Survivors had higher prevalence of new cancers or chronic health conditions than their siblings.
Older survivors of childhood cancer remain at risk for poor health outcomes well into middle age, according to study results.
Survivors aged 50 years or older exhibited elevated risk for premature mortality or new incident cancers compared with cancer-free controls.
They also had higher prevalence of chronic health conditions and frailty than their siblings.
Risk for comorbidities correlated with radiation exposure but no other form of treatment.
"Thanks to more effective treatments and supportive care strategies, childhood cancer survivors are living much longer than those who were diagnosed 4 or 5 decades ago," Rusha Bhandari, MD, MS, pediatric hematologist-oncologist at City of Hope, told Healio. "The opportunity to study an older population of survivors who are 30 or 40 years out from treatment is very important, as it helps us learn the risks they face as they get older, as well as how the treatment they had as a child might impact those risks much later in adulthood."
More than 511,000 survivors of childhood or adolescent cancers lived in the United States as of 2021, according to NCI statistics.
Prior studies demonstrated childhood cancer survivors have higher risk for mortality than the general population. They also are more likely than those without cancer to experience long-term health problems, including diabetes or other endocrine conditions, cardiovascular disease or musculoskeletal conditions.
However, most evidence related to these risks came from analyses of younger survivors of childhood cancer.
Limited data exist about risk for mortality or poor health outcomes among childhood cancer survivors as they move into the sixth decade of life, when development of aging-related comorbidities -- including cancer -- increases considerably in the general population.
Bhandari and colleagues assessed cause-specific mortality, chronic health conditions, incidence of new cancers and other health status measures among participants of the Childhood Cancer Survivor Study, a multi-institutional, retrospective research effort intended to improve understanding of long-term effects of pediatric cancer.
The researchers also examined if these risks were related to receipt of radiation therapy or chemotherapy.
Investigators calculated standardized mortality ratios (SMR), as well as standardized incidence ratios (SIR) and relative rates (RR) of new incident cancers, to compare survivors with the general U.S. population. They calculated RRs for chronic health conditions, as well as prevalence ratios for health status outcomes and frailty, to allow comparisons between survivors and their siblings.
The mortality analysis included 7,490 survivors who lived to age 50 years. Nearly 12% (n = 897) had died by data cutoff.
After age 50, subsequent mortality risks among survivors reached 8.6% (95% CI, 7.8%-9.3%) at 5 years, 18.4% (95% CI, 17%-19.7%) at 10 years and 32.7% (95% CI, 30%-35.4%) at 15 years. These rates appeared "considerably higher" than would be expected for the general population, researchers wrote.
"It's striking to see this divergence in the mortality curves even beyond age 50, which is a time when we start to see more health problems among aging individuals in the general population," Bhandari said.
Results showed an overall SMR of 3.2 (95% CI, 3-3.4). Hodgkin lymphoma survivors exhibited the highest relative and excess mortality risks (SMR = 5.5; 95% CI, 5-6.1; absolute excess risk, 30.2; 95% CI, 26.7-33.9).
Researchers identified subsequent malignant neoplasm as the most common cause of death among survivors (SMR = 4.7; 95% CI, 4.2-5.2).
Approximately 7.6% of evaluable survivors developed subsequent malignant neoplasms. Their risks exceeded those of the general population regardless of age.
Survivors had higher risks for multiple cancer types, including bone or soft tissue (SIR = 13; 95% CI, 7.3-21.4), hematologic (SIR = 2.7; 95% CI, 1.8-3.9), thyroid (SIR = 2.6; 95% CI, 1.4-4.4) and breast cancers (SIR = 2.1; 95% CI, 1.6-2.7).
Approximately 40% of new cancers among survivors could be attributed to receipt of radiation therapy, according to investigators.
Survivors who had not been exposed to radiation therapy had comparable rates of subsequent cancers as the general population. Results showed no significant association between chemotherapy exposure and subsequent malignant neoplasms.
Researchers used a subgroup of 2,723 evaluable survivors to analyze additional health outcomes.
Survivors had more than double the risk for any (RR = 2.6; 95% CI, 2.2-3.1) or multiple (RR = 3.3; 95% CI, 2.5-4.4) severe, life-threatening or fatal chronic health conditions compared with their siblings. Survivors exposed to radiation therapy had significantly greater magnitudes of risk.
Cumulative incidence of any grade 3 to grade 5 chronic health condition increased with age (age 50, 60.7% for survivors vs. 23% for siblings; age 65, 79.2% for survivors vs. 41.7% for siblings).
Survivors also had higher incidence than siblings of multiple grade 3 to grade 5 chronic health conditions (age 50, 30% vs. 6%; age 65, 55.2% vs. 17.1%).
Adjusted analyses showed survivors had higher risks than siblings for frailty (prevalence ratio = 2.3; 95% CI, 1.5-3.7), physical limitation (prevalence ratio = 2.3; 95% CI, 1.8-2.9), functional impairment (prevalence ratio = 2.1; 95% CI, 1.5-2.9) and poor general health (prevalence ratio = 1.6; 95% CI, 1.2-2.1).
Results showed an association between only one treatment exposure -- chest radiation -- and frailty risk.
"For both subsequent malignant neoplasms and chronic health conditions, the fact that most of the increased risk was associated with radiation exposure is very important to note, as it helps us understand which survivors may be at the greatest risk for these outcomes," Bhandari said.
The findings highlight the importance of communication between childhood cancer survivors and their health care providers to ensure appropriate long-term follow-up and adherence to screening guidelines.
"This is an integral component of patient care as they progress further beyond cancer treatment," Bhandari said. "It is critical that their primary care provider is aware of their prior diagnosis and treatment history. Ideally, patients also will stay connected with a survivorship program, as that team can be in contact with the primary care provider and educate and empower the patient to make sure they have the information they need."
The rapid evolution of cancer treatments -- including the adoption of immunotherapy and cellular therapy, the ability to de-escalate treatment by eliminating or reducing radiation doses when possible, and the need to intensify therapy for some harder-to-treat cancers -- support continued research into outcomes and risks among childhood cancer survivors who completed treatment more recently, Bhandari said.
She also wants to conduct further research into the effects of aging on health outcomes among cancer survivors.
"Cancer survivors show signs of accelerated aging. A considerable number of them have cardiovascular conditions or diabetes in their 20s or 30s, when you'd typically expect to see that among older individuals," Bhandari said. "There is a great deal of interest in better understanding how diagnosis and treatment impact the aging process, as well as what we can do to mitigate that, and this will be an important area of future research."