Journal of Clinical Oncology (JCO) Podcast – Details, episodes & analysis

In this episode of JCO Article Insights, Dr. Giselle de Souza Carvalho interviews Dr. Hatem Azim and Dr. Ann partridge on their JCO article “Fertility Preservation and Assisted Reproduction in Patients With Breast Cancer Interrupting Adjuvant Endocrine Therapy to Attempt Pregnancy,”

TRANSCRIPT

Giselle Carvalho: Welcome to the JCO Article Insights episode for the August issue of the Journal of Clinical Oncology. This is Giselle Carvalho, your host. I'm a Medical Oncologist in Brazil focusing on breast cancer and melanoma skin cancers, and one of the ASCO editorial fellows at JCO this year. Today, I will have the opportunity to interview Dr. Hatem Azim and Dr. Ann Partridge, two of the authors of the POSITIVE trial. We will be discussing their trial on “Fertility Preservation and Assisted Reproduction in Patients With Breast Cancer Interrupting Adjuvant Endocrine Therapy to Attempt Pregnancy,” which was published in May this year. 

Hello, Dr. Azim and Dr. Partridge. Welcome to our podcast.

Dr. Ann Partridge: Hi. Thanks.

Dr. Hatem Azim: Hello.

Giselle Carvalho: So, beginning with our interview for breast cancer survivors, in addition to the treatment itself, aging is one of the major contributors to infertility. The optimal duration of adjuvant endocrine therapy in patients with hormone positive early breast cancer ranges from five to ten years, depending on patient and tumor characteristics. This time interval can be critical for women who wish to attempt pregnancy. One of the main concerns in daily breast cancer oncology practice is whether breast cancer recurrence rates are increased either by temporary interruption of endocrine therapy for pregnancy or by the use of assisted reproductive technologies.

Dr. Azim, what about assisted reproductive technology is worrisome regarding breast cancer outcomes? And how do the POSITIVE study results address the concern about worsening breast cancer outcomes either with assisted reproductive technology or endocrine therapy interruption?

Dr. Hatem Azim: So, in the primary analysis of the POSITIVE trial, we tried to address one of these questions, whether temporary interruption with endocrine therapy affects breast cancer outcome. And what we found was that interruption did not appear to have a detrimental impact at the median follow up of 41 months. So in the current manuscript, we addressed the second question, whether assisted production of fertility preservation has an impact as well on breast cancer outcome. And we did not find any worsening of outcomes in patients who underwent these procedures compared to those who had a spontaneous pregnancy. Of course, we have relatively short follow up, but at least the outcomes at the median follow up of around 3 to 4 years appears to be reassuring.

Giselle Carvalho: I see. Thank you. These are really important outcomes regarding premenopausal patients.

So, moving on, results from your study show that after 24 months, 80% of women under 35 years old had at least one successful pregnancy, while the same was true for 50% of women aged 40 to 42. These results are particularly impressive considering that over 60% of women over 35 had undergone chemotherapy. 

Dr. Partridge, other than age, what factors did you find were associated with a successful pregnancy? 

Dr. Ann Partridge: Yeah. The biggest factor, other than age, that was associated with successful live birth pregnancy was use of assisted reproductive technologies. So either having gone through IVF prior to diagnosis and banking eggs or embryos prior to diagnosis and then using them during the study, for undergoing stimulation of the ovaries during the study and then using it during the study. And that's what we also looked at in this most recent analysis of the initial POSITIVE data. 

Giselle Carvalho: I see. Thank you. The group of patients who underwent embryo oocyte cryopreservation at diagnosis were more likely to be nulliparous and treated with chemotherapy. Presumably these represent the patient group most afraid they will be infertile, as they would be receiving chemotherapy, and most desirous of pregnancy, as they had not yet had any children. Fertility preservation techniques are expensive and not easily available for all patients, particularly in less wealthy countries. Is there any group of your breast cancer patients with a high enough likelihood of pregnancy without assisted reproductive technology that you would not recommend this? 

Dr. Ann Partridge: Sure. So we are so glad to have assisted reproductive technologies available in many places, but as you know, they're not available everywhere. And even where they're available for some people, it's either inaccessible for a number of reasons or it doesn't feel right emotionally or ethically. And then finally, sometimes people need fairly quick treatment and they just don't have the time, even though we don't think there are long delays. And so we do and are able to know who can get pregnant after standard chemotherapy. Not perfectly, but we can give estimates. And the gestalt is, the younger a woman is, the less likely she is to become amenorrheic and the associated infertile, although it's not a perfect match in terms of amenorrhea being a surrogate. And then there are particular chemotherapy regimens that are more gonadotoxic than others. The more cyclophosphamide, for example, or alkylating agent, the more anthracycline, the higher the likelihood generally of causing at least amenorrhea and likely infertility. The huge caveat there is that for some of our newer therapies, we have no good information about how they might impact on menstrual status, let alone the actual rates of fertility. So we need to collect those data. But certainly, if someone's very young, they're going to get four cycles of TC or they have inflammatory breast cancer, we often take kind of a let the chips fall where they may approach, because they just aren't able to access it and we'll often do something like ovarian suppression through the chemotherapy to help support them and hope that it improves their menstrual functioning in the long run and/or fertility.

Giselle Carvalho: Thank you for your insight. So you found that pregnancy incidence over time differed by age group, although incidence of menstrual recovery over time was similar across all age groups, which I conclude that menstrual recovery does not translate into fertility. The addition of gonadotropin releasing hormone analogs to chemotherapy was not associated with time to pregnancy. However, of course, such use was not randomized. 

Dr. Azim, if assisted reproductive technology is not available to patients for reasons such as socioeconomic factors, would you recommend using GnRH analogs with chemotherapy for the purpose of fertility preservation? 

Dr. Hatem Azim: Yes. The short answer is yes. Of course, POSITIVE study was not designed to address the question around GnRH analogs, but we do have several randomized studies and meta analyses that have shown clearly that the use of GnRH analogs with chemotherapy reduce the risk of premature ovarian insufficiency. And subgroup analysis of some of these studies have shown a trend towards higher pregnancy rates as well. So, of course, if a patient does not have access to assist reproductive technology, GnRH analogs in combination with chemotherapy represent a very good alternative. 

Giselle Carvalho: I see. Thank you. Thank you for your response. At enrollment, 93.2% of women on POSITIVE trial had stage 1 or 2 disease and 66% had no negative disease. Therefore, one possible bias is that investigators might have been more comfortable with temporarily interrupting endocrine therapy if the risk of relapse was low.

Dr. Partridge, what recommendations would you have for women with stage three hormone receptor positive breast cancer who desire to attempt pregnancy?

Dr. Ann Partridge: Yeah, thank you. That's a really good question. It comes up in our tumor boards and discussions about patient care all the time, and I think, as you know, only a small proportion, about 6%, had stage 3 disease. Those patients are at higher risk of recurrence by nature of their stage. Not that all stage 3 are created equal, because, of course, if someone had a complete pathologic response to preoperative therapy and their stage 3 disease at diagnosis went to a PCR, then that person may have even better outcomes in the long run than someone who had postoperative treatment, and we don't know their likelihood even with stage 1 or 2 disease. But someone that you're concerned about their risk of recurrence, they still remain at risk of recurrence. And while we do not think, based on the POSITIVE data and all the data that we've had from retrospective studies and other data sets collected for other reasons, that a pregnancy would worsen their outcome, we certainly don't believe that a pregnancy at this point in time will dramatically improve their outcome or as a treatment for breast cancer. That's when I have a heart to heart conversation with the patient, really acknowledging they still remain at high risk. And most of my colleagues tend to want the patient to get more endocrine therapy into their system before they take a break. We've kind of discussed this, and we want someone to get more like at least three to five years. That may be a little bit paternalistic, because, as we know, taking the break for people with a little lower risk didn't seem to worsen outcomes. Maybe it's fine. I don't know that a break at five years is any better than a break at two years. I don't know. Hatem, how do you handle this in your practice?

Dr. Hatem Azim: Well, I completely agree with you, Ann. I mean, it's very much decided on a patient by patient basis. The level of uncertainty that some patients accept to take is not necessarily like others. And sometimes we as physicians, we adopt this. I agree with this paternalistic approach. Nevertheless, it's very important for the patient who is 32, is not necessarily counseled like the patient who’s 39, and her acceptance and the feasibility of waiting a bit longer as well in order to attempt pregnancy - the success of pregnancy afterwards is not necessarily the same. So I'm not sure we could adapt a one size fits all approach here. And I do not necessarily tend to factor much the elements around the stage. I think my point to patients is usually, well, you do have give and take this amount of risk of relapse, for example, and whether we accept to take such, what we could refer to as relatively unconventional approach of temporary interrupting endocrine therapy, and when we are comfortable to go ahead with this journey, depending on the feasibility of getting pregnant afterwards as well. So, yeah, I completely agree. It's very customized, based on and tailored according to the patients’ situation.

