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Survivors of childhood cancer had a fourfold higher risk of mortality decades after their diagnosis, typically from the same leading causes of death afflicting the general U.S. population, a report from the Childhood Cancer Survivor Study (CCSS) showed.

The 40-year all-cause mortality rate was 23.3% among the more than 34,000 pediatric cancer patients who had survived at least 5 years from the time of their diagnosis, compared with the under 5% rate expected in the general population, reported Stephanie Dixon, MD, of St. Jude Children's Research Hospital in Memphis, Tennessee, and colleagues in .

By 40 years from the time of diagnosis, survivors experienced 138 excess deaths per 10,000 person-years, of which 131 were attributable to health-related causes, including those due to the top three causes of mortality:

• Cancer: 54 excess deaths per 10,000 person-years
• Heart disease: 27 excess deaths per 10,000 person-years
• Cerebrovascular disease: 10 excess deaths per 10,000 person-years

Although 5-year survival after childhood cancer has improved dramatically over the past 50 years, "it is well known that cancer and cancer treatment contribute to an increased risk of late morbidity and mortality among long-term survivors," Dixon and her colleagues wrote. They observed that while this study showed that many of the causes of death experienced in late survivors are the same as the major causes of death in the general U.S. population, "survivors are dying at a younger and higher rate."

However, the researchers found that when survivors were stratified by lifestyle score and cardiovascular risk factors, the excess risk of health-related death was lowest in the survivors with a healthy lifestyle.

In multivariable models adjusted for therapy exposures and sociodemographic factors, a healthy versus unhealthy lifestyle was associated with a 20% decreased risk of health-related mortality independent of traditional cardiovascular risk factors. Meanwhile, a moderately healthy lifestyle was associated with a 10% decreased risk.

The absence of reported hypertension or diabetes were each associated with a 30% decreased risk of health-related mortality overall, including a 30% to 50% decreased risk of cardiac mortality, independent of lifestyle and other cardiovascular risk factors.

"Fortunately, the potential exists to mitigate this risk by healthy lifestyle and absence of traditional cardiovascular risk factors," wrote Dixon and colleagues. "Continued reductions in intensity of primary cancer therapy and future research targeting interventions for modifiable lifestyle and cardiovascular risk factors in survivors could offer an opportunity to reduce morbidity and extend the lifespan for survivors."

In a , Emily Tonorezos, MD, MPH, of the National Cancer Institute in Rockville, Maryland, and Valérie Marcil, RD, PhD, of the University of Montreal, said the findings "provide a roadmap for reducing late mortality among childhood cancer survivors and have implications for providers, researchers, and policymakers."

"Although advances in treatment continue to improve prognosis for children diagnosed with cancer, health-related late mortality must be reduced to have a lasting effect," they continued. "Clearly, strategies to reduce smoking and heavy alcohol use, and improve body weight and physical activity among childhood cancer survivors are urgently needed."

The CCSS cohort in the study included 34,230 pediatric cancer patients who were 5-year survivors. They were diagnosed between 1970 and 1999 from 31 participating centers in the U.S. and Canada. The study had a median follow-up from diagnosis of 29 years.

Within the study population, there were 5,916 deaths, with 34.0% attributable to recurrence or progression of the primary cancer and 51.2% attributable to health-related causes other than recurrence.

Compared with the general population, survivors were at elevated risk of death (standardized mortality ratio 5.6, 95% CI 5.4-5.7) with an 18-fold increased risk at 5 to 9 years from diagnosis that eventually plateaued at about a fourfold increased risk at 20 years after diagnosis.

Absolute excess risk differed by diagnosis. For instance, survivors of acute lymphoblastic leukemia had fewer than 100 excess deaths per 10,000 person-years at all follow-up timepoints, while Hodgkin lymphoma survivors saw their risk of late mortality increase (from 100 excess deaths per 10,000 person-years 25 years from diagnosis, to nearly 400 per 10,000 person-years 40 years or more from diagnosis).

Importantly, specific treatment exposures were independently associated with dose-dependent mortality, and increased risk for all-cause and health-related mortality. Dixon and her colleagues noted that 30 years after diagnosis, alkylator chemotherapy and radiation exposure to the brain or chest were significantly associated with increased all-cause and health-related mortality, and anthracycline chemotherapy with cardiac-specific mortality.

"[C]hanges in primary cancer therapy that reduce exposure to treatments known to cause late effects decades after treatment should remain a priority," they observed.

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