Multiple Factors Need to Be Addressed to Improve Late Mortality for Survivors of Childhood Cancer

Matthew J. Ehrhardt, MD, MS

It is likely necessary to mitigate multiple factors that can affect health outcomes and may increase the risk of late mortality in survivors of childhood cancer, according to Matthew J. Ehrhardt, MD, MS. He added that addressing a single factor along may not be enough to create positive change.

In findings from a cohort study published in JAMA Network Open, Ehrhardt and colleagues found that survivors of childhood cancer who lived in socioeconomically disadvantaged areas or had modifiable chronic health conditions were associated with an increased risk for death 5 years or more following the diagnosis of pediatric cancer.

“This is a multifactorial problem, and we cannot address any 1 component and expect highly impactful changes,” Ehrhardt said. “We have to think about all these [factors] together when thinking of interventions to improve the health and well-being of these [childhood] cancer survivors.”

In an interview with OncLive^®, Ehrhardt, discussed the importance of taking a multifactorial approach to improve long-term outcomes for survivors of childhood cancer and expanded on the findings from the study of the factors associated with risk of late mortality. Ehrhardt serves as a pediatric hematologist-oncologist at St. Jude Children's Research Hospital and is an associate member of the St. Jude Faculty in Memphis, Tennessee.

OncLive^®: What key questions was this research aiming to address?

Ehrhardt: In the realm of cancer survivorship, we have known for quite a while that cancer survivors are at an increased risk for chronic health conditions, and we have known that they are at increased risk of early death in relationship to their cancer experience and treatments. For a few specific outcomes, such as heart failure, for example, we have known that individual chronic health conditions, like high blood pressure, dramatically increase the risk of development of heart failure above and beyond that of treatment exposures that are associated with [heart failure] in the first place.

This got us thinking. Could looking at a similar analysis with respect to mortality or causes of death give us key targets of intervention when we are thinking about studies to reduce those increased causes of death in cancer survivors? That is what prompted this [study], the idea of looking at chronic health conditions that we have treatments for or those that we considered modifiable, in the context of other potentially important factors like sociodemographics and treatment exposures themselves, to better learn what future targets for intervention might improve the health and well-being of these long-term survivors.

What methodologies were used to evaluate these potential factors? What individuals were included in this study?

The [individuals] that we used for this analysis [were from] the St. Jude Lifetime Cohort study [NCT00760656]. This is a long-standing cohort that has been prospectively followed, and to be a participant in the cohort, [individuals needed to be] childhood cancer survivors treated at St. Jude Children's Research Hospital who must have survived at least 5 years from their cancer diagnosis. Anyone who met those criteria, whether they were currently living or deceased, was eligible for the analysis.

For this specific part of the analysis, where we looked at relationships between modifiable risk factors and social determinants of health and mortality, that required individuals be participants in the [St. Jude Lifetime Cohort] study. We had more than half of the eligible 5-year survivors who were participants in the association part of the study.

What were the key findings revealed in the study of modifiable chronic health conditions and social determinants of health associated with late mortality?

There were 3 key associations. The first was that, as we suspected, [the presence of] modifiable chronic health conditions, such as high blood pressure, obesity, or dyslipidemia, were associated with increased risk of mortality in [childhood] cancer survivors. In addition, we saw that frailty, which is a well-stablished measure of aging [consisting of] a composite of low lean muscle mass, self-reported exhaustion, low energy expenditure, slowness, and weakness, was associated with increased mortality in these survivors.

The last key association was that we saw the area deprivation index [ADI], which is a well-established marker of regional-level deprivation [accounting] for education level, employment status, housing quality, and poverty measures at the census block level, was associated with an increased risk of death in cancer survivors, even when adjusting for chronic health conditions and treatment exposures.

Were any of these findings surprising?

To some degree, we saw what we expected. We hypothesized that those [factors] would be associated [with risk of late mortality]. However, I was surprised to the degree with which the ADI was associated with an increased risk of mortality. We saw significant increases, even when accounting for things like treatment exposures, which we know are key drivers of late health risk or adverse health risk in cancer survivors.