Giselle Carvalho: Thank you. I really appreciate your response to this. So, moving forward, tamoxifen alone was the most commonly prescribed endocrine therapy, followed by tamoxifen plus ovarian function suppression. The latter was preferred over aromatase inhibitors ovarian function suppression in the selected population. Endocrine therapy prescription changed in the second half of the recruitment period after July 2017 across all continents, likely due to the results of the SOFT and TEXT trials. It demonstrated absolute improvements in all disease outcomes by escalating endocrine therapy, which was more clinically meaningful in patients with high risk disease. Dr. Azim, how do you imagine this change could impact positive outcomes?

Dr. Hatem Azim: Honestly, I'm not necessarily sure that it impacts significantly the way you interpret the data and the way we counsel our patients. So, in our study, some 50% of patients received GnRH analogs and around 15% received AI. And most of the patients, I would say, were recruited in the second half of the study after we had the results from, for example, SOFT and TEXT. Furthermore, as we alluded to earlier, we had 60% of patients who received chemo. So most of our patients had a stage 1 and 2 disease in which you would argue that the absolute difference between the different hormonal therapy options is not necessarily massive. Whether or not this would impact much, I'm not sure. I think the main counseling recommendations would apply, that patients who receive endocrine therapy would be asked to interrupt it for at least three months and then they attempt pregnancy afterwards.

I don't know what you think, Anne, but I'm not sure that if we have more patients, and this is pretty much the case now, we have more patients treated with AI. I tend to do this a lot, especially if I'm thinking of interrupting, so I think I'm giving them maybe the best option first. I'm not sure this is necessarily, I mean, affecting me much, while interpreting that it does not appear that temporary interruption on the short term has an impact.

Dr. Ann Partridge: I completely agree with your strategy. Depending on the patient and their tolerance, if they have enough risk to warrant ovarian suppression with AI or tamoxifen, of course I recommend that. And yet, at the same time, I agree with you in this group that was in POSITIVE, I think the groups are relatively low enough risk. Although 40% had no positive disease, the majority got chemo, so they weren't that low risk. And so I think over time, these kinds of patients are more and more going to get ovarian suppression. I'm doing that more in my practice as tolerated. And I hope that all that means is that their breast cancer outcomes will be better independent of a pregnancy.

Giselle Carvalho: And on the topic of women with higher risk disease, CDK4/6 inhibitors are now used in the high risk adjuvant setting. How do you envision this impacting fertility?

Dr. Hatem Azim: Well, this is a very good question. Of course, this is something, this is an area of research that we have to address. Some analysis from some of the adjuvant studies, for example, the PENELOPE-B, I think they reported on some of the results of their study in which they were evaluating palbociclib in the adjuvant setting and did not appear that there was significant differences in terms of the level of estradiol levels and FSH and anti-Müllerian hormone, for example. I think these were the parameters that were evaluated in this study. So, of course, more information. Of course, palb is not the CDK4/6 inhibitor approved in the adjuvant setting. So we need more information as well about the other CDK4/6 inhibitors and longer follow-up. 

In my view from a counseling perspective, I think maybe you would have a certain level of uncertainty regarding whether or not this could have a mental impact on fertility. But the concept as well of possibly proposing a temporary interruption as we adopted in POSITIVE, would still apply. These patients would be treated as well, often, because if they are receiving CDK4/6 inhibitors in the adjuvant setting, it means that they have a high stage disease, so often they will be treated as well with GnRH analogs. I would counsel them pretty much the same, acknowledging a certain level of uncertainty regarding the data we have today on CDK4/6 inhibitors.

Dr. Ann Partridge: Yeah, if they got a full course, they would generally be further out than many people on POSITIVE, because we treat with, for example, the abemaciclib for two years and then you want to wash out and things like that. In POSITIVE, the average was two years. And so you'd expect people of higher risk to be a little further out, which I think would make everybody a little more comfortable too, because someone who's very high risk, you'd worry about very early bad recurrence, too.

Giselle Carvalho: Yeah. Thank you.

So, Dr. Partridge, regarding adherence to endocrine therapy resumption after the two year break, what was the percentage of patients who resumed treatment and which strategies would you suggest to increase adherence in this case?

Dr. Ann Partridge: That's a really great question. In the study, it was well over 70%, which is actually higher than you see in the general population of breast cancer survivors, especially young women. So in some cases, and I can tell you anecdotally, I experienced in my clinic that patients were more likely to start and take their endocrine therapy when they had the promise of the POSITIVE trial, to take a break to have a baby, because some of them don't want to start it, let alone stay on it, if they're told they have to take a full five to ten years. So it actually promoted adherence, ironically. And then for the people who got back on in the real world, the data suggests that by four years, somewhere close to half to 30% to half are no longer taking it. And so in POSITIVE it was, I think, 74% got back on, and that was only at the time point cut off when we did the initial primary data report. And of course more people will have gone back on because some people were still having babies and in the middle of things. And so I think that it's not as much of an issue with POSITIVE. In part, these are very compliant people, right? They're participating in a clinical trial to share the data with the rest of the world. They could have gotten pregnant on their own and they want to do it with their doctors. And so I think this is a little bit of a different group, but it was very reassuring to see that most people got on hormonal therapy after their interruption.

Giselle Carvalho: And recurrence of hormone receptor positive breast cancer may occur late. How long do you plan to follow patients enrolled in the POSITIVE trial?

Dr. Ann Partridge: So our plan is to follow them for at least 10 years. And it's interesting because we're starting to get close to that. We started enrollment in 2015, so I saw someone earlier this week who will have her 10 year mark next year because she got on in 2015. And that's very exciting. Obviously, it would be great to follow them even longer because ER positive breast cancer can recur many years later. But I do think that we feel as though at least 10 years will give us a good, very evidence-based feeling about the safety.

Giselle Carvalho: Thank you. Thanks for sharing. With enrollment occurring at 116 institutions in 20 countries across four continents, this representation of different races and ethnicities provides strength to support this recommendation for this group of patients worldwide.

Dr. Azim, what are your hopes for future analysis from this study and what future research in the area are you planning or would like to see performed? 

Dr. Hatem Azim: So Ann mentioned, of course, it would be crucial to conduct the long term follow up of these patients, and provide more reassuring evidence on the safety of this approach of adjuvant endocrine therapy. So this is something we're really looking forward to. Other analysis that we are working on is the breastfeeding analysis. So looking at patients who underwent breastfeeding and how far the feasibility of this approach, obviously, but how far as well this had an impact on their breast cancer outcome. So this is something that hopefully we are going to report on soon, expected end of this year. As well, we are working on evaluating, we had a large translation research program within POSITIVE, addressing several questions, including the evolution of ovarian function parameters over time and the ovarian reserve. Also, we are working on reporting on this information. We hope that this could happen maybe in the coming year.

Giselle Carvalho: Great. And finally, what advice do you give young women in your clinic who have been diagnosed with early stage hormone positive breast cancer and who are hoping to attempt pregnancy.

Dr. Hatem Azim: We address these kinds of questions relatively early in their treatments and often they are very much concerned about their chance of future fertility. Usually early on, for example, before going for chemo and so on, I just share the information that this is something that we certainly could discuss and certainly there are the possibility that we could consider in the future that it's not a ‘no go’ at least. And definitely it's something that we could work on once treatment is completed and recover from the adverse events of therapy. And because throughout the journey of treatments as well, women's wishes evolve over time and their perception of their pregnancy project as well evolve and change over time. So I think it's important to acknowledge, in my view, it's very important to acknowledge that this is feasible, this is possible, and because this as well provides an important psychological boost for them. And then as the patient comes over for their follow up after therapy and so on, start understanding, getting a little bit deeper into these kind of questions regarding feasibility, timing. If they are ER positive, then if it's okay to interrupt, not to interrupt, to explain a bit better and to consider a bit better regarding what kind of risk we're talking about. Articulating better, what do we mean by risk? So that sometimes you have a patient that is willing to accept a 10% risk, although others 1% risk for them represent a major threat. Also, it matters nulliparous versus a patient who already has two or three kids. So I think I tend to go a bit more granular in this kind of information as patients are out of chemo and on hormonal therapy and start addressing these matters. But I think it's important early on to share the information that nowadays we do have sufficient information not to discourage women who would like to have a pregnancy in the future.

Giselle Carvalho: Thank you. Thank you. Dr. Partridge, would you like to add some final comments on this?

Dr. Ann Partridge: Yeah, I think this is just such an important issue for our young breast cancer survivors and cancer survivors diagnosed at a young age, regardless of the type of cancer. So I think paying attention to this at diagnosis and through their survivorship is critical, both for their thriving in survivorship as well as for their long term health and cancer outcomes. Getting back to that adherence issue, people, if they're unhappy, won't do all the right things for themselves, sometimes medically and emotionally. And we know that infertility can be associated with long term distress for patients with and without cancer. So we need to pay attention to this and I'm really happy that ASCO is doing a podcast on this and I'm really happy that JCO is doing a podcast on this. 

