitute the antigen recognition domain, which is the functionally active portion of the HLA molecule that ultimately interacts with T-cell and NK-cell receptors. Research has shown that matching at allele-level is associated with lower risks of GVHD and better survival compared to historical serotyping-based methods, and DNA-based HLA-typing is the current standard of care. 

Further advances in technology to next-generation sequencing or ultra-high-resolution typing can now allow characterization of the full HLA gene sequence. This has raised the question of the clinical significance of HLA polymorphisms in regions outside the antigen recognition domain. Prior studies in smaller cohorts of patients have raised the possibility that transplants using ultra-high-resolution matched donors may be associated with better survival and lower risks of acute GVHD. To definitively validate these findings, Mayor et al conducted a study in a cohort of >5,000 allogeneic transplant recipients from the Center for International Blood and Marrow Transplant Research. Patients had received a matched unrelated donor transplant for acute leukemia or MDS between 2008 and 2017. The manuscript that accompanies this podcast provides details of their study population, but overall their cohort was fairly representative of unrelated bone marrow and peripheral blood stem cell transplant recipients.  

To summarize some key findings of their study, first, among donor-recipient pairs deemed HLA 10/10 match using high-resolution typing, 18% were found to not be a 10/10 match on ultra-high-resolution typing. Overall, only 12% of patients had a 12/12 ultra-high-resolution matched donor. Second, overall survival was comparable between patients receiving 12/12 ultra-high-resolution matched and mismatched transplants. Furthermore, there was no association of survival with the degree of ultra-high-resolution mis-match, that is, the number of loci where there was a mismatch. Similarly, when considering a subgroup of patients who were ultra-high-resolution matched at 10/10 loci, there was no difference in survival between patients who were 12/12 matched, that is, matched at DPB1, and those permissively or non-permissively mis-matched at DPB1. The authors did report an association of ultra-high-resolution matching with acute GVHD for their whole cohort, and associations with GVHD and transplant-related mortality in some subgroups, and I refer you to their JCO manuscript for details.   

There are some caveats to consider in applying their findings to clinical practice, and a good study always leads to more questions. The probability of finding an adult HLA 8/8 high-resolution matched unrelated donor varies from 16% to 75% depending on recipients race and ethnicity – the chances of finding a 10/10 or 12/12 donor who is ultra-high-resolution matched is going to be significantly lower. How do we factor in the role of other known non-HLA unrelated donor selection factors such as donor age, donor sex, CMV status, ABO type, and graft source vis-à-vis ultra-high-resolution matching? Even in this highly selected cohort of patients who were actually able to get a transplant, nearly 90% did not have a 12/12 ultra-high-resolution matched donor – in this setting, how do mismatches at different loci compare with respect to outcomes? Do we change our transplant conditioning and GVHD prophylaxis regimens in ultra-high-resolution mis-matched unrelated donor transplants to reduce the risk of GVHD? Several studies have indicated comparable survival between matched unrelated donor and haploidentical related donor transplants – does the use of an ultra-high-resolution 10/10 or 12/12 HLA matched donor offer any outcome advantage compared to the haploidentical transplantation? Taken together and at this time, their findings are primarily applicable to patients who have the luxury of choosing from several young 10/10 HLA matched unrelated donors. Cost of HLA typing using next-generation sequencing is also a factor that needs to be considered. 

Notwithstanding these 'yet to be answered' questions, there are advantages to ultra-high-resolution typing, and current technology does allow for rapid and unambiguous characterization of HLA genes with a rapid turnaround time. Many HLA labs are already implementing third-generation typing methods, and with increasing use and demand, it is expected to become cheaper and will no longer be cost-prohibitive. 

Overall, with HLA-identical sibling, matched unrelated, haploidentical related, mis-matched unrelated, and umbilical cord blood, nearly all patients who need a transplant have a donor. It is heartening to see that our research has pivoted from "Is there a donor available?" to "What is the best donor?" for a given patient.    

This concludes this JCO podcast. Thank you for listening. 

The PENELOPE-B phase III trial did not show a benefit to the addition of one year of the CDK4/6 inhibitor palbociclib to adjuvant endocrine therapy in patients with hormone receptor-positive/HER2-negative breast cancer and residual disease after neoadjuvant chemotherapy.

TRANSCRIPT

This JCO podcast provides observations and commentary on the JCO article "Palbociclib for Residual High-Risk Invasive Hormone Receptor-positive, HER2 negative Early Breast Cancer – The PENELOPE-B Trial," by Sybille Loibl and colleagues. My name is Erica Mayer, and I am a clinical investigator at the Dana-Farber Cancer Institute in Boston, MA who specializes in breast cancer.

Since the initial approval of the CDK4/6 inhibitor palbociclib in 2015, this class of agents has become a standard part of management for most patients with hormone receptor positive HER2 negative advanced breast cancer. Use of one of the available CDK4/6 inhibitors - palbociclib, abemaciclib, or ribociclib - in combination with endocrine therapy, improves progression-free, and even overall survival, in the advanced disease setting, as shown in the respective trial series PALOMA, MONARCH, or MONALEESA. Although differentiated by their toxicity profiles, with palbociclib and ribociclib contributing more neutropenia and abemaciclib more diarrhea, across-the-board the benefit gained from use of these agents is remarkably preserved between trials, without apparent differential drug activity.

Following the observation of benefit from use of CDK 4/6 inhibitors in the advanced setting, clinical trials evaluating the three available agents were subsequently launched to evaluate these agents in the adjuvant setting, after prior treatment with surgery, chemotherapy, and radiation if necessary. The first two trials to report in 2020, PALLAS and MONARCH-E, enrolled patients with early hormone receptor positive HER2- breast cancer, randomizing them to receive a CDK 4/6 inhibitor, palbociclib or abemaciclib respectively, for a planned 2-year duration, in addition to ongoing adjuvant endocrine therapy, versus ongoing adjuvant endocrine therapy alone. Notably, PALLAS enrolled patients with stage II and III breast cancer, whereas MONARCH-E targeted a high-risk group identified by tumor size, nodes, and Ki67 status. Initial reports from these trials were presented at an interim follow-up of about 20-24 months, a time when many were still receiving the combination therapy. The MONARCH-E analysis demonstrated a benefit from the addition of abemaciclib to endocrine therapy in prolonging invasive disease-free survival. This benefit was not observed with the addition of palbociclib in the PALLAS trial. The ongoing NATALEE trial, offering 3-years of reduced dose ribociclib in a similar setting, continues accrual.

It is within this context that we place the PENELOPE-B trial. This trial enrolled the highest risk patients with early HR+/HER2- breast cancer: those with residual disease after preoperative chemotherapy and a high CPS-EG score, which is a calculation of anatomic stage and tumor biology meant to identify patients at highest risk of cancer recurrence. A total of 1250 patients were randomized to receive either one year of adjuvant palbociclib with ongoing adjuvant endocrine therapy, or placebo with endocrine therapy, and followed for a primary endpoint of invasive disease-free survival.  As expected, the study enrolled a very high-risk population, with many patients having at least T2 disease and 4 involved lymph nodes at time of surgery. At a median follow-up of 43 months, no difference in invasive disease-free survival was observed, with a 4-year iDFS of 73% in the intervention arm, versus 72.4% in the placebo arm. No clinicopathologic subgroup appeared to derive benefit from the research intervention. The toxicity experience was similar to that seen in the metastatic setting, with notable and expected hematologic toxicity, but no significant difference in overall non-hematologic adverse events. Overall, drug exposure was satisfactory, with about 17% of patients unable to complete the planned 1-year duration of therapy.

The PENELOPE-B study makes its mark in the adjuvant CDK4/6 landscape in several important ways. First, PENELOPE-B has the greatest duration of follow-up, allowing analysis of mature data and outcomes during and following adjuvant CDK4/6 inhibition. Although it is tempting to interpret a slight visual divergence of the Kaplan Meyer curves during the palbociclib exposure, where there is an absolute difference in iDFS of 4.3% at 2 years, there is no statistical evidence that the 2-year iDFS estimates are different between the two arms, and therefore no evidence of time-dependent efficacy. Importantly, in regard to experiences within the other CDK4/6 inhibitor trials, which have reported at an earlier time point, longer-term follow-up of those trials will be necessary to determine stability and maturity of the observed results. Additionally, PENELOPE-B is the only placebo-controlled trial presented to date. For that reason, the toxicity data presented represents the purest description of the experience of receiving a CDK4/6 inhibitor in the adjuvant setting in a population with prior chemotherapy exposure. Finally, when discriminating among the CDK4/6 inhibitors study populations, it is important to remember that PENELOPE-B enrolled a population of greatest established risk, suggesting any apparent differential outcome among the trials is unlikely related to differing baseline risk of accrued patients.

Overall, PENELOPE-B represents a significant contribution to the breast cancer field, and substantially adds depth and dimension to the exploration of CDK4/6 inhibitors in the adjuvant setting. At the time of publication, it is unclear if an approved role will emerge for a CDK4/6 inhibitor in adjuvant therapy for our early breast cancer patients. Many questions remain regarding patient/tumor selection, agent differentiation, duration of therapy, and potential biomarkers. Importantly, the correlative analyses planned for all of the CDK4/6 inhibitor trials and molecular exploration of patient samples will substantially improve our understanding of the impact of these drugs in the early setting, and our overall ability to treat this subset of breast cancer. While waiting for these data, we should continue our focus on providing the best possible care for our patients with hormone receptor-positive, HER2-negative breast cancer who are being treated with endocrine therapy.

This concludes this JCO podcast. Thank you for listening.

Current clinical characteristics and demographics are not sufficient to capture aggressive disease in clinical trials of newly diagnosed DLBCL. Novel tools, such as measurement of tumor burden via ctDNA, are needed.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "Short Diagnosis-to-Treatment Interval is Associated with Higher Circulating Tumor DNA Levels in Diffuse Large B-Cell Lymphoma" by Alig et al. My name is Matthew Maurer, and I am a statistician at the Mayo Clinic in Rochester, MN. My oncologic specialty is lymphoid malignancies. I have no relevant conflicts to disclose.

The impact of any clinical research critically depends upon participating subjects being representative of the study population afflicted with the disease of interest and research efficiency is markedly enhanced when cohorts can be compared across studies. In newly diagnosed diffuse large B-cell lymphoma (DLBCL), there is a standard group of clinical variables that is typically captured and reported across studies. The International Prognostic Index, or IPI has been utilized as a prognostic model in aggressive lymphoma for nearly 30 years and remains relevant today. The IPI and its components, which consist of age, performance status, LDH, stage, and number of extranodal sites, provide the clinical characteristic backbone for trial eligibility and defining high risk disease in frontline DLBCL trials. Assessment of genomic features of the tumor using pathological techniques such as IHC and FISH can further identify high risk subsets of patients. However, despite these well-tested clinical tools to measure the aggressiveness of the disease, there remains significant heterogeneity in patient presentation and outcomes.

Clinically, some patients will present with a real or perceived clinical urgency to initiate therapy as soon as possible. This clinical urgency often precludes these patients from enrolling on frontline trials. My colleagues from the University of Iowa / Mayo Clinic Lymphoma SPORE and I explored this phenomenon in our observational lymphoma cohort study by evaluating the time between a patient's diagnostic biopsy and their initiation of chemotherapy.  We found that this simple measure of diagnosis to treatment interval, or DTI, was highly informative in the setting of newly diagnosed DLBCL.  Patients with a shorter DTI were more likely to be symptomatic, have advanced stage disease, poor performance status, and elevated LDH. Further, patients with a short DTI had significantly inferior outcomes, even after accounting for the standard clinical details of the IPI. These results were validated in a cohort of clinical trial patients from the French Lymphoma Study Association as well as subsequent studies. These data suggest that clinicians are managing patients with aggressive disease more urgently, and our current set of clinical variables is not sufficient to describe and compare patients across studies.

Despite its simplicity and retrospective prognostic ability, DTI lacks specificity as a clinical characteristic for future studies. It can be easily influenced in an individual patient by numerous aspects unrelated to disease biology, such as physician preference or a patient's available access to health care resources. In additional, the typical DTI can vary widely across health systems or institutions. In the paper accompanying this podcast, Alig and colleagues examine the relationship between DTI, conventional risk factors, circulating tumor DNA, and clinical outcomes. A strong association was observed between shorter DTI and increasing tumor burden as measured by baseline metabolic tumor volume and circulating tumor DNA. This is a key biologic confirmation that treatment urgency is directly related to disease biology. Importantly, the authors also showed that ctDNA was a highly informative variable in regards to prognosis in their dataset. ctDNA was an independent prognostic variable after adjusting for the IPI in Cox models for event-free and overall survival, and the prognostic ability of ctDNA was far superior to DTI in univariate models.

The association between DTI and disease biology has direct implications for clinical trials in frontline DLBCL. Clinical trials that did not adequately enroll patients in need of urgent therapy were likely biased towards enrollment of patients with lower tumor burden.  In particular, single arm trials of novel therapies are particularly at risk, as these results are often evaluated in light of conventional clinical characteristics and compared to previous studies and/or clinical experience. This may also have contributed to the better than expected outcomes on the control arms in recent randomized trials of newly diagnosed DLBCL. Evaluation of tumor burden using ctDNA or metabolic tumor volume should allow us to better understand the impact of a study's design on patient enrollment.

The amount of tumor is a long-standing prognostic feature for newly diagnosed DLBCL. This has standardly been measured by broad clinical features such as stage, number of extranodal sites, and bulky disease. As the retrospective studies on DTI have shown, however, these features are not sufficient. Novel tumor burden measures like circulating tumor DNA are needed. ctDNA is not without its drawbacks in frontline DLBCL.  It is not clinically available for real-time assessment and significant work remains to be done to make it a routinely available and standardized biomarker, which includes independent validation of the results reported by Alig and colleagues. However, as we continue to develop and test new treatment strategies for DLBCL, we must also develop and test novel prognostic and predictive tools. Alig and colleagues have shown us that ctDNA has the potential to identify features of aggressive disease that our current tools do not. Capturing these features more precisely is vital for us to understand and interpret clinical trial results, as well as ensure future trial designs are enrolling the study's intended patient population. As part of these efforts, clinical trials in newly diagnosed DLBCL should collect and store the necessary biospecimens to evaluate ctDNA in anticipation of a new generation of standard clinical characteristics.

This concludes this JCO Podcast. Thank you for listening.

This podcast considers the impact of exclusion criteria on clinical trials, generalizability, and the complexity of modernizing eligibility while maintaining trial integrity.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "Impact of Organ Function-Based Clinical Trial Eligibility Criteria in Diffuse Large B-cell Lymphoma (DLBCL) Patients. Who Gets Left Behind?" by Khurana et al. My name is Richard Little, and I am at the National Cancer Institute. My oncologic specialty is lymphoid and myeloid malignancies. I am a federal employee with no conflicts of interest to disclose. 

The authors have contributed a timely and provocative analysis examining the lack of generalizability and disappointing results of repeatedly negative randomized phase 3 trials conducted over the past 15 years failing to improve on R-CHOP.  The authors have proposed that these failures may be in part explained by enrollment onto clinical trials patients who are not really representative of those with the disease, because eligibility criteria too often unnecessarily eliminate patients with laboratory values that reflect organ impairment not pertinent to the agents under study.  To test this inference, the authors leveraged a unique resource:  The Molecular Epidemiology Resource of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence, or SPORE. This SPORE is an NCI-funded research project initiated in 2002 and collects data in a uniform manner among consenting participants with newly diagnosed DLBCL who undergo treatment managed by their physician. This rich database enabled the evaluation of data in patients treated with R-CHOP or R-CHOP-like immunochemotherapy.   The investigators were able to categorize the SPORE participants in reference to the eligibility criteria of the important phase 3 studies recently conducted as either meeting eligibility of the phase 3 studies or not meeting eligibility due to out-of-range laboratory values.  Additionally, the SPORE data in some ways mimics clinical trial data in that events such as disease progression and death are captured, and these outcomes could be evaluated comparatively between patients categorized as clinical trial eligible and not eligible.  They indexed 7 trials, and for example, found that 12.9% of the SPORE participants did not meet eligibility for the PHOENIX study—that is the phase 3 trial of ibrutinib-R-CHOP vs placebo-R-CHOP showing no benefit of the addition of ibrutinib. Not surprisingly, those scored as ineligible had worse outcomes compared to those scored as eligible. For example, indexing eligibility for the PHOENIX trial, the overall survival hazard ratio for those scored not eligible versus eligible was 1.49 with a p-value of .002. The median survival of the SPORE cohort scored as ineligible for PHOENIX had a median overall survival of around 80 months, and the median survival for those sored as eligible had not yet been reached. Interestingly, treatment-related deaths were not found to be increased in the SPORE patients scored as ineligible compared to those scored as eligible,  but death due to progressive lymphoma was higher among those scored as ineligible. 

So how does this relate to the inability to improve upon standard DLBCL therapy? 

Khurana and colleagues' data highlight several features of clinical trials conduct related to trial outcomes.  The unnecessary exclusion of patients based on criteria not specific to the treatment can translate into eligible patients having a more favorable prognosis compared to individuals with the disease who are excluded from studies, but who nevertheless are treated with standard therapy used as a control in DLBCL clinical trials.  Populating randomized trials with the best prognosis patients can lead to reduced power to detect an outcome difference, even if one exists. 

But what about the unnecessary exclusion of patients from clinical trials based on laboratory values that reflect organ dysfunction and poor outcomes as shown in the SPORE patients?  The authors document unequivocally that those patients deemed ineligible are at higher risk of death due to treatment failure: that is they die due to progressive lymphoma more than the SPORE patients scored as meeting clinical trial eligibility criteria. What we don't know from the study as presented, is whether there were more dose delays and dose reductions among those scored as ineligible. This is fundamental toward an improved understanding of how to repair our clinical trials enterprise in DLBCL.  And what I mean by repair, is to broaden and expand clinical trials access to as many patients as possible and to have rigorous design and conduct of trials to detect true signals. There are two essential elements to address, and this data points the way but does not fully answer the questions.  To make trials generalizable, we must include as broadly as possible those patients with DLBCL.  However, if the SPORE outcomes are explained by an inability to administer therapy as planned in those scored as trial ineligible, then just broadening eligibility criteria could undermine the ability to detect a difference with new effective treatment by including too many patients unable to tolerate the therapy.  For example, some have suggested the negative results of the PHOENIX trial may be due to treatment intolerance among those aged 60 years and over. So it appears that trials increasing generalizability and reaching a positive trial endpoint for a novel treatment have a complex interaction, to say the least. It will be essential as diffuse large B-cell lymphoma therapeutic trials are developed to be mindful of differential prognosis and perhaps interrelated treatment tolerance of patients due to multiple factors, including degree of organ dysfunction.  The exclusion of patients with the disease understudy from clinical trials should be minimized.  Efforts to modernize clinical trial eligibility are being embraced by most stakeholders, and in my opinion is an essential social and medical responsibility for clinical trialists to meet.  The challenge is how to accomplish this important objective and appropriately design studies to enhance the ability to detect the desired study endpoint. To answer the question posed by the authors, we must endeavor to leave no one behind. We can accomplish this through statistical designs such as stratification of the randomization,  powered for the groups of interest -- as one such solution. Separate and specific trials for older or more frail patients is another solution.  And I dare say, we should focus on efforts to eliminate the CHOP backbone and develop better-tolerated therapy that those with organ dysfunction can benefit from. The VIPOR regimen presented by Melani and colleagues at the 2020 ASH meeting provides an example of the type of DLBCL research that could be of interest. The challenge of generalizability and its relevance to negative clinical trial results is becoming clearer if only to recognize the increasing complexity in meeting the needs of our patients.  But isn't that what motivates us?

This concludes this JCO Podcast. Thank you for listening.

This multi-institutional study highlights the heterogeneity of Phyllodes tumors of the breast and the importance of accurate pathology assessment and individualized surgical approaches.

LEE WILKE: This JCO podcast provides observations and commentary on the JCO article, Contemporary Multi-institutional Cohort of 550 Cases of Phyllodes Tumors from 2007 to 2017 Demonstrates a Need For More Individualized Margin Guidelines by Rosenberger, et al. My name Lee Wilke and I am a professor of surgery and the Hendrix chair in breast surgery research at the University of Wisconsin School of Medicine and Public Health in Madison, Wisconsin. My oncologist specialty is breast surgical oncology. I have no relationships to disclose related to these studies.

As medical students we are asked to adopt an expanded vocabulary to describe a multitude of diseases. The word phyllodes is frequently one of those memorable medical school terms whose origin is Greek and describes a leaf-like growth. Phyllodes are rare tumors accounting for less than 1% of breast malignancies, with just over 2,000 patients diagnosed annually in the United States.

Originally, the phyllodes tumor was described as cyst like and, therefore, the historic term cystosarcoma phyllodes was applied. Though these tumors are of connective tissue and fibroepithelial origin, they are infrequently cystic and not a true sarcoma. And therefore, the World Health Organization now classifies them as simply phyllodes tumors. They are importantly, for treatment approaches, sub-categorized into benign, borderline, and malignant based on detailed pathologic review of celularity, atypia, overgrowth, mitotic rate, and the borders of the tumor.

Phyllodes tumors are listed in the National Institute of Health's genetic and rare diseases program. On the center's website, surgery is described as the primary treatment for these rare malignancies and 1 centimeter margins or greater are recommended for all subtypes of phyllodes tumors, with a note that these tumors are quote, "often treated with mastectomy", unquote. As specialists caring for patients with breast malignancies, we are rapidly learning that the one-size-fits-all approach is not appropriate, and the same is true for those individuals with phyllodes tumors.

In the article that accompanies this podcast, to support a shift towards more individualized treatment, Dr. Laura Rosenberger from Duke University in North Carolina assembled a group of key collaborators from 11 US academic cancer centers to pool and evaluate their treatment approaches and outcomes for patients with phyllodes tumors. The investigators identified a total cohort of 550 patients with phyllodes tumors treated between 2007 and 2017.

Consistent with systematic reviews of phyllodes tumor data sets, such as that by Lu et al in Annals of Surgical Oncology, with this JCO publication being the largest, the patients have a median age of 44. The malignant cohort is approximately 10%. And median tumor size is three centimeters, with a range to as high as 29 centimeters. Key facts found within this analysis are that 2% of patients underwent nodal evaluation, all with negative nodes.

The addition of either a sentinel node or axillary surgery is not without risks to the patient. And unless the pre-surgical diagnosis raises the question of a simultaneous adenocarcinoma, patients undergoing surgery for a phyllodes tumor should not undergo nodal mapping or axillary surgery as these tumors are primarily local malignancies and do not metastasize via the lymphatic network. This is the first key takeaway from this paper, supporting the work of others that nodal surgery in phyllodes tumors is unnecessary.

The second notable finding is the heterogeneity, even among academic medical centers, regarding the surgical approach. Approximately 38% of patients, or 209, proceeded to a second surgical intervention. 51 of these patients, or nearly 10% of the entire cohort, had negative margins at their first surgery. Of the group that underwent a second surgery, only six patients, or 3% of those proceeding to a second intervention, had residual disease.

On the opposite end of the spectrum, of those patients with a positive surgical margin, which was 42% of the entire group, 74, or 32% of those with positive margins, did not proceed with a second surgery. These outcomes highlight that even among patients being treated at centers that one would assume would function similarly, patients could have everything from positive margins to additional surgery in the setting of negative margins.

What is vital to note at this point, however, is that the recurrence rate for this cohort was only 3.3% or 18 patients-- 15 with a local recurrence and three with a distant recurrence. The recurrences were differentially associated with the phyllodes subtypes, with 1.3% in benign, 5.6% in borderline, and 6.9% in malignant phyllodes. In univariate logistic regression analysis, however, margin status and margin width did not predict for a recurrence and neither did type of surgery or patient age.

Clearly, a one centimeter margin for a phyllodes tumor is not needed, just as we are likely finding is true for our adenocarcinomas of the breast. The authors don't go so far as to state that a positive margin is acceptable, but highlight the need for a national registry to evaluate an individualized surgical approach in this rare patient population.

A final and third key point from this retrospective but important pooled patient analysis is the primary role the pathologist plays in determining the patient outcome. As I frequently comment to my cancer patients, the pathologist is the most important doctor you never meet. In Dr. Rosenberger's analysis, factors that were influential for local recurrence were all pathological variables-- grade, extent of atypia and overgrowth and tumor size.

Currently, there are no College of American Pathologists guidelines for reporting phyllodes tumors. With this and other patient data sets highlighting the importance of these pathologic factors in patient outcomes, perhaps a standardization and education program for identifying each of these key findings within a phyllodes tumor should be developed. Without a good pathologist or team of pathologists, oncologic surgeons lack the tools they need to advise the patient on additional surgery and potentially adjuvant therapy.

As the use of adjuvant therapy was small in this data set, conclusions could not be provided for or against radiation therapy. Thus, as with all rare tumors, a collaborative and team approach with development of a national registry is needed across community and academic institutions to standardize and evaluate the outcomes for these patients with the eventual goal of providing a more tailored treatment approach. This concludes this JCO podcast. Thank you for listening.

In this study of cancer operations conducted during the COVID-19 pandemic, rates of pulmonary complications and SARS-COV-2 nosocomial infections were compared between patients operated on in COVID-19-free facilities and those operated on in non-segregated facilities. Because lower rates of pulmonary complications and nosocomial SARS-COV-2 infection were observed in COVID-free facilities, the authors propose a restructuring of surgical facilities and pathways for cancer patients during the COVID-19 pandemic.

This JCO podcast provides observations and commentary on the JCO article "Elective Cancer Surgery in COVID-19-Free Surgical Pathways During the SARS-CoV-2 Pandemic: An International Multicenter Comparative Cohort Study, " by Bhangu et al.  My name is Ken Tanabe, and I serve as Chief of Surgical Oncology at Massachusetts General Hospital, Professor of Surgery at Harvard Medical School, and Deputy Clinical Director of the Massachusetts General Hospital Cancer Center in Boston, Massachusetts.  My oncologic specialty is surgical oncology.

The devastation and destruction brought about by the SARS-CoV-2 pandemic is difficult to fully comprehend.  At time of this podcast there are more than 28 million infections worldwide and nearly 200,000 deaths in the United States alone. Hospitals and healthcare networks have been uniformly challenged to provide care and safety for patients and providers. In response to this initial wave, elective operations were cancelled as a strategy to increase critical care resources, preserve Personal Protective Equipment – or PPE, and re-deploy surgical team members to support care for COVID-19 patients.  On a worldwide basis, this amounted to cancelation of a substantial number of operations.  And a significant fraction of these backlogged operations was for cancer. Once hospitals recognized they could handle the size and peak of the initial wave, they resumed elective cancer operations.  Some hospitals had the capacity to create COVID-19 free surgical units for these operations, as a strategy to reduce the risk of cross-infection of patients.  Subsets of cancer patients are known to be at higher risk from COVID-19 morbidity and mortality, including those with lung cancer.  However, creation of parallel pathways for COVID and non-COVID cancer patients diverts resources and is associated with significant costs.  The relative value of this maneuver is not known, but is of critical importance, particularly in light of catastrophic hospital finances created by the pandemic.

In the article that accompanies this podcast, the authors studied the impact of creation of COVID-19-free surgical facilities.  Specifically, they gathered data from 445 hospitals in which patients underwent operation either in a COVID-19-free surgical pathway, or alternatively underwent operation in a hospital that did not have separate, COVID-free surgical units. The study included over 9,000 patients that underwent cancer operations during the pandemic.  Hospitals in 54 countries are included, though the United Kingdom, Italy, Spain and United States accounted collectively for over 60% of the patients.  A surgical facility was defined COVID-19 free if it had a policy of segregation of COVID-19 patients in three specific areas of the hospital: the operating rooms, the ICUs, and the inpatient units.  Conversely, a surgical facility was not considered COVID-19 free if this segregation was absent in any of these three areas.

There are several key findings. 

• First and foremost, patients who underwent surgery within COVID-free units were younger and had fewer comorbidities compared to patients operated on in non-segregated surgical units.
• After adjustment for these differences, pulmonary complication rates were lower amongst patients operated on in COVID-free units compared to those operated on in non-segregated surgical units.
• The post-operative SARS-COV-2 infection rate was lower in COVID-free surgical units – 2.1% compared to the 3.6% observed in non-segregated units.
• The preoperative COVID testing rate was higher in the COVID-19-free surgical units.  Specifically, the testing rate was 39% in the COVID-19-free surgical units and only 23% in the non-segregated facilities.  However, in a sensitivity analysis for patients with a negative preoperative swab test, the benefit of COVID-19 free pathways remained apparent.
• The authors conclude it is likely that differences in SARS-CoV2 transmission rates are responsible for the lower pulmonary complication rates in those operated on in COVID-19-free surgical units.

The authors cite these observations as the basis for their recommendation for, quote, "major international redesign of surgical services -- based on local available resources -- to provide elective cancer surgery in COVID-19-free surgical pathways."  End quote.  Of note, there are many hospitals and healthcare networks in the U.S., let alone worldwide, that don't have the resources required to create COVID-19-free operating rooms, ICUs and in-patient wards amidst a devastating pandemic.  And thus, it's imperative to understand if that is really the lesson learned here.

It is relevant to point out that COVID-19-free surgical units – whether they cause a lower rate of post-operative complications or are merely associated with these outcomes – are sought out by patients.  In my own surgical practice, once we resumed operations after the initial COVID-19 wave, some patients declined or further delayed vital cancer operations for fear of SARS-COV-2 at the hospital, despite my assurances of the strict infection control policies in place. 

There are certainly limitations to this study.  The first is that selection bias was present: patients that underwent operation in COVID-19-free surgical facilities were significantly younger and healthier.  Although statisticians have developed strategies to adjust risk in scenarios like this, these approaches do not always completely remove bias.  The second limitation is that this study took place at a time during which relatively few patients were COVID-19 tested prior to operation.  Some of the observed effect in this study may be related to unknown SARS-COV-2 infection in asymptomatic patients.  Only 27% of patients underwent preoperative SARS-CoV-2 testing in this study.  Going forward, all patients are tested prior to surgical procedures.  The current study suggests an effect even when the analysis is limited to patients that were tested preoperatively, but a more robust analysis of post-operative transmission of infection in non-segregated facilities can be performed when all patients are tested preoperatively. 

