1. DiGiulio, Sarah

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For decades, oncologists and the wider medical community have used 5-year survival as a benchmark of success in treating childhood and other cancers.

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The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program annually publishes a Cancer Statistics Report, which informs health policy decisions made at all levels. This report uses 5-year survival to track progress across various cancers.


But survivors of childhood and adolescent cancers are different from adults in that they can have several decades of life beyond 5 years of survival during which they're dealing with late-occurring consequences and toxicities of cancer treatment. This point is made by researchers in a recent Journal of Clinical Oncology Comments and Controversies article (2021; doi: 10.1200/JCO.20.03681).


"Despite risk-stratified therapy, premature mortality risk from causes such as subsequent neoplasms, cardiac disease, pulmonary disease, and other chronic health conditions remains significantly elevated in long-term survivors. Therefore, using 5-year overall survival as the primary benchmark of success does not adequately reflect the increased risk of morbidity and mortality experienced throughout the lifespan of childhood and adolescent survivors," the coauthors noted.


The researchers propose an additional measure of success: annual excess death rates. This measure is calculated by subtracting the expected number of deaths for a population (matched for age, sex, and race) in a given calendar year from the deaths among survivors of childhood and adolescent cancers.


Currently, 85 percent of patients with childhood cancers survive beyond 5 years in the United States, explained study coauthor, Yutaka Yasui, PhD, Member of the Department of Epidemiology & Cancer Control at St. Jude Children's Research Hospital. This figure is a result of decades of gradual improvements in diagnosis, treatment, and care.


"Because of this success, the survivor population has been increasing," Yasui told Oncology Times. "These survivors have excess risk of death in their long adult life due to the very treatment that saved their lives through premature aging and elevated risk of chronic health conditions. In addition to the 5-year survival, it is important to consider these late effects risks and excess death after 5 years in considering our success of childhood cancer and survivorship care," Yasui said.


Annual excess death rates can better capture these late effects risks and long-term deaths. In the JCO article, Yasui and his team applied this metric to existing SEER data to show what annual excess death rates for childhood and adolescent cancers looked like in the United States from 1985 to 2016.


The measure would indicate whether survivors of childhood and adolescent cancers have similar lifespans compared with individuals without a history of cancer-or no excess risk of early death, Yasui explained. "No excess risk means complete cure."


How the Model Works

The model from Yasui's group includes three categories of excess deaths:


1. Excess deaths within the first 5 years of diagnosis (the majority of these deaths are likely related to progressive disease or acute toxicity, the authors noted in the paper)


2. Excess deaths between 5 and 10 years of diagnosis (these deaths would likely represent a mixture of recurrence or progressive disease and deaths associated with treatment exposures)


3. Excess deaths 10 or more years from diagnosis (which would likely be a result of treatment exposures, according the authors)



The SEER cohort the researchers used to model this approach included 445,647 individuals under age 20, who had been diagnosed with cancer between 1975 and 2016. The overall excess number of deaths was 126,952. There were 101,674 excess deaths within 5 years of cancer diagnosis; 10,999 excess deaths between 5 and 9.9 years after cancer diagnosis; and 14,279 excess deaths 10 or more years after cancer diagnosis.


Looking at trends year over year for these rates, the data showed:


* annual excess deaths within 5 years of diagnosis steadily declined from 1985 to 2016;


* annual excess deaths between 5 and 9.9 years after cancer diagnosis declined only modestly from 1985 and 2016; and


* annual excess deaths at 10 or more years after diagnosis increased over time, nearly canceling the reduction of annual excess deaths in the first 5 years post-diagnosis.



The researchers also modeled what the data looked like by cancer type, for which the trends differed significantly by cancer type. The data overall shows that with the refinement and advancement of cancer therapy more patients survive, but they are at greater risk of late morbidity and premature mortality, the authors noted in the paper.


Measure of Survivorship

This article is "timely and pertinent," said Christopher Weldon, MD, PhD, Associate in Critical Care Medicine in the Department of Anesthesiology, Critical Care and Pain Medicine, and Assistant in Surgery in the Department of Surgery at Boston Children's Hospital.


"Considering our results for survivors in pediatric cancer must be measured over 5 decades (plus) and not 5 years," he noted, "the time is nigh for suitable descriptors of not just survival, but 'survivorship.'"


The measure of annual excess deaths provides a more accurate measure of the "cost of cure," said Weldon, who is also Associate Professor of Surgery at Harvard Medical School. Considering the widespread use of new molecularly targeted therapies and immunotherapies in pediatric cancer, it is important to be able to measure and track long-term risks, too, he added.


"As evidenced by the overwhelming and impactful data put forth in the last 5 decades, we have become quite adept at obtaining cure in pediatric cancer patients. But at what cost? And more importantly, what measures do we have to monitor this cost as the pediatric patient ages?" Weldon said. "Far-reaching and intensive education is required for the entire medical community at large-not just oncologists."


It's usually not oncologists who are diagnosing and treating many of these long-term and late comorbidities that survivors of childhood and adolescent cancers experience decades later, Weldon noted.


It's also worth noting that measuring annual excess death rates should not be the only measure of success in managing survivors of childhood cancer. "It is also critical to assess the risks of long-term comorbidities/toxicities for individual survivors and prevent and manage these risks in our survivorship care," Yasui said.


He is part of a team conducting the Childhood Cancer Survivor Study with 32 institutions in North America, as well as the St. Jude Lifetime Cohort Study (both with the support of National Cancer Institute), to investigate these issues.


Additionally, the NCI and other researchers in the United States are working on the Childhood Cancer Data Initiative, which comprehensively collects data on childhood cancer and shares them among clinicians, patients, and researchers.


Sarah DiGiulio is a contributing writer.