Giselle Carvalho: Thank you. I really would like to thank you both, Dr. Azim and Dr. Partridge for attending this interview.

This is Giselle Carvalho. Thank you for listening to JCO Article Insights. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows 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.

 Dr. Azim
Employment Company name: Pierre Fabre, EMERGENCE THERAPEUTICS Stock and Other Ownership Interests Company name: Innate Pharma, Diaacurate Travel, Accommodations, Expenses Company name: Novartis

Dr. Partridge
Research Funding Company name: Novartis Patents, Royalties, Other Intellectual Property Company name: UpToDate

Host Dr. Davide Soldato interviews Dr. Sana Raoof to discuss the JCO article Turning the Knobs on Screening Liquid Biopsies for High-Risk Populations: Potential for Dialing Down Invasive Procedures.

TRANSCRIPT

Dr. Davide Soldato: Hello, and welcome to JCO After Hours, the podcast where we sit down with others 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 author Dr. Sana Raoof, Physician at Memorial Sloan Kettering, to talk about her article, “Turning the Knobs on Screening Liquid Biopsies for High-Risk Populations: Potential for Dialing Down Invasive Procedures.”  

Thank you for joining us today, Dr. Raoof.

Dr. Sana Raoof: Thank you so much. It's lovely to be here.

Dr. Davide Soldato: So, Dr. Raoof, I just wanted to start a little bit about the theme of your article, which is really centered around multi-cancer early detection tests. And this comes from the results of several studies that showed their reliability and efficacy in identifying cancer in the average risk population. But I just wanted to ask you if you could give us and our readers a brief overview of how these tests work and how they were designed for this specific population.

Dr. Sana Raoof: Of course. Well, there's an interesting story. The origin of multi-cancer early detection tests actually begins with insights that come from the field of obstetrics and gynecology. So about six or seven years ago, in the peripheral blood of pregnant women, we discovered that you can actually find fetal DNA floating around. And that was an early discovery of cell free DNA coming from the baby into the mother's bloodstream. But in some of those young, otherwise healthy women, we also discovered that there's another clonal signal, unfortunately not coming from the fetus, but coming from an undiagnosed tumor. And that led to the entire field of circulating tumor DNA and all of its applications. 

Of course, scientists in the last six or seven years have harnessed the fact that DNA and the methylation patterns on the circulating tumor DNA, as well as other analytes like glycosaminoglycans, proteins, and other analytes, are secreted by tumors into the peripheral blood in order to try and screen for tumors, hopefully at early stages, when there are still curative, definitive interventions that are available. There's several different tests now that are providing the ability to detect cancers at many stages, including early stages. They're in different phases of preclinical to clinical development, and one is even commercialized and available by prescription in the United States.

Dr. Davide Soldato: Okay. So I think that in most of these tests, they really look at the tumor DNA, so they identify mutations or, for example, methylation patterns. But do we also have some tests that integrate some other type of biomarkers that we can identify in the blood? Like, are they integrated all with the others, or are we just relying on circulating tumor DNA?

Dr. Sana Raoof: It's a great question. There's a lot of really fascinating biology that different companies predominantly are using in order to find signs of early cancer. One of the analytes that I find really interesting, other than looking for small variants in circulating tumor DNA and looking at methylation patterns, as you mentioned, is looking at fragment length. So, for example, the company DELFI looks at the different patterns of the length of DNA fragments that are floating around in the peripheral blood. And not only is fragment length tissue specific, so in theory, a fragmentomics based multi-cancer early detection test could tell us what is the tissue that this aberrant signal is coming from, but they can also tell you if there's likely a cancer present, because there's a difference in fragment length patterns in cancer versus non cancer. 

There are also other analytes. I mentioned glycosaminoglycan. There's another company that doesn't yet have prospective data, to my knowledge, that is making a test that looks at these analytes instead. There are other companies, again, without prospective data yet, that are looking at circulating tumor cells. And I'm sure that in the next few years, we're going to start getting prospective data from all of these players and also hear about other analytes that scientists have found can predict cancer from non cancer and maybe even protect tissue of origin based on artificial intelligence.

Dr. Davide Soldato: So you mentioned artificial intelligence. So, basically what you're suggesting, but correct me if I'm wrong, is that when we use this test, we are actually measuring something in the bloodstream, but at the same time, we are actually applying some type of artificial intelligence to actually interpret these results and then give us the definitive results, or what we would call like a positive and a negative of the tests, is that right?

Dr. Sana Raoof: Yeah, absolutely. And it's an important distinction that you're making, we are measuring something in the blood, but we're not just measuring it. We're using machine learning algorithms that have been trained on thousands and thousands of patients with cancer and thousands and thousands of patients without cancer, and have measured various analytes and analyzed the patterns, for example, of DNA sequence, or bisulfite sequencing of methylation patterns of patients with and without cancer, and have been trained to look for the differences between them. And so the analyte that we're looking for is not a specific mutation per se, but is a pattern that looks like patterns that you typically find more so in cancer patients.  

There's many different companies, they are trained on different types of cancer. So some companies, like GRAIL, have a test that looks for a very expanded list of over 50 cancer types. Other tests have a narrower focus and were trained and validated on a smaller list of cancer types. So there's just a great diversity in this space. These tests are trained to look for different types of cancer. They're trained and validated on different populations of interest. So, for example, some of the populations that these tests were trained on are predominantly white, and that will have impacts, potentially on how these tests perform in non-white populations. And that's a really interesting area of future research. These tests may or may not have included cancer survivors in their populations, and that could ultimately impact how these tests perform in those populations. 

So there's just so much to learn, so much data that's going to be coming out in the next few years from all of these different key players in the multi-cancer early detection space. But one thing that I'm sure of is between all of the different analytes, all of the different training and validation studies, and all of the different prospective studies, we're going to learn a tremendous amount about the potential clinical utility of using multi-cancer early detection tests to complement the few standard of care surveillance cancer screening tests that we have recommended today.

Dr. Davide Soldato: So just taking a step back and going back to the fact that we actually use machine learning algorithms to identify a pattern that can give us an idea of whether cancer is present or not, I believe that there is also some room for calibration of these types of tests. And I think that this is one of the key arguments that you make in your paper where you say that we can actually personalize a little bit more these types of tests to understand and then to decide what we are looking for. Is that correct and can you expand a little bit on that?

Dr.Sana Raoof: Yeah, absolutely. This is the central concept of the paper that we're discussing. Because these tests are machine learning based, as I said, they're trained to say cancer versus not cancer, and some of them are further trained to say, coming from this organ or coming from that organ. But what does it mean to say cancer or not cancer? There are specific thresholds that are defined to say, above this threshold of signal detection, we're going to say this is a positive cancer signal detected, and below it we're going to say negative. And so right now, these tests are kind of designed to have this binary output, and the concept that I wanted to put forth in the paper is it doesn't necessarily have to be binary, and the thresholds don't have to be static. So, for example, you can imagine that in an average risk population where the pretest probability of cancer in your lifetime for Americans, it's pretty high, roughly 40% for lifetime. But at any given moment in time when you're getting a test, it's lower. For example, in Americans, 50 to 80, the chance of having cancer at any given moment is just under 3%. So you don't necessarily want a test that is very nonspecific, you don't necessarily want to tell a lot of perfectly healthy people that are asymptomatic screening populations that they have cancer if they don't. And so these tests were designed to have very high specificity, predominantly across the board, across the different companies making them at the cost of, in some cases, having lower or moderate sensitivity in early stages.  

And it's important to keep in the back of your mind that we cannot ever expect the types of early stage sensitivities from multi-cancer early detection tests that we're used to thinking about for single cancer screens that are just optimized for one single organ. They work in a completely different way. So I don't expect a future where the sensitivity of a mammogram, which is only for breast cancer, is going to be analogous to the sensitivity of a blood-based test that's looking for all cancers in your entire body. I don't think it's fair to expect that. But I do think it's possible to imagine a future where we do change the thresholding of these tests that were trained and validated in average risk screening populations, and say, “Let's turn the knob on the dial and let's take the sensitivity a little bit higher, even if it means the specificity drops from 99%, for example, which is the very high number of the gallery test, down to 98%, down to 97%. Let's see how this affects the positive predictive value and the negative predictive value of the test.” And how having a higher negative predictive value by having a higher sensitivity may or may not make it more clinically useful for higher risk populations that have higher pretest probabilities, in which case we are kind of more interested in being sure that we're ruling out cancer. 