Another important limitation of the study is that the definition of COVID-19 free surgical pathway was arbitrary in the degree of completeness.  In the context of this retrospective, multi-institutional international study, the definition was relatively broad for purposes of inclusion, but simultaneously lacks some common sense, requiring only complete segregation of operating rooms, surgical ICUs, and inpatient wards to separate COVID-19 infected patients from those without infection. 

To be designated as a COVID-19 free facility for purposes of this study, it was not required to have segregated facilities for preoperative check-in, separate recovery rooms, separate emergency rooms for patients presenting with post-operative complications, or even separate equipment and staff.  What is the impact of sharing with COVID-19 areas patient transporters, EKG and X-Ray machines, food service racks, language translators, or use of common elevators and corridors, or even common pneumatic tube cannisters in a pneumatic tube system that runs throughout the facility?  If the best performing hospitals that don't have COVID-19 free pathways perform better than the worst performing hospitals that do have COVID-19 free pathways, what is it that these hospitals are doing that makes the difference? 

In short, it seems more than just plausible that establishing infection control Standard Operating Procedures – or SOPs, staff training, and staff adherence to these SOPs are key to controlling spread of infection.  These are likely as important as segregation of just three parts of perioperative care.  In other words, this study demonstrates an association between having separate peri-operative facilities and a reduction in pulmonary complications.  But this type of study is unable to address whether a causal link exists.  Perhaps hospitals with the capability of achieving this segregation through duplicate facilities simply have more resources.  Perhaps they have more capable hospital administration and support that can more quickly implement the newest infection control policies.   Perhaps they have more PPE for hospital staff.  Given that many hospitals and health care networks do not have sufficient resources to create parallel, segregated COVID-19-free facilities for operations, drilling down on these important operational aspects for control of disease transmission is key.

The time period involved in the current report was one during which hospitals were struggling to cope with several challenges.  Of note, between May 14 and July 14 CDC data reveal that an average of 120 patients a day became infected with SARS-COV-2 inside U.S. hospitals.  During this time hospitals were managing gaps in testing – as were evident in the current report – and shortages of PPE required to protect staff and patients.  CDC data suggests hospitals have improved at controlling nosocomial SARS-COV-2 infections since then, with the risk dropping from 2% in mid-May to 1.2% as of mid-July.   These promising results are likely the result of better infection-control methods employed over time.  The impact of this downward trend was exemplified in a study from Brigham and Women's Hospital that demonstrated only 1 case of nosocomial SARS-COV2 transmission over 12 weeks of the pandemic in which 9,149 patients were hospitalized and 8,656 days of COVID-19-related care were provided.  The infection-control strategies they implemented were thorough, improved over time, and did not involve a COVID-19-free surgical pathway.  The most recent changes implemented in the Brigham and Women's study included enhanced eye protection for employees, universal testing on admission, daily nursing screening for COVID-19 symptoms, and a hospital-wide shift to N95 masks for routine COVID-19 care. 

The current study focused on cancer operations, but does control of SARS-COV-2 transmission inside hospital surgical units have as much impact on other kinds of operations? Yes, the observations are relevant more broadly.  Cancer patients are at greater risk for developing severe complications from COVID-19.  But a large segment of the adult population has at least one underlying risk factor for increased susceptibility to infection, as well as increased likelihood of severe complication or mortality.    Razzaghi et all have determined that the prevalence of any of five underlying, non-cancer conditions associated with increased risk for severe COVID-19–associated illness among U.S. adults is 47.2%.  Moreover, particular races have significant higher risk of infection and higher risk of severe complications. 

Some health care systems have the resources to create separate surgical units to control nosocomial transmission.  But going forward, it appears that reducing in-hospital transmission of SARS-COV-2 to cancer surgery patients will rely primarily on rigorous implementation of aggressive and widely accepted infection control policies.

This concludes this JCO Podcast. Thank you for listening.

This podcast reviews the results of the whole genome sequencing study by Samur and colleagues that identified a genomic signature associated with superior survival in patients with newly diagnosed multiple myeloma.

Disclosures: SAH has served on advisory boards or as a consultant for Adaptive Biotechnologies, Amgen, Celgene, Genentech, GSK, Oncopeptides, Sorrento; Takeda; has received research funding from Oncopeptides.

This JCO Podcast provides observations and commentary on the JCO article "Genome-Wide Somatic Alterations in Multiple Myeloma Reveals a Superior Outcome Group" by Samur et al. My name is Sarah Holstein, and I am an Associate Professor at the University of Nebraska Medical Center in Omaha, Nebraska in the United States. My oncologic specialty is plasma cell dyscrasias. I do not have any relationships to disclose related to these studies.

The clinical heterogeneity of myeloma has long been appreciated as it is clear there is a broad range of disease behavior, with some patients having indolent disease and others having very aggressive disease. As a result, there has been significant interest in developing risk stratification systems that classify patients into different risk groups, thus providing some information about prognosis and potentially inform treatment decisions. Historically, staging systems were based on factors related to tumor burden. However, it is increasingly evident that the underlying disease biology is a key modulator of risk. Our ability to detect disturbances in the myeloma genome has changed dramatically over time. Metaphase karyotyping represents our lowest "power of magnification". These studies led to the recognition that in general, hyperdiploidy involving odd-numbered chromosomes is associated with lower-risk disease while high-risk disease can involve translocations of chromosome 14, monosomy 13 and monosomy 17. Use of fluorescent in-situ hybridization (FISH) allowed for a higher power of magnification and identification of more subtle chromosomal abnormalities. Next, gene expression profiling studies utilizing small panels of genes, enabled classification of patients into different risk categories, although there was little concordance between the panels used in the various studies. The advent of deep whole genome sequencing technology has facilitated a much more "high-powered" view of the myeloma genome.

In the article that accompanies this podcast, diagnostic bone marrow specimens were obtained from 183 patients enrolled in the IFM/DFCI 2009 study. This phase 3 study enrolled newly diagnosed transplant-eligible patients (up to age 65). All patients received three cycles of lenalidomide, bortezomib, dexamethasone (RVD) induction, underwent stem cell collection and then received consolidation with either 5 cycles of RVD or a single autologous stem cell transplant followed by 2 cycles of RVD. Of note, in the French portion of this study, all patients subsequently received one year of lenalidomide maintenance, while in the US portion, all patients received lenalidomide until progression. The French portion has already been published and showed a 14 month PFS benefit for the transplant arm compared to the non-transplant arm. Results from the US portion have not yet been released, but I would speculate that the PFS and OS for both arms will be superior to the French counterparts, given the existing data supporting the benefit of prolonged lenalidomide maintenance.

Deep whole genome sequencing, with a median tumor depth of 75X, was used to interrogate the myeloma genome. Mutational signatures were based on identified single nucleotide variants, small insertions and deletions. The genomic scar score (GSS) was calculated based on allele-specific copy number alterations. A GSS of 5 or less was the cut-off for inclusion in the low GSS group. The goals of the study were to describe mutational loads and processes in order to establish genomically-defined subgroups, gain insight into patterns of evolution from clonal to subclonal mutations, and correlate these findings with clinical outcomes and more traditional risk factors.

There were several key findings. First, mutational load varied amongst myeloma subgroups, with hyperdiploid myeloma having the lowest mutational load and t(14;16) having the highest mutational load. Second, analysis of mutational patterns led to identification of five separate mutational processes that contributed to eight mutational signatures. These five processes included: 1) an age-related process, 2) an AID/APOBEC process, 3) somatic hypermutation, 4) DNA repair, and 5) processes with unidentified etiology including the clock-like signature. Samur et al., found that these various processes contributed to different myeloma subgroups in different ways. For example, the age-related process was high in hyperdiploid myeloma, the APOBEC-related process was high in t(14;16) myeloma, the clock-like signature was high in t(4;14) myeloma and the DNA repair process was high in del(17p) and t(11;14) myeloma. Furthermore, analysis of these mutational patterns from a clonal vs subclonal perspective enabled insight into mutational development patterns of different subgroups of myeloma.

Next, the GSS was correlated with mutational signature and clinical outcome data. The authors found that the frequency of a low GSS was higher in t(11;14) myeloma and lower in del17p, gain1q21, del1p and del13 subgroups. Patients in the low GSS group had a trend towards a longer median PFS and a statistically significant longer 4-year OS rate than other patients. In particular, patients with both low GSS and gain of chromosome 9 had a superior outcome compared to all other subgroups, with an OS probability of 100%. Patients with either low GSS and no gain(9) or with high GSS and gain(9) had intermediate outcome while those with high GSS and t(4;14), gain(1q) or no gain(9) had the worst OS. Although the numbers are quite small, an interesting finding was that for patients in the low-risk group (low GSS + gain(9)), there was a significantly superior PFS in favor of those patients in the transplant arm compared to the non-transplant arm. Overall, no statistically significant differences were found between the four subgroups and factors such as ISS stage, response, or achievement of MRD negativity.  The numbers in each subgroup were quite small though. Finally, the authors demonstrated that the low GSS could separate hyperdiploid myeloma into low-risk and high-risk subgroups.

Overall, these studies are interesting because they provide insight into the mutational processes that drive different subgroups of myeloma and offer a potential method by which to differentiate low-risk hyperdiploid myeloma from high-risk hyperdiploid myeloma. The finding that there was a difference in PFS for patients who underwent transplant vs no transplant in the low-risk group (low GSS, gain(9)) is very intriguing. There has been much discussion centered around whether low-risk patients really "need" to go through a stem cell transplant since in general their outcomes are good. The present study, aside from highlighting the fact that our traditional methods of identifying low-risk disease are likely inadequate, raises the hypothesis that patients with low-risk disease may benefit even more from transplant than other risk groups. However, it is noted that this subgroup consisted of only 28 patients. In addition, it is not clear from the manuscript whether patients were in the US vs French portion of the study, thus differences in study design (i.e., lenalidomide maintenance duration) could impact PFS findings. Clearly, this type of whole genome sequencing analysis will need to be applied to additional prospective studies in order to validate the novel risk stratification system.

For now, these results are not practice-changing. However, they provide a potential glimpse into the future, where whole genome sequencing analysis is performed as readily as FISH analysis, and where enrichment strategies using genomic markers are used to design clinical trials. Aside from studies evaluating the use of venetoclax in t(11;14)-positive myeloma and other studies focused on high-risk disease that encompass a variety of high-risk chromosomal abnormalities, the field of myeloma has not yet moved into an era of precision medicine. Whether whole genome sequencing can finally usher us into that era remains to be determined. While this plasma cell-centric analysis is certainly revealing, it is likely that in order to maximally target myeloma, the genomics analysis must be coupled with an equally in-depth understanding of the host's immune system.

This concludes this JCO Podcast. Thank you for listening.

This podcast describes a study addressing the use of dexrazoxane as a cardioprotectant in a cohort of more than 1,000 pediatric acute myeloid leukemia patients.

Transcript

This JCO Podcast provides observations and commentary on the JCO article "Effect of Dexrazoxane on Left Ventricular Systolic Function and Treatment Outcomes in Patients with Acute Myeloid Leukemia: A Report From the Children's Oncology Group" by Getz et al. My name is Elvira van Dalen, and I am an epidemiologist at the Princess Máxima Center for Pediatric Oncology in Utrecht, The Netherlands and a Coordinating Editor of Cochrane Childhood Cancer. My oncologic specialties are cardiotoxicity and systematic reviews and guidelines in the field of pediatric oncology. I have nothing to disclose.

Anthracyclines are widely used in pediatric oncology. Unfortunately, one of their most serious adverse effects is cardiotoxicity, which can occur during or shortly after treatment, but also decades later. In the Dutch LATER Childhood Cancer study, we found a 10.5% cumulative incidence of symptomatic heart failure 40 years after cancer diagnosis in survivors treated with cardiotoxic chemotherapy. The Childhood Cancer Survivor Study and St Jude LIFE show similar results. Siblings report significantly less congestive heart failure than survivors. These are high risks, especially in this young patient population. Cardiotoxicity impairs quality of life and can lead to premature death. Prevention is thus very important.

Extensive research has been devoted to the identification of possible cardioprotective interventions, like liposomal anthracyclines, increasing the anthracycline infusion duration and reducing the cumulative anthracycline dose. Concerning the cumulative anthracycline dose, it should be kept in mind that there is no safe dose. Another option is the use of cardioprotective agents like dexrazoxane.

As shown in our Cochrane systematic review published in 2011 which is currently being updated, it prevents cardiac damage. But unfortunately, the majority of the evidence comes from studies addressing adult patients with breast cancer and these data cannot be extrapolated to children. In children as of yet only a few randomized trials have been performed, none including acute myeloid leukemia patients. In these pediatric studies, for clinical heart failure there were no significant differences between dexrazoxane and control groups, while results for asymptomatic cardiotoxicity varied with the outcome definition used. All studies were relatively short-term, and we don't know how longer follow-up will influence these results.

Thus far only a few small non-randomized studies including 50 children or less evaluated dexrazoxane in pediatric acute myeloid leukemia, all with limitations. The article by Getz and colleagues that accompanies this podcast adds important new information to the current knowledge of the use of dexrazoxane in pediatric acute myeloid leukemia patients and pediatric patients in general. It presents the results from the Children's Oncology Group AAML1031 trial investigating the use of dexrazoxane during frontline treatment of pediatric acute myeloid leukemia. Between 2011 and 2016, patients younger than 30 years at diagnosis were enrolled. Almost 98% were younger than 21 years. The analyses included 1014 patients, of which 10% received dexrazoxane consistently at every anthracycline course and 90% were never exposed to dexrazoxane. Anthracycline treatment involved both daunorubicin and mitoxantrone. Low risk patients received a cumulative anthracycline dose of 444 mg/m2, while high risk patients received 294 mg/m2 assuming the daunorubicin equivalency conversion employed by the Children's Oncology Group at the time of this protocol. Patients were followed for a median of 3.5 years, with an interquartile range of 2.5 to 4.7 years. Cardiac function was assessed using either echocardiography or multigated acquisition scans which were performed at regular intervals. Compliance with cardiac monitoring was more than 90% on-protocol, but less than 60% off-protocol. Left ventricular systolic dysfunction was primarily defined as a shortening fraction of less than 28% or an ejection fraction of less than 55%.

In the report by Getz and colleagues that accompanies this podcast, 26.5% of patients consistently treated with dexrazoxane and 42.2% of patients that never received any dexrazoxane developed left ventricular systolic dysfunction. The hazard ratio was 0.55 with a 95% confidence interval of 0.36 to 0.86. There was a trend towards a worse grade of left ventricular systolic dysfunction without dexrazoxane. Some evidence pointed to recovery of systolic function, but as this was based on mean values instead of number of patients below the cut-off value it is possible that patients with good and bad values balanced each other out resulting in an adequate mean value. This can give the impression that there is no problem, while for some patients this might not be true.

It is important to note that this was not a randomized trial, which would have provided the highest level of evidence to answer this type of question. Dexrazoxane was administered at the discretion of treating physicians. However, characteristics like sex, age, risk group, treatment arm, compliance with cardiac monitoring and follow-up were similar in both groups. Unfortunately, cumulative anthracycline dose was not reported for both groups, but it was stated that patients completed a median of 4 courses regardless of dexrazoxane exposure.

An important question regarding any cardioprotective intervention is whether it can reduce cardiotoxicity without negative effects on anti-tumor efficacy and non-cardiac toxicities. At the moment, despite its clear cardioprotective effects, at least in adults, dexrazoxane is not routinely used in clinical practice. This might be explained by the suspicion of interference with anti-tumor efficacy and the occurrence of secondary malignancies. However, as shown in our Cochrane systematic review no significant differences between treatment groups were identified, which is in line with more recently published randomized trials.

Studies often do not report data on anti-tumor efficacy and non-cardiac toxicities, but fortunately Getz and colleagues did. This is important as extrapolation of many of these data to other types of malignancies is difficult. Survival and relapse risk were comparable between groups. And even though this study did report on only a few non-cardiac toxicities, those that were reported were similar. Despite the relatively short follow-up period, four secondary malignancies occurred, three in the non-dexrazoxane group. This was not statistically significant different. None of the secondary malignancies was acute myeloid leukemia, but it might have been difficult to distinguish a secondary malignancy from a relapse.

In summary, although this is not a randomized trial, this large study provides new knowledge on the use of dexrazoxane in pediatric acute myeloid leukemia patients with regard to cardiac function, anti-tumor efficacy and non-cardiac toxicities. Overall, dexrazoxane seems to be cardioprotective, at least within the relatively short follow-up period of maximal 4 years, without negative effects on anti-tumor efficacy and non-cardiac toxicities including secondary malignancies. Hopefully the authors will continue to follow these patients for long-term results. Even though this study does have limitations, it definitely adds to the knowledge of the use of dexrazoxane in children. It can help to inform the development of a much-needed evidence-based clinical practice guideline that is currently being developed by the International Late Effects of Childhood Cancer Guideline Harmonization Group.

This concludes this JCO Podcast. Thank you for listening.

This podcast reviews the results of the observational study by Ladas and colleagues that found protective associations between dietary antioxidant intake and the occurrence of bacterial infections and mucositis. 

TRANSCRIPT

This JCO podcast provides observations and commentary from the JCO article "The Protective Effects of Dietary Intake of Antioxidants and Treatment-Related Toxicity in Childhood Leukemia, A Report From the DALLT Cohort" by Ladas et al.

My name is Wendy Demark-Wahnefried, and I am Webb Endowed Chair and Professor of Nutrition Sciences at the University of Alabama at Birmingham, as well as the Associate Director for Cancer Prevention and Control at the O'Neal Comprehensive Cancer Center at UAB in Birmingham, Alabama in the United States. I do not have any relationships to disclose regarding these studies, and my review is grounded by the fact that I am a nutrition scientist with particular expertise in cancer survivorship.

The topic of nutrition and cancer generates a great deal of interest, especially once individuals are diagnosed with cancer. This is particularly germane with regard to antioxidants, since some scientists hypothesize that high levels of antioxidants may be beneficial for cancer control while others speculate that high levels may prevent apoptosis of cancer cells and actually impede the effectiveness of cancer therapy. However data are sparse, and there are very few studies of high quality, therefore the paper by Ladas and colleagues is both timely and important.

The study enrolled 794 children ages 1 through 18 who were diagnosed with acute lymphoblastic leukemia. These children were enrolled from 10 institutions across the continental United States, Puerto Rico, and Canada. The children or their guardians completed age appropriate food frequency questionnaires that assessed dietary intake over the previous month and did so at two time points, soon after diagnosis and after the induction phase of treatment, or roughly a month after the first questionnaire.

The nutrients that were studied were vitamins A, C, and E, as well as alpha, beta and total carotenoids-- these are the substances in plant foods that give the food its color-- and zinc. It should be noted that the antioxidant selenium was not studied.

Nutrient intake was statistically analyzed in relation to bacterial infection and higher grade mucositis or inflammation of the digestive tract resulting in mouth sores or ulceration of the esophagus. Nutrient intake also was studied in relation to disease-free survival and minimal residual disease. Children were followed for up to 10 years.

Of the 513 participants who completed the dietary surveys at both time points, 23% experienced a bacterial infection, and 16% experienced higher grade mucositis. Only 9% had higher levels of minimal residual disease, and 2% did not achieve complete remission.

Results showed that children having diets with higher levels of antioxidants had a significantly lower risk of bacterial infection, with risk lowered by 10% to 27%, depending upon the antioxidant. Similarly, children having diets with higher levels of antioxidants had a significantly lower risk of higher grade mucositis, with risk lowered by 17% to 67%, again, depending upon the antioxidant.

Importantly, evidence of protection was only observed for nutrients obtained through the diet and not nutritional supplements. In addition, no significant associations were observed between antioxidant intake, either through diet or supplements, and disease-free survival.

This study has several strengths, in that it involved the participation of a diverse and ample sample of several children and their parents across several sites. Furthermore, data were collected at two time points.

As always, there are limitations, and when relying on self-reported data there is always the risk of inaccurate reporting and misclassification. In addition, and thankfully, the number of children who had higher levels of minimal residual disease or who had not experienced complete remission was very small. And therefore, the study was likely under power to detect any associations between nutrient intake and these outcomes.

Finally, because these results emanate from an observational study, cause and effect cannot be inferred. Thus the title of this manuscript, which begins with "The Protective Effects" in quotations, may be a bit of an overstatement. So what are the implications of this study?

As noted previously, there are few data in this area, therefore more studies are needed to either confirm or refute these results. And such research is necessary in other cancer populations, such as among adults with other cancers who receive different therapies. Until such time, these data reinforce that a healthy diet may associate with lower risk of common treatment-related toxicities.

It is noteworthy that investigators were only able to detect protective associations from antioxidants from dietary sources and not from supplements. These data reinforce both the American Institute of Cancer Research and the American Cancer Society guidelines that recommend that nutrients be obtained from foods rather than from supplements.

As such, both clinicians and patients may have an interest in the dietary sources of antioxidants that were studied. Many people already know that citrus fruits are rich sources of vitamin C, but there are also other fruits and vegetables, such as strawberries, cantaloupe, and mangoes, as well as tomatoes, peppers and vegetables in the cabbage family, which also contain high levels of this nutrient. Foods that are high in vitamin E include plant oils, nuts, and seeds.

Dark green and orange vegetables, and fruits, such as spinach, broccoli, sweet potatoes, apricots, and peaches are rich sources of carotenoids, which ultimately can be converted to vitamin A. Alternatively, preformed vitamin A in the diet can be obtained from animal products such as dairy products and eggs. Finally, foods rich in zinc include shellfish, poultry, legumes-- meaning dried beans, peas, and peanuts-- and red meat.

In sum, these data reinforce current guidelines that encourage consumption of a well-balanced plant-based diet that has ample amounts of vegetables and fruit, at least 2 and 1/2 cups a day, as well as whole grains, nuts, seeds, and legumes. Such a diet may be beneficial in preventing common treatment-related toxicities, and larger studies may be able to discern potential associations with cancer-related outcomes such as disease-free survival. However, more study is required.

This concludes this JCO podcast. Thank you for listening.

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.

Host Davide Soldato and guest Dr. John K. Lin discuss the JCO article "Racial and Ethnic Disparities Along the Treatment Cascade Among Medicare Fee-For-Service Beneficiaries with Metastatic Breast, Colorectal, Lung, and Prostate Cancer."

TRANSCRIPT

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

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

Today, we are joined by Dr. Lin, assistant professor in the Department of Health Services Research at the University of Texas MD Anderson Cancer Center. Dr. Lin and I will be discussing the article titled, "Racial and Ethnic Disparities Along the Treatment Cascade Among  Medicare Fee-for-Service Beneficiaries With Metastatic Breast, Colorectal, Lung, and Prostate Cancer."

Thank you for speaking with us, Dr. Lin.

Dr. Lin: Thank you so much for having me. I appreciate it.

Dr. Davide Soldato: So, just to start, to frame a little bit the study, I just wanted to ask you what prompted you and your team to look specifically at this question - so, racial and ethnic disparities within this specific population? And related to this question, I just wanted to ask how this work is different or builds on previous work that has been done on this research topic.

Dr. Lin: Yeah, absolutely. Part of the impetus for this study was the observation that despite people who are black or Hispanic having equivalent health insurance status - they all have  Medicare Fee-for-Service - we've known that treatment and survival differences and disparities have persisted over time for patients with metastatic breast, colorectal, lung, and prostate cancer. And so, the question that we had was, "Why is this happening, and what can we do about it?"

One of the reasons why eliminating racial and ethnic disparities in survival among Medicare beneficiaries with metastatic cancer has been elusive is because these disparities are occurring along a lot of dimensions. Whether or not it's because the patient presented late and has very extensive metastatic cancer; whether or not the patient has had a difficult time even seeing an oncologist; whether or not the patient has had a difficult time starting on any systemic therapy; or maybe it's because the patient has had a difficult time getting guideline-concordant systemic therapy because, more recently, these treatments have become so expensive. Disparities, we know, are occurring along all of these different facets and areas of the treatment cascade. Understanding which one of these is the most important is the key to helping us alleviate these disparities. And so, one of our goals was to evaluate disparities along the entire treatment cascade to try to identify which disparities are most important.

Dr. Davide Soldato: Thank you very much. That was very clear. So, basically, one of the most important parts of the research that you have performed is really focusing on the entire treatment cascade. So, basically, starting from the moment of diagnosis up to the moment where there was the first line of treatment, if this line of treatment was given to the patient.

So, I was wondering a little bit, because for this type of analysis, you used the SEER-Medicare linked database. So, can you tell us a little bit which was the period of time that you selected for the analysis? Why do you think that that was the most appropriate time to look at this specific question? And whether you feel like there is any potential limitation in using this type of database and how you handled this type of limitations?

Dr. Lin: Yeah, absolutely. It's a great question. And I want to back up a little bit because I want to talk about the entire treatment cascade because I think that this is really important for our research and for future research. We weren't the first people to look at along the treatment cascade for a disease. Actually, this idea of looking along the treatment cascade was pioneered by HIV researchers and has been used for over a decade by people who study HIV. And there are a lot of parallels between HIV and cancer. One of them is that with HIV, there are so many areas along that entire treatment cascade that have to go right for somebody's treatment to go well. Patients have to be diagnosed early, they have to be given the right type of antiretrovirals, they have to be adherent to those antiretrovirals. And if you have a breakdown in any one of those areas, you're going to have disparities in care for these HIV patients.

And so, HIV researchers have known this for a long time, and this has been a big cornerstone in the success of getting people with HIV the treatment that they need. And I think that this has a lot of parallels with cancer as well. And so, I am hoping that this study can serve as a model for future research to look along the entire treatment cascade for cancer because cancer is, similarly, one of these areas that requires multidisciplinary, complex medical care. And understanding where it is breaking down, I think, is crucial to us figuring out how we can reduce disparities.

But for your question about the SEER-Medicare linked database, so we looked between 2016 and 2019. That was the most recent data that was available to us. And one of the reasons why we were excited to look at this is because there were some new treatments that were just released and FDA-approved around 2018, which we were able to study. And this included immunotherapy for non–small cell lung cancer, and then it also included androgen receptor pathway inhibitors, the second-generation ones, for prostate cancer. And the reason why this is important is because for some time, as we have developed these new therapies, there's been a lot of concern that there have been disparities in access to these novel therapies because of how expensive they are, particularly for the Medicare population. And so one of the reasons why we looked specifically at this time period was to understand whether or not, in more recent years, these novel therapies, people are having increasing disparities in them and whether or not increasing disparities in these more expensive, newer therapies is contributing to disparities in mortality. That being said, obviously, we're in 2025 and these data are by now six years old, and so there are additional therapies that are now available that weren't available in the past. But I think that, that being said, at least it's sort of a starting point for some of the more important therapies that have been introduced, at least for non–small cell lung cancer and prostate cancer.

And the database, SEER-Medicare, is helpful because it uses the population cancer registry, which is the SEER registry cancer registry, linked to Medicare claims. So, any type of medical care that's billed through Medicare, which is going to basically be all of the medical care that these patients receive, for the most part, we're going to be able to see it. And so, I think that this is a really powerful database which has been used in a lot of research to understand what kind of care is being received that has been billed through Medicare.

So, one of the limitations with this database is if there is care that's received that was not billed through Medicare, we're not going to be able to see that. And this does not happen probably that frequently, particularly because most patients who have insurance are going to be receiving care through insurance. However, we may see it for some of the oral Part D drugs. Some of those drugs are so expensive that patients cannot pay for the coinsurance during that time. And it's possible that some of those drugs patients were getting for free through the manufacturer. We potentially missed some of that.

Dr. Davide Soldato: So, going a little bit into the results, I think that these are very, very interesting. And probably the most striking one is that when we look at the receipt of any type of treatment for metastatic breast, colorectal, prostate, and lung cancer - and specifically when we look at guideline-directed first-line treatments - you observed striking differences. So, I just wanted you to guide us a little bit through the results and tell us a little bit which of the numbers surprised you the most.

Dr. Lin: So, what we were expecting is to see large disparities in receiving what we called guideline-directed systemic therapy. And guideline-directed systemic therapy during this time kind of depended on the cancer. So, we thought that we were going to see large disparities in guideline-directed therapy because these were the more novel therapies that were approved, and thus they were going to be the more expensive therapies. And so, what this meant was for colorectal cancer, this was going to be any 5-FU–based therapy. For lung cancer, this was going to be any checkpoint inhibitor–based therapy. For prostate cancer, this was going to be any ARPI, so this was going to be things like abiraterone or enzalutamide. And for breast cancer, this was going to be CDK4 and 6 TKIs plus any aromatase inhibitor. And so, for instance, for breast, prostate, and lung cancer, these were going to be including more expensive therapies. And so, what we expected to see was large disparities in receiving some of these more expensive, novel therapies. And we thought we were going to see fewer disparities in receiving some of the cheaper therapies, such as aromatase inhibitors, 5-FU, older platinum chemotherapies for lung cancer, and ADT for prostate cancer.

We were shocked to find that we saw large racial and ethnic disparities in seeing some of the older, cheaper chemotherapies and hormonal therapies. So for instance, for breast cancer, 59% of black patients received systemic therapy, whereas 68% of white patients received systemic therapy. For colorectal, only 23% of black patients received any systemic therapy versus 34% of white patients. For lung, only 26% of black patients received any therapy, whereas 39% of white patients did. And for prostate, only 56% of black patients received any systemic therapy versus 77% of white patients. And so, we were pretty shocked by how large the disparities were in receiving these cheap, easy-to-access systemic therapies.

Dr. Davide Soldato: Thank you very much. So, I just wanted to go a little bit deeper in the results because, as you said, there were striking differences even when we looked at very old and also cheap treatments that, for the majority of the patients that were included inside of your study, were actually basically available for a very small price to these patients who had the eligibility for Medicare or Medicaid. And I think that one of the very interesting parts of the research was actually the attention that you had at looking how much of these disparities could be explained by several factors. And actually, one of the most interesting results is that you observed that low-income subsidy status was actually a big determinant of these disparities in terms of treatment. So, I just wanted to guide us a little bit through these results and then just your opinion about how these results should be interpreted by policymakers.

