Guest Dr. Rusha Bhandari and host Dr. Davide Soldato discuss JCO article "Health Outcomes Beyond Age 50 Years in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study, " with a particular focus on mortality data, development of secondary malignancies and the importance of education for both patients and healthcare providers regarding long-term follow-up and care.

TRANSCRIPT

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

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

Today, we are joined by JCO author, Dr. Rusha Bhandari, a Pediatric Hematologist-Oncologist and Assistant Professor in the Department of Pediatrics and Population Science at City of Hope, California. Today, we will be discussing the article titled "Health Outcomes Beyond Age 50 Years in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study."

So, thank you for speaking with us, Dr. Bhandari.

Dr. Rusha Bhandari: Thanks so much for having me.

Dr. Davide Soldato: So, I just want to go straight ahead in the paper and start from the title. So, we heard that you included in this study childhood survivors of pediatric cancer that were aged 50 years or higher. So, this is a very critical life stage when we know that there are a lot of aging-related comorbidities that can happen, also in the general population but potentially specifically in childhood cancer survivors. So, first of all, I wanted to ask you, why this specific study in this very specific population? Because I think that we had already some data in younger survivors, but now we are focusing specifically on patients aged 50 or more.

Dr. Rusha Bhandari: Absolutely. So, to answer that question, I'll take a little bit of a step back in terms of where we are now and where we came from in terms of treatment for childhood cancers. So, thankfully, we now have great curative therapies and survival rates for many childhood cancers, including the most common ones. But this was not necessarily the case 50 or more years ago. So, we essentially are now seeing the first generation of older survivors who are 30, 40, or more years from completion of their cancer treatment.

As you pointed out, we know from younger survivors that they have a markedly higher risk of malignancies and health conditions than the general population. You don't typically expect to see things like heart disease or diabetes, for example, in a young adult. But the question that remained was what the health status and risk of these conditions are in survivors who are entering this critical age, as you mentioned, 50 or older, when you do start to see these aging-related changes in the general population. And the question is whether we're still observing increased risks related to cancer treatment that was delivered 30 or more years ago in these survivors who are now entering ages 50 and beyond.

Dr. Davide Soldato: Thanks so much. You used the data from a study that is called the Childhood Cancer Survivor Study. So, just a little bit of explanation for our listeners. How is the study conducted? What type of data are you collecting? And specifically for the interest of the study that was reported in this manuscript, which outcomes were really important for you and were so evaluated in the manuscript?

Dr. Rusha Bhandari: Yes. So, the Childhood Cancer Survivor Study is a really excellent resource that combines information from children who were treated across North America at various different centers and sites. So it gives us a really good understanding of how different survivors are doing as they do progress through their survivorship journey.

The Childhood Cancer Survivor Study includes a baseline questionnaire when participants are first eligible or first enter the study, and then includes a series of follow-up questionnaires to really understand how they're doing, like I mentioned, as they progress throughout their survivorship journey. And so for this study, we really wanted to take a global look at how these patients were doing as they entered that older age range. And so we wanted to look at outcomes ranging from mortality through the health conditions that we've seen from other survivorship studies, including subsequent malignant neoplasms, other health conditions, I mentioned earlier heart disease and other comorbidities we know survivors can be at increased risk for, and also things like frailty, which we know is, you know, the most widely recognized phenotype of aging. And we see that earlier on in our younger survivors. We want to see how this translated to these older survivors and then also other health outcomes like their health status. What is their self-report of their physical health, their mental health? Things like that. So we wanted a very comprehensive understanding of their health.

Dr. Davide Soldato: This is a very comprehensive study. Right now it includes more than 30,000 patients that have been treated for childhood cancer, but specifically looking at the question of survivors aged 50 years or higher, you included more than 7,000 patients inside of this study. So, looking at the first outcome that you mentioned, which I think it's also one of the most important, you look specifically at mortality, and in this specific population, you saw a striking three-fold increase in mortality when comparing these survivors with the general population. I just wanted to dive in this result and ask you: What do you see as the main driver for this excess mortality in this population of survivors? And as you were mentioning, the study also collects information about the treatment received. So, was there any association with a specific kind of treatment that was received for curing these childhood cancers?