Another concept that I talk about in the paper, aside from just turning the knobs, is to make it a continuous variable rather than a binary report. Rather than saying signal detected or not signal detected, I can also imagine a future where we personalize the output of multi-cancer early detection tests to return a score, for example, from 1 to 100 or 1 to 10, and give physicians the ability to use that continuous variable in addition with other clinical findings, physical exam findings, other labs, symptoms, patient’s past medical history, family history, all of that together to make decisions about should we pursue further workup, should we do an invasive biopsy. This is kind of the way that we use other scoring tests in oncology, like the oncotype tests for breast cancer, decipher test in prostate cancer. And I think physicians like having continuous variables to work with and to help them make very personal decisions for patients' diagnostic workups.

Dr. Davide Soldato: To summarize a little bit, what you're arguing in the paper is that we could potentially modify a little bit these tests as they fit the type of population that we are looking for. For example, if we are looking at the average risk person in America, there we just want to be sure that we are just doing additional workout and additional follow ups and additional invasive procedure, for example, biopsy, when we have a very high probability of finding that cancer. At the same time, if we have someone who has a baseline risk which is higher, like cancer survivors, in that case, we are more interested in seeing if there is really cancer at that point, and so we can increase the sensitivity and go down on specificity, but still looking at the overall outcome that we want to have for that specific patient. 

One thing that I was wondering is, do you also see a future where we personalize a little bit more also including additional information that comes from risk factors, environmental or behavioral patterns, type of diet, or these types of risk factors that we already know from epidemiology are associated with a higher risk? So could we potentially customize this test even more, saying, this patient has a higher risk of developing colorectal cancer, so could we look more specifically to that specific cancer type and that specific risk compared to tobacco associated cancers, that for that specific patient, they are not so relevant? 

Dr. Sana Raoof: What you're saying is actually a fascinating and really compelling idea, and it reminds me of the way that noninvasive prenatal testing works. So, again, back to the world of obstetrics and gynecology, you have a woman at the end of her first trimester having fetal DNA testing to look for chromosomal abnormalities. And when you order that test, you actually do put in various features about the woman to help you understand her baseline risk for carrying a fetus that has chromosomal abnormalities, including her age, the status of her other children, and other things in order to help you calculate a pretest probability. And so after that, the non invasive prenatal test takes that into consideration and returns a probability of carrying a fetus that might have those aberrations, and it's not a binary risk. It's, as I said, a continuous variable.

So I think what you're proposing actually goes beyond what I wrote about in the article. I think it's a fabulous idea. And I think that in the near future, I can imagine that as natural language processing is exploding, and in general, large language models and the ability to extract features about a patient from the EMR are exploding, we might have a better stratification in general of patients into average risk, low risk, high risk, and really high risk, using EMR data, using real world data that could help us feed a really accurate picture of a patient's pre-test probability into this test, so that these tests could be further refined and further trained and validated on patients, taking into consideration more factors and help us improve the predictive power of the tests as they're returned in a report to the physician. So I think maybe you should even write an article about the idea just proposed. It's a great idea.

Dr. Davide Soldato: So another aspect that I was really interested in is I've looked at one of the papers that you cited, and I wanted to discuss this with you as you are an expert on the topic. In one of the articles that you cited that used this type of test, they identified some of the cancers that we also normally identified with standard screening procedures, like breast or lung or colorectal. So for those cancers, we add a certain proportion, or like, for example, for breast cancer, a higher proportion identified with conventional screening. But still we had some other cancer that eluded those types of screening and were identified using liquid biopsy tools. So do you envision a strategy where we would use the screening methods that we already add as a complement to those liquid biopsies, or do you think that someday liquid biopsy could potentially completely substitute standard screening procedures? 

Dr. Sana Raoof: I think we're too far from a day where liquid biopsies are going to replace standard of care screens. The scope scans and smears that the United States Preventive Services Task Force has recommended are gold standard screening interventions because, number one, for all of them, except for cervical cancer screening, we have randomized data with definitive endpoints that tell us that there are mortality benefits from doing those screens. We don't have that type of data yet from the world of multi-cancer early detection. And as we talked about earlier in this podcast, those tests are kind of designed with a different approach where they have higher sensitivity and much lower specificity than multi-cancer early detection tests. 

So I think that the molecular cancer screening companies have done a very careful job of creating tests that are really more optimized to be complementary tests rather than a standalone catch all test, to have higher specificity at the cost of lower sensitivity. So I don't imagine a near future, at least not in my career, where we're going to stop doing colonoscopies and mammograms and pap smears. I don't think that that's going to happen. But I do think that whereas right now 75% of cancers that Americans die from, we lack cancer screening mechanisms for them, I think that that number has the potential to really drop. If in the next few years, one of these multi-cancer early detection tests is ultimately approved and covered, then I think that a lot more cancers could be detected by screening rather than by symptoms, and we might ultimately see a big stage shift. 

Dr. Davide Soldato: Yeah, I think you're absolutely right. In the same article that I was mentioning before, there were several of those cancers which can be lethal if diagnosed at an advanced stage, that were diagnosed at an early stage, for example, ovarian cancer, bladder cancer. So I really think that we really have potentially the way to screen, or at least have a signal for cancer that currently we just diagnosed when symptoms associated with higher stage appear. 

But moving on to turning the knobs on this type of test, and so going to the higher risk population, for example, cancer survivors, which is something that you speak a lot about in the manuscript. So you also discuss a little bit the question of whether we should use multi-cancer testing versus single cancer testing. So are we looking at a specific recurrence from that specific tumor, or are we looking at a general risk of cancer in a population that has a common risk factor, like tobacco? And so I was wondering if you think, and this is probably just your perception or just your opinion, that that is another way that the physician should turn the knob. Should we evaluate the risk of those cancer survivors and say, in this specific patient right now, the risk of recurrence is higher so I should use or I should be more in favor of a test that is more centered on the risk of recurrence versus I have a general risk of several cancers that could appear, and so should I use something that is more multi-cancer? This, of course, is merely speculative because we still don't have definitive data regarding the efficacy of this test. But it is just your perspective on this type of approach in the near future or not so near future. 

Dr. Sana Raoof: Well, I think if we're speculating, then I think that the fantasy situation for any oncologist is that you have two types of liquid biopsies. One is a multi-cancer early detection liquid biopsy. And it would be great if you could select whether you want it to be optimized for highest NPV, negative predictive value, or highest PPV, positive predictive value. And then you also have a host of single cancer screening liquid biopsies that can help you specifically figure out if there's a recurrence of a single cancer type that you're suspicious about.  

So, for example, in the article, I talk about how there will be clinical gray areas, and it's not always going to be obvious which test you should reach for. But one example that I think we can all relate to in the oncology community is you have some indeterminate imaging finding, and you don't know what to do about it. So, for example, you have a woman that has a history of breast cancer, has had no evidence of disease for a few years, now, has back pain. You do a spine MRI, you see a lesion. Maybe it's an atypical hemangioma that's causing pain, maybe it's a breast cancer metastasis. You're not sure. What should you do? Should you do a biopsy of that lesion in the spine? Should you wait and see if it grows and do another MRI in two or three months? What are your options? And so in this situation, I think we can all agree that if you had a liquid biopsy that was optimized for really high sensitivity, specifically for breast cancer, and had a very high negative predictive value, and if it came back negative, then in that setting, it might help you avoid an invasive test, like a biopsy in the spine, and give you a little bit more comfort as a physician to say, “You know what? I'm going to come back in two or three months and do another spine MRI. I'm going to see how this woman is feeling, and I don't need to biopsy this right now. Maybe it really is just hemangioma.” 

Dr. Davide Soldato: And in this specific setting, let's take the same patient. So it's a female patient, she had a previous diagnosis of breast cancer. Do you think that there is a difference between tumor-informed tests, really based on the molecular aberration that the primary tumor had for these women, versus just a standard test that gives us information regarding the presence of breast cancer cells or not? And if you think that there is a difference, what would you think would be the advantage of one? And the disadvantages, for example, is a tumor informed essay more complex to obtain? Do we need more time? Is it more expensive versus a commercial test that is already available or something like this? This is my understanding as someone who's not so much in the topic, but I think that this is a point that many oncologists probably wonder about, and probably we should speak a little bit more about with someone who is an expert on the topic. 

Dr. Sana Raoof: Absolutely. And I think that you've actually hit all of the major points on the head. So comparing a tumor informed versus a tumor agnostic test is like really comparing apples and oranges. A tumor informed test where you're starting with a patient's pathology and you are looking specifically for mutations and other molecular features that you know the patient has in their tumor, is going to, of course, result in a test that is, number one, more expensive and harder to make, but also, number two, more sensitive, more specific, more predictive, and in every way probably just more powerful than a test that is, in general, optimized for a single cancer type, but is almost certainly going to be trained and validated on people with a mix of histologies, a mix of molecular features, and will not be as sensitive or specific as a test that is actually informed by that single individual's tumor. One of the things that matters a lot to me is health equity in oncology. There are just huge disparities in outcomes in patients that are advantaged and disadvantaged. And it stems from lots of different things. In no small part, it stems from later stages of diagnosis in disadvantaged patients, and then even once you have a diagnosis, delays to confirmatory workup, delays to starting treatment, disparities in the treatments offered. 