Dr. Lin: Yeah, absolutely. I'm going to explain a little bit about what low-income subsidy status is and dual-eligibility status. Some of the listeners may not know what low-income subsidy status or dual-eligibility status is. Low-income subsidy status is part of Medicare Part D. Medicare Part D is an insurance benefit that allows patients to receive oral drugs. So these are drugs that are dispensed through the pharmacy, such as the CDK4/6 inhibitors, as well as second-generation ARPIs in our study. For patients who have Medicare Part D and whose income is low enough - falls below a certain federal poverty level threshold - those patients will receive their oral drugs for much cheaper. And this is really important for some of these more novel therapies because for some of these more novel therapies, if you don't have low-income subsidy status, you may be paying thousands of dollars for a single prescription of those drugs. Whereas if you have low-income subsidy status, you may be paying less than $10. And so that difference, greater than $1,000 or $2,000 versus less than $10, one would think that the patient who's paying less than $10 would be much more likely to receive those therapies. So that's low-income subsidy status.

Low-income subsidy status, importantly, doesn't apply for infused medications like immunotherapy. But it's important to know that most people with low-income subsidy status - about 88% - are also dual-eligible. What dual-eligible means is that they have both Medicare and Medicaid. Medicare being the insurance that everybody has in our study who's greater than 65. And Medicaid is the state-run but federally subsidized insurance that patients with low incomes have. And so patients who are dual-eligible - and about 87% of those with low-income subsidy status are dual-eligible - those patients have both Medicaid and Medicare, and they basically pay next to nothing for any of their medical care. And that's because Medicare will reimburse most of the medical care and the copays or coinsurance are going to be covered by Medicaid. So Medicaid is going to pick up the rest of the bill. So, most of the patients who have low-income subsidy status who are dual-eligible, these patients pay almost nothing for their medical care - Part B or Part D, any of their drugs.

And so, one would expect that if cost were the main determinant of disparities in cancer care, then one would expect that dual-eligibles, most of them would be receiving treatment because they're facing minimal to no costs. What we found is that when we broke down the racial and ethnic disparity by a number of factors - including LIS status/dual eligibility, age, the number of comorbidities, etcetera - what we found was that the LIS or dual-eligibility status explained about 20% to 45% of the disparities that we saw in receiving treatment. And what that means is despite these patients paying next to nothing for their drugs, these are the most likely patients to not be treated for their cancer at all. So they're most likely to basically be diagnosed, survive for two months, see an oncologist, and then never receive any systemic therapy for their cancer. And this is not just chemotherapies for colorectal or lung cancer. This includes cheaper, easier-to-tolerate hormonal therapies that you can just take at home for breast cancer, or you can get every six months for prostate cancer, that people who even have poorer functional status are able to take. However, for whatever reason, these dual-eligible or LIS patients are very unlikely to receive treatment compared to any other patient. The low likelihood of treating this group of patients, that explains a large portion of the racial and ethnic disparities that we see.

Dr. Davide Soldato: And one thing that I think is very interesting and might be of potential interest to our listeners is, did you compare survival outcomes in these different settings? And did you observe any significant differences in terms of racial and ethnic disparities once you saw that there was a significant difference when looking at both receipt of any type of treatment and also guideline-directed treatments?

Dr. Lin: We saw that there were large disparities in survival by race and ethnicity when you look overall. However, when you just account for the patients who received any systemic therapy at all - not just guideline-directed systemic therapy - those differences in survival essentially disappeared. And so, what that suggests is that if black patients were just as likely to receive any systemic therapy at all as white patients, we would expect that the survival differences that we were seeing would disappear. And this is not even just looking at guideline-directed systemic therapy. This was looking just at systemic therapy alone. And so, while guideline-directed systemic therapy should be a goal, our research suggests that if we are to close the gap in disparities in overall survival among black and white patients, we must first focus on patients just receiving any type of treatment at all. And that should be the very first focus that policymakers, that leaders in ASCO, that health system leaders, that physicians, that we should focus on: just trying to get any type of treatment to our patients who are poorer or black.

Dr. Davide Soldato: Thank you very much. And this was not directly related to the research that you performed, but going back to this very point - so, increasing the number of patients that receive any kind of systemic treatment before looking at guideline-directed treatments - what would you feel would be the best way to approach this in order to decrease the disparities? Would you look at interventions such as financial navigation or maybe improving referral pathways or providing maybe more culturally adapted information to the patients? Because in the end, what we see is disparities based on racial and ethnicity. We see that we can reduce these disparities if we get these patients to the treatment. But in the end, what would you feel is the best way to bring patients to these types of treatments?

Dr. Lin: I think the most important thing is to understand that these disparities are not primarily happening because of the high cost of cancer treatment. These disparities are happening because of other social vulnerabilities that these patients are facing. And so these vulnerabilities could be a lot of things. It could be mistrust of the medical system. It could be fear of chemotherapy or other treatments. It could be difficulty taking time off of work. It could be any number of things.

What we do know is when we've looked at the types of interventions that can help patients receive treatment, navigation is probably the most effective one. And the reason why I think that is because when patients don't receive treatment because of social vulnerability, I sort of look at social vulnerability like links in a chain. Any weakest link is going to result in the patient not receiving treatment. This may be because they have a hard time taking time off of work. This may be because they had a hard time getting transportation to their physician. It may be because they had an interaction with a physician, but that interaction was challenging for the patient. Maybe they mistrusted the physician. Maybe they're worried about the medical system. If any of these things goes wrong, the patient is not going to be treated. The patient navigator is the only person who can spot any of those weak links within the chain and address them.

And so, I think that the first thing to do is to get patient navigation systems in place for our vulnerable patients throughout the United States. And this is incredibly important because in Medicare, patient navigation is reimbursable. And so this is not something that's 'pie in the sky'. This is something that's achievable today.

The second thing is that it's really important that we see these vulnerabilities happening for patients who are dual-eligible, who have both Medicare and Medicaid. One of the reasons why this is important is because there has been a lot of research outside of what we've done that has shown vulnerabilities for dual-eligible patients who have Medicare for a number of different diseases. And the reason why is because, although patients are supposed to have the benefits of both Medicare and Medicaid, usually these two insurances do not play nicely together. It creates a huge, bureaucratic, complex mess and maze that most of these patients are unable to navigate. And so many of these patients are unable to actually receive the full reimbursement from both Medicare and Medicaid that they should be getting because those two insurers are not communicating well. And so the second thing is that national cancer organizations need to be supporting policies and legislation that is already being discussed in Congress to revamp the dual-eligible system so that it facilitates these patients getting properly reimbursed for their care from both Medicare and Medicaid and these systems working together well.

The third thing is that Medicaid itself has many benefits that can allow patients to receive care, like they have transportation benefits so that patients can get to and from their doctor's appointments with ease. And so I think this will be additionally very, very helpful for patients.

The last thing is, you know, it's possible that future innovations such as telemedicine and tele-oncology and cancer care at home can also make it easier for some of these patients who may be working a lot to receive care.

But what I would say is that our study should be a call for healthcare delivery researchers to start piloting interventions to be able to help these patients receive systemic therapy. And so what this could look like is trying to get that care navigation and implement that in clinics so that patients can be receiving the care that they need.

Dr. Davide Soldato: Thank you very much. That was a very clear perspective on how we can tackle this issue. So, I just wanted to close with a sort of personal question. I was wondering what led you to work specifically in this research field that is very challenging, but I think it's particularly critical in healthcare systems like in the United States.

Dr. Lin: Yeah, absolutely. One of the most important things for me as an oncologist and a researcher is being able to know that all patients in the United States - and obviously abroad - who have cancer should be able to receive the kind of care that they deserve. I don't think that patients, because their incomes are lower or because their skin looks a certain color or because they live in rural areas, these shouldn't be determinants of whether or not cancer patients are receiving the care that they need. We can develop and pioneer the very best treatments and breakthroughs in oncology, but if our patients are not receiving them - if only 20% of our patients with colon cancer or lung cancer are receiving any type of systemic therapy, who are black - this is a big problem. But this is something that I think that our system can tackle. We need to get these breakthroughs that we have in oncology to every single cancer patient in America and every single cancer patient in the world. I think this is a goal that all oncologists should have, and I think that this is something that, honestly, is achievable. I think that research is a powerful tool to give us a lens into understanding exactly why it is that certain patients are not getting the care that they deserve. And my goal is to continue to use research to shed light on why our system is not performing the way that we all want it to be.

Dr. Davide Soldato: Circling back to your research, actually the manuscript that was published was supported by a Young Investigator Award by the American Society of Clinical Oncology. So, was this the first step of a more broad research, or do you have any further plans to go deeper in this topic?

Dr. Lin: Yeah, absolutely. First, I want to thank the ASCO Young Investigator Award for funding this research because I think it's fair to say that this research would not have happened at all without the support of the ASCO YIA. And the fact that ASCO is doing as much as it can to support the future generation of cancer researchers is incredible. And it's a huge resource, and having it come at the time that it did is critical for so many of us. So I think that this is an unbelievable thing that ASCO does and continues to do with all of its partners.

For me, yeah, this is definitely a stepping stone to further research.  Medicare Fee-for-Service is only one part of the population. I want to spread this research and extend it to patients who have other types of insurances, look at other types of policies, and also try to conduct some of the cancer care delivery research that's needed to try to pilot some interventions that can resolve this problem. So hopefully this is the first step in a broader series of studies that we can all do collectively to try to eliminate racial and ethnic disparities in cancer care and survival.

Dr. Davide Soldato: So, I think that we've come at the end of this podcast. Thank you again, Dr. Lin, for joining us today.

Dr. Lin: Thank you so much. It was a pleasure to be a part of this.

Dr. Davide Soldato: So, we appreciate you sharing more on your JCO article, "Racial and Ethnic Disparities Along the Treatment Cascade Among Medicare Fee-for-Service Beneficiaries With Metastatic Breast, Colorectal, Lung, and Prostate 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/podcasts.

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.

This podcast summarizes and provides commentary on the recent article by Yadav et al. in which the authors demonstrate that expansion of the current NCCN guidelines for genetic testing in breast cancer patients to include all women diagnosed at or below the age of 65 markedly improves the sensitivity for detecting pathogenic germline variants without requiring the testing of all breast cancer patients.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "Evaluation of Germline Genetic Testing Criteria in a Hospital-Based Series of Women with Breast Cancer" by Yadav et al. My name is Erin Cobain, and I am a Clinical Lecturer at the University of Michigan Rogel Cancer Center in Ann Arbor, Michigan United States. My oncologic specialty is breast cancer.

In this study, the authors sought to determine the sensitivity and specificity of current genetic testing criteria for the detection of pathogenic germline variants in women with breast cancer. Current national comprehensive cancer network (NCCN) guideline criteria, updated in January 2020, recommend that genetic testing be offered to all women diagnosed with breast cancer at age 45 or younger, those diagnosed with triple negative breast cancer at age 60 or younger as well as those with family history of breast, ovarian, prostate or pancreatic cancer that meet specific criteria. In addition, any patient with Ashkenazi Jewish ancestry is recommended to undergo testing. This most recent update to the guidelines also incorporates a recommendation to offer testing to individuals who have a greater than 5% risk of having a BRCA1 or BRCA2 mutation by prior probability models such as Tyrer-Cuzick or BRCAPro who would not otherwise meet criteria.  Prior to the publication of the present study by Yadav and colleagues, several recent articles including those by Beitsch et al. and Yang et al. indicate that many patients with pathogenic or likely pathogenic germline variants in genes associated with hereditary breast and ovarian cancer syndromes are missed by current testing criteria. The Beitsch et al. study analyzed results from a prospective registry whereby patients with previously or newly diagnosed breast cancer were consented and underwent genetic testing with an 80-gene panel test. Approximately 1,000 patients were enrolled and approximately half met NCCN guideline criteria for genetic testing. Among the patients who met NCCN guideline criteria, 9.4% had a pathogenic or likely pathogenic variant identified. For those patients not meeting NCCN guideline criteria for testing, 7.9% had a pathogenic or likely pathogenic variant. This led the authors to conclude that nearly half of breast cancer patients with pathogenic germline variants would be missed by NCCN criteria. Similarly, Yang and colleagues examined a cohort of patients with personal or family history of breast or gynecologic cancer from a Medicare database undergoing genetic testing. Data from over 4,000 patients tested indicated that the rate of identifying a likely pathogenic or pathogenic germline variant was nearly identical in the cohorts that met NCCN guideline criteria for testing versus those that did not, with the rate of pathogenic germline variants being approximately 10% in both groups. Indeed, the results from these studies lead the American Society of Breast Surgeons to issue a recommendation in October 2019 that all patients with personal history of breast cancer undergo genetic testing. While this recommendation would undoubtedly identify more patients with genetic susceptibility to breast cancer and other malignancies, the implications of this recommendation must be considered. Large scale testing would more readily identify patients with moderate penetrance genes that are without established cancer risk reduction guidelines. More testing also leads to increased identification of variants of uncertain significance, presenting challenges both for patients and their providers attempting to best counsel individuals with an ambiguous result. Finally, inequities in access to testing and genetic counseling resources as well as increased healthcare costs that result from broad testing are of major concern. If cost of testing is not covered by insurance, paying out of pocket may not be feasible for many patients.  In the present study, Yadav and colleagues attempted to address some of these apprehensions regarding the adoption of widespread genetic testing in breast cancer patients. The investigators enrolled patients with personal history of breast cancer over a 16 year period of time into a registry and evaluated for pathogenic germline variants in 9 cancer predisposition genes, including ATM, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, and TP53. These genes were selected because there are clear management recommendations in the NCCN guidelines when they are identified.  The authors found that among almost 4,000 women tested, those meeting current NCCN guideline criteria for testing (comprising 48% of the cohort) were more likely to harbor a pathogenic germline variant than those women who did not meet criteria. The rate of detection of pathogenic germline variants was 9% and 3.5% in these groups respectively. Despite the updated NCCN guideline criteria identifying patients with pathogenic germline variants more readily, there are undoubtedly still patients missed by these criteria. The authors conducted subsequent analysis to include all women diagnosed with breast cancer at age 65 or younger, which achieved 90% specificity for the 9 cancer predisposition genes selected and greater than 98% specificity for identification of pathogenic germline variants in BRCA1 and BRCA2. Given this, the authors concluded that expanding the NCCN genetic testing criteria to include all women diagnosed with breast cancer at or before the age of 65 will markedly improve the sensitivity of genetic testing and avoid the need to evaluate all patients with personal history of breast cancer. The major limitations of this study were that cost-effectiveness of this approach was not analyzed, and the majority of the patients included in the registry were White, limiting the applicability of these findings to a diverse patient population. Despite these limitations, this study offers a promising and considered approach to genetic testing in patients with personal history of breast cancer. While validation of this approach in additional study cohorts would be of great value, this data strongly suggests that testing all patients at or below age 65 at the time of breast cancer diagnosis achieves a balance between the two current testing paradigms, identifying the vast majority of patients at risk, and avoiding unnecessary testing of many.

This concludes this JCO Podcast. Thank you for listening.

The combination of pembrolizumab and lenvatinib is a promising second line option for metastatic or recurrent MSS endometrial cancer, although there can be considerable toxicity and choosing appropriate patients is key.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "Lenvatinib and Pembrolizumab in Patients With Advanced Endometrial Cancer" by Makker et al. My name is Meghan Shea, and I am an Instructor of Medicine at Harvard Medical School at Beth Israel Deaconess Medical Center in Boston, Massachusetts. My oncologic specialty is gynecologic oncology.

Patients with advanced endometrial carcinoma have limited options after receiving the carboplatin and paclitaxel doublet for recurrent or metastatic disease. The study that accompanies this podcast evaluates the combination pembrolizumab and lenvatinib, providing a much needed second-line option for this patient population. The approval of single-agent pembrolizumab for tumors with microsatellite instability (from here on referred to as MSI high) does not have immediate relevance for the majority of patients with advanced endometrial carcinoma who have microsatellite stable disease (from here on referred to as MSS). Makker et al. now report the results of an ongoing phase 1b/2 study of pembrolizumab, an anti-PD1 antibody, and lenvatinib, an oral tyrosine kinase inhibitor that targets the VEGF-receptor, in patients with metastatic endometrial carcinoma. Eligibility criteria included patients with an ECOG 0 to 1 who had confirmed metastatic disease with less than or equal to 2 prior lines of systemic therapy. Notably the majority were not heavily pre-treated; 52.8% of patients in the study had only one prior line of systemic treatment.

Patients received lenvatinib 20 mg once daily orally continuously and pembrolizumab 200 mg intravenously every 3 weeks – with a maximum duration of 2 years for pembrolizumab. All patients had imaging at baseline and then every 6 weeks for first 24 weeks and then every 9 weeks thereafter. The primary end point was objective response rate at 24 weeks. Forty-one of the 108 patients, 38%, had a response at 24 weeks with a median follow up of 18.7 months.  As expected, the MSI high tumors had a higher response rate of 63.6%, although this was a minority of the study population, only 11 patients. Most importantly, the patients with MSS tumors had a response rate of 37.2% with a median duration of response of 21.2 months. The histology did not appear to impact the response rate – the majority of patients had endometrioid (50.9%), although the study population also contained a reasonable proportion of serous and clear cell (38%) compared to the expected frequency in the general population of advanced uterine cancers. The PD-L1 status positive or negative did not correlate with response.

One might question, before accepting a complicated regimen with both oral and IV chemotherapy as a new second-line standard option, whether anyone has studied the activity of either single agent lenvatinib or single agent pembolizumab in a similar population, especially for those with MSS disease. With the caveats of cross study comparisons, it appears that neither single agent is as active as the current combination. For instance, Vergote et al reported results of a phase 2 study of lenvatinib monotherapy for advanced endometrial cancer, where the response rate was only 14.3% with median progression free survival of 5.4 months. Likewise, Ott et al studied single agent pembrolizumab in endometrial cancer with 18 of 19 patients having MSS cancer, resulting in only a 13% response rate and progression free survival of 1.8 months.

             So you may be wondering, what's the catch? The issue is the potential toxicity of this doublet regimen, with 66.9% or 83 of 108 patients, having a grade 3 or 4 treatment-related adverse event. Overall 17.7% of the patients discontinued one or both drugs. Notably, pembrolizumab was never dose reduced - only dose held or discontinued. Most strikingly, 62.9%, roughly two thirds of patients, required a dose reduction of lenvatinib. Only 11 patients (that is 8.9%) stayed on full dose 20 mg of lenvatinib for greater than 6 months. The average dose for lenvatinib was 14.4 mg daily. The toxicity profile of lenvatinib may be related to the fact that it is a multi-targeted tyrosine kinase inhibitor that targets not only vascular endothelial growth factor receptors, but also fibroblast growth factor receptors, platelet-derived growth factor receptor alpha, RET and KIT.

There were 51 deaths during this study; the majority occurred during follow up due to progression of disease. However, there were 16 deaths while on study, 4 considered treatment emergent adverse events and 2 judged to be treatment related.  The four deemed treatment emergent were due to gastrointestinal perforation, intestinal obstruction, general health deterioration and metabolic encephalopathy. The two deemed treatment related were from septic shock and intracranial hemorrhage.

The National Comprehensive Cancer Network (NCCN) guidelines have added the combination of pembrolizumab and lenvatinib to their list of second line therapeutic options, and it also has been approved by the Food and Drug Administration (FDA). This recognizes the fact that this combination has the highest response rate of the available drugs listed, and thus should be a strong consideration for second line therapy for patients with MSS endometrial carcinoma. However, ensuring that this treatment is appropriate for a given patient is of the utmost importance.  First the patient must be a candidate for immunotherapy – ideally not on chronic prednisone and/or have an active autoimmune disease. In contrast to prescribing single agent anti-PD-1 or anti-PD-L1, a performance status of 0 to 1 is important with this combination. The most appropriate patient should have controlled blood pressure prior to initiating drug, be able to monitor their blood pressures, take their oral chemotherapy as prescribed, and readily report any new symptoms. I avoid prescribing this drug combination if the patient has a bleeding disorder, recent clotting, uncontrolled hypertension, or is at high risk of a fistula or bowel obstruction. Lenvatinib is a renally-cleared drug, and thus patients with a reduced glomerular filtration rate (GFR) require renal dosing. This is especially relevant for patients with recurrent uterine cancer, whose kidney function is dynamic, especially in the setting of hydronephrosis. In my practice, I consider starting patients with normal renal function at 14 mg lenvatinib daily, given that the vast majority of patients on study were eventually dose-reduced. Furthermore, I might start the lenvatinib dosing even lower for patients with dynamic renal function and for those who have a baseline GFR lower than 30.

Overall this study provides a promising second line option for metastatic or recurrent MSS endometrial cancer, with responders having a durable response.  Patient selection and dose adjustments are key considerations to avoiding and managing toxicity.

This concludes this JCO Podcast. Thank you for listening.

This podcast will discuss the findings from a phase II trial of gemcitabine, cisplatin and PARP inhibitor therapy in germline BRCA/PALB2 mutant pancreatic cancer and discuss an optimal treatment strategy in this setting.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "A Randomized, Multi-Center, Phase II Trial of Gemcitabine, Cisplatin with or without Veliparib in Patients with Pancreas Adenocarcinoma and a Germline BRCA/ PALB2 Mutation" by O'Reilly et al. My name is Daniel Renouf, and I am a medical oncologist at the BC Cancer Vancouver Centre in Vancouver, Canada. My oncologic specialty is pancreatic cancer.

In this podcast, we will be discussing an important and evolving area that is changing our standard treatment strategies for pancreatic cancer. Progress has been slow for pancreatic adenocarcinoma, which is now the third leading cause of cancer-related death in North America and is projected to become the second leading cause of cancer-related death within the next decade. Modest gains in our treatments have been achieved with new chemotherapy combinations, including FOLFIRINOX and gemcitabine and nano-albumen bound-paclitaxel, yet still the majority of patients diagnosed with advanced disease will live for less than one year.

There is a critical need for improved treatment options as well as clinically relevant predictive markers to guide our therapeutic decision making. The first clinically important predictive marker in pancreatic cancer is germline BRCA/PALB2 mutation status, which is present in 5-9% of pancreatic adenocarcinomas. Multiple translational studies and case series have demonstrated distinct molecular features of these tumors, as well as unique clinical characteristics. Germline BRCA/PALB2 mutant pancreatic adenocarcinomas have been noted to be sensitive to platinum agents and be associated with a better prognosis. Despite this data, and a general acceptance within the community that platinum agents are the preferred therapies in this setting, there is minimal prospective trial data specifically assessing the activity of platinum combinations in germline BRCA/PALB2 mutant pancreatic adenocarcinoma.

At a plenary session at ASCO 2019 and its subsequent publication, the POLO trial assessed the role of maintenance therapy with a poly-ADP ribose polymerase (PARP) inhibitor (olaparib), compared to placebo, in patients with metastatic pancreatic adenocarcinoma and germline mutations in BRCA/PALB2 who had responded or had stable disease after initial therapy with FOLFIRINOX. This was a positive trial, demonstrating that maintenance olaparib significantly improved progression-free survival compared to placebo. There was no difference noted in overall survival, but this data was not yet mature. The role of combining a PARP inhibitor with platinum-based chemotherapy as upfront treatment in this patient population is yet to be defined.  A previous Phase I trial of gemcitabine, cisplatin and the PARP inhibitor veliparib determined a recommended phase II dose for velipirib in this combination and demonstrated promising efficacy in germline BRCA-mutant pancreatic adenocarcinoma.

In the article that accompanies this podcast, Dr. O'Reilly and colleagues report on the results of a phase II prospective trial comparing gemcitabine and cisplatin versus gemcitabine, cisplatin and veliparib in patients with advanced pancreatic adenocarcinoma with germline aberrations in BRCA/PALB2. In the trial, patients with locally advanced or metastatic pancreatic cancer who had not received chemotherapy in the advanced setting, had a good performance status, and who harbored germline aberrations in BRCA/PALB2 were randomized.

A total of 50 patients were enrolled, and the results demonstrated good efficacy in both arms, with a response rate of 74.1% in the veliparib arm and 65.2% in the control arm. Median progression-free survival was 10.1 months and 9.7 in the veliparib and non-veliparib arms respectively, and median overall survival was 15.5 and 16.4 months. Of note, for the entire cohort, 2-year overall survival was notably high at 30.6%, and 3-year overall survival was 17.8%. Grade 3-4 toxicities, including neutropenia, thrombocytopenia, and anemia were greater in the veliparib arm.

The authors concluded that gemcitabine and cisplatin demonstrated significant activity in BRCA/PALB2 germline mutant pancreatic adenocarcinoma, and the addition of concurrent veliparib did not improve efficacy. Given this promising data, it was concluded that gemcitabine and cisplatin should be considered a standard treatment for BRCA/PALB2 germline mutant pancreatic adenocarcinoma.

This is an important trial, as it is one of the first to specifically assess platinum chemotherapy prospectively in this patient population and has important implications for treatment strategies for pancreatic cancer, the first of which is that testing for germline BRCA/PALB2 mutations should now be considered standard of care for all newly diagnosed pancreatic adenocarcinomas. Not only does this have important treatment implications for the patient; it also has strong relevance to the patients' family members, as it was found to also harbor a germline BRCA/PALB2 mutation. Screening and potential prevention strategies could be considered for other cancers, such as breast and ovarian.

Secondly, if a patient is found to have a germline BRCA/PALB2 mutation, the data from this trial in combination with the body of literature in this setting would suggest that first line therapy with a platinum agent should be considered. In this setting, one could consider either FOLFIRINOX or gemcitabine and cisplatin. The efficacy of gemcitabine and nano albumen bound-paclitaxel in this patient population is not clearly defined, but in the context of data from other disease sites also demonstrating increased sensitivity to platinum in this patient population, and given many patients with advanced pancreatic adenocarcinoma are often not well enough to received multiple lines of therapy, a first line platinum combination should be strongly considered. Thirdly, this trial demonstrates that there is no additional benefit from adding a PARP inhibitor to chemotherapy in this setting, but there is added toxicity, and thus this strategy should not be considered at this time.

Finally, given that toxicity from platinum-based chemotherapy is cumulative, the question of an optimal maintenance strategy remains. The POLO trial demonstrated that there is activity and a progression-free survival benefit when using olaparib as a maintenance post upfront platinum-based chemotherapy when compared to placebo, and therefore this represents one potential strategy. One criticism of the POLO trial is that many centers do not stop treatment and instead continue therapy without the platinum after an initial response. In patients responding to initial treatment with FOLFIRINOX, maintenance FOLFIRI is often considered. Data from a second line trial of FOLFIRI with or without veliparib presented as a poster discussion at ASCO 2019 by Dr. Chiorean and colleagues noted that BRCA/PALB2 mutant tumors also appear to have increased sensitivity to FOLFIRI. At this time, the optimal maintenance strategy after upfront platinum therapy is yet to be fully defined, and further research in this setting is needed. In addition, to what extent these strategies should be applied to patients with pancreatic adenocarcinomas that are germline BRCA/PALB2 wildtype but have other homologous recombination deficiency defects requires further investigation.

In summary, this is an exciting time in pancreatic adenocarcinoma as we now have a clinically important biomarker to guide treatment strategies. This important trial by Dr. O'Reilly and colleagues further solidifies the importance of BRCA/PALB2 germline testing in pancreatic adenocarcinoma and that first line platinum-based chemotherapy should be considered in these patients.

This concludes this JCO Podcast. Thank you for listening.

Towards improved characterization of immune-related adverse events in the setting of pre-existing autoimmune disease.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "Immune Checkpoint Inhibitor Therapy in Patients with Preexisting Inflammatory Bowel Disease", by Abu-Sbeih et al. My name is Katy Tsai, and I am Assistant Professor of Medicine in the Division of Hematology/Oncology at the University of California, San Francisco. My oncologic specialty is the treatment of advanced melanoma and non-melanoma skin cancers.

Immune checkpoint inhibitors, referred to as ICIs in this podcast, have transformed the landscape of treatment options in oncology. While ICIs were first approved for the treatment of advanced melanoma in 2011, since that time, ICIs have shown activity in a variety of other histologies. Anti-PD-1 or anti-PD-L1, with or without anti-CTLA-4, are now approved for the treatment of lung cancer, head and neck squamous cell carcinoma, renal cell carcinoma, and many others. While ICIs can result in durable responses, their continued use can be limited by the development of immune-related adverse eventsimmune-related adverse events. Because these events are believed to be autoimmune in nature, there are intuitive safety concerns about ICI use in patients with known autoimmune disease. Can patients with pre-existing autoimmune disease be safely treated with ICI? Are these patients more likely to experience immune-related adverse events related to their autoimmune disease? Is this risk increased if their autoimmune disease is severe, with a history of required immunosuppression? These are all important questions faced by healthcare providers, questions which are not well studied due to the exclusion of patients with known autoimmune disease from pivotal ICI clinical trials.

To address these questions, Abu-Sbeih and colleagues chose to focus on ICI use in patients with pre-existing inflammatory bowel disease. This is a clinically relevant population of interest, given the relatively high incidence of immune-related diarrhea and colitis with ICI use; these immune-related adverse events occur in almost half of patients receiving combination anti-CTLA-4 and anti-PD-1 or PD-L1, about one-third of patients receiving anti-CTLA-4, and less frequently in patients receiving anti-PD-1 or PD-L1 alone. Abu-Sbeih and colleagues conducted a retrospective, multicenter study in which 102 patients – half with Crohn's disease, half with ulcerative colitis – received ICI between 2010 and 2019. 17 patients received anti-CTLA-4, and 85 received anti-PD-1 or anti-PD-L1. This is a notable cohort of patients, as previous meta-analyses have reported on the safety of ICI use in much smaller numbers of patients with inflammatory bowel disease, and with less detailed clinical characterization of their inflammatory bowel disease. Univariate and multivariate logistic regression were used to assess the risk of gastrointestinal, or GI, adverse events, and was compared to a control population of 11,377 ICI-treated patients without inflammatory bowel disease, from the same participating institutions.