Dr. Rusha Bhandari: I agree. I would say it's striking to see that mortality risk among the survivors relative to the general population. And we do know, again from prior studies, that survivors of childhood cancer do have an increased risk of mortality compared to the general population, but I think looking at those curves of the cumulative mortality risk was really quite striking as they diverge, and that's, you know, just so long past their initial diagnosis and treatment.

We know that subsequent malignant neoplasms or secondary cancers are a really an important contributor to mortality among survivors. And I think it was important to note that even in these older survivors, it's still such an important contributor to mortality, and I think this really highlights the need for us to better understand what is driving specific secondary cancers and what are the differences in the biology and treatment approaches for some of these cancers? And how might that then be contributing to the mortality risk?

Dr. Davide Soldato: Related to the treatment mortalities - because I think that one of the main forces of the study, as it is conducted, is that it contains a lot of information regarding radiotherapy, allogeneic transplant, surgery, type of chemotherapy received by these survivors - so, are we able right now with the data that we have to pinpoint which of these treatments can potentially lead to such increased risk of mortality?

Dr. Rusha Bhandari: So, we weren't able to look at the comprehensive treatment exposures and mortality risk for this paper. So that might be one of the questions I would put on the side. We were able to look at that in relation to subsequent malignant neoplasms and health conditions though, as you mentioned.

Dr. Davide Soldato: Another thing that I think is very important is that you were able to look at specific causes for mortality. So for example, you mentioned the increased rate of neoplasm in this population and specifically, more or less 7.6% of the patients that were included in the study developed another neoplasm after the ones they were cured for in the childhood period. So, you saw a wide range of cancer, for example, bone and soft tissue sarcomas, breast cancer, genitourinary cancer. And as you were mentioning, there were some associations for treatment modalities that were associated with a higher risk of developing this type of cancer. Can you expand a little bit on this?

Dr. Rusha Bhandari: Absolutely. And so the key part here was that we really looked at any of these outcomes that occurred beyond age 50. What we found was there is still an increased risk of secondary cancers beyond that initial childhood cancer diagnosis, but when we really looked at that data, it was specifically among survivors who had a history of receiving radiation. And we did not necessarily see an association between different chemotherapy exposures and secondary cancers. And I think this speaks to what we're now learning in terms of the very long-term effects of radiation and how that impacts ongoing health risk even in patients who are 30 or more years out from their treatment. And I think it really highlights the importance of these- the efforts that have been made in the more recent decades to really try and reduce or eliminate radiation where possible, you know, as we've come to understand more about these long-term effects from it.

Dr. Davide Soldato: A clear association with radiation therapy but no association when we look at specific types of chemotherapy that were used for curing this childhood cancer.

Another thing that I think it's very interesting and you briefly mentioned before is that potentially when we look at these secondary malignant neoplasm that develop in this situation, we might also see some outcomes that are not comparable to the one of the general population, meaning that we managed to cure less this type of cancer when they develop in these childhood survivors. So, I just wanted to understand if you could provide us with a little bit of perspective also from a clinical standpoint being a pediatric hematologist-oncologist as to why this might be happening and how can we potentially increase the cure rate also in this population of childhood cancer survivors?

Dr. Rusha Bhandari: Absolutely. While that was not the focus of this study, it was something that we were certainly interested in is understanding how even once a childhood cancer survivor, for example, develops a health condition or a secondary cancer further into survivorship, how does that outcome then differ from someone in the general population? And there's a lot of interest in ongoing studies actually evaluating that and understanding what are the differences from the initial presentation, biology, the characteristics of that cancer, through how they're treated. So I don't know if we have all of the answers for that quite yet, but you can imagine if someone hypothetically had a history of receiving a lot of anthracycline chemotherapy or already having received a lot of radiation, that might impact what treatment they might receive for that secondary cancer or if they already have other existing comorbidities that need to be taken into consideration.