I don't imagine a world where everyone on earth is going to have access to tumor-informed liquid biopsies. I do imagine a future where tumor agnostic liquid biopsies, both for single and multi-cancer screening, should be a lot more economical than they are now, and should be more available for multiple cancer types, and should be more available to patients that aren't at just the Memorial Sloan Ketterings and the Dana-Farbers of the world. And so I do think that those types of off the shelf tests have the potential to really revolutionize the way that we work up suspicion of cancer, not just in advantaged patients, but also in patients that are diverse, in patients that are not at academic cancer centers, but at other cancer centers around the world. And I think it's a really exciting prospect.  

Thinking about the chance of recurrence in the breast cancer patient is a perfect example of when you want to test that is optimized just for breast cancer, because you see something in the spine, you know her history, and you're less worried about a new primary and a new MET from that primary. But there are other situations that are also interesting to consider. For example, patients that have had lung cancer and have a history of smoking, because they've had a history of smoking, they're actually at risk for a dozen different cancers, not just lung cancer. And when you think about what we do to follow lung cancer survivors, we're just doing CTs of their chest and of course, physical exams. But the vast majority of cancers that people with lung cancer history will get may not be present in the field of view of a CT of the chest. They may also get renal cancer, bladder cancer, they might get leukemias, they might get pancreatic cancer. So there are a lot of things that you're not going to catch in a CT of the chest. And so in that situation, you care not only about recurrences, which in thoracic oncology, it's kind of a gaussian probability distribution, where the tail is almost close to 0 after five years, but also a uniform distribution of roughly 3% per year of a second cancer, a new primary cancer that goes on for the rest of their life. And so in that clinical setting, you can imagine that having an off the shelf multi-cancer early detection test may be dialed up for higher negative predictive value, would be extremely useful.

Dr. Davide Soldato: Yeah, I totally agree, but thank you for clarifying these points, because I think that there is a little bit of confusion also in the oncology community, as this type of tests, they're also based on very complicated molecular biology, sometimes could be potentially integrated, and we could potentially integrate them in the clinic. 

And so I wanted to close up with kind of a personal question. I was wondering how you came to be so interested in this field of molecular screening or early diagnosis and prevention associated with molecular data. 

Dr. Sana Raoof: Well, it's an interesting story. I did my MD PhD at Harvard Medical School, and my PhD was in the opposite world from molecular cancer screening. I was designing drug combinations that could be used in advanced oncogene mutant lung cancers. And I thought I would become a medical oncologist and spend my life designing new systemic therapies for advanced malignancies. And what I saw every day in the lab during my PhD is drug resistance emerges and it's a process of evolution by natural selection happening on a cellular level. And although we have some really great slam dunk drugs that come to mind, for example EGFR inhibitors in certain lung cancers, immunotherapy in melanoma, on average, the median overall survival gain from all of the FDA approved drugs in the last 10 years is roughly two months.  

By the end of my PhD, I really started feeling like, is the best use of my life to continue fighting a battle against natural selection in cancer cells, or is it a better strategy, to me, it seemed like a more sensical strategy to just try and find cancers in these patients earlier, when you don't have to engage with the complex signaling mechanisms of a cancer cells biology, and instead can just provide a definitive local intervention, like surgery or radiation, which already is curing many patients with non metastatic cancers. And as I looked around the world, I just didn't see that many people investing heavily in early detection research at the time. It was the very early days of multi-cancer early detection. And so I became involved with all of the groups, the companies, the organizations that were developing these tests, and really fell in love with, number one, just the concept of the tests, the concept of multi-cancer early detection, rather than single cancer screening alone, because no one knows what cancer they're ultimately going to get. But I also really fell in love with methylation biology, fragmentomics. I fell in love with the types of clinical trials that were being designed and the new types of endpoints that we have to think about when we're designing clinical trials for a multiverse of single cancer screening. And it's just such an exciting time in that community, it's the early days. So that's how I came to this space, and it's just the perfect time to be in this space, because everything is exploding. 

Dr. Davide Soldato: Thank you very much. And thank you also for sharing the personal side of the story.

Dr. Sana Raoof: Thank you so much. I'd like to thank Razelle Kurzrock, who's an amazing medical oncologist who's worked with me on two really fun papers so far, one on real world data, and this one on turning the knobs on liquid biopsies. It's always great to bounce ideas around about multi-cancer early detection with friends and collaborators, and Razelle did an absolutely amazing job helping write this piece. 

Dr. Davide Soldato: So this brings us to the end of the episode. Thank you Dr. Raoof, for joining us and sharing more on your JCO article titled, ”Turning the Knobs on Screening Liquid Biopsies for High-Risk Populations: Potential for Dialing Down Invasive Procedures.”  

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

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

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

 Disclosures:

Dr. Raoof

Stock and Other Ownership Interests Company name: Illumina Radiopharmaceuticals Honoraria Company name: AstraZeneca Consulting or Advisory Role Company name: Verily Company name: GRAIL Company name: Exact Sciences Travel, Accommodations, Expenses Company name: Grail

Dr. Shannon Westin and her guests, Dr. Emily S. Tonorezos and
Dr. Michael Halpern, discuss their article, "Myths and Presumptions About Cancer Survivorship" recently published in the JCO.

TRANSCRIPT

The guests on this podcast episode have no disclosures to declare.  

Shannon Westin:Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we go in depth on manuscripts published in the Journal of Clinical Oncology. I am your host, Social Media Editor of the JCO, Shannon Westin, and also a GYN Oncologist by trade. I'm thrilled to bring a topic that is very close to my heart. We're going to be talking about a Comments and Controversies article published in the JCO on November 16, 2023, entitled "Myths and Presumptions about Cancer Survivorship." I know you all will find this topic as enthralling as I have, and the authors do not have any conflicts of interest. 

I'm joined by two of the authors on this important work. The first is Dr. Michael Halpern, he’s the Medical Officer in the Health Assessment Research Branch of the Health Care Delivery Research Program. Welcome, Dr. Halpern.

Dr. Michael Halpern: Thank you for having us on.

Shannon Westin: We're also accompanied by Dr. Emily Tonorezos, the Director of the Office of Cancer Survivorship, and both of them work in the Division of Cancer Control and Population Sciences at the National Cancer Institute, National Institutes of Health. Welcome. 

Dr. Emily Tonorezos: Thank you for having us.

Shannon Westin: So, let's get right into it. I want to level set first. I would love for one or both of you to speak a little bit about the state of cancer survivorship currently. What's the prevalence of cancer survivors here in the US? Globally? What do we expect as time passes?

Dr. Emily Tonorezos: Thank you for starting with this question. In the Office of Cancer Survivorship, we use a definition of cancer survivor that we got from the advocacy community many years ago. We use a definition that says “a person is a cancer survivor from the time of diagnosis through the balance of life.” That means in the United States, we estimate that we have a little over 18 million cancer survivors, and globally, it's a little more difficult to estimate those numbers. Not every country has a cancer registry to count the number of cases, but we think there are upwards of 53 million cancer survivors diagnosed within the last five years in the world.

Shannon Westin: Wow. And so this is why it's so important, such a large number, and that's just an estimate. And we know this is only going to be growing. I personally learned so much from your manuscript, which is critically based on the understanding that our beliefs as practitioners truly impact the way we care for our cancer survivors. I admit, I definitely held or hold some of these beliefs, and I'm certainly grateful that you're providing that objective evidence to support or refute these claims. 

So, with that being said, let's tackle the first one that you all approached: Shared care results in the best outcomes for cancer survivors. I think first I'd love to hear about what your definition of shared care is. What does that really mean in the context of cancer survivorship?

Dr. Michael Halpern: Shared care is a deliberate process to coordinate and integrate components of survivorship care between specialty, in this case, oncology providers, and primary care providers. And part of the issues with this belief about shared care being the best have to do with the broad practice experience of survivorship care. While the ideal definition is this integrated and coordinated care, shared care can range from one extreme to being essentially oncologist-led care - where the oncologist also sends information to the primary care providers; and to the other extreme - care led by primary care providers and an oncologist is available to answer questions as needed. So part of the issue with the available literature is that there is a tremendous range in terms of the definition of shared care that's being used in studies.

Shannon Westin: So, understanding those limitations, obviously, based on what you just said, what have we seen in some of the studies that have been exploring shared care and what it might mean for cancer survivors?

Dr. Michael Halpern: So there have been some wonderful studies and some very well-done research in shared care. The majority of it indicates essentially no benefits, not any worse, but definitely not any better than other survivorship care models among multiple domains, quality of life, patient preference, clinical outcomes, in some cases, costs. So there isn't at this point a rationale for believing that shared care leads to better outcomes than does other types of models of care. And that's not to say that we don't think that shared care is a valuable model, that it's potentially very useful and beneficial for certain groups of cancer survivors. It's just that at this point, we don't have evidence to say who it is going to have optimal outcomes for compared to other kinds of survivorship care models. 