An important observation made by the authors was that the rate of GI immune-related adverse events in the inflammatory bowel disease cohort was significantly higher at 41%, compared to 11% in the non-inflammatory bowel disease cohort. Univariate analysis identified anti-CTLA-4 (given as monotherapy or in combination) as a risk factor for GI immune-related adverse events compared to anti-PD-1/L1 therapy but showed only a tendency toward significance in multivariate analysis, as did inflammatory bowel disease involving the colon. Although none of the collected clinical variables reached significance in multivariate analysis, the authors' analysis of outcomes in the inflammatory bowel disease cohort is illuminating. Of the 41 inflammatory bowel disease patients who developed diarrhea, 51% had peak grade 3 or 4 diarrhea, 76% received glucocorticoids, and 29% required additional immunosuppression with infliximab or vedolizumab. 4% developed colonic perforation, with half of those patients requiring surgical intervention. Also of note, patients who were identified as having active inflammatory bowel disease within 3 months of ICI start had higher grade diarrhea compared to patients with inactive inflammatory bowel disease. Endoscopy data were also available for 48 inflammatory bowel disease patients. Interestingly, of the 41 patients who were noted to have normal or mild inflammatory findings, 18 (43%) developed any GI immune-related adverse events, 5 (12%) of which were grades 3-4. In the 7 patients with moderate/severe inflammatory findings, 5 (71%) had GI immune-related adverse events of any grade, 2 (29%) of which were grades 3-4.

Despite the higher rate of GI immune-related adverse events and associated complications in the inflammatory bowel disease cohort compared to the non-inflammatory bowel disease cohort, there were no fatalities. Additionally, 48% of patients in the inflammatory bowel disease cohort were identified as having complete response, partial response, or stable disease to ICI therapy, a clinical benefit rate similar to those reported in ICI clinical trials. It seems, then, that the benefits of ICI therapy in this population may well outweigh the risks, particularly for patients with inflammatory bowel disease who may have no viable alternative therapy available for their malignancy.

Overall, despite the inherent limitations of retrospective analysis, this work represents the largest study to date investigating the risk of GI immune-related adverse events in patients with cancer and comorbid inflammatory bowel disease who were treated with ICIs. It provides evidence for increased incidence and severity of GI immune-related adverse events, and complications thereof, in a well-annotated cohort of patients with inflammatory bowel disease. As these patients continued to receive clinical benefit from their ICI therapy, these findings can help better inform pre-ICI treatment counseling in patients with preexisting inflammatory bowel disease, and better prepare them for expected risks of treatment. At the same time, this work also raises a number of questions for further investigation. Is anti-CTLA-4 truly safe to use in this population, or was this limited by the small number of patients receiving anti-CTLA-4 in this study? Should ICI therapy be delayed to allow for optimal treatment of active inflammatory bowel disease, to decrease the risk of severe GI immune-related adverse events? What additional guidance can be given to providers regarding when to initiate additional immunosuppressive therapy, and should this be driven by endoscopic findings? These questions and more can and should be investigated in future larger-scale prospective studies. For the time being, based on the data presented, I would certainly be more cautious about giving a more aggressive immunotherapy regimen – that is, combination anti-CTLA-4 and anti-PD-1/L-1 – in a patient with highly symptomatic inflammatory bowel disease. Also, while numbers in this study were small, it seems that endoscopic evaluation prior to ICI start could be helpful in risk stratifying for severe GI IRAE. While inflammatory findings on endoscopy may not necessarily be an absolute contraindication to use of ICI, it seems these results would certainly be helpful in shared decision-making with the patient regarding their risk of developing GI IRAE and weighing other potential treatment options. Finally, and most importantly, this data demonstrates that some patients with inflammatory bowel disease who receive ICI for their malignancy can derive clinical benefit with manageable toxicities, suggesting that the mere presence of comorbid inflammatory bowel disease should not be a blanket exclusion criterion for ICI clinical trials.

This concludes this JCO Podcast. Thank you for listening.

This podcast describes a study examining aerobic capacity in a cohort of over 1200 adult survivors of childhood cancer and related impairments of cardiac, pulmonary and neuromuscular body systems, to understand how aerobic capacity influences all-cause mortality.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article 'Exercise Intolerance, Mortality, and Organ System Impairment in Adult Survivors of Childhood Cancer' by Ness et al. My name is Kristin Campbell, and I am a licenced physical therapist and associate professor in the Faculty of Medicine at the University of British Columbia in Vancouver, Canada. My oncologic specialty is in rehabilitation, primarily related to breast cancer.

Exercise intolerance is a global measure of functional capacity that reflects the complex integration of body systems. It is well established in the general population that exercise intolerance is predictive of future cardiovascular health and mortality. Whether this relationship also existed for adult survivors of childhood cancer was examined by Ness and colleagues in the article that accompanies this podcast. . In the largest study to date of its kind, this manuscript reports on a comprehensive and methodologically rigorous examination of exercise intolerance measured by a gold standard maximal cardiopulmonary exercise test in over 1200 adult survivors of childhood cancer who are part of the St. Jude's Lifetime Cohort Study.

The first main finding is the low levels of exercise capacity in this sample of childhood cancer survivors despite a relatively young mean age of 35 years. The observed maximal aerobic capacity, or VO2peak, ranged on average between 25-27 ml/kg/min, which fall into the "poor" or "very poor" categories of age and sex matched normative values. Compared to 285 community controls who were friends or family members of the cohort patients, the observed maximal aerobic capacity values for childhood cancer survivors were on average 22% lower. In fact, these values are actually more consistent with values seen in healthy adults in their seventies or eighties. Furthermore, the low value of maximal aerobic capacity may also be an underestimate. Thirteen percent of individuals in the St. Jude's cohort who agreed to participate in the study were not cleared to undertake the maximal cardiopulmonary exercise test due to recent diagnosis of cardiac or pulmonary disease, or lab values and symptoms indicating cardiac or pulmonary issues. This suggests that the prevalence of exercise intolerance may be even greater in a real-world clinical setting than that observed in this cohort.

To examine the association between exercise intolerance and mortality, the authors defined exercise intolerance as a maximal aerobic capacity of < 85% of predicted VO2peak. Using this approach. 56% of childhood cancer survivors were categorized with exercise intolerance compared to only 26% in controls. In addition to the high prevalence, exercise intolerance in childhood cancer survivors increased hazard of death nearly four-fold compared to those without exercise intolerance. Of the 24 deaths observed, 21 were seen in those categorized as having exercise intolerance compared to only 3 in those categorized without exercise intolerance. This highlights the potential importance of developing and implementing effective interventions that aim to increase physical activity levels and exercise tolerance in childhood cancer survivors with the goal of improving long-term health and survival.

A unique feature of this study is that the authors also undertook comprehensive measures of host, treatment, and lifestyle factors to better understand how these factors influence exercise intolerance. These additional measures included cardiac imaging at rest, autonomic response, measured by blood pressure response to the maximal graded exercise test, standard pulmonary function testing, quadriceps strength testing, and peripheral sensorimotor function using the modified total neuropathy scale. This data provides a rare look into the acute and chronic responses to exercise of the cardiovascular, pulmonary, autonomic and neuromuscular systems in those exposed or not exposed to cardiotoxic agents and will appeal to those an interest in exercise physiology. Odds of exercise intolerance were highest with reporting <150 minutes per week of moderate to vigorous physical activity, lower quadriceps strength, chronotropic incompetence, FEV1 <80% of predicted, non-white race, and poorer diet quality. These findings provide guidance around key factors that could be used to design effective interventions and monitor response to interventions, with a goal to improve exercise tolerance in childhood cancer survivors.

Of note, the type of treatment received impacted the presentation of exercise intolerance. Lower exercise tolerance was observed in individuals who received >350 mg/m2 of anthracyclines, >30 Gy of chest radiation, >20 Gy of cranial radiation and receipt of carboplatin. As a result, the authors suggest that even asymptomatic childhood cancer survivors who have received these treatments be screened by medical providers for any required medical management prior to recommending or implementing an exercise program.  Furthermore, while ejection fraction of <53% was not associated with exercise intolerance, global longitudinal strain > 1.5 SD above age- and sex-predicted increased the odds of exercise intolerance with an odds ratio of 1.71 in those exposed to cardiotoxic agents and an odds ratio of 1.29 in those not exposed to cardiotoxic agents. The authors suggest that the use of echocardiology derived strain be expanded from current published guidelines from the American Society of Clinical Oncology on Prevention and Monitoring of Cardiac Dysfunction to identify early cardiac dysfunction in childhood cancer survivors with exercise intolerance and normal ejection fraction.

The study does have some key limitations. It is cross-sectional in design, making it difficult to assign temporal relationships between impairments in body systems and exercise tolerance. For example, is it the treatment that causes impairments in body systems that then limit exercise tolerance, or does situational inactivity due to side-effects of cancer treatment drive exercise intolerance and this in turn negatively impacts the exercise response of body systems? Furthermore, while there was a high participation rate and participants did not differ from non-participants by age, race or sex, not all eligible survivors enrolled. This may over or underestimate the prevalence of exercise intolerance or impact on mortality.

In considering the implications of these findings to clinical oncology, the authors acknowledge that adult survivors of childhood cancer face unique challenges in engaging in physical activity. In light of the high prevalence of exercise intolerance in childhood cancer survivors and the association to all cause mortality, the authors suggest that survivors may require referral to trained exercise specialists to learn how to accommodate specific impairments and deficits in order to reap the benefits of engaging in exercise. In the United States, the appropriate exercise specialists could include physical therapists, occupational specialists, certified exercise physiologists or physical medicine and rehabilitation specialists. Oncology providers are encouraged to include these individuals on their care teams and establish a connection to available programming in their healthcare facility or community to provide adult survivors of childhood cancer with greater access to appropriate exercise programming aimed at improving exercise tolerance.

This concludes this JCO podcast. Thank you for listening.

This podcast describes the results of the BLOOM study, evaluating the efficacy of osimertinib in EGFR-mutated lung cancer with leptomeningeal disease after failure of prior EGFR TKI therapy.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "Osimertinib In Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer and Leptomeningeal Metastases: The BLOOM Study" by Yang et al. My name is Jürgen Wolf and I am the medical director of the Center for Integrated Oncology at the University Hospital of Cologne in Germany. I am a medical oncologist with expertise in personalized lung cancer care.

About 10% of patients with advanced EGFR-mutated lung cancer suffer from leptomeningeal disease. While this disease manifestation in non-small-cell lung cancer is generally associated with a particularly poor prognosis, with survival times of only a few months, the question arises whether treatment with specific tyrosine kinase inhibitors might enable a better disease control. Most studies evaluating the efficacy of 1st and 2nd generation EGFR-TKIs in leptomeningeal disease were retrospective and difficult to interpret, given the heterogeneity of the disease as well as of the preceding treatment procedures. Small prospective studies with patient numbers below 20 tested standard dose erlotinib or afatinib as well as high-dose pulsatile EGFR TKI treatment and reported disappointing results with survival times of around 4 months only.

The 3rd generation EGFR TKI osimertinib initially was approved for T790M positive failure of 1st and 2nd generation EGFR TKIs and is now commonly regarded as 1st line standard treatment for EGFR-mutated lung cancer based on a superior progression-free survival, overall survival and toxicity profile. In studies with primates and healthy volunteers, osimertinib has been shown to exert a higher blood-brain barrier permeability and a higher brain exposure compared with other TKIs. In the AURA clinical development program for osimertinib, 22 patients with T790M-positive relapse after EGFR TKI treatment and leptomeningeal disease were retrospectively identified, and an impressive median overall survival of 18.8 months was reported. A small prospective Japanese trial evaluated osimertinib in 13 patients with T790M-positive leptomeningeal disease which, however, could be confirmed only in 5 patients. Responses were seen in some patients, and the median progression free survival for all patients was reported with 7.2 months.

The BLOOM study part B, which is discussed in this podcast, is a multicenter phase I study evaluating osimertinib in EGFR-mutated lung cancer patients with leptomeningeal metastases and failure of previous EGFR TKI treatment. Study objectives were the assessment of clinical parameters like response, overall survival neurological status, and safety but also pharmacokinetics in blood and cerebrospinal fluid. Main inclusion criteria included confirmed diagnosis of EGFR Exon 19 deletion or L858R mutation and confirmation of leptomeningeal disease by positive cytology of cerebrospinal fluid and at least one leptomeningeal site assessable by MRI. There were two sequential cohorts, one unselected for the T790M mutation and with stable non-CNS disease at enrollment, and one for T790M positive patients without the requirement for stable non-CNS disease. Osimertinib dose was 160 mg once daily, which is twice the approved dose. Besides investigator-based response assessment, according to RECIST, leptomeningeal disease was also assessed by a neuroradiological blinded central review according to the RANO-LM working group criteria, which integrates clinical examination, cerebrospinal fluid cytology and neuraxis MRI.

41 patients from South Korea and Taiwan were included, 20 in the unselected and 21 in the T790M-positive cohort. About 70% of the patients had co-existing brain mets and about 50% prior radiotherapy. For 4 patients, no response data from the independent review were available.

The confirmed overall response rate for leptomeningeal disease was impressive at 62% as assessed by blinded independent review and nearly identical between both cohorts.  By comparison, the overall response rate was only 27% by investigator assessment, which, in turn, revealed a higher stable disease rate. Prior brain radiotherapy had no influence on efficacy. Median duration of response was comparable between blinded independent review and investigator, with 15.2 and 18.9 months, respectively. In about one third of the evaluable patients confirmed CSF clearance could be observed. PK analysis indicated that plasma concentration of osimertinib and its active metabolites reached steady state by day 15; the ratio for osimertinib exposure in cerebrospinal fluid vs. plasma was around 16%.

Surprisingly, only half of the patients had an abnormal neurological baseline assessment, most of them with mild symptoms. Symptom stabilization occurred in 54% during treatment; only 5% showed regression of neurological functions.

Overall, median progression-free survival, as assessed by the investigators, was 8.6 months and median overall survival 11 months. Progression-free survival and overall survival differed markedly between both cohorts. For instance, overall survival was 16.6 months in the unselected and 8.1 months in the selected group. Possibly, the requirement for stable non-CNS disease in the unselected group was partly responsible for the better survival outcome in this subset . However, this has to be interpreted cautiously in view of small patient numbers and large confidence intervals.

Osimertinib 160mg was well tolerated in the majority of patients with the known osimertinib side-effect profile. However, 24% of the patients suffered from adverse events grade 3 or more—possibly related to osimertinib, according to the investigators' assessment. Dose reduction had to be performed in 12% and discontinuation of treatment in 22% of the patients due to adverse events. 17% of the patients had fatal events that did not appear to be causally related to osimertinib.

What can we learn from this study? This is the largest prospective study so far in this setting and osimertinib clearly shows clinical efficacy. The study methodology was sound, with response assessment by blinded independent review and based on RECIST criteria as well as on the RANO criteria established in particular for leptomeningeal disease. The overall response rate of leptomeningeal disease of around 60% and the duration of response of around 15 months is clinically relevant in particular, as it is correlated with improvement or at least neurological stabilization in most patients. Although the toxicity of the treatment is substantially higher than reported in osimertinib trials so far, it is manageable, and the risk/benefit ratio appears to be favorable.

What are the limitations of the study? Patient numbers are small, and the patients are heterogeneous with respect to several important factors such as pretreatment whole-brain radiotherapy, occurrence of simultaneous CNS metastases and neurological symptoms. Thus, absolute values for efficacy have to be interpreted cautiously, and comparison with already published trials remains difficult. Also, unfortunately in view of the toxicity, the question remains open whether the 160mg dose, which is not approved, is actually necessary. Finally, since osimertinib increasingly becomes the first-line treatment standard in EGFR-mutated lung cancer, the number of patients with failure of 1st- or 2nd-generation EGFR TKI treatment will decrease.

Despite these limitations, the trial provides the most convincing data so far in this special patient population and, in my opinion, defines  an important new option to consider for patients with EGFR-mutated lung cancer and leptomeningeal disease after failure of previous EGFR TKI treatment.

This concludes this JCO Podcast. Thank you for listening.

This podcast reviews the results of KEYNOTE 164 investigating the use of pembrolizumab for mismatch repair deficient metastatic colorectal cancer, the place of this agent in the current clinical paradigm, and future directions to identify which patients are most likely to benefit from this treatment strategy.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article 'A Phase II, Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: KEYNOTE-164' by Le et al. My name is Dustin Deming, and I am an associate professor at the University of Wisconsin Carbone Cancer Center in Madison, Wisconsin. My oncologic specialty is gastrointestinal oncology.

Microsatellite instability high status or mismatch repair deficiency is found in approximately 15% of early stage colorectal cancers, but only 3-4% of metastatic colorectal cancer. The mechanisms by which these cancers acquire their DNA repair aberrations can vary, including germline mutations, somatic mutations and promoter methylation, which is often observed in the setting of the hypermethylation phenotype associated with BRAF mutations. This distinct colorectal cancer subtype is of particular interest for immunotherapy strategies as the lack of adequate mismatch repair can lead to 1000s of mutations and also fusions leading to the potential for expression of more neoantigens.

This world-wide phase 2, open-label study enrolled 124 patients with microsatellite instability high or metastatic mismatch repair deficient colorectal cancer following 2 or more lines of standard therapy in cohort A and following 1 or more lines of therapy in cohort B. Patients received pembrolizumab 200 mg every 3 weeks, up to 2 years, until progression, unacceptable toxicity, or withdrawal. The primary endpoint was objective response rate by Response Evaluation Criteria in Solid Tumors version 1.1 by independent central review and secondary endpoints included duration of response progression-free survival, overall survival, safety and tolerability.

At the time of this report the median follow-up for cohort A was 31.3 months and 24.2 months for cohort B. The objective response rate was 33% for both cohorts. This includes 7 patients who achieved a complete response. The median PFS was 2.3 months for cohort A and 4.1 months for cohort B. For those patients that developed an objective response the duration of response was quite prolonged with the median duration of response not reached in either cohort. The median overall survival was 31.4 months for cohort A and not reached in cohort B. This treatment was well-tolerated in this population with the most common toxicities being fatigue, pancreatitis, and increased alanine aminotransferase or lipase.

Overall pembrolizumab is an exciting addition to the treatment strategy for patients with metastatic mismatch repair deficient cancers. Based on these results, in part, this agent is now FDA approved for patients with previously treated microsatellite instability high or mismatch repair deficient metastatic colon cancers after fluoropyrimidine, oxaliplatin, and irinotecan, and for patients also for non-colorectal solid tumors following at least one prior therapy, regardless of tumor type or origin. This was the first FDA approval of a tumor histology agnostic anticancer therapy.

Long-term follow-up from this, and similar cohorts, is required to further define the duration of response for these patients, as there is hope that some of these patients could even be cured. Unfortunately, it is only a minority of patients that seem to benefit from this approach as demonstrated by the short median progression free survival in both cohorts. A better understanding of which patients are likely to benefit from immunotherapy approaches are clearly needed. 

The presence of Lynch syndrome was not captured in this study to evaluate for differential response in this setting. The BRAF mutation status was collected and across both cohorts 14 patients had BRAF mutant cancers. The response rate for these patients was 43%. A similar benefit was also observed in KRAS or NRAS mutant and wild-type cancers. This study was limited in its ability to further assess those factors that could influence pembrolizumab response given the relatively small sample size and limited biospecimen collection.

Further clinical trials are investigating the use of anti-PD1 therapies for these patients in the first-line and adjuvant settings, in combination with chemotherapy and with other immune checkpoint agents, such as CTLA4 and LAG3, among others. This includes Checkmate 142, which is a phase II study that is examining nivolumab and ipilimumab in a cohort of 46 patients with microsatellite instability high or mismatch repair deficient colorectal cancer in the first-line setting. Preliminary results were presented at the 2018 European Society of Medical Oncology meeting demonstrating a 60% objective response rate and a 12 month progression free survival of 77%. These early results are promising, but further investigation is needed.

As we look forward to which factors could be leading to a lack of clinical benefit from these agents it is important to consider those factors that are intrinsic to the cancer cells, tumor microenvironment, and patient specific factors. Tumor cell intrinsic factors include important cell attributes for the immune response such as the tumor mutation burden, MHC class I expression, including beta-2-microglobulin expression, the mutation profile, including alterations in WNT signaling shown to be important for immunotherapy resistance in metastatic melanoma, and tumor heterogeneity. There is also a growing understanding of factors that are important within the tumor microenvironment for tumors to be permissive to immune cell infiltration. These factors include differences in the immune and fibroblast cell subtypes present and also the presence of certain matrix proteins. This includes a matrix proteoglycan called versican that my laboratory and others have demonstrated has immunosuppressive properties, but can be cleaved by ADAMTS proteases to an immunostimulatory fragment. Additionally, patient specific factors need to be considered such as the microbiome, immunosuppression and adverse event management.

In summary, the results of KEYNOTE 164 are a significant advance for patients with microsatellite instability-high and mismatch repair deficient cancers. Long-term follow-up from this study and further studies into the most efficacious clinical setting to use these agents will continue to advance the clinical use of immunotherapy options for these patients.

This concludes this JCO Podcast. Thank you for listening.

This podcast evaluates results from a phase II clinical trial of pembrolizumab for relapsed Mycosis Fungoides and Sezary Syndrome in the context of the current systemic treatment landscape for this disease.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "Pembrolizumab in Relapsed and Refractory Mycosis Fungoides and Sezary Syndrome: A Multicenter Phase II Study" by Khodadoust et al. My name is Jennifer Amengual, and I am an Assistant Professor of Medicine at the Columbia University Irving Medical Center in New York, New York, USA. My oncologic specialty is lymphoma.

Mycosis fungoides, otherwise known as MF, and Sezary Syndrome, its leukemic variant, are rare subtypes of cutaneous T-cell lymphoma. Although most patients with MF have indolent disease, those with advanced stage MF often experience resistance to systemic therapy with a persistent and progressive disease course, which has a negative impact on overall well-being and survival. Patients may have intense pruritus, which can then put them at increased risk for staphylococcus infection, sepsis and in turn can trigger disease flare.

Advanced-stage MF is a chronic disease that is not considered curable; therefore, it is necessary to consider management strategies that provide symptom relief and can be maintained over a long period of time. Most patients cycle through a multitude of therapies, often including skin-directed and, later, systemic therapies. Many of the acceptable therapies are derived from retrospective studies or single-arm trials; therefore, it is not possible to objectively compare outcomes and toxicity. In order to put the outcomes of pembrolizumab in context of other acceptable treatment modalities, I will discuss some of these treatments now.

Systemic retinoids, such as bexarotene, are taken orally and can induce an overall response of 45-55%. The drug is well tolerated but can lead to hypertriglyceridemia and hypothyroidism, requiring monthly monitoring and frequent treatment with lipid-lowering agents and thyroid hormone replacement.

Low-dose methotrexate, administered either orally or by intravenous infusion weekly, can lead to response rates between 30 and 50%. Common side-effects include mucositis, cytopenias and gastrointestinal upset. Pralatrexate is a novel antifolate drug that when studied using half the dose of that which is approved for PTCL , induced a 45% response rate for patients with MF. The treatment is also well tolerated, with the most common side-effects being mucositis and thrombocytopenia.

There are 2 histone deacetylase inhibitors approved for use in MF and Sezary Syndrome. Both romidepsin and vorinostat have overlapping toxicity profiles, including gastrointestinal disturbances, fatigue, anorexia, and cytopenias. Romidepsin is also associated with ECG abnormalities. In patients with cutaneous T cell lymphoma, romidepsin has demonstrated a response rate of 34% and is associated with a median duration of response of 15 months. Vorinostat, an oral drug, has demonstrated a response rate of 30%.

Recently, 2 biologics have been in used for patients with MF. Brentuximab vedotin is an antibody drug conjugate which targets the surface marker CD30 and brings monomethyl auristatin E into the cell. It is associated with a response rate of 70% in MF. Responses are significantly better in those with greater than 5% of CD30 expression. The most common side-effect is peripheral neuropathy. Mogamulizumab is a humanized antibody directed against the chemokine receptor CCR4.  This agent was studied in a randomized trial compared to vorinostat, where it led to a PFS of 7.7 months and response rate of 28%. The most common adverse events were attributed to infusion reactions, rash, diarrhea, and fatigue. There was also an increased risk of graft-versus-host disease in patients who subsequently went on to allogenic transplant, which needs to be considered when using this treatment strategy. As you can see, there are many different approaches to the treatment of advanced-stage MF and Sezary Syndrome, and the drugs I have discussed do not encompass an exhaustive list.

Immune checkpoint antibodies against Programmed cell death protein 1 otherwise known as PD-1 interfere with inhibitory signaling pathways expressed on exhausted T-cells and wake up these cells allowing them to perform anti-tumor activities. The investigators rationalize the use of PD-1 inhibitors in MF and Sezary syndrome given PD-1 dysfunction and altered expression on MF cells and  the skin microenvironment.

The Cancer Immunotherapy Trials Network performed a multicenter phase II single-arm study of pembrolizumab in 24 patients across 8 centers with relapsed or refractory MF or Sezary Syndrome. Of the 24 patients enrolled, 9 had MF and 15 had Sezary syndrome. Most had advanced disease represented by tumor stage disease, erythrodermic presentation, or were stage IIIB or higher. Patients received a median of 4 prior lines of systemic therapy. In addition, 4 patients had evidence of histologic large cell transformation. These represent some of the most challenging clinical situations.

Pembrolizumab was administered every 3 weeks for 24 months or until withdrawal of consent, adverse reactions or investigator's decision. The therapy was well tolerated, with no grade 4 or 5 immune-related adverse events. There were, however, 11 immune-related adverse events observed among 9 patients. This led to discontinuation of treatment in 4 patients, all due to grade 3 events including pneumonitis, duodenitis, hepatitis, and a corneal ulcer.

Interestingly, over half of the patients with Sezary Syndrome experienced a flare of their symptoms early in their treatment course. This manifested as increased erythema, pruritus, and peripheral edema. Patients were managed with topical steroids and close observation. Only 1 patient had a prolonged reaction requiring systemic therapy, and no patients were discontinued from therapy due to flare of their disease. Patients with MF did not experience any skin toxicity. The authors investigated the relationship of this reaction to response and found that 3 of 8 Sezary patients who experienced a skin flare went on to achieve a response, whereas only 1 of the 7 Sezary patients who did not have a flare achieved a response. Using mass cytometry profiling of PBMCs, the authors observed a sevenfold increase in PD-1 expression on circulating Sezary cells in patients who experienced a flare. Although these observations were made across a small number of patients, it will be worthwhile to pay attention to this in future studies to determine if this is a true predictor for flare reaction or response.

Pembrolizumab demonstrated significant clinical responses in 9 of 24 patients, leading to an overall response rate of 38%. This falls right into the range with other acceptable treatment options. Patients were heavily pretreated, yet the number of prior lines of therapy did not impact the response to pembrolizumab, possibly owing to non-overlapping mechanism of action. In addition, responses were seen in both MF and Sezary patients and those with erythrodermic and tumor stage presentations. There was a trend toward better outcomes in the MF patients. Responses were durable, and the median duration was not reached within a follow-up period of 58 weeks. The 1-year PFS was 65%, and OS was 95%. Two responding patients relapsed 8 to 12 weeks after discontinuation of treatment. The authors discuss that this may indicate the need for continuous treatment in this patient population, which is contrary to the general treatment strategy used for checkpoint inhibitors in other malignancies.

Although this study only enrolled 24 patients, pembrolizumab appears to have similar outcomes as other drugs used in advanced-stage MF and Sezary Syndrome, with an acceptable toxicity profile. It produces a long duration of response, making it an attractive addition for patients suffering from this disease. Pembrolizumab does not have overlapping mechanism of action with most of the drugs used today and can therefore be easily integrated into the sequence of treatment for patients with MF and Sezary Syndrome. Finally, it is possible that pembrolizumab's effects will enhance those seen with other agents. We should look forward to confirmatory clinical trials of pembrolizumab for the management of patients with MF or Sezary Syndrome.

This concludes this JCO Podcast. Thank you for listening.

This podcast discusses the results and implications of a recent study on gender bias in speaker introductions at an international oncology conference.

This JCO Podcast provides observations and commentary on the JCO article "Evaluating Unconscious Bias: Speaker Introductions at an International Oncology Conference" by Duma et al. My name is Dr. Tatiana Prowell. I am an Associate Professor of Oncology at Johns Hopkins Kimmel Cancer Center and Breast Cancer Scientific Liaison at the U.S. Food and Drug Administration in Silver Spring, Maryland. My oncologic specialty is breast cancer.

In the article that accompanies this podcast, Duma and colleagues report the results of a retrospective observational study of speaker introductions at two consecutive years of ASCO Annual Meetings. The investigators hypothesized that female speakers in oral sessions would be introduced with a professional form of address less frequently than male speakers. For the purposes of the study, they defined a professional address as use of a title such as Professor or Doctor, followed by the speaker's full name or last name, or the speaker's full name followed by doctoral degree. A team of four male and four female reviewers analyzed 781 video recordings of oral sessions from the 2017 and 2018 ASCO Annual Meetings and recorded the gender of the introducer and speaker and how the speaker was introduced. They found that female speakers received a professional form of address 62% of the time whereas male speakers were introduced professionally 81% of the time, a difference that was statistically significant. Duma and her colleagues also assessed whether the gender of the introducer was associated with a difference in the likelihood of receiving a professional introduction. They found that male moderators introduced female speakers professionally a little more than half the time, whereas they introduced men professionally in 80% of cases.  Interestingly, when serving as introducers, women were more likely than men to include a professional form of address, which they did about three-quarters of the time, regardless of whether they were introducing men or women.  Perhaps the most striking result of the study was that one in six female speakers was introduced by her first name only, a surprising degree of informality for a high-profile conference like the ASCO Annual Meeting, which draws more than 40,000 attendees per year. By comparison, male speakers were introduced by first name alone in just 3% of presentations. In a multivariate analysis that included gender, degree, academic rank and geographic location of the speaker's institution, male speakers were 2.5 times more likely to receive a professional introduction compared to female speakers. 