The findings published in JAMA Network Open stated that this was the first research of its kind to evaluate the association of ADI with risk of late mortality among pediatric cancer survivors. How could these data be used to address changes to help these survivors?

We have known that ADI is associated with poorer health outcomes in other groups of patients. There has been some work done with cancer survival in general, but when we’re talking about long-term or 5-year survivors and their long-term health, this [research] was novel.

Cancer survivorship research has been around for a few decades now and has [produced] a robust knowledge and understanding of what challenges cancer survivors face. We are shifting that research body into more of a paradigm of interventions, trying to reduce those risks moving forward. What this [research] tells us is that we can't just have a specific intervention for a specific problem and necessarily expect meaningful impact on the outcome.

For example, if you are trying to reduce mortality [by] just addressing high blood pressure, diabetes, or other modifiable health conditions, [that] may not be enough. We need to involve multidisciplinary teams, such as our social work partners, and try to address the access to resources that can improve those individual health outcomes. While that seems intuitive, it is an important step to show it, because that is a key part of building those research interventions and protocols going forward.

The study suggested that efforts to increase access to medicine, combined with policies that seek to facilitate this access, may improve the well-being and lifespan of childhood cancer survivors. Can you continue to expand on how these efforts will be of importance moving forward?

I want to make clear that what we have identified is an association, and that doesn't always mean causality. We don't know for sure that these markers of deprivation, for example, actually cause or contribute to increased mortality. However, we see a strong association. That is where these types of [hypotheses] start and where the research begins. Knowing that there is an association there provides a key target for intervention.

We need multi-step approaches. Improving access to medication may reduce the risk of late mortality in some of these patients. [This includes] access to specific medications, like treatment for high blood pressure, for example. However, it is likely not enough. We need to improve, for example, access to green space or access to healthy food sources, so that patients can take a multifaceted approach to addressing those health conditions that they have.

From the policy standpoint, policies can help improve access to those resources, that we would then hypothesize could have an important impact down the road. However, we need the studies to start to evaluate these things and demonstrate a stronger body of evidence.

Regarding this research, are there any next steps that you would like to see taken?

[It is] maybe not necessarily as an extension of this study, but the next logical step in this body of research is starting to develop the actual interventions. The interventions themselves are not new; we have had interventions to try to reduce heart failure or improve exercise, for example. The component that has not been robustly done thus far is including these other aspects such as access to resources.

However, we are starting to see frontline clinical trials, for example, where investigators are trying to incorporate access to healthy foods for patients undergoing cancer treatment. These are all key first steps, and that is where we need to go in survivorship research, where the intervention is actually a package of interventions instead of [addressing just one aspect], such as showing that taking a medication improves your outcome. We should improve access to the medication, improve support for taking the medication, and improve access to other resources that can also contribute to the same outcome.

What does this research ultimately mean for addressing the factors for late mortality among childhood cancer survivors?

The research community is working within multidisciplinary teams to think about how we can target the multiple aspects in the same clinical trials or intervention studies that may be contributing to these adverse outcomes.

We are pulling in experts regarding chronic health management, those who have more experience with ADI, and potentially policy makers that could help to improve [these factors]. Putting those people all under the same roof, so to speak, [can help us] develop robust studies to help attack this from a multi-pronged approach. That would be the message to the research community.

For the clinical community, practitioners need to, as much as they can, try to take the time to understand some of these other factors that we are not as well equipped to address, such as ADI. Our health-care structure somewhat restricts the amount of time that we can spend with patients. We often have a very focused approach about understanding the immediate things we can fix. However, particularly in the oncology world, we often have access to strong multidisciplinary teams.

Taking the time to understand what environments patients are coming from and what access to resources they have, either directly or with the assistance of multidisciplinary teams, can help us to think about how to counsel patients better, and, more importantly, how to help identify and improve their access to resources that will hopefully result in better outcomes.

Reference

Ehrhardt MJ, Liu Q, Dixon SB, et al. Association of modifiable health conditions and social determinants of health with late mortality in survivors of childhood cancer. JAMA Netw Open. 2023;6(2):e2255395. doi:10.1001/jamanetworkopen.2022.55395