Shannon Westin: And that makes sense. I mean, I think we're seeing this over and over again in all aspects of cancer care that one broad stroke or one broad plan isn't right for everybody, whether that's therapeutic or surgical or prevention, so it makes sense to me that that's what we're seeing here in survivorship as well. So I see this manuscript as a call to action about what are we missing, what data do we need to generate to really be able to move this care forward. So that makes total sense to me. And I guess in line with that, another belief, and I've heard this all the time from my patients, too, is this idea that primary care providers feel unable to provide survivorship care. They're not comfortable. “Oh, you have a diagnosis of cancer. You have to be seen there at the cancer center.” What does our evidence demonstrate here?

Dr. Emily Tonorezos: This is another belief that was found to be a presumption. So that means that this is a belief that we think was true, but which convincing evidence does not confirm or disprove. So what the available evidence tells us is that primary care providers do have challenges in taking care of cancer survivors, particularly with regards to certain cancer-related care needs. But at the same time, we found lots of evidence that primary care providers are more than willing and able to take care of cancer survivors. They express confidence in their skills. They think that they are capable of taking care of cancer survivors. And especially for survivors of more common cancers, primary care providers, in general, express a lot of confidence in their ability to take care of those patients. What they might lack could be things along the lines of survivorship-specific knowledge. So that is a gap that we identified. But this idea that primary care feels unable to take care of survivors really was not supported by the evidence.

Shannon Westin: I mean, and that makes sense, right? If we're seeing more and more cancer survivors, primary care is going to adapt to that. We adapt to the things we see commonly in our clinics, and that goes across all specialties. So that certainly makes sense. I guess you've already kind of said this, and I'll just highlight it for the listeners. You know, clear guidelines seem to be a clear, nice option to potentially improve this situation. 

So let's discuss this next myth that you all identified, that oncology providers are hesitant to transition survivors to primary care. Now, I understand this one because I definitely, we get this a lot, and I'm a center medical director in GYN, and we've definitely tried to put patients that are free of disease out back in the community to be able to free up space for other patients. And we definitely get pushback because seeing patients that are in this state of being free of disease and they're living their life, it's inspiring. We remember why it is we're doing the things we do. What did the data show us about this myth? And are we creating barriers to this transition to survivorship care outside of the oncology centers?

Dr. Emily Tonorezos: Exactly. So this belief is a myth. We found evidence that this belief is not true, and it seems to be one of those things that feels true, that oncologists want to take care of cancer survivors, that it contributes to the joy of medicine. But that evidence really does not suggest that that's the case. In fact, the opposite is true in the evidence. We found when we looked at the available research Oncologists want to take care of people who are diagnosed with cancer and need treatment. That is really what they think their role is. That's what they feel they're contributing. And so, even though there is a pleasure in seeing a person who has finished treatment, most oncologists say that the amount of time that they spend taking care of people who are done with treatment is appropriate - meaning they're not looking to expand their panel of post-treatment patients. They really want to take care of people who need treatment currently and then perhaps have a little bit mixed in of people who are done with treatment or who are in that survivorship phase.

We found a lot of evidence, also hard evidence, that oncologists are, in fact, transitioning survivors to primary care. There is a lot of evidence that people who have been diagnosed with cancer are being seen in primary care and that that proportion increases over time. So if oncologists were really creating these insurmountable barriers to transition to primary care, we would not be seeing so many survivors in the primary care setting. But the fact is they're there, and they are being moved there by their providers.

Shannon Westin: I love hard evidence. I do have a few patients that have said, "Can I just come see you every once in a while?" And I love seeing them, but I agree, we can't fill our panels with that. So that makes good sense. 

So the next topic centers around finances, and this is the idea that survivorship clinics lose money. What truth did you all discover here regarding reimbursement for this type of care? 

Dr. Michael Halpern: We discovered that this is a presumption. It's a belief that there isn't compelling evidence one way or the other. Part of the issue with this is probably some confusion about what constitutes survivorship care. There are certainly difficulties in obtaining reimbursement for certain survivorship services, such as sexual health and fertility counseling, and wellness and exercise services. It's understandable that there may be problems getting reimbursement or appropriate reimbursement for those. But when looking at overall survivorship care, there are actually very few studies that have done a financial analysis of the cost of providing that care versus the reimbursement. And those that have done more detailed analyses generally show that the reimbursement for survivorship care is greater than the cost. Survivorship care clinics actually do break even or make money. 

Now, it's also true that providing survivorship care likely doesn't provide the same level of reimbursement as providing oncology treatments, which involves administering systemic agents and different kinds of imaging or diagnostic procedures. And so there are other streams of reimbursement possible for that. But overall, there really isn’t compelling evidence to indicate that survivorship clinics lose money. There is a concern that having this widespread belief that they do may be a disincentive for hospitals or healthcare systems to start different kinds of survivorship clinics.

Shannon Westin: I think this is an area where it would really behoove us to do more work so that we can encourage institutions to do this. And, I know in our center, the things that you're mentioning, it's exactly like the problems that these people are having around sexual health and fertility and exercise, wellness in general, I mean, those are the soft things that I feel like it's harder to kind of gain momentum to really develop established programs that really make an impact. And so I was so glad to see that you mentioned that in this paper, and I hope it will encourage people to really move that forward. 

So finally, I was interested in this presumption around the shared electronic health records and how that might help with survivorship care coordination. Is this our solution for smooth communication and care of these people?

Dr. Emily Tonorezos: This one was actually almost something that's sort of funny to think about, how naive we were about electronic health records. We found a number of examples from five or ten years ago where leaders in survivorship research and clinical care were saying, "Well, once we have electronic health records, we will not have these same problems of care coordination or communication." And that has just not been true, unfortunately. So this one was also a presumption, meaning the evidence of a benefit for electronic health records just was not out there. So we know that consolidation and transfer of diagnostic and treatment information can increase knowledge. So you can show that you can increase knowledge about diagnosis and treatment with a shared electronic health record. So the primary care provider is able to look, for example, at the pathology from the original diagnosis. But whether that actually results in anything in terms of improved care is an open question.

Shannon Westin:I think that's what we've learned a lot about electronic health records in general. I remember when we were transitioning to our new system, and everyone thought, "Oh, this is going to be the end all, be all." And it has been good in a lot of ways, but it certainly hasn't been the cure for everything that ails us. 

Well, I'm just so thrilled. Thank you all so much. This has been really educational and so important, given what we've already talked about, about the increasing population of cancer survivors that we're seeing in the clinic and globally. I think just to kind of tie a bow on it, I would just love to hear each of your bottom lines regarding kind of where we are right now with the care of our cancer survivors and what we need to be addressing maybe in the short term to move things forward.

Dr. Emily Tonorezos: So I'll go first. I just want to say it's really important, I think, when we are around other investigators and in our meetings and talking about clinical care, that we think critically about the things that we hear people saying. This idea, especially the one that oncology providers don't want to transition their survivors to primary care, but the others as well. I think the way that we need to address this or carry this forward is to just be aware when we're in those settings and we hear people say things, to ask the question, "Is that really supported by the evidence?" And you may find that there are even more of these commonly held beliefs that really aren't supported by the evidence or that deserve a little bit of a deeper dive.

Dr. Michael Halpern: I very much agree with that. And it's critical that we be willing to question some of these beliefs, be willing to discuss them, and not accept them as facts in order to be able to develop new research programs, hypotheses, to explore really what can help produce the best outcomes for survivors, because that's really what we're all about.  

The other bottom-line issue, I think, one, Dr. Westing that you brought up, is that survivorship isn't a one-size-fits-all. The best survivorship care is the care that is tailored towards the survivor - the individual needs and wants. What kind of supports will be most effective in terms of enhancing their health? So, we really need to pay attention to the individual and, most importantly, what outcomes for survivorship care matter most to the survivor? What do they want to see happen? What do they want their subsequent future to look like? And how do we measure those outcomes to ensure that they get the best care on the terms that they want? 

Shannon Westin: Well, great. I think that's a perfect place to end. I just want to, again, thank my guests. This went by so fast, and I learned a ton, and I hope all of you did as well. Again, we were discussing the Comments and Controversies manuscript "Myths and Presumptions about Cancer Survivorship" published in the JCO on November 16, 2023. 

Thank you again to our listeners for joining JCO After Hours. And please do check out our other offerings wherever you get your podcasts. Have an awesome day. 

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

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

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.

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.

This JCO Podcast provides observations and commentary on the JCO article Durable Tumor Regression and Overall Survival in Patients with Advanced Merkel Cell Carcinoma Receiving Pembrolizumab as First-Line Therapy by Paul Nghiem, MD, PhD et al. My name is Reed Drews, and I am a member of the Cutaneous Oncology Program at Beth Israel Deaconess Medical Center in Boston, MA. My oncologic specialty is non-melanoma skin cancers.