This study adds to a growing body of literature in medicine investigating the prevalence of gender bias in speaker introductions. For example, previous studies of speaker introductions over a 3 year period of Mayo Clinic Internal Medicine Grand Rounds and at an American Society of Colon and Rectal Surgeons Annual Meeting reported similar findings. In both cases, female speakers were less likely than men to be introduced using a professional form of address, and women introducers more consistently referred to speakers by a professional title, regardless of whether the speaker they were introducing happened to be a man or a woman.

This study raises two key questions: why do we see this, and how can we fix it? A speaker introduction, especially at an international conference, is by definition a formal ritual, and yet one so familiar to us that we may have lost sight of its purpose. It would be easy enough for speakers to introduce themselves. Every speaker has an opening slide that shows his or her name and institutional affiliation. So why choose someone, and often someone well-known within the field, whose role is to introduce the speakers at all?  What leads us to say, "Dr. Carol Greider is Bloomberg Distinguished Professor, Director of Molecular Biology and Genetics at Johns Hopkins University, and a recipient of the 2009 Nobel Prize in Medicine"? I believe we do this for two reasons. First, formal introductions provide a moment, however brief, to demonstrate our collective respect for the speaker and his or her scientific contributions. Second, the information in the introduction signals to any who are not familiar with the speaker that the person is credible, knowledgeable, and worthy of our attention. Although more than 50% of medical school matriculants and about 40% of medical school faculty are women, they remain underrepresented at higher academic ranks and in leadership roles. Only about one-quarter of full professors are women, and fewer than 1 in 5 department chairs are women. Women are also less likely than men to be the first or senior author of manuscripts and thus less likely to be standing at the podium. As a result, the names and work of women in medicine may well be less familiar to the audience. Female introducers may therefore be more likely to assign value to use of a professional form of address. If this were true, one might expect to see women more consistently use a professional form of address when introducing speakers, and this is in fact what Duma and her colleagues observed. 

The more troubling question is why men approached the introduction of male and female speakers so differently and why male speakers were 2.5 times more likely to be introduced with a professional title than women. I believe that most moderators, if presented with data from their own sessions, would be surprised to learn that they introduce men and women differently. This is called unconscious bias, and we are all susceptible to it. While the root causes of unconscious gender bias are numerous, one of these is surely the dearth of women occupying senior positions in medicine. As a community, we have tremendous power to remedy this source of unconscious bias. But while we can all re-commit ourselves to mentoring and sponsoring women in order to create more visible examples of female leaders in medicine, these efforts will not change the face of medicine, nor eliminate our unconscious gender bias, overnight. And yet, this is a change that needs to be made now. A male colleague of mine described introducing a woman at the podium by her first name as the verbal equivalent of rubbing the shoulder of a female professional acquaintance, then extending a handshake to a male professional acquaintance, that is to say, an inappropriate degree of familiarity with the woman. However, even in circumstances where the introducer and speaker are well-known to one another, formal settings call for formality. I call my physician husband "honey" at home, but if I were moderating an ASCO Annual Meeting session in which he was a panelist and said "Honey, why don't you take that question?" it would of course be ridiculous.  Using respectful forms of address in formal settings like conference sessions is ultimately a mark of professionalism and, in 2019, non-negotiable. 

The good news is that, unlike many problems in medicine, this one has a couple of solutions that we can implement immediately. We can provide a simple standardized script at the podium that ensures all speakers receive an equitable introduction. All conferences should implement this now, and in fact, motivated by Duma and her colleagues' work, session chairs will receive such a script for introductions at the 2020 ASCO Annual Meeting. Perhaps more importantly, though, we can appreciate the formal introduction as a ritual that has been conserved through generations of scientists for a reason. Regardless of our gender, all of us as physicians remember that feeling when were July interns and the attending said of us on rounds something like, "Dr. Smith will be back to explain the plan to you in more detail." In that moment, when we were called Doctor before an audience of our patients and our peers, we felt respected, capable, confident, and proud. Let's commit to ensuring that all of our colleagues have that feeling every time they take the podium. 

This concludes this JCO Podcast. Thank you for

Treatment-free survival is a novel endpoint in immunotherapy.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "Treatment-Free Survival: A Novel Outcome Measure of the Effects of Immune Checkpoint Inhibition—A Pooled Analysis of Patients With Advanced Melanoma" by Regan et al. My name is Adil Daud, and I am Professor of Medicine and Dermatology and Director of the Melanoma Program at the University of California, San Francisco. My oncologic specialty is medical oncology.

Cancer therapy has achieved great success in the last 40-50 years. Where treatment with chemotherapy required inpatient hospitalization and gut-wrenching toxicity, therapy today can often be achieved with lower grade side effects and limited time in the hospital or outpatient infusion center. While these changes have brought enormous benefit to patients, many patients feel that the tug of ongoing therapy for metastatic or advanced cancer and long for a time where therapy is not continuing, and the word "cure" is not completely out of mind.

Allied to these concerns is the rise and expansion of immunotherapy for cancer. The growth and spread of neoplasm often triggers the immune system, which mobilizes in response. While cancers can use a variety of adaptive mechanisms to evade the immune system, blocking these evasive mechanisms can produce lasting responses and, in some cases, durable tumor-free intervals. Cytokine therapy as exemplified by IL-2 offered this benefit since its approval in the 1990's for renal cell cancer and for melanoma for approximately 10-20% of patients treated. The CTLA4 antibody, ipilimumab has had a similar long-term disease control rate with a better toxicity profile. However, it is the anti-PD-1 monoclonal antibodies, used by themselves or with ipilimumab that have made treatment-free survival a tangible and achievable goal for many patients with cancer especially those with cutaneous melanoma.

Measuring the effect of treatment is traditionally done with measures of disease control. These include tumor shrinkage as measured by an agreed upon method such as RECIST or irRECIST or by lengthening of time-either lifespan or time without progressive disease (progression-free survival). However, it is possible that a similar lifespan could be achieved in one of 2 different ways-either continuous treatment with a drug or a shorter-term treatment that stops within a few months and then the patient has no further treatment. Comparing these treatments that are profoundly different for a patient but similar in terms of standard time or disease control measures demands new measures that can help describe the benefit of one or the other treatment.

In the JCO article that accompanies this podcast, Regan et al, in an analysis of 1077 patients across 2 different randomized trials, attempt to provide such a measure. They define treatment-free survival as interval between time to ICI cessation to the time to subsequent therapy or death.  With this measure, the shorter the therapy and the more delayed the need for subsequent therapy (or death) the longer this interval is. Combination immunotherapy is notoriously toxic and while treatment duration can be short, the side effect duration can be prolonged. Could TFS be contaminated with toxicity ? to answer this question, Regan et al introduce another endpoint, TFS with and without toxicity and partition this with persistent and late onset grade ≥3 toxicity.

These endpoints are illustrated in Figure 1. Below the familiar Kaplan-Meier overall survival curve is a slice showing survival after subsequent therapy initiation (so factoring in progression). Below this is the TFS without toxicity. Below this slice is the TFS with toxicity and below this is the time on IO therapy. With this division, the familiar KM curve gives a lot more information and illustrates the difference between nivo-ipi combination therapy and nivolumab monotherapy. While the overall survival is not statistically different between these 2 treatments (as shown in previous publications) the TFS lets us see what is going on with patients. In Figure 4 we can see that in the combination nivo-ipi arm the TFS (mean) is 11.1 months vs 4.6 months for nivo alone and 8.7 months for ipi alone. These numbers indicate that TFS alone does not convey the full picture as ipi beats nivo in this measure due to the short duration of ipi treatment while extensive previous data including from keynote 006 show us that pd-1 therapy exceeds ctla4 therapy in virtually every other measure of health.

If we look at TFS subtracting toxicity, again ipi nivo beats nivo handily with 10 months vs 4 months but again ipi with 8.5 months slots in the middle. Figures 5A, 5 B and 5C show us the TFS partitioned by grade ≥3 treatment-related adverse events, grade ≥2 TRAEs or by the use of  immune suppressants.

To summarize this interesting manuscript, overall survival can be subdivided into TFS and time on therapy and time following subsequent therapy. The TFS can be further subdivided into TFS with or without toxicity (≥2 or ≥3 TRAE or use of immune suppressants). These additional  measures give some granularity to the survival and let us see what exactly survival constitutes, time off treatment and toxicity or time on treatment and with side effects.

These measures have several limitations: one of the important ones is introducing differences between treatment arms which by primary outcome measures have no difference by standard PFS or OS and by favoring short duration high toxicity treatments (such as ipi) over low toxicity, low intensity chronic treatments (such as nivo). These are value judgements which matter to many patients but need to be understood as such. In oncology, we need to make these value judgements explicit and make the tradeoffs clear. Ultimately though, the importance of TFS and similar outcome measures may be that they encourage this conversation and help our field open up to what matters.

This concludes this JCO Podcast. Thank you for listening.

In this JCO Article Insights episode, Dr. Joseph Matthew interviews authors Dr. Yang Zhang and Dr. Haiquan Chen about their recently published JCO article, "Phase III Study of Mediastinal Lymph Node Dissection for Ground Glass Opacity–Dominant Lung Adenocarcinoma"

TRANSCRIPT

Joseph Mathew: Welcome to the Journal of Clinical Oncology Article Insights episode for the August issue of the JCO. This is Joseph Mathew, editorial fellow for JCO, and today, it is my pleasure to have with us Dr. Haiquan Chen and Dr. Yang Zhang, authors of the recently published manuscript, "Phase 3 Study of Mediastinal Lymph Node Dissection for Ground-Glass Opacity-Dominant Lung Adenocarcinoma," which we will be discussing today. Dr. Chen is the Director of the Institute of Thoracic Oncology at Fudan University and the Chief of Thoracic Surgery at Fudan University Shanghai Cancer Center, where he is also the Head of Thoracic Oncology MDT and the Director of the Lung Cancer Center. Dr. Chen is a surgeon-scientist and a pioneer in developing individualized surgical strategies for early-stage non-small cell lung cancer. Dr. Zhang is a surgical oncologist and a member of the team which Dr. Chen leads at the Fudan University Shanghai Cancer Center.

Welcome Dr. Chen and Dr. Zhang. Thank you very much for accepting our invitation and joining us today as part of this podcast episode.

To summarize the salient points, this study presented the interim analysis of a multi-center, open-label, non-inferiority, randomized controlled trial investigating the necessity of systematic mediastinal lymph node dissection at the time of segmentectomy or lobectomy in patients with clinical stage T1N0M0 ground-glass opacity-dominant invasive lung adenocarcinoma, as defined by a consolidation-to-tumor ratio of 0.5 or less on thin-section computed tomography and a maximum tumor diameter of 3 cm or less. Eligible participants with intraoperatively confirmed invasive adenocarcinoma on frozen section analysis were randomized to either the systematic mediastinal lymph node dissection arm or to no mediastinal lymph node dissection. In the latter experimental group, mediastinal lymph nodes comprising the N2 nodal stations were not dissected, and the hilar nodes were variably addressed at the discretion of the operating surgeon.

The primary endpoint of the trial was disease-free survival at 3 years. Secondary endpoints included perioperative outcomes, the status of lymph node metastasis in the systemic lymph node dissection arm, and 3-year overall survival. Before the trial reached its accrual target, a pre-planned interim safety analysis set for the time point when enrollment reached 300 patients was performed. It was noted that while none of the patients in either arm had nodal metastasis on postoperative pathological evaluation, lymph node dissection-related intraoperative and postoperative complications were more commonly observed in the systematic lymph node dissection arm, including one life-threatening episode of massive bleeding. Since this met the predefined criteria for trial termination, and in accordance with the principle of non-maleficence, further recruitment was stopped and the trial terminated.

Although the 3-year disease-free survival and the overall survival for the enrolled patients were comparable, operative outcomes, including the duration of surgery, blood loss, chest tube duration, length of postoperative stay, and the rate of clinically significant complications, were significantly lower in the experimental arm compared with the systematic lymph node dissection group. The authors concluded that for well-selected patients, mediastinal nodal dissection could be omitted without adversely affecting oncological outcomes, representing a significant shift in current surgical practice, given that guidelines the world over recommend systematic lymph node dissection or sampling for all invasive lung cancers.

In summary, this study addressed a clinically relevant question with regard to the extent of nodal dissection, especially in the light of recent evidence recommending less extensive parenchymal dissections for early-stage non-small cell lung cancer, with the findings suggesting that invasive lung adenocarcinoma associated with ground-glass opacities of consolidation-to-tumor ratio up to 0.5 was an excellent predictor of tumor biology, and in clinical T1N0M0 lesions, a reliable predictor of negative mediastinal lymph node involvement.

So Dr. Chen and Dr. Zhang, could you tell us some more about what led you to do this research and the challenges which you faced while recruiting patients for this trial?

Dr. Yang Zhang: Dr. Mathew, thank you for your summary. The current clinical guidelines recommend systematic lymph node dissection or sampling for every patient with early-stage lung cancer, regardless of their lymph node status. And in our clinical practice, we observe that this procedure causes a lot of surgical complications including chylothorax and recurrent laryngeal nerve injury. Furthermore, dissecting the tumor-draining lymph nodes actually may potentially damage the body's anti-tumor immunity. So, Dr. Chen proposed the concept of selective lymph node dissection, which we aimed to dissect the metastatic lymph nodes, while at the same time we try to preserve as many uninvolved lymph nodes as possible.

So previously, we have conducted a series of retrospective studies to identify reliable predictors of nodal negative status in certain mediastinal zones, and we have performed a prospective observational phase 2 clinical trial to validate that the six criteria we proposed are 100% in predicting node-negative status. And this forms the basis for our phase 3 clinical trial.

Dr. Haiquan Chen: This trial is only one of the series of trials. The meaning of this trial you already said. And for a long time, from the surgeon's point of view, we considered minimally invasive surgery. It minimizes the size of the incision and minimizes the number of the holes we made. So, the true and the high-impact of minimally invasive, we make a concept of minimal dissection, that means organ-level minimally invasive. So we proposed the concept of minimally invasive 3.0, that means minimal incision, minimal dissection (that means organ-level minimal), and systemic minimally invasive.

So at first, we judged from the point of minimally invasive surgery. As long as immunotherapy is widely used in the clinical practice, we know immunotherapy, that means you use drugs to stimulate and activate the lymph node site. If we dissect all the metastatic lymph nodes, cut them out, how can we restimulate that lymph node site? So, from minimally invasive trauma and second, from the functional aspect, to try to save as many uninvolved lymph nodes as possible.

Joseph Mathew: Thank you, Dr. Chen. That's a very interesting concept that you alluded to even in the discussion of this paper, as to the potential role of the non-metastatic lymph nodes as immune reservoirs.

So, coming back to this paper, were there any challenges which you faced while recruiting patients for this trial?

Dr. Haiquan Chen: The criteria is very clear. That means invasive adenocarcinoma, that means most of the centimeter is 3.0 centimeter and also CTR ratio less than 0.5. And we can see that, you know, we did study about that. Even the invasive component of the subsolid nodule, it's bigger than the solid part. That means even the pure GGO, we can find out that there's still some invasive component. From this point of view, pure GGO and subsolid GGO, from this part of invasive carcinoma, that means it's a special clinical subtype that we, from retrospective study and also prospective study, we find out this group of patients, there are no mediastinal lymph node metastasis. So I think it's very important for this kind of group that we can avoid doing the mediastinal lymph node dissection. And we can do organ-level minimally invasive surgery. And also, we try to keep the patient's immune function as normal as possible.

Dr. Yang Zhang: Well, Dr. Mathew, we believe that the biggest challenge when we are enrolling these patients is that there needs to be a paradigm shift in the mind because systematic lymph node dissection has long been the standard of care. And some patients may misunderstand. Before the enrollment, we have to give them informed consent, but if the patient hears that they may be enrolled in the no-lymph-node-dissection group, they may feel that they do not receive radical, curative-intent surgery. So we believe, as Dr. Chen has said, after the release of our results, the no-lymph-node dissection may be incorporated in the future guideline for those patients without lymph node involvement, we can just omit the lymph node dissection.

Joseph Mathew: The study described two pre-planned interim points during the course of subject enrollment when the data was analyzed. So Dr. Chen and Dr. Zhang, could you please explain a little more about these two interim points of analysis that were planned and the rationale behind it?

Dr. Yang Zhang: When conducting this trial, we have two concerns. One is if there is any lymph node metastasis, there may be omission of metastatic lymph nodes not dissected in the no-lymph-node-dissection group. And there is another concern is that if all these lymph nodes are uninvolved, then dissecting these lymph nodes may cause life-threatening complications. So, we set the 150 interim analysis to ensure that there is no lymph node involvement in this group. And the other early termination criteria is set because if there is no lymph node involvement found in both groups, then a severe complication which is life-threatening is unacceptable because it threatens the patient's safety.

Joseph Mathew: So, although you did briefly allude to in the paper, what was the basis for selecting DFS as the primary endpoint when the objective of this trial was to assess nodal involvement in this subset of tumors?

Dr. Yang Zhang: Well, previously, we have done a series of retrospective studies and one prospective phase 2 trial. And in these studies, we have identified that GGO-dominant lung adenocarcinoma, even if it's invasive, it has no lymph node involvement. So this phase 3 trial was primarily designed to compare the survival outcomes. But as the trial went on, as Dr. Chen has concerns that if the patients have no lymph node metastasis at all, it may be unfair to dissect the lymph nodes for patients enrolled in the systematic lymph node dissection group. So there is one life-threatening complication that happens due to dissecting the lymph nodes and injury to the superior vena cava, which leads to massive bleeding. It is at this point that we decided to terminate this trial for patient safety concerns.

Joseph Mathew: Yeah, that's a very fair point. So you made sure that the ethical considerations were kept intact.

So another point was, there was a mention in the study of the historical data from your institution suggesting a 3-year disease-free survival of 96.6% for patients with clinical T1N0M0 ground-glass opacity-dominant invasive lung adenocarcinoma. So could you please elaborate on the patterns of recurrence which you noted for this group of patients who had developed a recurrence?

Dr. Haiquan Chen: Yeah, I think over 90% 3-year DFS, that's the least. From our retrospective data for this kind of group of patients, their DFS is so good. To the best of my knowledge, almost 100%. So this is very conservative, 94, 90% is very conservative. I think the trial eventually would have been positive. It's a special clinical subtype, even for invasive adenocarcinoma, their prognosis is much better than the other type of invasive adenocarcinoma.

Joseph Mathew: So this question may be slightly outside the purview of this study, but in your clinical practice, would you advocate either segmentectomy or lobectomy for all patients meeting the trial criteria, that is, lesions measuring 3 cm or less with a CTR of up to 0.5? Or is there a subgroup of patients you would recommend a wedge dissection for?

Dr. Haiquan Chen: I think CTR ratio is one parameter and also the location is another very important parameter. So we put it together to make a decision, the patient should do a lobectomy or segmentectomy. Even for an ongoing trial, for even the patient, invasive adenocarcinoma, we can do in the right location, even wedge, it can achieve enough negative margin in the ongoing trial to verify the comparable result for the patient, we can do the wedge dissection. So not just the CTR ratio, that's not the only parameter to make a decision on what kind of procedure we'll do.

Joseph Mathew: Yeah, great point, Dr. Chen. So from my perspective, this study was a well-designed, randomized control trial based on a relevant and clinically valid research question. So what, in your opinion, are the main strong points of this study?

Dr. Yang Zhang: We believe that this study represents the first randomized clinical trial published, yet, regarding the topic of selective lymph node dissection. It basically offers the highest level of evidence. We believe our results should be incorporated in the future clinical guideline.

Joseph Mathew: Given the increasing incidence of these lesions, I think it was- a randomized control trial in this arena was much awaited. And the other point is that GGO-dominant lung adenocarcinomas, the specific clinical guidelines are not very clear. So I think your study brought out that lymph node dissection for these tumors which satisfy the eligibility criteria could be omitted safely. Important consideration here is that the conclusions of the trial were based on an interim analysis, and this analysis was not planned for an early assessment of the primary endpoint. In other words, the study was not adequately powered to detect a significant difference in DFS at 3 years.

So Dr. Chen and Dr. Zhang, what do you perceive are the most important limitations of this study which you feel should be addressed in future research?

Dr. Haiquan Chen: So the surgery now is more individualized. I think the surgery from the last two decades, from the maximum tolerable intervention to minimum effective treatment, there's a big shift. So I think that the consensus, we can preserve normal lung parenchyma as much as possible. For the lymph nodes, I think that the big shift, we should shift it to keep as many as uninvolved lymph nodes as possible. So that's very important, not just to reduce the intraoperative trauma, but also to keep the immune environment as normal as possible.

Joseph Mathew: Another point was the limited long-term follow-up data to determine the actual impact of omitting lymph node dissection on local-regional disease control. So is any future follow-up planned to assess the long-term survival outcomes for the 302 patients which were enrolled in this trial?

Dr. Haiquan Chen: Yeah, I think that's very important for us. This trial we terminated just because if we keep the trial going, it's unfair for the mediastinal lymph node dissection group. We tried to just stop here, and we shifted to the single-arm trial. So, 2 or 3 years, this trial and another trial, they will give our final result to demonstrate more if selective mediastinal lymph nodes have a better result than ever before. And we will support the mediastinal lymph node dissection. That's one way.

And the American College just asked me, how can we put this policy into clinical practice in the United States? Because most of the patients they meet have solid tumors. So we have another trial, try to figure out how we can make sure before and intraoperative the lymph node status is negative or positive, and then we can solve that problem and put this policy into clinical practice in the Western society.

Joseph Mathew: Great. So that would be something we should all be looking forward to. So, this brings me to the final point of discussion on future research in this field. Dr. Chen, you commented in the paper that future studies should focus on improving the reproducibility of CTR evaluation. What are your thoughts on this subject?

Dr. Haiquan Chen: The CTR ratio, the concept from the JCOG 0201, just a concept from that prospective study, the phase 2 study, only subgroup analysis they give the concept of CTR ratio and the diameter. How can we reproduce? In our group and also I believe in Japan and in China, in Korea, and in our daily practice, I think CTR ratio is not a big issue. There are two very important things. One, you make sure the CTR ratio, not in a common CAT scan, but in a high-resolution CAT scan. So the imaging, that's the first thing. And the second, not from the single section and a two or three section, you make sure that your calculation is accurate. That's not just the single section, you make sure that you got the conclusion, the CTR ratio is the same number. We make sure that totally we, from the top to the bottom of the whole lesion, we make sure that the CTR ratio is accurate.

Joseph Mathew: Thank you, Dr. Chen. I think that would involve training our radiologists also to be aware of the CTR ratio and how it should be interpreted.

So another very interesting concept which you had alluded to in the discussion was the potential role of non-metastatic lymph nodes as immune reservoirs. So how do you think we could preserve these nodes and do you think sentinel node biopsies would play a role in future?

Dr. Yang Zhang: Actually, Dr. Chen has also led some basic research on this topic. We are investigating the immunological role of the tumor-draining lymph nodes. And our preliminary results have already shown that the tumor-draining lymph nodes of lung cancer, especially those uninvolved lymph nodes, have a vital role in the anti-tumor immunity and also effective response to the current anti-PD-1 immunotherapy. In the future, we believe that by incorporating our clinical evidence and those findings from our basic research, we will be able to provide very strong rationale to support selective lymph node dissection.

Joseph Mathew: So lastly, what are the questions that still remain to be answered and what do you perceive as the next step in this field?

Dr. Haiquan Chen: I think for the lung cancer surgery, especially for the cT1N0M0, they are more individualized. We can, based on the patient, the location, the CTR ratio, we can do wedge dissection, or segmentectomy, or lobectomy. For the lymph node dissection, we can do no mediastinal lymph node dissection or selective, only to dissect the positive one, or we have to do the systemic mediastinal lymph node dissection. So we can see there are too many combinations. So in the near future, for the surgery perspective, we have it more individualized. In the future, we just try to make sure we do not cut as many as possible. We just make sure that we can avoid over-diagnosis or overtreatment or over-dissected. I think that in the near future, that goal will come true.

Joseph Mathew: That's a great point, Dr. Chen. So that would be something also for the thoracic oncology community to work towards.

This wraps up today's episode of JCO Article Insights. Dr. Chen and Dr. Zhang, thank you very much for taking the time to join us today in what has been a very insightful session.

Dr. Haiquan Chen: Thank you.

Dr. Yang Zhang: Thanks.

Joseph Mathew: To our audience, thank you for listening. Please stay tuned for more interviews and articles, summaries, and be sure to leave us your comments and ratings. For more podcasts and episodes from ASCO, please visit asco.org/podcasts.

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.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "Progression of Disease Within 24 Months (POD24) in Follicular Lymphoma Is Associated With Reduced Intratumoral Immune-Infiltration" by Dr. Tobin and colleagues. My name is Dr. Carla Casulo, and I am Associate Professor of Medicine, Hematology and Oncology at the Wilmot Cancer Institute of the University of Rochester in Rochester, NY, USA. My oncologic specialty is Lymphoma.

Follicular lymphoma is the most frequently occurring indolent non-Hodgkin lymphoma and has a long natural history, with median overall survival nearing two decades. Patients with follicular lymphoma may experience a variable clinical course, with periods of long remission punctuated by episodes of recurrent lymphoma requiring re-treatment. Among all patients, up to one third will have early disease recurrence, defined as occurring within 24 months of diagnosis. Please note that progression of disease within 24 months will be referred to as POD24 for the remainder of this podcast. These patients have inferior survival, ranging from 25-50% at 5 years. Consequently, POD24 has become a robust and well accepted indicator of identifying high-risk patients.

The implications of POD24 were first identified through our analysis of the National Lymphocare Study, which sought to test the hypothesis that time to disease progression had an impact on subsequent patient outcomes. 588 patients treated with RCHOP were included. Patients with POD24 were defined as early progressors, and those without relapse or death within 24 months were defined as the reference group. Patients with POD24 had OS of 50% at 5 years compared to 90% in the reference group. These findings have subsequently been independently validated by numerous investigators worldwide, corroborating the adverse prognostic impact of an early disease related event in follicular lymphoma. The largest of these validation studies pooled individual patient data from 5,453 patients on 13 Clinical Trials using the Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) Investigation.  

In the FLASH analysis, we identified that male gender, poor performance status, high follicular lymphoma international Prognostic index (FLIPI) score, and elevated baseline beta 2 microglobulin B2M as predictors of early death and progression. Moreover, it confirmed POD24 as an early clinical endpoint of poor survival in follicular lymphoma that should be utilized to identify patients for prospective clinical trials.

The current status of biomarkers in follicular lymphoma has emerged from a wealth of clinical and laboratory-based factors to classify risk, towards a biologic based, molecular approach merging clinical factors with our current understanding of the follicular lymphoma genomic landscape.  

There are numerous well-established and emerging clinical prognostic indices used at the time of diagnosis in follicular lymphoma that can help discriminate general outcome. These include the FLIPI and FLIPI -2. To an extent, these prognostic markers can identify subsets of patients with an expected POD24 with a sensitivity between 60-78%, and a specificity between 56-58%. However, in an attempt to use a precision approach, investigators from the German Low-Grade Lymphoma Study Group harmonized clinical and pathologic data to create a clinico-genetic risk model aimed at more accurate risk prognostication in patients receiving front line chemoimmunotherapy. They performed deep DNA sequencing from formalin fixed pre-treatment biopsies to analyze the mutational status of genes in 151 patients with follicular lymphoma tumor samples. The resulting prognostic tool, called the m7-FLIPI, distilled down 74 genes into 7 genes with non-silent mutations occurring at a variant allele frequency of 10% or greater, and combined these with high risk FLIPI status and ECOG performance status. These included genes that increased risk of progression, including EP300, FOX01, CREBBP, CARD11, and those that decreased risk of progression, including EZH2, ARID1A, and MEF2B. The cumulative risk score was calculated by combining relative weights of these genes in a multivariate analysis predicting failure-free survival. This m7-FLIPI score was tested to identify POD24 but only captured about 50% of patients as high risk. A later model included only 3 genes, including EP300, FOX01 and EZH2, performance status and FLIPI score. Defined as the POD24-PI, this was more sensitive at identifying POD24 patients but did not outperform other metrics due to lower specificity.

Biologic classification of POD24 patients remains an ongoing international research priority to seek actionable targets that might change the natural history of follicular lymphoma and improve survival of patients more likely to have morbidity and death from their disease. Several years ago, in the pre-rituximab era, the Leukemia and Lymphoma Molecular profiling project identified the importance of the follicular lymphoma tumor microenvironment in predicting favorable or poor outcome. The follicular lymphoma tumor microenvironment is composed of tumor infiltrating T cells, regulatory T cells, and lymphoma-associated macrophages. The immune survival score or ISS established that differential expression of gene expression signatures from intratumoral immune cells in the tumor microenvironment affected survival, and particular increased expression of macrophages was associated with poor prognosis.

The impact of the follicular lymphoma immune microenvironment on survival is changing in the current era of chemotherapy combined with antiCD20 immunotherapy, and particularly by available drugs that reverse tumoral immunosuppression by blocking programmed cell death. Studies from solid tumor literature demonstrate that low levels of tumor infiltration immune cells are associated with inferior survival. In follicular lymphoma, then, precise characterization of high or low immune infiltrating cells in the tumor microenvironment may have a critical effect on understanding the mechanisms of POD24. This particular relationship is what Tobin and colleagues investigated in the current study.

In this analysis, targeted gene sequencing using NanoString technology from paraffin-embedded tissue and multi-spectral immunofluorescence on a tissue microarray was applied to two groups: a discovery cohort of 132 patients from Princess Alexandria Hospital with early- and advanced-stage follicular lymphoma who received either chemotherapy or observation and two independent validation cohorts of 198 patients with advanced-stage disease treated with RCHOP and RCVP from the German Low grade lymphoma Study Group and the British Columbia Cancer Agency. They also performed T cell repertoire analysis, flow cytometry, immunofluorescence, and next-generation sequencing.

Here, they defined POD24 as primary refractory disease following treatment, transformation to a more aggressive histology, and relapse within 24 months of diagnosis, which is a more liberal definition from what was initially described in the national lymphocare study but does encompass patients at highest risk of lymphoma-related death.