Dr. Davide Soldato: Speaking about comorbidities, you were mentioning in the beginning that one of the focuses of this scientific work was really to try and see whether also this type of adverse health outcomes that can be potentially related to treatments were more frequent among these childhood cancer survivors. So I think that it's very interesting that for this comparison, you were able to use the data from the siblings of the patients who were included inside of the study. So, just a little bit of a comment on why you decided to use this specific methodology, which I think has a very nice touch to it when we look at these outcomes like, for example, diabetes or cardiovascular disease, and in general, do we see an increased number of chronic health conditions among survivors who were treated for childhood cancers?

Dr. Rusha Bhandari: Yes, so this is a really excellent strength of the Childhood Cancer Survivor Study is that they have information, longitudinal information, on survivors as well as their siblings. So, you know, when we were discussing the design of the study, I mentioned that we have initial baseline questionnaires as well as multiple follow-up questionnaires, and that is for both the survivors and the siblings. And so we're able to really understand their health course over time. We chose to evaluate sibling data because then you're really able to look at people who have similar characteristics, right? Similar environmental exposures in theory, potentially similar genetic predispositions and makeups and things like that. And so you can really try and have as good of a comparison as possible.

Dr. Davide Soldato: Did we see any increase in chronic health condition when looking at survivors compared to the siblings?

Dr. Rusha Bhandari: We did. And while that's been reported before, again, I think it's important to demonstrate that in this older population when you would expect that these siblings would now also be starting to develop different health conditions.

Dr. Davide Soldato: One thing that was very interesting is that when we look at the coexistence of multiple comorbid conditions and chronic condition in this population, we also see that for some of these survivors, they basically have the same rates of comorbidities as compared to siblings who are potentially 20 years older than them. So I think that there is really that striking point, as you were mentioning before, of accumulation of changes, also physiological changes that can potentially drive a higher frailty index, which was also higher when looking at these survivors compared to their siblings.

One outcome that was really not that worse when we look at survivors of childhood cancer was actually mental health. And as I read the paper, it was something that really surprised me a little bit because you would imagine that going through such a harsh diagnosis, such very complex treatment, very early in their life could potentially lead to some worse health outcomes also in terms of mental health over time. But this was not seen. And just a comment on this, because I think it's a very surprising data.

Dr. Rusha Bhandari: Yes, I appreciate that question. So, as you mentioned, mental health is such an important issue for patients, both those undergoing treatment as well as those in long-term survivorship. And in our study, we found that survivors were not more likely, as you mentioned, to report poor mental health compared to their siblings. And I think there's a few possible reasons for this.

You know, again, this is self-reported data amongst siblings and survivors who survived to at least 50 years of age and completed a questionnaire. And so that is the group of individuals that we were able to evaluate this in, so we have to keep that in mind. But I think our findings may also reflect the resilience of this particular cohort of aging survivors that we included. This finding has been reported in other studies of survivors as well, and so I think it very well may speak to the resilience of the cohort that we're looking at.

Dr. Davide Soldato: Going back just a little bit, you mentioned that the majority potentially of these survivors who were included in the current analysis were treated between 1970s and 1980s. So, as you were mentioning before, radiotherapy was seen as a significant contributor to second neoplasm and also to the increase of this chronic health condition. So, do you believe that there is still a role for these survivorship studies as we are approaching treatment modalities where radiotherapy is administered less frequently or with lower doses or omitted at all in the treatment course of these survivors?

Dr. Rusha Bhandari: Absolutely. I think you mentioned a very important point, which is these findings are most applicable to the patients who were included in this cohort or similar cohorts, those who were treated in the 1970s and 80s who now are 50 years or older at this point in time. And as you know, treatment modalities have really changed. You know, as you mentioned, we'll use less radiation in many cases whenever possible, but there are so many new modalities, so many different chemotherapeutic agents, immunotherapy. There's so much more we need to learn about the long-term effects of some of these newer treatment modalities. And also, we've been able to really intensify our treatment regimens with improvements in both treatment approaches and supportive care. And so I think we have a lot to learn about those late effects, and ongoing studies are certainly needed as we continue to have this growing population of older survivors.