Merkel cell carcinoma is a rare, aggressive neuroendocrine skin malignancy with high propensity for local recurrence and regional lymph node and systemic metastases. Its incidence rises exponentially with aging and is 10-fold higher in chronically immunosuppressed patients. When Merkel cell carcinoma is advanced and/or unresectable, historical 5-year overall survival rates are low, from 14 to 27%. Cytotoxic chemotherapies, like platinum plus etoposide used in other high-grade neuroendocrine malignancies, have not yielded durable response rates.

The cutaneous cell (or cells) of origin in Merkel cell carcinoma remains controversial. Nevertheless, scientists have identified 2 pathogenetic pathways leading to Merkel cell carcinoma. In 80% of cases, clonal integration of a polyomavirus leads to Merkel cell polyoma virus-positive Merkel cell carcinoma. In the other 20% of cases, ultraviolet light-induced DNA damage leads to polyoma virus-negative Merkel cell carcinoma. Polyoma virus-negative Merkel cell tumors display predominant cytosine to thymine transitions, a signature of DNA damage from UV light, and they have a 100-fold greater mutational burden than virus-positive Merkel cell cancers. For both subtypes, loss of immune surveillance, as with aging or chronic immunosuppression, contributes to Merkel cell carcinoma development, with diminished non-self-antigen recognition of UV-induced neo-antigens in virus-negative tumors and viral oncoproteins in Merkel cell polyoma virus-positive tumors.

Given these factors, investigators have recently studied whether immune checkpoint inhibitors might hold promise for managing advanced Merkel cell carcinoma. To date, 3 antibody inhibitors of the programmed cell death-1 pathway (abbreviated PD-1), including anti-PD-ligand-1 avelumab, anti-PD-1 nivolumab and anti-PD-1 pembrolizumab, have been tested in patients with chemotherapy-refractory and/or treatment naïve Merkel cell carcinoma. The 62% objective response rate from avelumab in treatment-naïve Merkel cell carcinoma was nearly twice that observed in chemotherapy-refractory disease. In 2017 avelumab became the first immune checkpoint inhibitor approved by the FDA for advanced Merkel cell carcinoma. Nivolumab yielded similar results, as did pembrolizumab according to a 2016 report from Nghiem and colleagues of a multicenter, phase 2, non-controlled study with 26 patients.

As reported in this JCO publication, Nghiem and colleagues have now increased their cohort to 50 patients through the multicenter expanded phase 2, Cancer Immunotherapy Trials Network-09/Keynote-017 trial. They administered pembrolizumab 2 mg/kg intravenously every 3 weeks for up to 2 years. Median follow-up time was 14.9 months, with a range from 0.4 to 36.4 months. This represents the longest follow-up to date of any anti-PD-1 pathway inhibitor for first-line treatment of advanced Merkel cell carcinoma. The 50-patient cohort included 43 patients with (stage IV) distant metastatic disease and 7 with stage IIIB recurrent locoregional disease not amenable to definitive surgery or radiation therapy. All patients had normal organ and bone marrow function and an Eastern Cooperative Oncology Group performance status of 0 to 1. Key exclusion criteria were previous systemic therapy for unresectable Merkel cell carcinoma, immunodeficiency or systemic immunosuppressive therapy, active autoimmune disease, concurrent second cancer, and active central nervous system metastases.

The median age of enrolled patients was 70.5 years, with 80% age 65 or older. 64% of patients had Merkel cell polyoma virus-positive tumors. For previous management of their primary Merkel cell carcinoma, 42 patients had had surgery, and 35 patients had had radiation treatment. While no patient had previously received systemic therapy for advanced Merkel cell carcinoma, 3 patients had received adjuvant chemotherapy greater than 6 months prior to study enrollment.

Patients received a median of 10.5 doses of pembrolizumab – range 1 to 35 doses—and the median treatment duration was 6.6 months – range 1 day to 23.6 months. Radiographic responses were assessed centrally per Response Evaluation Criteria in Solid Tumors, version 1.1. Responses were generally rapid and durable with 2.8 months as the median time to response – range 1.5 to 9.7 months. The objective response rate to pembrolizumab was 56%, with complete and partial responses of 24% and 32%, respectively; 10% had stable disease; and 32% had progressive disease.

At time of data analysis, 20 of 28 responses were on-going, and the median durability of response had not been reached. The Kaplan-Mier estimation of response durability at 24 months was 79.1%. Median progression free survival was 16.8 months, and the Kaplan-Mier estimation of progression free survival at 24 months was 48.3%. Median overall survival had not yet been reached. The Kaplan-Mier estimation of overall survival rate at 24 months was 68.7%.

Tumor viral status, as determined by small T-antigen specific antibodies in serum or large T-antigen expression in tumor biopsies by immunohistochemistry, did not correlate with any study outcomes, such as progression free survival or overall survival. However, a trend towards improvement of these outcomes appeared in patients with PD-L1-positive tumors, as defined by cell-surface PD-L1 expression on at least 1% of tumor or immune cells.

The safety profile of pembrolizumab in advanced Merkel cell carcinoma was similar to that in other studies of anti-PD-1 pathway inhibitors: 28% of patients had grade 3 or greater treatment-related adverse events, causing 14% of patients to discontinue treatment. A 73-year old male patient with widely metastatic Merkel cell carcinoma and pre-existing atrial fibrillation died after developing pericardial and pleural effusions 1 day after one infusion of pembrolizumab. Other adverse events were generally manageable and typical of complications of anti-PD-1 pathway inhibitors, including adrenal insufficiency, colitis, hyperthyroidism, hypothyroidism, infusion-related reaction, myocarditis, pancreatitis, pneumonitis, maculopapular rash and thyroiditis.

With such impressive rates of durable tumor regression and overall survival, on December 19, 2018, the FDA granted accelerated approval to pembrolizumab for treating patients with recurrent locally advanced or metastatic Merkel cell carcinoma. Today’s standard of care for advanced Merkel cell carcinoma is an anti-PD-1 pathway inhibitor, and the NCCN Clinical Practice Guidelines in Oncology in 2018 recommended avelumab, nivolumab and pembrolizumab as preferred first-line therapy for advanced Merkel cell carcinoma, ahead of cytotoxic chemotherapy.

Future studies must determine what role anti-PD-1 pathway inhibitors will play in the neo-adjuvant and adjuvant settings when managing early stage Merkel cell carcinoma with high-risk features. Prior to immune check point inhibitors, neo-adjuvant and adjuvant chemotherapy were considered case-by-case, absent strong evidence for benefit.  However, now with impressive results from anti-PD-1 pathway inhibitors in advanced Merkel cell carcinoma, adjuvant nivolumab and avelumab are being evaluated in 2 randomized phase II trials. Nivolumab is also undergoing study in the neoadjuvant setting, and researchers presented promising preliminary results of a phase I/II study at the 2018 American Society of Clinical Oncology Annual Meeting. We look to Nghiem, his colleagues and other investigators to keep us informed regarding future advances, including insights into mechanisms of resistance to the immune checkpoint inhibitors.

This concludes this JCO Podcast. Thank you for listening.

This JCO Podcast provides observations and commentary on the JCO article Gonadal Functioning and Perceptions of Infertility Risk among Adult Survivors of Childhood Cancer: A Report from the St. Jude Lifetime Cohort Study by Lehmann et al. My name is Leslie Schover, and I am retired from the faculty of MD Anderson Cancer Center and currently Founder of Will2Love.com a digital health company in Houston, Texas. My oncologic specialty is cancer-related problems with reproductive health, i.e. sexual function and fertility.

Damaged fertility is unfortunately quite common in survivors of childhood cancer. A variety of chemotherapy drugs, as well as surgery affecting parts of the reproductive system or radiation therapy focused on the pelvis or brain, can damage spermatogenesis, reduce ovarian reserve, or interfere with uterine function. In general, males are more at risk than females for cancer-related infertility. Some survivors do not undergo puberty without hormonal support. For others, fertility may recover over time. However, many young women who have menstrual cycles in their teens or twenties are at risk for premature ovarian failure, leaving a narrowed window of time to become pregnant. Men do not know whether they have normal sperm counts, motility, or form unless they have had a recent semen analysis. People diagnosed with cancer before puberty may never have been counseled about fertility. Even survivors treated as teens or young adults typically do not know their fertility status unless they have consulted an expert in reproductive endocrinology or andrology. Surveys of young survivors suggest that the majority want to have children, particularly those who are childless.