Gene expression profiling revealed distinct clustering of follicular lymphoma samples based on high or low expression of immune infiltrating cells. Low expression of four immune markers, including PDL-2, TNFalpha, CD4, and CD68 were all associated with poor outcome, but the most specific marker with the highest specificity and sensitivity was PD-L2. They then dichotomized PD-L2 expression into "immune infiltration high" and "immune infiltration low" in subsequent analyses. PD-L2 is an immune checkpoint present broadly on both tumor cells and the tumor microenvironment. To localize its distribution, they performed flow cytometry in fresh FL samples and quantified PD-L2 expression by PCR. They identified that PD-L2 gene expression was distributed in both CD20+ tumor cells as well as non CD20+ cells in the tumor microenvironment. However, the proportion of PD-L2 was lower in the CD20+ cells. Overall, there was lower expression of all immune cells in the immune infiltration low phenotype compare to the immune infiltration high phenotype.

They tested the relevance of immune infiltration and POD24. Consistent with numerous other studies, POD24 events occurred in about 24% of patients. Patients with POD24 events in the Princess Alexandria discovery set were more enriched for the immune infiltration low phenotype. These findings were also validated in the British Columbia cancer agency and German lymphoma study group populations. Nearly 50% of patients with low PD-L2 had POD24 events, compared to 16% in those with high PD-L2, concluding that low PD-L2 identifies a subset of patients enriched for POD24. When evaluating the mutational profiles of those with immune infiltration high versus immune infiltration low based on the m7-FLIPI genes, mutations were detected equally among both populations, suggesting that this mutational profiling is not influenced by the immune infiltration phenotype.

The data presented by Tobin and colleagues makes an important contribution to our understanding of the biological and immune-based mechanism influencing early disease-related events in follicular lymphoma. They demonstrate that reduced immune infiltration is associated with greater chance of POD24. While the sensitivity of this was high, similar to other prognostic markers, it still did not capture the entire subset of future POD24 cases, underscoring the significant heterogeneity within this high-risk patient population. However, there remains opportunity to include PD-L2 as a surrogate for poor risk disease. If further applied to immunohistochemistry or other widespread diagnostic methods, it has the potential for more widespread application. Further validation is still required, particularly to patients treated with novel agents or other immunotherapies. However, the assessment of immune infiltration as described by these findings appears to be an encouraging step in determining risk of POD24.

This concludes this JCO Podcast. Thank you for listening.

This podcast summarizes the findings of the Lunenburg Lymphoma Biomarker Consortium systematic evaluation of MYC rearrangements in DLBCL, and discusses the prognostic impact of MYC, BCL2 and BCL6 rearrangements, and implications for FISH testing in newly diagnosed DLBCL.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "Prognostic Significance of MYC Rearrangement and Translocation Partner in Diffuse Large B-Cell Lymphoma - A Study by the Lunenburg Lymphoma Biomarker Consortium" by Rosenwald et al. My name is Jeremy Abramson, and I am an attending physician at the Massachusetts General Hospital and an Associate Professor of Medicine at Harvard Medical School. My oncologic specialty is lymphoma.

MYC rearrangements occur in approximately 10% of diffuse large B-cell lymphomas and have been associated with a worse prognosis.  When the MYC translocation occurs in concert with translocations of BCL2, BCL6, or both, initial series have suggested particularly poor outcomes with few patients achieving long term survival with conventional therapies.  This entity has been classified in the current WHO classification as high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 and is more conventionally known as double (or triple) hit lymphoma.  Though initial series painted a grim prognosis for these patients, more recent larger series have suggested that approximately 40% of double hit lymphoma patients may be cured, and that outcomes may be improved with more intensive regimens such as dose-adjusted EPOCH-R.  Most of these published series to date, however, continue to be limited by significant selection bias whereby cases with the most aggressive clinical or histopathologic features are likelier to be tested for MYC translocations, thus potentially excluding more prognostically favorable patients.  The small size of series to date has also made it difficult to assess more granular questions in MYC translocated diffuse large B cell lymphoma, hereafter referred to as DLBCL, such as the prognostic impact of MYC translocations when occurring without other translocations, the impact of translocation partner with MYC (Ig or non-Ig gene locus) in double hit lymphoma, and the significance of MYC/BCL6 double hit lymphomas which are far less common than MYC and BCL2.  Another practical question is who should we be testing for MYC translocations in the first place? Do we need to test every new case of DLBCL?  Or should we routinely test only an enriched population, such as those with MYC protein expression by immunohistochemistry, or GCB-like DLBCLs, which include the majority of double hit lymphomas?

In the article that accompanies this podcast, the Lunenberg Lymphoma Biomarker Consortium  presents the single largest and most systematic analysis to date of MYC translocations in DLBCL, and sheds significant light on many of the most outstanding questions in this population. The Consortium studied over 2000 cases of DLBCL with available tissue and clinical data, drawn from large prospective cooperative group studies as well as population-based registries in Canada, the United Kingdom and the United States. The median age of the cohort was 66 years, and the median follow up was mature at greater than 6 years. All patients were treated with R-CHOP or R-CHOP-like therapy.  MYC rearrangements were found in 11% of patients. One third of these occurred as a sole rearrangement, 39% in concert with a BCL2 rearrangement, 15% with a BCL6 rearrangement, and 12% with both (i.e. triple hit lymphoma).

Patients with MYC rearrangements had higher risk features by the IPI score than the entire DLBCL population, and patients with double/triple hit lymphoma had higher clinical risk factors than patients with MYC rearrangements alone. Patients with double or triple hit lymphoma had a significantly inferior outcome in terms of both progression free and overall survival compared to the overall DLBCL cohort, while no negative prognostic impact was conferred by a MYC translocation alone. Notably, the prognostic impact was only observed in the first 2 years from diagnosis.  They also compared the 31 MYC/BCL6 double hit patients with 82 MYC/BCL2 double hits, and found similar outcomes in the groups, validating that MYC/BCL6 double hit lymphomas should be considered high risk along with their BCL2 translocated counterparts. Prognosis for triple hit lymphoma was no worse than double hit lymphoma.  Perhaps most striking, however, was how well double and triple hit lymphoma patients did when compared to previously published retrospective studies. In this comprehensive evaluation by the Consortium, approximately 60% of double and triple hit lymphoma patients remained progression free beyond 5 years, and two thirds remained alive.  These remarkable data suggest that the majority of double and triple hit lymphomas identified by broad screening of the DLBCL population may be cured with chemoimmunotherapy and should offer encouragement to patients and providers alike.  Importantly the Consortium's analysis includes only patients with DLBCL morphology, so excluded double/triple hit patients with Burkitt or Burkitt-like histology who may have an inferior outcome compared to the double hit lymphoma patients in this analysis.

MYC and BCL2 protein expression (so called dual expressor lymphomas) was also analyzed in 1414 cases with available tissue. MYC (≥40%) and BCL2 (≥50%) co-expression was associated with an inferior outcome compared to he general DLBCL population, though better than double/triple hit lymphomas, and notably the majority of dual expressor patients remained free from progression and alive at greater than 2 years of follow up after treatment with R-CHOP-like therapy. On evaluation by cell of origin, patients with GCB-like DLBCL had a slightly more favorable outcome compared to non-GCB, as defined by immunohistochemistry.  GCB-like DLBLC more commonly had MYC rearrangements, and exclusively contained the MYC/BCL2 subset of double hit lymphoma, while MYC/BCL6 cases occurred within both cell of origin subgroups.

These robust data from this large systematic analysis address several pressing questions regarding MYC-rearranged DLBCL.  First, they tell us that a MYC rearrangement in the absence of a rearrangement of BCL2 and/or BCL6 does not predict an adverse outcome in DLBCL and may be treated as a routine DLBCL with R-CHOP-like therapy. Second, we learn that MYC translocation partner in the setting of a double/triple hit lymphoma matters, with the negative prognosis driven by MYC/Ig translocations rather than MYC rearranged with a non-Ig partner which does not appear to confer negative prognostic influence. Third, while MYC/BCL6 double hit lymphomas are uncommon, they appear to predict similarly inferior outcomes as MYC/BCL2 double hit lymphomas and triple hit lymphomas.  And fourth, very importantly, the outcome of double/triple hit DLBCL, though inferior to the entire DLBCL population, appears much better than previously estimated with approximately two thirds of patients achieving long term progression free and overall survival when treated with standard chemoimmunotherapy.  It warrants emphasis that this applies to cases morphologically classified as DLBCL, not necessarily to cases with Burkitt-like or blastoid features which were not included in the LLBC study and likely have a less favorable outcome.  For this reason, it is essential that pathologists signing out cases as aggressive B-cell lymphoma with translocations of MYC and BCL2 and/or BCL6 also indicate the morphologic subtype as DLBCL versus a higher grade appearance as this information will be essential for clinicians in applying the LLBC findings to prognostication in the clinic.

Finally, this study provides us critically needed guidance in determining which cases warrant evaluation with fluorescence in situ hybridization (FISH) to detect MYC, BCL2 and BCL6 rearrangements. Presently, practice patterns are mixed with some centers testing all cases for MYC, while others test only enriched populations such as GCB-like DLBCL or double expressor DLBCL, and still other centers not routinely evaluating MYC at all in DLBCL.  The Consortium data validate that MYC translocations in DLBCL affect a sufficient proportion of the population and confer sufficient prognostic importance as to warrant testing.  They also show us that conventional immunohistochemistry for either cell of origin or MYC/BCL2 double expression status are not sufficient to direct FISH testing. Testing only GCB-like DLBCL would indeed identify all cases of MYC/BCL2 double hit lymphomas but would fail to identify a significant proportion of MYC/BCL6 double hit cases.  Performing FISH only on cases meeting current immunohistochemical thresholds for MYC and BCL2 double expressor lymphomas would fail to identify more than one quarter of cytogenetically defined double hit lymphomas, which would also be unacceptable. These data therefore support testing all newly diagnosed cases of DLBCL and high-grade B-cell lymphoma with FISH for MYC.  A positive FISH assay for MYC should prompt reflexive testing for both BCL2 and BCL6, which would then differentiate cases of single hit cases with MYC translocations alone from the higher risk double and triple hit lymphoma patients.

The fact that the prognostic impact of double and triple hit lymphoma is seen only within the first 2 years from diagnosis underscores the need to optimize upfront therapy in these diseases. The data from the Lunenburg Lymphoma Biomarker Consortium suggest that R-CHOP-like therapy remains an acceptable standard of care in double expressor lymphomas, DLBCL cases with isolated MYC rearrangements, and perhaps even double/triple hit lymphomas with DLBCL morphology, though these cases have increasingly been treated with more intensive regimens such as dose-adjusted EPOCH-R or Burkitt-like regimens based on prior series.  In the absence of data clearly supporting one approach versus the other, I would consider either intensive approaches or standard R-CHOP as reasonable considerations in cases of double hit lymphoma with DLBCL morphology and should be individualized to the patient. Ultimately, we would like to overcome biological liabilities with biologically directed therapies, and the US Intergroup is now conducting a randomized clinical trial evaluating chemoimmunotherapy with or without the BCL2 inhibitor venetoclax specifically in double hit and double expressor lymphomas, with the chemoimmunotherapy backbone being dose adjusted EPOCH-R for double hits, and R-CHOP for double expressors. Participation in this important study is encouraged.

This concludes this JCO Podcast. Thank you for listening.

This podcast discusses the work of Sheetz and colleagues describing the impact of centralization of high-risk cancer surgery within health care systems and networks in the United States.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "Centralization of High-Risk Cancer Surgery Within Existing Hospital Systems" by Sheetz et al. My name is Stephen Edge, and I am Vice President of Healthcare Outcomes and Policy and Professor of Surgery and Oncology at the Roswell Park Comprehensive Cancer Center and the University at Buffalo in Buffalo, NY. My oncologic specialty is surgical oncology.

Recent years have seen substantial consolidation of hospitals and practices into networked care systems. The benefits of health networks may include efficiencies of scale, better ability to thrive in the shifting health care economy, and enhanced quality.

In the article that accompanies this podcast, Dr. Sheetz and colleagues at the University of Michigan studied the impact of health care networks on the outcome of high-risk cancer surgeries for pancreas, esophagus, lung, colon and rectal cancer. They examined the distribution of these surgeries in health care networks, and the relationship between outcomes and the degree of centralization of surgeries to a high-volume network hospital.

There is a well-established relationship between hospital case volume and operative mortality for complex cancer surgery, most pronounced for pancreas and esophagus cancer. Some countries now mandate regionalization of these procedures to high volume centers. Most, but not all, studies show that regionalization improves outcomes for these procedures. Organized regionalization of cancer surgery in the United States has been limited though market forces have led to some consolidation of high-risk surgeries. This has been encouraged through recommendations of the Leapfrog Group that for the last 25 years has set minimum hospital volume standards for high risk surgeries.

Sheetz and colleagues used the Medicare Provider Analysis and Review (MedPAR) files that include all beneficiaries of Medicare Part A to identify persons age 65 and older undergoing pancreatectomy, esophagectomy, lung resection, colectomy and proctectomy for the years 2005 – 2014. They used American Hospital Association data to identify hospital characteristics such as size, teaching status and which hospitals are in the same health system if any. They combined these data with information from the National Inpatient Sample to derive estimates of the total number of cases of each type beyond Medicare beneficiaries.

They defined a "high volume hospital" and "high volume system" as one that met the Leapfrog Group volume criteria; and centralization of surgery as the proportion of surgeries of each type performed at the highest volume hospital in a given health network. Outcomes assessed were 30-day mortality after surgery, major complications, and hospital readmission.

The procedures most centralized in networks were pancreatectomy and esophagectomy with a mean of 71% and 51%, respectively. However, for pancreas surgery 74% and for esophagus surgery 84% of systems did not meet or have a hospital that met the Leapfrog Group volume recommendations for pancreatectomy.

Complications were about 20% lower for pancreas and esophagus surgery at health systems with the highest surgery centralization. The impact on complications of lung and colorectal surgery was less. More important was the reduction in risk-adjusted 30-day mortality. For pancreas and esophagus surgery the mortality at the most centralized systems mortality was 60% and 53% lower, respectively, then the least centralized systems. The absolute rates dropped from 8.9% to 3.7% for pancreas and 10.3% to 4.8% for esophagus surgery. The reduction for lung resection was less and there was no significant mortality difference for colorectal surgery. Importantly, the team observed the same level of reduction associated with system surgery centralization for low volume and high-volume systems, and those with and without a high-volume hospital.

Certainly, this study is not without its limitations. Because the MedPAR files include primarily fee-for-service Medicare, they had to estimate the total number of cases. They did not have specific information on the health systems or the distance of patients from a high-volume center. They did not know the systems' governance relationships or the degree of coordination between system hospitals, services and providers.

However, the study reinforces the well-established volume-outcome relationships in the context of hospitals with common governance. While individual surgeons may be excellent at low volume hospitals the finding of a greater relative impact on mortality than complications suggest that it not just the surgeon, but that high-volume hospitals with their larger teams and resources are less likely to "fail to rescue" a patient with a major complication. This was realized within these health systems.

Networks with a common governance and shared financial and reputation risk should be motivated to assure best outcomes and limit inefficiency. Networks have central program oversight and should pay more heed to factors that impact quality and have the ability to foster providing the right care at the right place. They also should be more attuned to the needs of their customers and their unique geographic and economic situations and can meet the needs of people in dense metropolitan areas and the vast expanses of rural America.

However, referral to the network flagship cannot be a one-way street. Health systems should establish programs that address these cancers across the continuum of the disease. Evidence shows that some of those who might benefit from these high-risk surgeries never see a team to help determine this. Conversely, many or people with pancreas, esophageal and lung cancer present with disease not amenable to surgery. It makes sense for a health system to assure that all patients with these cancers get a full, multidisciplinary evaluation and that those who cannot have resection receive appropriate referral or return to providers close to home who can provide the necessary care, clinical trials, and supportive services.

When the volume/outcome associations were first described, organized medicine was slow to address the issue and instead tried to fathom what factors led to better outcome with volume. In the absence of policy and professional leadership, market forces slowly changed practices so that now many or most of the very high-risk procedures are done at high volume centers. But this has taken 30 – 40 years and likely impacted many lives. Conversely, surgeons and policy makers have led the charge to regionalize other high-risk services such as trauma care, cardiac surgery, and pediatric surgery. The findings of Sheetz et al. support renewal of efforts in policy and practice to assure cancer patients receive the best options.

Sheetz and colleagues are to be congratulated for their insightful work. Despite its inherent limitations, they have shed light on a key area needing attention of health systems, professional societies and policy makers.

This concludes this JCO Podcast. Thank you for listening.

Dr. Osama Rahma, an Assistant Professor of Medicine at Harvard Medical School, Dana-Farber Cancer Institute, discusses the role of MSI in gastric cancer.

TRANSCRIPT

This JCO Podcast provides observations and commentary on the JCO article "Individual Patient Data Meta-Analysis of the Value of Microsatellite Instability as a Biomarker in Gastric Cancer" by Pietrantonio et al. My name is Osama Rahma, and I am an Assistant Professor of Medicine at Harvard Medical School, Dana-Farber Cancer Institute in Boston, Massachusetts. My oncologic specialty is Gastrointestinal Cancer and Cancer Immunotherapy.

Despite the advances in surgical approach and perioperative multimodalities in gastric cancer, the recurrence rate remains over 50%. While many patients benefit from perioperative chemotherapy many others don't derive such benefits and experience toxic side effects. Accordingly, there is an unmet need to identify prognostic markers to guide  chemotherapy decisions in the neoadjuvant and adjuvant settings. Microsatellite instability has been well established as a prognostic marker in colon cancer that correlates with better overall survival and potential lack of benefit from adjuvant chemotherapy in stage II disease.

The question is whether microsatellite instable gastric tumors have similar behavior? To answer this question, subgroups analyses of patients with MSI high tumors were performed in both the MAGIC and the CLASSIC trials which established perioperative ECF chemotherapy in non-Asian population and adjuvant capecitabine and oxaliplatin in Asia, respectively as the standard of care in resectable gastric cancer. Although MSI tumors were found to be less likely to benefit from chemotherapy, the low incidence of MSI tumors in both trials of 8-10% made it very challenging to draw  meaningful conclusions.  

In the article that accompanies this podcast, Pietrantonio et al performed individual patient level data meta-analysis testing the prognostic significance of microsatellite instability in both the MAGIC and CLASSIC trials. In addition, the analysis included the ARTIST study, which tested adding radiation to adjuvant capecitabine and cisplatin in Asia and the ITACA-S study which tested adjuvant FOLFIRI, docetaxel and cisplatin vs 5-fluorouracil and folinic acid in Europe in radically resected gastric cancer. The meta-analysis included 1556 patients, 63% Asian and 37% Europeans. Patients were stratified using microsatellite instability status and based on whether they received multimodality therapy in all 4 trials or surgery only in the MAGIC and CLASSIC trials. 7.8% of patients had MSI high tumors and  70.8 % received multimodality treatment.

Consistent with prior reports of individual trials, patients with MSI high tumors had better outcomes compared to MSI low or MSS tumors. Specifically, the 5-year disease free survival rate was 71.8% vs 52.3% and 5-year overall survival was 77.5% vs 59.3%. MSI remained a significant independent prognostic factor for improved disease-free survival and overall survival in a multivariate analysis in addition to Asian ethnicity, low TNM staging, and receiving multimodality therapy. In addition, MSI was noted to be more prevalent in the Asian population and was a better prognostic factor in Asians compared to Europeans.  

Importantly, MSI high tumors did not benefit from perioperative chemotherapy with 5-year disease free and overall survival of 70% and 75%, respectively for those who received chemotherapy compared to 77% and 83% for MSI high patients who did not receive chemotherapy. In contrast patients with MSI low or MSS experienced benefit from perioperative chemotherapy compared to surgery alone. Finally, MSI status did not affect post-recurrence survival. However, this was limited by the small number of MSI high patients who experience disease recurrence.  

This study has several limitations including its retrospective nature, the relatively small number of patients with MSI high tumors of 121, and the heterogenicity of administered treatment in the 4 trials including different regimens of neoadjuvant and adjuvant chemotherapy with or without radiation. In addition, D1 surgery was performed in Europe while D2 surgery was performed in Asia.

In summary, I think this study supports the adoption of microsatellite testing as a routine biomarker in patients with operable gastric cancer. The result of microsatellite testing should be discussed in a multidisciplinary fashion since perioperative chemotherapy may result in more harm than benefit in MSI high tumors.

This study among others highlights the unique behavior of microsatellite instable tumors which is driven by their unique immune profile including increased T-cell infiltration and activation due to higher mutational load and neoantigens compared to microsatellite stable tumors. PD-1 inhibitors are effective in more than 50% of MSI tumors in the advanced setting and in 15-25% of gastric tumors with positive PD-L1 expression.  Accordingly, future clinical trials should stratify gastric cancer patients based on their microsatellite status and PD-L1 expression while incorporating immunotherapy in the early disease setting.  

This concludes this JCO Podcast. Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article, "Treatment of Childhood Nasopharyngeal Carcinoma with Induction Chemotherapy and Concomitant Chemoradiotherapy: Results of the Children's Oncology Group ARAR0331 Study" by Rodriguez-Galindo et al. My name is Suzanne Wolden, and I am the Director of Pediatric Radiation Oncology at Memorial Sloan Kettering in New York City, USA.  My oncologic specialty is Pediatric Radiation Oncology.

This important manuscript summarizes the results of Children's Oncology Group protocol ARAR0331 for childhood nasopharyngeal carcinoma.  The study enrolled 111 patients, of whom 75% were male and 47% were African American, with a median age of 15.  Eligible patients had AJCC stage IIb-IVC disease and received three cycles of induction chemotherapy with 5-fluorouracil and cisplatin followed by concurrent cisplatin and radiotherapy.  Three patients had progressive disease during induction chemotherapy, eight were removed from the study due to physician or parent preference, and another three were not evaluable.  This left 97 patients evaluable for response and concurrent chemoradiotherapy.  Responses and radiotherapy treatment plans were not centrally reviewed but were left to the judgement of the treating institution. 

All patients received 45 Gy to comprehensive head and neck fields encompassing the nasopharynx and bilateral level I-V lymph nodes.  A boost to the nasopharynx and residual gross nodal disease was prescribed based on response.  The full dose of 70.2 Gy indicated for stable disease was given to 18.6% of patients while 77.3% received the protocol specified dose for complete or partial response of 61.2 Gy or lower.  Another 4.1% of patients received intermediate non-protocol doses of 63.9-66.6 Gy.  The trial was amended to reduce the cycles of concurrent cisplatin during radiotherapy to two from three after unacceptable rates of renal and gastrointestinal toxicities were reported. 

This trial was limited to patients age 18 years and younger and consisted primarily of American patients.  It is notable that the demographics of nasopharynx cancer in these young patients differ significantly from adults with this diagnosis.  Most patients are teens since nasopharynx cancer is vanishingly rare in younger children.  The majority were male, and nearly half were African-American.  Nasopharynx cancer is quite rare in teens of Asian descent, in stark contrast to the adult population.  In international series, it has been noted that teens in countries around the Mediterranean also have a relatively high incidence of this rare cancer.  The study illustrates that pediatric patients are much more likely than adults to have advanced disease and WHO type III, Epstein Barr virus-associated histology.

Despite a lack of central review, the response rate appears to be quite high to induction therapy as one might expect with WHO type III carcinoma.  It is surprising that any patients had progressive disease, and I suspect that the rate of partial and complete response may have been even higher than what is inferred from the radiation boost doses given.  Nonetheless, the strategy of induction therapy was highly successful in allowing a large majority of patients to receive reduced doses of radiation.  It is important to note that all patients received 45 Gy to initial comprehensive fields rather than the 50 Gy typically used for adults and that smaller, more forgiving fractions of 1.8 Gy were used in comparison to the standard 2 Gy for adult head and neck cancer.  While some patients received a standard adult boost dose of 70.2 Gy, 81.4% received a lower boost dose.  In most cases, this was the protocol specified 61.2 Gy, a 13% dose reduction.  Even with these significantly lower doses, local control was exceptionally high, with only 5.5% of patients experiencing local failure with or without a distant relapse.

The successful reduction in radiotherapy doses in this study is incredibly important and by far the most newsworthy aspect of this paper.  Even full or nearly grown teens experience dramatically more severe late effects of radiotherapy compared to older adults.  The severity of soft tissue fibrosis 10 or more years after full doses of radiation to the head and neck is so great that many patients require feeding tubes and tracheostomies.  The rate of second malignancy is also much higher in young patients. 

The rate of distant relapse of 10.5% was low, considering that patients with metastatic disease at diagnosis were enrolled.  It is possible that with more advanced staging scans such as FDG-PET, metastatic lesions can be more easily detected and defined.  In that case, they can be targeted with radiotherapy to decrease the risk of relapse.  This approach has been shown to be effective in achieving cure in adults.  It is unlikely that an increase in chemotherapy beyond what was used in this protocol would be tolerated or worth the added toxicity.  Indeed, it is unclear whether the 3rd cycle of concurrent cisplatin was beneficial since there was only a trend for improved EFS and the cumulative toxicity is significant.  One must be mindful that increases in systemic therapy have been shown to decrease tolerance for head and neck radiotherapy.  This can be counterproductive to outcome if there are delays, breaks or failure to complete the course of radiation.

This trial was so successful in its ability to decrease radiation exposure in young patients, that we should be inspired to go further.  My thoughts regarding the next trial would be to use PET scans for staging and response assessment and to push the radiotherapy doses lower.  This approach is currently being investigated for adult HPV associated head and neck cancer with doses as low as 30 Gy.  Perhaps in pediatric (or even EBV positive adult) nasopharynx cancer, 30-36 Gy would be enough for the comprehensive initial fields with boost doses in the range of 50-60 Gy for those who respond favorably to induction chemotherapy.  Dose reductions of this magnitude would make major differences in the acute and especially the late toxicities.  In addition, modern radiation technologies such as proton therapy allow improved avoidance of normal tissue exposure for these young, curable patients.

In summary, this article provides evidence that response-based radiation dose reduction is possible for pediatric nasopharynx cancer.  Even with numerous limitations, the outstanding results of this trial inspire us to continue moving forward in the direction of reducing radiation exposure for these young patients.  Long-term follow up is also urged to quantify the expected benefits of these therapeutic changes.

This concludes this JCO Podcast.  Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article "Maintaining Outstanding Outcomes Using Response and Biology-Based Therapy for Intermediate-Risk Neuroblastoma: A Report From the Children's Oncology Group Study ANBL0531" by Twist et al. My name is Javed Khan, and I am Deputy Chief and Senior Investigator at the Genetics Branch and an Attending for the Pediatric Oncology Branch of the National Cancer Institutes of the NIH in Bethesda, Maryland. My oncologic specialty is Pediatric Hematology Oncology.

Childhood cancer is a life-threatening disease where survival rates have increased exponentially to over 75% over the past three decades. However, this has come at a considerable cost with significant incidence of late effects including hearing loss, scoliosis, hypothyroidism, growth and development delay, infertility, psychological, emotional, cognitive and neurological sequelae, and secondary malignancies. Most of these late effects have been attributed therapy including chemotherapy, surgery and radiation.

In the manuscript that accompanies this podcast, Twist et al report on the results of the Children's Oncology Group study ANBL0531, whose primary aim was to reduce therapy for subsets of children aged <=12 years old, with intermediate-risk neuroblastoma using a biology- and response-based algorithm that assigns the length of treatment duration while maintaining a 3-year overall survival (OS) of >=95% for the entire cohort.

Neuroblastoma is an extracranial pediatric malignancy of neural crest origin that has often been described as an enigmatic cancer due to its significant clinical, molecular and biological heterogeneity. For example, some patients with widely metastatic disease are cured with minimal or no therapy whereas others have relentless progression to death despite intensive therapies.  There has been considerable progress in dissecting out the causes of this heterogeneity and developing prognostic biomarkers to stratify the risk based on several clinical, histological and molecular markers. At the time this clinical study was performed, and the manuscript written, the authors stratified patients using several clinical and biologic parameters including age, the International Neuroblastoma Staging System, MYCN amplification status, the International Neuroblastoma Pathology Classification of histopathology, and tumor DNA index. An additional marker utilized in this study was loss of heterozygosity determination of the tumors at chromosome bands 1p36 and 11q23. This stratification strategy has led to the identification of low and high-risk groups where therapy is more clearly defined and patients with low risk have excellent outcome for most patients with surgery alone and watchful waiting. For high-risk disease, significant strides have been made using a combination of surgery, aggressive chemotherapy, radiation followed by Chimeric Antibody 14.18 anti GD2 therapy, GM-CSF, IL-2 and Isotretinoin, however the five-year survival remains guarded at 40-50%. In the intermediate-risk group, the subject of this study, although the 5-year survival rates of 90-95% have been achieved, this group is significantly heterozygous raising the possibility of reducing therapy for subsets of patients within this group. This was the motivation for this study.

Thus, the goal of this clinical protocol, ANBL0531, was to refine the minimal therapy needed to achieve excellent outcomes for patients with intermediate-risk neuroblastoma, with the aim to maintain an overall 3-year OS rate of > 95% for the entire cohort. Patients were stratified into Groups 2, 3, or 4, who were assigned to receive a minimum of 2, 4, or 8 cycles of chemotherapy, respectively. Chemotherapy was identical to that used on a previous study A3961.

Reduction of therapy was planned to be achieved for patients with biologically favorable tumors (Groups 2 and 3) by using the achievement of Partial Response (PR) to chemotherapy +/- surgery to be the endpoint of therapy, rather than the achievement of Very Good Partial Response (VGPR) as was previously used on A3961. If the treatment endpoint was not achieved after completion of the scheduled chemotherapy courses, additional cycles of therapy could be administered, and patients re-evaluated following every 2 cycles to determine if the treatment endpoint has been achieved. VGPR, a more stringent response criteria, was used for Group 4 patients which includes those with age< 365 days, stage 4 disease, MYCN-not amplified, and either Unfavorable Histology (UH) or DNA Index or Ploidy (DI)=1. Patients within this subgroup received 8 cycles of chemotherapy on A3961, which was a reduction in therapy for these patients compared to prior studies. Group 4 patients also includes 2 subgroups who were previously stratified as high risk including those who had stage 3 disease, age 365- < 547days, stage 3, MYCN-NA, UH, any ploidy and also those with stage 4 disease, age 365 - < 547 days, MYCN-NA, FH, DI>1). These patients also received Isotretinoin (13-cis-retinoic acid, Accutane) for maintenance therapy, as they would have previously received this treatment on high-risk protocols. Thus, these patients would receive a significant reduction in therapy compared to prior studies.  These patients were closely monitored by interim stopping rules. Rescue therapy for this study for patients with an inadequate response to initial therapy and for patients with progressive, non-metastatic disease utilized standard cyclophosphamide and topotecan.