Dr. Davide Soldato: And now a more general question which builds on the results of the study but goes a little bit beyond what was the scope of the research. So we have just discussed that there is an excess mortality in general, there is a higher risk for secondary malignancies in this population, we see higher accumulation of chronic comorbid conditions that need to be treated. So building on these results, in your opinion, what would be the best framework to follow up these patients over time? Because I imagine that for some of these patients who have been treated 30, 40 years before the moment where we see this type of events, they can be potentially also discharged from more specialistic medical care. So what is the best course of action? Should we keep all of these patients under observation in a very specialistic environment under the care of the oncologist or the pediatric oncologist? Should we create a stronger bond with general practitioners so they know that there is this problem?

Dr. Rusha Bhandari: Yes, I mean, I think you're reading my mind. We thankfully do have evidence-based guidelines. We utilize the Children's Oncology Group Long-Term Follow-Up Guidelines, which include screening recommendations for secondary cancers, chronic health conditions, everything based on the underlying diagnosis and treatment that these patients received. But we recognize that a large proportion of these survivors do not continue to have lifelong follow-up at a survivorship center, but really do need that specialized screening based on their treatment that they received. And I think for that reason, it's so important that we continue to build relationships with their primary care providers and really make sure that both patients and their providers have this information at hand regarding what their treatment is and what the screening is that they need and that we be able to have this community whereby we are able to help inform the screening in our own survivorship clinics, but also help guide some of the primary care providers who are going to be seeing these patients in the long run.

Dr. Davide Soldato: Do we have any data showing what is the adherence rate of these patients to this type of continuous screening and monitoring over time? Because I imagine that that might also be a point for improvement in terms of quality of care. Can we retain as much childhood cancer survivors as we want as we are learning that there are all these potential negative health outcomes over time?

Dr. Rusha Bhandari: We definitely within the survivorship community do want to help make sure as many survivors as possible are being engaged, again, whether it's at their specific cancer center or whether it's in the community, recognizing that for many reasons, it's not feasible to always return to that cancer center for your regular survivorship care. I think there's a lot we can do. Going a little bit outside the scope of your question, but I think there's a lot that we can do nowadays in terms of telehealth and being able to communicate with patients and their providers even if they're geographically not located right near us. But we do have data that shows that the further out many patients get from their initial diagnosis and treatment, the less often they might follow up with a survivorship provider. Some of this varies by different treatment.

Dr. Davide Soldato: So, basically the final question is that we need more education and potentially more resources for survivorship clinics and in general to better inform patients and providers about these potential long-term outcomes.

Dr. Rusha Bhandari: That's certainly a focus of our survivorship program, for example, is to make sure that we're able to educate patients, inform them of their risks, and why certain screening tests are recommended at certain times in their survivorship journey. And then I think again, thankfully nowadays with all of the electronic medical records and different methods for us to communicate, there's a lot of opportunity for us to continue building these relationships with those primary care providers and making sure they have the information at their fingertips as well as to be able to work in conjunction with these patients to continue to formulate their plans and carry out these screenings and then again, like I was saying, have an easy open line of communication with the oncology centers if they do have any questions.

Dr. Davide Soldato: Thanks so much.

This brings us to the end of this episode. I would like to thank again Dr. Bhandari for joining us today.

Dr. Rusha Bhandari: Thank you so much. It's been a real pleasure speaking with you.

Dr. Davide Soldato: And we appreciate you sharing more on your JCO article titled "Health Outcomes Beyond Age 50 Years in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study."

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Health Outcomes in Older Childhood Cancer Survivors

Journal of Clinical Oncology (JCO) Podcast

Health Outcomes in Older Childhood Cancer Survivors