A number of studies have documented markers of infertility or reduced rates of offspring in survivors of cancer, but little has been known about their perceptions of their fertility status. In the paper that accompanies this podcast, Lehmann and colleagues present novel data about the risk perceptions for infertility compared to indicators of actual gonadal function in over a thousand long-term survivors of childhood cancer participating in the St. Jude Lifetime Cohort. None of the participants already had children or a previous pregnancy. The mean age of the sample was 29, with a mean follow-up of 22 years since cancer diagnosis. 85% were white and 32% had at least a 4-year college degree. 52% were married or in a relationship. Only 10% of men and 16% of women had been tested for infertility outside of the study.

Gonadal function was measured by a semen analysis in 56% of men and by a panel of hormones in the others. In women under age 40, status as fertile vs. sub-fertile was assigned by chart review based on menstruation, diagnosed premature ovarian failure, or hormonal assays. Perception of risk for infertility was based on one question with a Likert scale of 5 response options, comparing one’s own fertility to that of peers who had not had cancer. Answers were dichotomized into two categories: perceived at risk for fertility or perceived normal fertility.

62% did perceive themselves as at risk for infertility. Those who perceived their fertility as damaged had characteristics that would indicate potentially more knowledge about cancer and fertility, including being older, white, in a relationship, having a college education, a history of gonadotoxic treatment, having tried unsuccessfully to conceive, or having sexual dysfunction.

In actuality, 24% of women and 56% of men had evidence of impaired gonadal function. However, actual medical status had no significant relationship to perceptions of risk. The most common discordance was that the survivor believed him or herself to have damaged fertility when medical tests appeared normal. This included 20% of men and 44% of women. Inaccurate perceptions were more common in respondents who were white, had more education, had more gonadotoxic cancer therapy, were very concerned about their fertility, and had sexual dysfunction. In contrast only 16% of men and 5% of women overestimated their fertility potential.

In terms of clinical implications, it is common for young survivors to overestimate their risk of infertility. Such beliefs can diminish quality of life. A young person who feels like “damaged goods” may be distressed about the future and perhaps reluctant to date or to enter into a committed relationship. For women, risky drinking was another factor associated with overestimating fertility risk. Risky drinking, and the notion that pregnancy is impossible, may contribute to findings in other studies of excess rates of unintended pregnancies and failure to use consistent contraception in young adult female survivors. Those unaware of their damaged fertility maybe in for distress and disappointment if they try for a pregnancy. Clearly a greater effort should be made to inform young survivors about risks to fertility and to refer them for testing at intervals of fertility status.

It appears that women are much more likely than men to perceive themselves as potentially infertile, despite the fact that men are more likely to be infertile. However, the measures of gonadal function used in women were not sensitive enough to predict the likelihood of diminished ovarian reserve in the future. Many young survivors of cancer can conceive in their teens or twenties, yet have a steeper than normal drop-off in ovarian reserve with aging, so that their menopause occurs far before the average age of 51. In fact, women’s fears in this study that they will have trouble getting pregnant in the future may be more accurate than they appear. Age at first pregnancy has steadily increased in our society, with women postponing childbearing until they have completed educational goals or established a working life. More cancer survivors are likely to run out of time before they are ready to have a child. One solution may be commercial egg banking before age 25-30, if fertility preservation was not accomplished before starting cancer treatment. Egg banking is expensive, however, and does not guarantee a future pregnancy.

This survey adds to our knowledge of the informational needs of survivors of cancer in childhood or teen years. Both medical and counseling support should be more readily available. Survivors with lower health literacy would be particularly good targets for such services.

This concludes this JCO Podcast. Thank you for listening.

This JCO podcast provides observations and commentaries on the JCO article entitled "Indeterminate Pulmonary Nodules at diagnosis in Rhabdomyosarcoma: Are they clinically significant?"  A report from the European Pediatric Soft Tissue Sarcoma Study Group by Bas Vaarwerk, MD et al.

My name is Alberto Pappo and I am the head of the division of solid tumors at St Jude Children’s Research Hospital in Memphis, TN. My oncology specialty is pediatric oncology. 

In this report, Bas Vaarwerk, and investigators from the European Pediatric Soft Tissue Sarcoma Study Group evaluated the significance of indeterminate pulmonary nodules at diagnosis in children with rhabdomyosarcoma defined as the presence of less than 5 pulmonary nodules measuring less than 5mm or 1 pulmonary nodule that measured between 5 and 9 millimeters.

This analysis included 316 patients who were enrolled on the EpSSG RMS 2005 study for non-metastatic rhabdomyosarcoma from September 2005 through December 2013 and for whom chest computed tomography scans were obtained at diagnosis and were available for review. Treatment in the EpSSG RMS 2005 study was stratified according to risk group, pathology, post-surgical stage, site, nodal involvement, size and age. All patients received multi agent chemotherapy with ifosfamide (except for low risk patients), vincristine and actinomycin D (IVA chemotherapy). High risk patients were randomized to IVA or IVA with doxorubicin and after 9 courses if in complete remission, were eligible for a second randomization between end of therapy and additional maintenance therapy with 6 courses of vinorelbine and cyclophosphamide

Local control was determined by risk group, tumor site, age and response to therapy and radiotherapy was given at week 13 in doses ranging from 36 to 51.4Gy. All chest computed tomography scans were reviewed by the local radiologist at the treating center. Data was obtained and recorded using case report forms.  All computed tomography scans were performed with minimum slice thickness of 3 to 5 mm. 

The median age at diagnosis for the 316 eligible patients was 5.4 years and the median follow up time for the cohort was 75 months.  There were 249 (78%) patients who did not have a pulmonary nodule and 67 (21%) who had at least one indeterminate pulmonary nodule. Patient and treatment characteristics were similar between the 2 groups; 80% of the patients presented with Group III  unresectable disease, 54% had high risk disease, and 71% had favorable histology tumors such as embryonal histology tumors.  Twenty four percent of patients received maintenance chemotherapy and 77% were treated with local radiotherapy

A total of 100 nodules were identified in the 67 patients. Nodules ranged in size from 1 to 8 mm.  69% of the patients presented with one pulmonary nodule, 92% of the patients had nodules that measured less than 5 mm 85% of the nodules were unilateral. The 5-year event-free survival for patients with indeterminate pulmonary nodules was 77% and for those without nodules 73.2%. These differences were not statistically significant with a p value of 0.68. The 5-year overall survival rates were 82% for patients with indeterminate pulmonary nodules and 80.8% for those without nodules. The differences between these 2 groups were not statistically significant with a p value of 0.76.   There were no significant differences in outcomes based on the number or size of the nodules.  Similarly, there were no differences in clinical outcome based on histology, fusion status, age and type of chemotherapy received. Lung metastases developed in 3% of patients with indeterminate pulmonary nodules and in 1.6% of patients without nodules a value that was not statistically significant. The authors conclude that the presence of indeterminate pulmonary nodules in newly diagnosed children with rhabdomyosarcoma as defined in this report does not adversely affect the outcome of these patients and these children can be adequately treated with non-metastatic risk-based clinical protocols.

This report highlights the challenges of assigning risk and therapy based on the presence of a limited number of small pulmonary nodules in children with newly diagnosed rhabdomyosarcoma when they are detected using newer imaging modalities such as thin cut computed tomography of the chest. The authors have successfully demonstrated in this retrospective study that newly diagnosed patients with rhabdomyosarcoma who present with indeterminate oligometastatic disease to the lung which in this study was defined as the presence of 4 or fewer pulmonary nodules measuring less than 5 mm or one nodule that measures 5 to 9 mm, have similar outcomes to patients who present without pulmonary nodules. More importantly, these patients can be treated with less intense trials that may include the use whole lung irradiation which is known to significantly increase the risk of breast cancer in childhood cancer survivors. The authors have implemented a standardized definition for indeterminate oligometastatic lung disease which is highly reproducible and easily implemented.  Their results are thought provoking and deserve further validation in a well- designed prospective clinical trial.

Because of the lack of pathologic correlation with imaging findings in this report, it is not possible to determine which patients truly had oligometastatic disease to the lung. It is conceivable that some of the 67 patients with indeterminate nodules did not have actual metastatic rhabdomyosarcoma in the lung, or alternatively these results may also indicate that current risk-based therapies for localized disease are effective at eradicating small oligometastatic disease. It is important to point out however, that in this report, about one fourth of the patient population was assessed using reconstruction widths of ≤ 1.25 mm, which might have identified a larger number of small nodules of uncertain significance. In addition, 69% of the patients with indeterminate nodules had only one nodule, 92% had nodules that measured less than 5 mm and 85% had unilateral disease.  All of these factors have been associated with a significantly lower likelihood of identifying biopsy proven metastatic disease in pediatric patients with sarcomas. These findings raise questions as to whether thin cuts < 5mm in thickness are of any value in the assessment of pulmonary metastases in children with rhabdomyosarcoma.

In summary, this report opens new areas for clinical research that could lead to a uniform strategy for defining metastatic pulmonary disease in pediatric rhabdomyosarcoma and a more precise method for  risk-stratifying disease in this patient population.  

This concludes this JCO Podcast. Thank you for listening.