Reduction of therapy was also planned and achieved on their study by reducing potential surgical morbidity for patients with stage 4S disease, who would no longer be required to undergo resection of their primary tumor.

In the manuscript, the authors report that 404 evaluable patients were enrolled between 2007 and 2011, They found that compared to legacy COG studies, subsets of patients with locoregional disease, infants with stage 4 or 4S tumors, and toddlers with stage 3 or 4 disease had a reduction in treatment. The 3-year event-free survival (EFS) and OS were 83.2±1.9% and 94.9±1.1%, respectively.

Infants with stage 4 favorable biology tumors (n=61) had superior 3-year EFS compared
to patients with >= unfavorable biological feature (n=47; 86.9±4.4% versus 66.8±7.0%; p=0.02), with a trend towards OS advantage (95.0±2.8% and; 86.9±5.1% respectively p=0.08. For patients with localized disease OS was 100%.

They conclude that comparable/excellent survival was achieved with this biology- and response-based algorithm, with reduction of therapy for subsets of intermediate-risk neuroblastoma patients.

However, more effective treatment strategies are still needed for infants with unfavorable biology stage 4 disease. For the 32 infants with hyperdiploid, favorable histology (FH) stage 4 tumors with LOH at 1p36 or 11q23, or missing LOH data, intensification of treatment on ANBL0531 compared to A396110 did not reduce the risk of relapse previously reported for infants with tumors that harbor these genetic anomalies. Three-year EFS for this cohort was 68.6% (95% CI: 52.2-85.1%) versus 86.9% (95% CI: 78.3-95.4%) for stage 4 infants with favorable biology (p=0.04). Overall survival was not significantly different, indicating that many of the infants with 1p36/11q23 aberrations were successfully salvaged. Of the 20 patients who received CPM/TOPO due to an inadequate response to initial therapy, 9 achieved ≥VGPR. However, 6 of the 20 patients developed PD or relapsed, and 1 died, indicating that more effective treatment is needed for patients who do not meet the defined treatment endpoint after 8 cycles of chemotherapy.

Take home messages:

This is an important study with clinical implications for intermediate-risk neuroblastoma where the authors show that it is possible to reduce therapy based on a clinical Partial Response (PR) endpoint compared to Very Good Partial Response (VGPR). This most likely reflects the biology of the disease such that tumors that are responding to therapy will continue to involute. However, more effective therapy is needed for those patients who develop progressive disease (PD) or relapse or do not meet the defined treatment endpoint after 8 cycles of chemotherapy as these patients continue to have poor outcome.

This will await the result of current biological and genomic studies and the development of novel therapies targeting ALK or RAS, or epigenetic targeting of MYC or MYCN activated tumors, or immunotherapeutic approaches such as adoptive cell therapies consisting of chimeric antigen receptor (CAR T cell) or, NK cells, or the use of immunocytokines such as hu14.18-IL2 or antibody drug conjugates. All these holds promise for future sub-stratification and new therapies for children with intermediate and high-risk neuroblastoma.

This concludes this JCO Podcast. Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article "Dose-Adjusted EPOCH-R Compared to R-CHOP as Frontline Therapy for Diffuse Large B Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial CALGB 50303 (Alliance)" by Bartlett et al. My name is Patrick Stiff, and I am Division Director of Hematology-Oncology at Loyola University Stritch School of Medicine in Maywood, Illinois. My oncologic specialty is hematologic malignancies and stem cell transplantation.

CHOP has remained the chemotherapy backbone of choice for the treatment of diffuse aggressive non-Hodgkin lymphoma since the 4 arm randomized SWOG study was performed 25 years ago1. Since then, only the addition of rituximab has improved patients' outcome2.   Investigators have tried to improve outcomes by employing other strategies like increasing drug intensity, shortening the interval between cycles, adding newer agents, changing the method of administration, and adding transplantation, but none clearly demonstrated a survival advantage.

Among these strategies is an infusional one designed to increase apoptosis and inhibit BCL6 and p-glycoprotein in resistant cells.  While SWOG tested infusional CHOP in 2001 and found no difference in outcomes, compared to bolus CHOP3, the NCI group has explored a modified CHOP infusional regimen known as EPOCH consisting of etoposide, vincristine, and doxorubicin given simultaneously as a continuous 4 day infusion with a bolus dose of cyclophosphamide at the end of the 4 days along with daily oral prednisone Combined with aggressive dose escalations based on nadir myelosuppression, they tested this regimen with rituximab, EPOCH-R, reporting an impressive 5 year PFS of 79% in an unselected study of 72 patients from 3 centers4.  Based on this, 18 CALGB institutions treated 69 patients with dose adjusted EPOCH-R, demonstrating a similar 62 month TTP of 81%, with an impressive 100% TTP for the germinal center B cell subgroup as defined by the Hans algorithm, all seemingly superior to R-CHOP5.  Equally impressive was a Phase II study in mediastinal B cell NHL with a 5-yr EFS of 93% administered without consolidative radiotherapy, added frequently to R-CHOP6.  Therefore, a head-to-head comparison was the natural next step.

The trial that accompanies this podcast was designed to compare the PFS and OS at 3 years between patients treated with 6 cycles of dose adjusted EPOCH-R to the standard R-CHOP.  The trial opened in 2005 and enrolled 524 patients with either DLBCL, primary mediastinal BCL or intravascular large cell NHL over an 8+ year period to its close in 2013.  Seventy-four % had stage III/IV disease and 12% high IPI disease.   Eighty-eight percent of the R-CHOP and 82% of the dose adjusted EPOCH-R cycles were administered with 75% of the dose adjusted EPOCH-R patients receiving initial dose escalations per protocol. At a median follow-up of 5.2 years the 5 year PFS and OS were 66 and 85% for the R-CHOP treated patients no different from the 68 and 77.5% for the dose adjusted EPOCH-R  patients.  Prognostic factors for PFS were age > 60, IPI, and double expressers (15.6% of the 270 with complete data) for MYC, BCL-2 and BCl-6. 

There were a number of post hoc subgroup analyses performed. Of these, the PFS for the combined High and High intermediate IPI group was higher for the dose adjusted EPOCH-R group (p = 0.041) but no difference in OS was noted.  In none of the other subgroups was a benefit seen for dose adjusted EPOCH-R including CNS relapses, mediastinal B cell NHL, double expressors or those with MYC positivity although percentages of these subgroups were small.  There were however significantly increased grade III-IV myelotoxic and non-myelotoxic complications for the infusional regimen.

Should we take these results as the final word on the lack of a benefit of dose adjusted EPOCH-R in the treatment of DLBCL?  In other words is this a case of "déjà vu all over again"?.  This trial recruited slowly, 524 patients over more than 8 years, with < 5% of US eligible patient enrolled. The reasons seem obvious.  Encouraging enrollment on a trial comparing a familiar outpatient regimen administered over hours, versus a 4+ day in-patient regimen was at best difficult. Recall also that this trial took place during the Great Recession, with patients/families fearful of losing their jobs dealing with an in-pt regimen. Slow accrual in and of itself should not have been impacted outcome. But these were not a unselected group as the authors concluded. First by design, all who had an ECOG PS of > 2 (20% of the phase II study5) were excluded.  Second there was the requirement for submission of fresh/frozen material including a second biopsy if needed thereby likely eliminating mostly patients with rapidly progressing disease.  Together possibly with some investigator bias, given the promising Phase II data, there was a decrease in High IPI enrollment of only 12% versus the 20% in the Phase II study, which extended to other high risk patients including double expressors, C-Myc positive, and mediastinal B cell disease. Combined these led to the 3 year PFS for R-CHOP of 72%, 17% better than the planned outcome. However, considering the trial exclusions, and ultimately a PFS similar to that of other recent R-CHOP experiences7,8 one could argue that the 3-yr 55% PFS endpoint for this trial was far too conservative. 

While the R-CHOP PFS was 17% better than planned, the dose adjusted EPOCH-R 5-yr PFS was 7% worse than the Phase II results, which is difficult to explain considering the earlier studies, in which the more favorable patients did better5. A lower administered dose intensity compared to prior studies4,5 was not apparent with the incidence of grade III/IV febrile neutropenia and neurotoxicity similar to the Phase II trial.  However 82%  vs 91% of those in the Phase II study completed all dose adjusted EPOCH-R cycles with the decrease mostly due to on treatment deaths and AEs, suggesting that when used in a more 'real world setting' this regimen is more toxic than initially seen.  Might those who completed therapy also have had dose reductions or delays that could also have impacted PFS?  Finally, this report does not include PFS based on cell of origin(COO), which for patients with  germinal center B cell of origin in the Phase II study was 100%.  Perhaps the germinal B cell percentage was lower than in the Phase II studies as well.

So what can be concluded about these negative results?  The authors conclude that there was a "potential patient selection bias", at least partially explainable by trial design, and that this "may preclude generalizibility….to specific subgroups".  I would conclude that given the outcome and toxicity data, for the low and low intermediate IPI patient, R-CHOP remains the treatment of choice.  The post hoc PFS improvement for the high risk subgroup might argue for dose adjusted EPOCH-R, but the lack of an OS advantage in this subgroup needs to be acknowledged. However, other compelling phase II studies in high risk subsets, e.g double hit, underrepresented in this trial, still makes the efficacy of dose adjusted EPOCH-R in certain circumstances an open question.

 This concludes this JCO Podcast. Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article "Erlotinib Versus Gemcitabine Plus Cisplatin as Neoadjuvant Treatment for Stage IIIA-N2 EGFR-Mutant NSCLC (EMERGING-CTONG 1103): A Randomized Phase II Study" by Zhong et al. My name is Tony Mok, and I am a Professor of Clinical Oncology at the Chinese University of Hong Kong in the Prince of Wales Hospital in Hong Kong. My oncologic specialty is Medical Oncology.

With the advent of molecular targeted therapy, patients harboring driver oncogenes may now survive longer and better than before, and EGFR mutation is the prime example of such achievement. However, evidence for "cure" of patients with metastatic EGFR mutation positive lung cancer remains scanty. In contrast, It may be more reasonable to first attempt cure of patients with earlier stage disease using molecular targeted therapy. CTONG 1103, published in this issue of Journal of Clinical Oncology, is the first randomized study comparing neoadjuvant erlotinib with chemotherapy for patients with stage IIIA EGFR mutation positive lung cancer.

CTONG 1103, the report that accompanies this podcast, is not an easy study to conduct. Between December 2011 and December 2017, investigators from 17 centers across China managed to screen 386 patients with stage IIIA non-small cell lung cancer (NSCLC) and identified only 72 (which is about 19%) eligible EGFR mutation positive patients. They were randomized to receive either erlotinib 150mg daily for 42 days or two cycles of chemotherapy using gemcitabine and cisplatin as neo-adjuvant therapy. After neoadjuvant therapy, 73% of the erlotinib arm, and 63% of the chemotherapy arm, received curative surgery, including two patients in erlotinib arm who received pneumonectomy. The primary endpoint of this study is tumor response rate, which is 54.1% for erlotinib and 34.3% for chemotherapy. However, the odds ratio of 2.26 for tumor response rate was not statistically significant. Two other important and impactful endpoints include major pathological response and progression free survival (PFS). Major pathological response is defined as less than 10% residual viable tumor cell and it occurred only in 10.7% of patients who received erlotinib and none with the chemotherapy. But on the other hand, PFS was significantly better with erlotinib arm, reporting median of 21.5 month comparing with 11.4 months with chemotherapy arm.

In reference to the primary endpoint of tumor response rate, we should conclude that CTONG 1103 is a negative study. Zhong et al has reasonably estimated the sample size based on a presumptive response rate of 70% in the erlotinib arm and 36% in the chemotherapy arm.  The reported response rate at 54.1% with erlotinib in this study has significantly fallen short of the expected rate of 70%, which was actually the widely accepted response rate in patients with stage IV disease. The authors selected to offer 42 days of neo-adjuvant erlotinib in order to match the two cycles of neo-adjuvant chemotherapy. While there is no biologic reason to explain the low response rate in earlier stage disease, the shorter duration of treatment may contribute to the relatively lower response rate. The other important outcome is the major pathological response of 10.7% with neo-adjuvant erlotinib, which is supposed to be a surrogate for overall survival. Hellman et al were among the first groups to suggest the predictive power of major pathological response for neo-adjuvant chemotherapy for patients with early stage lung cancer. The lower than expected major pathological response may be considered a surrogate indicator for overall survival but it is more important to wait for the mature survival outcomes.

A negative study can still be impactful. This study has established the feasibility of neo-adjuvant EGFR TKI for patients with potentially resectable EGFR mutation positive lung cancer. The first single arm phase II study on pre-operative gefitinib published in 2009 in the Journal of Clinical Oncology enrolled 36 patients but only 6 harbored the activating EGFR mutations. Tumor response was observed in 4 patients and all were positive for the mutations. Another single arm study published in 2018 in the journal The Oncologist enrolled 19 patients with EGFR mutation positive stage IIIA NSCLC and treated with neoadjuvant erlotinib for 56 days. Tumor response rate was 42.1% and resection rate was 68.4%. Only 5 of the 14 patients (35.7%) with surgical resection had documented pathologic downstaging from N2 to N0/N1 disease. The median PFS and OS was 11.2 and 51.6 months respectively. CTONG 1103 is the first and only randomized comparative study that confirmed the feasibility and efficacy of neo-adjuvant EGFR TKI. Tumor response rate is higher than chemotherapy by 20% although not statistically significant, but toxicity profile is better, which is an established fact from multiple phase III studies on advanced stage disease. The resection rates were similar between the two arms but it was unclear how many of the enrolled patients had unresectable disease prior to neo-adjuvant therapy. Key objectives of neo-adjuvant therapy are to down-stage tumor/nodal disease and to improve resectability. This randomized study may potentially document if erlotinib is more capable of converting unresectable stage IIIA disease to being resectable, however, this data is not currently available.

The authors of the current study have also reported improvement in progression free survival, but we cannot conclude that the improvement is solely due to the neo-adjuvant therapy. As per study protocol, patients from neo-adjuvant EGFR TKI arm did receive 12 months of erlotinib as adjuvant therapy while the chemotherapy arm received only 2 more cycles of similar treatment. Considering the duration of therapy, the adjuvant erlotinib may in fact  contribute more to prolongation of progression free survival than the neo-adjuvant therapy. In 2017 in the journal Lancet Oncology, the same group of investigators have reported a randomized phase III study comparing adjuvant gefitinib with chemotherapy and the median disease free survival was 28.7 months and 18.0 months, respectively. All patients enrolled in this study had resectable lung cancer with over 60% of patients having N2 disease, and the authors had concluded on the potential survival advantage of adjuvant EGFR TKI. Thus, the improvement in progression free survival should be explained by both neo-adjuvant and adjuvant erlotinib.

In summary, CTONG 1103 is a negative study but it has significant impact on management of stage IIIA EGFR mutation positive lung cancer. With high screening failure rate at 80%, it took the authors 6 years to enroll 72 patients. This study will remain the only randomized study on this patient group for a long time as similar  large scale phase III trials of this strategy will be unlikely. Clinicians are obligated to share and explain CTONG 1103 to patient with stage IIIA EGFR mutation positive lung cancer. For patients with resectable disease at presentation, the benefit of neo-adjuvant EGFR TKI may be debatable. But for patients with un-resectable stage IIIA disease, neo-adjuvant EGFR TKI may potentially downstage the disease status and facilitate resection.  

This concludes this JCO podcast. Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article 'Late Relapses in Patients With Diffuse Large B-Cell Lymphoma Treated With Immunochemotherapy' by Yang et

My name is Ann LaCasce, and I am an Associate Professor of Medicine at the Dana-Farber Cancer Institute in Boston, USA.  My oncologic specialty is lymphoma.

This podcast discusses the recent paper evaluating the risk of late relapse in patients with diffuse large B-cell lymphoma who are event free 24 months after diagnosis.

The goal of upfront chemoimmunotherapy in patients with diffuse large B-cell lymphoma (DLBCL) is the permanent eradication of disease. In the era of rituximab, few studies with sufficient follow-up have examined the risk of late recurrence.  An analysis of patients with DLBCL from the University of Iowa/Mayo and validated in a separate cohort from the French Study Group of Adult Lymphoma demonstrated that patients who were alive and disease free at 24 months from diagnosis had overall survival rates equivalent to the age and sex matched general population.  Despite this finding suggesting cure, late relapses are not uncommon.

In this manuscript, patients enrolled in the Molecular Epidemiology Resource of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence with newly diagnosed diffuse large B-cell lymphoma or DLBCL with concurrent indolent lymphoma were identified.  847 of the 1324 patients treated with chemoimmunotherapy with or without radiotherapy between 2002 and 2015 were event free at 24 months.  These patients were subsequently analyzed for late relapse.  The majority of patients (87%) had DLBCL without evidence of co-existing indolent lymphoma.

With a median follow-up of 62.9 months, 78 patients developed recurrent disease, and the cumulative incidence of late relapse was approximately 7% at 3 years, 9% at 5 years and 10 % at 8 years after achieving EFS24.  Of the patients who developed recurrent lymphoma, 55 had DLBCL alone at baseline and 23 had DLBCL with concurrent indolent lymphoma. Among the patients with DLBCL alone.  36 developed recurrent DLBCL and 13 ad indolent lymphoma (12 with follicular lymphoma and 1 with marginal zone lymphoma).  6 patients did not have pathologic confirmation of disease subtype at the time of recurrence. For the 59% of patients with cell of origin data determined using the Hans algorithm, rates of relapse in patients with DLBCL alone did not differ between those with germinal center derived (GCB) versus non-GCB subtypes.  Individuals with GCB DLBCL were more likely to relapse with indolent lymphoma. Of the 23 patients with concurrent indolent lymphoma at baseline, 9 relapsed with DLBCL and the remaining 11 relapsed with indolent lymphoma 10 of whom had the same subtype at initial presentation (7 with follicular lymphoma, 1 marginal zone lymphoma, 1 chronic lymphocytic leukemia, one unspecified).  One patient who had current DLBCL and FL relapsed with MCL and the subtype was unknown in 3.  Patients with concurrent indolent lymphoma at initial diagnosis were more likely to experience late relapse which was driven by indolent recurrence.  In multivariable analysis, concurrent indolent lymphoma and GCB subtype were independent predictors of relapse.  In patients with DLBCL alone, GCB subtype was associated with indolent relapse but not DLBCL relapse.  Advanced stage and higher IPI score were associated with higher risk of recurrent DLBCL but not indolent relapse.  In terms of outcome, median survival after recurrence was approximately 39 months after EFS24, 30 months for those with DLBCL and the median was not reached in patients with indolent lymphoma.

This study emphasizes the importance of long- term follow-up of our patients with DLBCL.  Hematologists/oncologists typically see patients frequently after the completion of initial therapy but over time, visits become less frequent or not at all for some patients who remain in remission beyond the 5 year mark. Multiple studies have examined surveillance strategies in this setting. The likelihood of identifying recurrent disease in an asymptomatic patient with a normal physical exam is extremely low. In addition, there is no clear evidence that surveillance imaging or early detection of an asymptomatic recurrence impacts on overall survival. This is particularly true for patients who relapse with indolent disease, some of whom may be followed expectantly.   Others may be candidates for low-dose palliative radiation or reduced intensity therapies.  The National Comprehensive Cancer Network Guidelines , which are widely used by physicians as well as payors to determine insurance coverage, recommends symptom guided imaging in patients with a history of early stage DLBCL and CT scans no more often than 6 months for up to 2 years after the completion of therapy in patients with advanced stage disease. Imaging is associated with false positives, radiation exposure and is expensive for our health care system. In addition, anxiety associated with scans is common and may have negative impact on patients.

None-the-less, given that recurrences do occur, educating survivors and their physicians, including primary care providers, to be vigilant for the development of persistent symptoms without clear explanation, as well as B symptoms and lymphadenopathy is important. Setting expectations with patients is also essential, as is caution in using the term cure.  Although the vast majority of patients who remain in remission beyond 2 years after the completion of initial therapy are likely to remain disease free, a small minority will go on to develop recurrent aggressive or indolent lymphoma.  In patients with GCB subtype of DLBCL, discussion of the risk of the subsequent development of an indolent lymphoma may be warranted. Future studies examining changes in cell free DNA during and after therapy, as well as the development of other novel biomarkers may eventually allow us to be more accurate in our prognostication for patients.  In addition, understanding the biology of late recurrence to ascertain whether the recurrence represents the original clone or is distinct may ultimately be important for therapeutic approaches and outcome.

This concludes this JCO Podcast. Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article "Resumption of Immune Checkpoint Inhibitor Therapy After Immune-Mediated Colitis" by Abu-Sbeih et al. My name is David Oh, and I am an Assistant Professor at the University of California, San Francisco. My oncologic specialty is genitourinary medical oncology and cancer immunotherapy.

While immune checkpoint inhibitors, or ICIs, can lead to durable responses even when other standard therapies have failed, their therapeutic window is often limited by immune-related adverse events or IRAEs which are thought to be autoimmune in nature. Immune-mediated diarrhea and colitis are a frequent IRAE with ICIs, affecting up to a third of patients receiving anti-CTLA-4, approaching half of patients receiving anti-CTLA-4 in combination with anti-PD-1 or anti-PD-L1, and less frequently patients receiving anti-PD-1 or anti-PD-L1 alone. Since there is often overlap between IRAEs and response or survival with ICIs, and IRAEs such as colitis can require interruption of treatment and immunosuppression in patients who may have failed other treatment options, many providers are faced with an important question: is it safe to resume ICIs after patients have initial diarrhea and colitis, and what are the risk factors for another episode of diarrhea and colitis?

To address this question, which has not been well studied, Abu-Sbeih and colleagues in this issue of JCO performed a retrospective multicenter analysis of patients who had initial immune-mediated diarrhea and colitis requiring ICI interruption, and then subsequently resumed ICI from 2010 to 2018. From a starting population of 550 patients with initial diarrhea and colitis with ICI, they identified 167 patients who subsequently resumed ICI for a re-treatment rate of 30%. This represents a notable cohort with this degree of clinical annotation. For their initial therapy leading to diarrhea and colitis, about half of these patients had initially received anti-PD-1 or PD-L1 therapy, and a quarter each had initially received either anti-CTLA-4 therapy or combination. The majority of these patients had melanoma, with a smaller proportion of non-small cell lung and genitourinary cancer patients. At the time of re-treatment, 80% of these patients received an anti-PD-1 or anti-PD-L1 alone, while the others were re-treated with anti-CTLA-4 alone.

An important observation by the authors was that upon re-treatment of the 167 patients, 57 patients, or about a third, experienced recurrent diarrhea and colitis requiring permanent discontinuation of therapy. The grade of diarrhea and colitis most frequently seen was less severe, graded as less than or equal to Grade 2. As expected, 81% of these patients with recurrent diarrhea and colitis received steroids, while 12% of patients required further immunosuppression with either infliximab or vedolizumab which blocks the integrin alpha-4-beta-7.

Univariate and multivariate analyses were used to identify risk factors for recurrent diarrhea and colitis upon ICI resumption. Univariate analysis identified more severe initial diarrhea and colitis as a risk factor for having recurrent diarrhea and colitis on ICI re-challenge. Initial severity was determined either by longer duration of initial symptoms or requirement for initial immunosuppression. Multivariate analysis confirmed initial severity as a risk factor, and also found that a lower risk of recurrent diarrhea and colitis was associated with initial anti-CTLA-4 use, as well as with choice of anti-PD-1 or anti-PD-L1 therapy at the time of re-challenge regardless of their initial therapy. Importantly, even though resumption of anti-CTLA-4 was associated with a higher risk of recurrent diarrhea and colitis, the severity of recurrence, as determined by frequency of immunosuppression and grading of diarrhea and colitis, were actually similar to when anti-PD-1 or anti-PD-L1 were resumed.

Overall, then, despite the limitations of retrospective analysis, this work provides evidence from a substantial patient cohort across tumor and treatment types that recurrent diarrhea and colitis with ICI retreatment following initial interruption for diarrhea and colitis may occur in less than half of patients and is generally less severe. Furthermore, the risk of recurrent diarrhea and colitis is less likely in patients who had less severe episodes of initial diarrhea and colitis, who previously received initial anti-CTLA-4, or who are re-challenged with anti-PD-1 or anti-PD-L1 therapy. Although the choice of anti-PD-1 or anti-PD-L1 for re-treatment reduces the risk of recurrent diarrhea and colitis, the actual severity of recurrent episodes is similar to re-treatment with anti-CTLA-4 therapy. As a practical matter this can provide guidance to providers about whether to consider ICI resumption, and which agents to consider, based in part of characteristics of their initial treatment and IRAE. This will be particularly important for patients who experienced clinical benefit from their initial ICI therapy, or have limited other treatment options. At the same time, this work also prompts a number of questions for further investigation. Why does prior anti-CTLA-4 therapy leading to initial diarrhea and colitis yield a lower risk of recurrent episodes? Is there an association between recurrent diarrhea and colitis after ICI re-challenge and ongoing response to therapy? Finally, do different ICI-responsive cancer types exhibit higher or lower risk for recurrent diarrhea and colitis? These and other questions can be addressed by future studies involving larger and well-annotated patient cohorts at multiple centers.

                                                                                            
This concludes this JCO Podcast. Thank you for listening.

In this JCO Article Insights episode, Michael Hughes summarizes "International Myeloma Society and International Myeloma Working Group Consensus Recommendations on the Definition of High-Risk Multiple Myeloma" by Avet-Loiseau et al. published on June 09, 2025 along with an interview with author Dr Nikhil C. Munshi, MD.

TRANSCRIPT

Michael Hughes: Welcome to this episode of JCO Article Insights. This is Michael Hughes, JCO's editorial fellow. Today I am interviewing Dr. Nikhil Munshi on the "International Myeloma Society and International Myeloma Working Group Consensus Recommendations on the Definition of High-Risk Multiple Myeloma" by Avet-Loiseau et al.

At the time of this recording, our guest has disclosures that will be linked in the transcript.

While some patients with multiple myeloma live for decades after treatment, others exhibit refractory or rapidly relapsing disease irrespective of treatment administered. We term this "high-risk myeloma." Multiple risk stratification systems have been created, starting with the Durie-Salmon system in 1975 and evolving with the advent of novel therapeutics and novel treatment approaches.

In 2015, the Revised International Staging System (R-ISS) was introduced, which incorporated novel clinical and cytogenetic markers and remained, until recently, a mainstay of risk stratification in newly diagnosed disease. Myeloma as a field has, just in the past few years, though, undergone explosive changes. In particular, we have seen groundbreaking advances not only in treatments - the introduction of anti-CD38 agents and the advent of cellular and bispecific therapies - but also in diagnostic technology and our understanding of the genetic lesions in myeloma.

This has led to the proliferation of numerous trials employing different definitions of high-risk myeloma, a burgeoning problem for patients and providers alike, and has prompted attempts to consolidate definitions and terminology. Regarding cytogenetic lesions, at least, Kaiser et al's federated meta-analysis of 24 therapeutic trials, published here in the JCO in February of 2025 and recently podcasted in an interview with associate editor Dr. Suzanne Lentzsch, posited a new cytogenetic classification system to realize a shared platform upon which we might contextualize those trial results.

This article we have here by Dr. Avet-Loiseau, Dr. Munshi, and colleagues, published online in early June of this year and hot off the presses, is the definitive joint statement from the International Myeloma Society (IMS) and the International Myeloma Working Group (IMWG). What is high-risk multiple myeloma for the modern era?

The IMS and IMWG Genomics Workshop was held in July 2023 and was attended by international myeloma experts, collaborating to reach consensus based on large volumes of data presented and shared. The datasets included cohorts from the Intergroupe Francophone du Myélome (IFM); the HARMONY project, comprised of multiple European academic trials; the FORTE study, findings from which solidified KRd as a viable induction regimen; the Grupo Español de Mieloma Múltiple (GEM) and the PETHEMA Foundation; the German-Speaking Myeloma Multicenter Group (GMMG); the UK-based Myeloma XI, findings from which confirmed the concept of lenalidomide maintenance; Emory 1000, a large, real-world dataset from Emory University in Atlanta; the Multiple Myeloma Research Foundation Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile (CoMMpass) dataset; and some newly diagnosed myeloma cohorts from the Mayo Clinic.

Data were not pooled for analyses and were assessed individually - that is to say, with clear a priori understanding of whence the data had been gathered and for what original purposes. Consensus on topics was developed based on the preponderance of data across studies and cohorts.

In terms of results, substantial revisions were made to the genomic staging of high-risk multiple myeloma, and these can be sorted into three major categories: A) alterations to the tumor suppressor gene TP53; B) translocations involving chromosome 14: t(14;16) (c-MAF overexpression), t(14;20) (MAFB overexpression), and t(4;14) (NSD2 overexpression); and C) chromosome 1 abnormalities: deletions of 1p or additional copies of 1q.

In terms of category A, TP53 alterations: Deletion of 17p is present in up to 10% of patients at diagnosis and is enriched in relapsed or refractory disease. This is well-documented as a high-risk feature, but the proportion of the myeloma cells with deletion 17p actually impacts prognosis. GEM and HARMONY data analyses confirmed the use of 20% clonal cell fraction as the optimal threshold value for high-risk disease. That is to say, there must be the deletion of 17p in at least 20% of the myeloma cells on a FISH-analysis of a CD138-enriched bone marrow sample to qualify as high-risk disease.

TP53 mutations can also occur. Inactivating mutations appear to have deleterious effects similar to chromosomal losses, and the biallelic loss of TP53, however it occurs, portends particularly poor prognosis. This effect is seen across Myeloma XI, CoMMpass, and IFM cohorts. Biallelic loss is rare, it appears to occur in only about 5% of patients, but next-generation sequencing is nevertheless recommended in all myeloma patients.

Category B, chromosome 14 translocations: Translocation t(14;16) occurs in about 2% to 3% of patients with newly diagnosed disease. In the available data, primarily real-world IFM data, t(14;16) almost always occurs with chromosome 1 abnormalities. Translocation t(4;14) occurs in about 10% to 12% of newly diagnosed disease, but only patients with specific NSD2 alterations are, in fact, at risk of worse prognosis, which clinically appears to be about one in every three of those patients. And so together, the CoMMpass and Myeloma XI data suggest that translocation t(4;14) only in combination with deletion 1p or gain or amplification of 1q correlates with worse prognosis.

Translocation t(14;20) occurs in only 2% of newly diagnosed disease. Similar to translocation t(4;14), it doesn't appear to have an effect on prognosis, except if the translocation co-occurs with chromosome 1 lesions, in which case patients do fare worse.

Overall, these three translocations - t(14;16), t(4;14), and t(14;20) - should be considered high-risk only if chromosome 1 aberrations are also present. In terms of those chromosome 1 aberrations, category C, first deletions of 1p: Occurring in about 13% to 15% of newly diagnosed disease, deletion 1p eliminates critical cell checkpoints and normal apoptotic signaling. In the IFM and CoMMpass dataset analyses, biallelic deletion of 1p and monoallelic deletion of 1p co-occurring with additional copies of 1q denote high-risk.

In terms of the other aberration in chromosome 1 possible in myeloma, gain or amplification of 1q: This occurs in up to 35% to 37% of newly diagnosed disease. It upregulates CKS1B, which is a cyclin-dependent kinase, and ANP32E, a histone acetyltransferase inhibitor. GEM and IFM data suggest that gain or amplification of 1q - there was no clear survival detriment to amplification - is best considered as a high-risk feature only in combination with the other risk factors as above.

Now, in terms of any other criteria for high-risk disease, there remains one other item, and that has to do with tumor burden. There has been a consensus shift, really, in both the IMS and IMWG to attempt to develop a definition of high-risk disease which is based on biologic features rather than empirically observed and potentially temporally dynamic features, such as lactate dehydrogenase. Beta-2 microglobulin remains an independent high-risk indicator, but care must be taken when measuring it, as renal dysfunction can artificially inflate peripheral titers. The consensus conclusion was that a beta-2 microglobulin of at least 5.5 without renal failure should be considered high-risk but should not preclude detailed genomic profiling.

So, in conclusion, the novel 2025 IMS-IMWG risk stratification system for myeloma is binary. It's either high-risk disease or standard-risk disease. It's got four criteria. Number one, deletion 17p and/or a TP53 mutation. Clonal cell fraction cut-off, remember, is 20%. Or number two, an IGH translocation - t(4;14), t(14;16), t(14;20) - with 1q gain and/or deletion of 1p. Or a monoallelic deletion of 1p with 1q additional copies or a biallelic deletion of 1p. Or a beta-2 microglobulin of at least 5.5 only when the creatinine is normal.

This is a field-defining work that draws on analyses from across the world to put forward a dominant definition of high-risk disease and introduces a new era of biologically informed risk assessment in myeloma.

Now, how does this change our clinical approach? FISH must be performed on CD138-enriched samples and should be performed for all patients. Next-generation sequencing should also be performed on all patients. Trials will hopefully now begin to include this novel definition of high-risk multiple myeloma. It does remain to be seen how data from novel therapeutic trials, if stratified according to this novel definition, will be interpreted. Will we find that therapies being evaluated at present have differential effects on myelomas with different genetic lesions?

Other unanswered questions also exist. How do we go about integrating this into academic and then community clinical practice? How do we devise public health interventions for low-resource settings? To discuss this piece further, we welcome the esteemed Dr. Nikhil Munshi to the podcast. Dr. Munshi is a world-renowned leader in multiple myeloma and the corresponding author on this paper. As Professor of Medicine at Harvard Medical School, Director of the Multiple Myeloma Effector Cell Therapy Unit, and Director of Basic and Correlative Science at the Jerome Lipper Multiple Myeloma Center of the Dana-Farber Cancer Institute, he has presided over critical discoveries in the field. 

Thank you for joining us, Dr. Munshi.

Dr. Nikhil Munshi: Oh, it's my pleasure being here, Michael, to discuss this interesting and important publication.

Michael Hughes: I had a few questions for you. So number one, this is a comprehensive, shall we say, monumental and wide-ranging definition for high-risk myeloma. How do you hope this will influence or impact the ways we discuss myeloma with patients in the exam room? And how do we make some of these components recommended, in particular next-generation sequencing, feasible in lower-resource settings?

Dr. Nikhil Munshi: So those are two very important questions. Let's start with the first: How do we utilize this in our day-to-day patient care setting?

So, as you know well, we have always tried to identify those patients who do not do so well with the current existing treatment. And for the last 30 years, what constitutes a myeloma of higher risk has continued to change with improvement in our treatment.

The current definition basically centers around a quarter of the patients whose PFS is less than 2 to 3 years. And those would require some more involved therapeutic management. So that was a starting point of defining patients and the features.

As we developed this consensus amongst ourselves - and it's titled as "International Myeloma Society, International Myeloma Working Group Consensus Recommendation" - this IMS-IMWG type of recommendation we have done for many years, improvising in various areas of myeloma care. Now, here, we looked at the data that was existing all across the globe, utilizing newer treatment and trying to identify that with these four-drug regimens, with transplant and some of the immunotherapy, which group of patients do not do as well. And this is where this current algorithm comes up. So before I answer your question straight, "How do we use it?" I might like to just suggest, "What are those features that we have identified?"

There are four features which constitute high-risk disease in the newer definition. Those with deletion 17p with 20% clonality and/or TP53 mutation. Number two, patients with one of the translocations - t(4;14), t(14;16), or t(14;20) - co-occurring with 1q amplification or deletion 1p32. And that's a change. Previously, just the translocation was considered high-risk. Now we need a co-occurrence for it to be called high-risk. The third group is patients having biallelic deletion 1p32 or monoallelic deletion 1p32 along with 1q amplification. And finally, patients with high beta-2 microglobulin, more than or equal to 5.5 mg/dL, with normal creatinine less than 1.2 mg/dL.

And the question, "How do we use this?" There are multiple areas where we incorporate high-risk features in our treatment algorithm. One of the first areas is where we would consider the induction regimen. If a patient has a high-risk disease, we would definitely consider a four-drug regimen rather than a three-drug regimen, although we are beginning to incorporate four-drug for all groups. That's one important thing. Number two, those are the patients where we do consider consolidation with transplant or maybe in the new world, considering some of the immunotherapeutic consolidation more early or more aggressively. Number three, these are the patients who get a little bit more maintenance therapy. So normally, lenalidomide might end up being our standard maintenance regimen. In patients who have high-risk disease, we incorporate either addition of daratumumab or the anti-CD38 targeting antibody and/or addition of proteasome inhibitor, either bortezomib or carfilzomib. So you would have multi-drug maintenance therapy in these patients. And in high-risk patients, we follow them with maintenance longer periods of time.

One very critically important point to keep in mind is that to get the better outcome in high-risk disease, we must try to get them into MRD negativity because there is clear data that patients who do achieve MRD negativity, despite having high-risk disease, have a much superior outcome. They become near to standard-risk disease. And so, in high-risk patients, I would try to do whatever various options I have to try and get them into MRD-negative status. And when these patients relapse, we do not wait for the classic progression criteria to be met before we intervene. We would propose and suggest that we intervene earlier before the disease really blasts off. And so there are a number of areas in our setting where this high-risk definition will help us intervene appropriately and also with appropriate aggressiveness to achieve better outcome, to make this similar to standard-risk disease.

Michael Hughes: Thank you, Dr. Munshi. And thoughts on how to really integrate this not only into academic centers but also lower-resource settings?

Dr. Nikhil Munshi: So that's a very important question, Michael. And when we were developing this consensus, we were very cognizant of that fact. So wherever available, I think we are recommending that over a period of next 2, 3, 5 years, we should begin to switch over to sequencing-based methods because two components of this definition, one is TP53 mutation, which we cannot do without sequencing, and also reliably detecting deletion 1p requires sequencing-based method.

So in the low-resource countries - and there are many in this world, and also even in our own country, patients may not be able to afford it - the older method with FISH or similar such technology, which is more affordable, is also acceptable for current time. They may miss a very small number of patients, maybe 2% to 3%, where these finer changes are not picked up, but a majority of this would be captured by them. So the current practice might still be applicable with some limitation in those patient populations, and that's what we would recommend. What is happening, fortunately, is that actually sequencing-based method is becoming cheaper. And in many centers, it is cheaper to do the sequencing rather than to do the FISH analysis. And so my hope is that even in low-resource centers, sequencing might be more economical in the end. It's, I think, the access to technology, which is a little bit limited currently, but it's hopefully becoming available soon.

Michael Hughes: Thank you, Dr. Munshi. And staying for a minute and looking at the multiple myeloma subsets which might be missed by this really still very broad-ranging high-risk definition, at least by prior risk stratification systems, right, there is this group of patients who have standard-risk cytogenetics by R-ISS or R2-ISS, but they have primary refractory disease or they relapse early. We call these, as you are well aware, functionally high-risk disease. What proportion of previously FHR, functionally high-risk, myeloma patients do you expect to be captured by this novel definition?

Dr. Nikhil Munshi: So I think the newer definition - and we can look at it both ways, but the newer definition should capture most of the functionally high-risk definition. To put it differently, Michael, there are patients who we know are, as you mentioned, functionally high-risk. Those are the patients who might have plasma cell leukemia, those who might have extramedullary disease, those who might not respond to our four-drug induction. If you don't respond to the four-drug induction, almost by definition, they are high-risk. However, a majority of them have one of the abnormalities that we are describing here. There would be a very small proportion which may not have. And if they do not have, we know one of the important components of this definition here is also that the genome, we know, keeps on evolving. So there may be a very small clone with the high-risk feature which was not obvious in the beginning. Following treatments or following relapse, that clone predominates, and now the patient's disease becomes high-risk. 

So the definition would incorporate or would capture these functional high-risk patients, but as you said, in countries where resources are not available, using this functional high-risk would also be helpful and advantageous. Sometimes LDH ends up being a high-risk. In our studies, LDH has not come out to be high-risk anymore because the features we are describing captures most of those patients, but those alternatives, older, can still be considered if other newer techniques are not available.

Michael Hughes: Got you. And in terms of these older definitions, yes, that incorporate tumor burden, these empirical observations about how myeloma presents, do you foresee any additional tumor burden indicators being added to future definitions of high-risk disease? Or do you instead see this particular definition as a major waypoint on the journey towards a fully biologically grounded definition of high-risk disease?

Dr. Nikhil Munshi: I think your second part is what is going to happen. I think the tumor burden-related definition is being now replaced by the biological or genomic-based definition. And I think at some point, it will be quite fully replaced. One component not here, and it is because one thing, we don't have enough data; number two, we don't know how it will pan out, is also the influence of the microenvironment on the risk definition. For example, the immune system, the immune function, etc. But not enough data exists to suggest how it would change the current definition. So in future, would a definition be totally genomic or it could be more integrative? And my personal guess is that it would be more integrative and that some immune features might come into the picture, especially now that we are using immune-based therapy as a very important component of treatment - CAR T-cells, bispecific, and antibody-based treatments. What role the immune system plays in either supporting tumor or what role suppression of the anti-tumor immunity plays? They all will be important how patient outcomes end up being, and which in turn could translate into how patient's risk stratification might happen.

So I think the older tumor burden-related definitions probably will become things of the past. What we have currently proposed and consensus developed is the new path forward, and over time, some microenvironmental influences, if defined and found to be important, may get some more incorporation if it compares favorably with the genomic features.

Michael Hughes: Thank you, Dr. Munshi for that enlightening response. 

To conclude the podcast, I'd like to look to the future and to the immediate future, what are the next steps for high-risk disease definition between now and discussing an integrated genomic-microenvironment-based definition? Will we see attempts to refine? Will we see a multi-level system, things like this?

Dr. Nikhil Munshi: Yeah, so I think the current definition will be here to stay for the next 10 years or so. I think this has been developed using a large amount of data, so we do believe that this will remain fine. It has been validated now within the last six months by a few of the other studies. So there won't be a quick change. But we will try to, all of us will try to innovate. And as you very rightly bring up, the areas of research would include looking at the expression or transcriptomic component. Does that matter? And we do believe a small number of patients will have transcriptomic changes, not looked at the DNA changes, and may play a role. There are newer components, so long non-coding RNA, for example, is going to be an important component to look at, how it impacts the disease outcome, etc. There are also some of the proteomic-related changes which may become important in our studies. And then as we discussed, microenvironment and immunological changes. So these are the future areas of ongoing research where we all should collect data, and then in the next 5 to 10 years, we'll have another group meeting to see has anything changed or any of the features have become more important. 

Most of the time, some of the older features are lost because they are not as critically high-risk, and the newer features come in. And so the historical background for just one second, there was a time when chromosome 13 was considered a high-risk disease. We now don't even mention it because it's not high-risk. The newer treatments have improved the outcome. t(4;14) used to be a high-risk disease. Now by itself today, in this definition by itself is not; it needs to be with something else. And so I think this is a great sign of progress. As we improve the treatment and outcomes, some of the features will become less important, new features will come up, and we'll need to keep on evolving with time and with technology and make it better for patients.

Michael Hughes: Thank you so much, Dr. Munshi, for your wisdom, for your sagacity, for your historical perspective as well. 

Thank you for listening to JCO Article Insights. Please come back for more interviews and article summaries. And be sure to leave us a rating and review so others can find our show. For more podcasts and episodes from ASCO, please visit asco.org/podcasts.

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.

This JCO Podcast provides observations and commentary on the JCO article "PET Score Has Greater Prognostic Significance Than Pre-Treatment Risk Stratification in Early-Stage Hodgkin Lymphoma in the UK NCRI RAPID Study" by Barrington et al. My name is Brue Cheson, and I am at Georgetown University Hospital, Lombardi Comprehensive Cancer Center. My Hematologic-oncologic specialty is Lymphoma.

Hodgkin lymphoma is clearly one of the most dramatic success stories in modern oncology. More than 90% of patients with limited disease and about 85% with advanced disease are cured using conventional chemotherapy regimens.  As a consequence, current clinical trials are focusing on augmenting or modifying treatment for those at higher risk and decreasing the intensity or duration of therapy for those at a lower risk of treatment failure.

One important question has been: how best to distinguish those disparate groups?  Over the years, various prognostic scoring systems have been devised.  The International Prognostic Scoring System (IPSS) differentiated patients into 6 groups using 7 clinical and laboratory factors.  However, only 7% of patients are in both the most and least favorable groups.  The German Hodgkin study Group (GHSG) and the EORTC each published criteria slightly different from each other for treatment selection.  Nevertheless, it is not clear that any of these schemas remains relevant in the context of current Hodgkin regimens.  More importantly, they do not reliably dictate how to treat patients, nor do they offer therapeutic targets.

FDG-PET scanning has revolutionized our management of patients with lymphoma.  In 2005 we first demonstrated that integration of PET into standard response assessment improved the ability to distinguish between residual tumor and fibrosis in patients with diffuse large B-cell lymphoma, leading to a revision of standardized response criteria. More recent studies have confirmed this observation in Hodgkin lymphoma and other histologies. Patients with advanced Hodgkin lymphoma can be distinguished into high and low risk groups based on PET scan results after 2 cycles of standard ABVD chemotherapy, regardless of their pretreatment IPSS score.  In a number of studies, reacting to the positive interim scan by intensifying therapy achieved outcomes markedly improved over expected.

In the paper that accompanies this podcast, Sally Barrington and her colleagues performed a secondary analysis of the RAPID trial to evaluate the role of pre-treatment risk factors and PET results in predicting outcome of patients with early stage Hodgkin lymphoma.  This study accrued 602 patients who were treated with standard ABVD and underwent PET scanning after the third cycle.  Those with a negative scan (a Deauville score of 1-2) were randomized to no further treatment vs involved field radiotherapy.  Despite a failure to demonstrate non-inferiority of progression-free survival in this cohort, the overall survival was the same, thus sparing 90% of patients unnecessary radiotherapy.  Those with a positive scan (defined as a Deauville score of 3-5), the primary focus of the current manuscript, received an additional cycle of ABVD plus radiotherapy.  Only the 21 patients with a Deauville score of 5, defined as an SUV at least 3 times greater than that of the liver, had an inferior time to progression or greater risk of Hodgkin-related death.  Importantly, this finding was independent of pretreatment prognostic factors using either the GHSG or EORTC scores.  Whether this observation can be extrapolated to patients with features not eligible for the RAPID study, such as those with bulky mediastinal disease or B-symptoms, is presently unknown.  Nonetheless, these data support the role of metabolic imaging over standard clinical and laboratory risk factors.

But we are clearly doing this all wrong.  Why do we treat all patients the same and then wait until the disease has demonstrated resistance before we alter therapy?  Several recent papers support the notion that anticipatory, biologically-based, risk-adapted approaches may be feasible. Pre-treatment total metabolic tumor volume (defined as the sum total of all metabolically active lesions) can predict outcome in Hodgkin lymphoma as well as follicular, diffuse large B-cell and primary mediastinal large B-cell lymphoma.  High heterogeneity of intratumoral FDG uptake distribution on PET-CT may be a marker of chemoresistance in solid tumors as well as various lymphoma histologies.  Unfortunately, those tests do not provide a target against which to direct a specific agent.  In contrast, a number of investigators have demonstrated a correlation between bcl-2, p53, FOXP3, CD68, STAT1, pattern of PD-1 expression, mutational patterns derived from next generation sequencing, and other factors in pre-treatment Hodgkin node biopsies and outcome.  Thus, if we are able to predict outcome prior to treatment, why do we expose patients to drugs to which we know they will not benefit? The goal of treatment should be anticipatory, risk-adapted strategies whereby patients with a high likelihood of benefit may receive standard of care, unless there is another clinical question being addressed.  On the other hand, those unlikely to benefit as determined prior to therapy should be spared the waste of time and toxicity and treated with novel regimens directed at specific targets.  Both groups should be monitored during treatment for the emergence of mutations, with treatment altered accordingly.  Yes, we may be a long way from having the appropriate tools for such an approach.  But, to quote the geneticist, molecular engineer and chemist George M. Church, "The best way to predict the future is to change it".  Anticipatory, risk-adapted strategies could do just that.

This concludes this JCO Podcast. Thank you for listening.

This podcast provides observations and commentary on the JCO article "Randomized, Double-Blind, Phase II Study of Regorafenib in Patients with Metastatic Osteosarcoma" by Davis et al. My name is Brian Van Tine, and I am an Associate Professor of Medicine in the Division of Oncology at Washington University School of Medicine. My oncologic specialty is sarcoma.

Osteosarcoma (OS) is the most common type of primary malignant bone cancer, frequently occurring in children and adolescents. It can also be found in older adults around the age of 70, but unfortunately, though rare, can be found in patients of any age. Thus, Osteosarcoma is a disease that not only do pediatric oncologists need to know about, but also adult oncologists. Osteosarcoma occurs primarily at the metaphysis of the bone, in regions of rapid bone growth, in bone-forming cells called osteoblasts. Various risk factors for the development of osteosarcoma include underlying bone pathologies, such as Paget's Disease, prior radiation treatment, and genetic predisposition due to mutations, such as Li-Fraumeni Syndrome, caused by mutations to TP53, or in retinoblastoma mutation patients.

Currently, in the curative setting, OS is treated with chemotherapy with cisplatin, doxorubicin, and high-dose methotrexate (HD-MTX), followed by surgical resection of the tumor.  Patients who relapse with metastatic disease have limited options, regiments such as ifosfamide with etoposide and gemcitabine with docetaxel are used with an expected 4-month PFS of only 12%, but the standard of care for osteosarcoma has not changed in 30 years.

This is where the Sarcoma Alliance for Research and Collaboration, or SARC for short, comes in.  SARC is a non-profit organization dedicated to the development and support of research for the prevention, treatment and cure of sarcoma.  It is a collaborative group comprised of leading sarcoma physicians dedicated to performing clinical trials in rare diseases.  It is their 24th trial and is the subject of the JCO article that accompanies this podcast, where Dr. Lara Davis and colleagues report their findings of a Randomized, Double-Blind, Phase II Study of Regorafenib in Patients with Metastatic Osteosarcoma.

This trial took place across 12 US centers between 2014 and 2018 and enrolled 42 patients between the ages of 18 and 76. Once again, the age distribution highlights that osteosarcoma is not just a pediatric disease, and that there is a dedication to rare disease researchers to accrue to rare disease clinical trials at SARC.   In this trial, patients were randomized one to one to either Regorafenib or placebo on a 28-day cycle and responses were assessed using RECIST version 1.1 every 8 weeks.  At the time of progression on placebo, patients were allowed to crossover to Regorafenib.

Following the release of the European REGOBONE trial, a study of similar design that showed a significant benefit of regorafenib in osteosarcoma patients, an independent Data Safety and Monitoring Committee (DSMC) was convened by SARC due to concerns regarding continuing to enroll on a placebo-controlled study. The committee recommended closing the study after enrollment of 42 or the 48 planned patients.   

Here is what they found.  At the time of analysis, they found a progression free survival of 3.6 months for Regorafenib and 1.7 months for placebo with a hazard ratio of = 0.42; a 95% confidence interval of 0.21-0.85, and a p=0.017.  Given the crossover design, there was no overall survival seen with a p-value of 0.62.   In addition, no new safety concerns with regorafenib treatment were identified during SARC024 and adverse events were generally manageable with dose reductions.  Notably, the median dose at the end of blind treatment was 120 mg. Taken together, this makes this the second trial to clearly show benefit for the use of single agent Regorafenib for the treatment of Osteosarcoma

Highlighting the issues with using RECIST to evaluate tumors that make bone in their matrix, only 3 patients on Regorafenib achieved a partial response.  Whether this is a cytostatic response to Regorafenib or part of the bone biology of osteosarcoma will need to be determined in future work. 

There are a number of meaningful observations that come from this trial.  First, and most obviously, Regorafenib is active for the treatment of osteosarcoma and it is oral.  While at this time, it is not listed in the NCCN guidelines, this publication makes the second randomized trial supporting its use.  I would hope the guidelines change to reflect these publications soon.

Next, there was a very important paper published in JCO in 2016 by senior author Katy Janeway. It was a summary of seven negative phase II trials from the Children's Oncology Group (COG) that established the natural history of unresectable osteosarcoma to have an event free survival (EFS) of 12% at 4 months.  They concluded that, "This evaluation provides a baseline for disease progression in a population of children and young adults with recurrent/refractory osteosarcoma that can be used as comparison for the design of future phase II trials in osteosarcoma." In the current trial and the REGOBONE trial, the placebo arms of this trial and the REGOBONE study demonstrate similar rapid progression: 10% in 16-week PFS in SARC024 and 0% in 12-week PFS in REGOBONE. These become the 8th and 9th trials with a placebo arm that supports the data of the 2016 JCO publication that stated that the progression free survival of placebo for the treatment of osteosarcoma is well established. To be fair to the authors and to be clear, SARC24 was started two years before the Janeway publication, but are supportive of stopping placebo controls in phase II trials of osteosarcoma in future trial designs.

Once again, the authors are to be congratulated on their findings, which I find practice changing.  Their dedication to rare cancer research is benefitting patients that agree to participate in clinical trials.  Working together they have identified an active agent for the treatment of osteosarcoma.  It will be interesting to see what the next steps are for the SARC team, as they have proposed combination studies based on Regorafenib in their discussion. 

Finally, rare disease research and clinical trials in sarcoma are desperately needed to improve the outcomes of our patients.  Thank you to JCO for highlighting the work from Lara Davis and colleges and the Sarcoma Alliance for Research and Collaboration.  This national organization has sites across the country where sarcoma patients can enroll on clinical trials.  A list of adult and pediatric sarcoma referral centers and the clinical trials that are available in sarctrials.org. 

This concludes this JCO podcast. Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article "Therapy-Related Cardiac Risk in Childhood Cancer Survivors: An Analysis of the Childhood Cancer Survivor Study" by Bates et al. My name is Joseph Carver, and I am the Chief of Staff at the Abramson Cancer Center of the University of Pennsylvania in Philadelphia, Pennsylvania. My specialty is cardio-oncology.

It is universally accepted that therapeutic radiotherapy and/or anthracycline-based chemotherapy have a significant impact on the heart resulting in cardiac morbidity and mortality. High risk groups are now defined on the basis of a doxorubicin-equivalent anthracycline dose of ≥250 mg/m2 and/or total radiation dose of ≥30 Gy when the heart is in the treatment field.   It is universally accepted that therapeutic radiotherapy and/or anthracycline-based chemotherapy have a significant impact on the heart resulting in cardiac morbidity and mortality. High risk groups are now defined on the basis of a doxorubicin-equivalent anthracycline dose of ≥250 mg/m2 and/or total radiation dose of ≥30 Gy when the heart is in the treatment field.  Total dose delivered does not reflect specific cardiac exposure.  This has led to report the mean heart dose that is the percent cardiac volume within the radiation fields.  For most treated patients, discovery of anthracycline cumulative dosing is easily abstracted and straightforward. For modern therapeutic radiation, however, historical mean heart dose or other cardiac dosimetric parameters have not been traditionally reported and may be more difficult to obtain. This has led to a lack of consensus about the cardiovascular risk when the total dose is <30 Gy,

In the article that accompanies this podcast, Bates et al1 enhance our understanding of the association between cardiac volume exposure to different radiation therapy doses and rates of serious cardiac conditions among long term survivors of pediatric cancer and reaffirms the association of cumulative anthracycline dose and subsequent risk for cardiomyopathy.

With data from the Childhood Cancer Survivorship Study, they determined the rates of self-reported grade 3-5 cardiac conditions as defined by Common Terminology Criteria for Adverse Events  v4.03 in 24,214 >5-year survivors who were treated for a variety of cancers at a median age of 7 years.  Evaluation occurred at a median follow-up of 20.3 years with a median attained age of 27.5 years.  Late cardiac risk was compared to 5,046 untreated siblings.  For each survivor, radiation fields were reconstructed on age-specific phantoms to calculate estimated mean heart dose and the percent of heart volume receiving at least 5 Gy (low dose) and 20 Gy (higher dose).  Doxorubicin-equivalent doses were similarly abstracted.

Toxicity parameters were any cardiac disease, coronary artery disease and heart failure.  They found a cumulative incidence of cardiac disease, 30 years from diagnosis of 4.8% (95% CI 4.3-5.2). There was a dose relationship between mean heart dose and all parameters.  Both low-moderate doses (5-19.9 Gy) to a large volume of the heart (>50%) and higher doses (≥20Gy) to small cardiac volumes (0.1-29.9%) were associated with an increased risk of cardiac disease. Heart failure drove the risk of high doses to small volumes while CAD drove the risk of low doses to large volumes.

Similarly, they reconfirm the relationship between cumulative anthracycline dosing and any cardiac disease with an increased risk for those treated at a younger age (≤ 13 years of age).  An increased relative risk for any cardiac disease was also present with any anthracycline exposure (0.1-<250 mg/m2: RR 1.7%, 95% CI 1.1-2.5) compared to siblings.

This study shows that low-moderate dose RT to a large volume of the heart and higher-dose RT to a small volume of the heart increase the risk of late cardiac disease. It also reconfirms the association of cumulative anthracycline dosing and cardiac risk, especially in patients who were treated at < 13 years).  With a 4.8% risk for any cardiac toxicity at 30 years, the study provides an evidence-based long-term realistic risk estimate that can be part of pre-treatment conversations with patients and family as well as survivors.

What are the take-home points of this study?

1. In spite of modern techniques to deliver therapeutic radiation and avoid the heart, a "safe" cardiac dose has not been well-defined.  Two large retrospective, phantom-based studies have shown an increased risk of coronary heart disease of 7.4% per 1 Gy MHD in breast cancer and lymphoma patients. These studies have not only alerted radiation oncologists to the potential risk of even "low" radiation doses to the heart but have also driven them to push RT planning algorithms to optimize one parameter, mean heart dose. The problem with this single metric is that two treatment plans with vastly different dose maps can have the same mean heart dose: 1) low dose spread out to a large volume such as in an intensity modulated radiotherapy plan; or 2) high dose to a small volume (that may include the left anterior coronary artery) with almost no dose to the rest of the heart such as in breast tangents or a proton therapy plan. Even with current image-driven treatment planning algorithms that prioritize a low mean heart dose, it is still possible to deliver higher doses of radiation to cardiac substructures.  The results from this paper have major implications for treatment planning and delivery, informing us to be wary of low dose generic mean heart dose metrics and makes a case for universal adaptation of the quantification of structure-specific dose exposure and attention to the "low-dose cloud" in the rest of the heart.

1. For survivorship and surveillance, there are implications for guideline development evolving one step beyond binary "high risk/low risk" stratification to understand that any exposure to anthracyclines and/or therapeutic radiation is part of a continuum of risk: low risk is not no risk. This continuum informs health care providers to a proactive management approach for the late survivor population that includes aggressive management of cardiac risk factors present at initial evaluation and those that emerge over the decades of survivorship.

1. It is equally as important to reiterate that the late cardiac toxicity due to therapeutic radiation and anthracyclines pales in comparison to the risk associated with untreated traditional cardiac risk factors: (obesity, cigarette smoking, sedentary life style, diabetes, hypertension and the metabolic syndrome) and when they are present in this population, they magnify the 4.8% cardiac event risk defined by Bates.

1. This study also provides additional rationale for the field of cardio-oncology- for greater collaboration between medical and radiation oncologists and cardiologists at every step of the cancer treatment continuum.

I congratulate Bates and colleagues for this potentially paradigm changing contribution and am optimistic that further enhancements in radiotherapy planning and delivery will reduce late cardiac toxicity and improve survival.

This concludes this JCO Podcast. Thank you for listening.