Survivors of childhood cancer who reach the age of 50 and beyond show continued elevated risks for premature mortality, subsequent cancers, and other chronic health conditions, according to a report published in the Journal of Clinical Oncology.1 When compared with the general population or sibling controls, risks for such health consequences were increased, especially among survivors who had been exposed to radiotherapy.
The findings come from extended follow-up data reported in the Childhood Cancer Survivor Study and represent the first comprehensive evaluation of morbidity and mortality among older survivors of childhood cancer.
Rusha Bhandari, MD, MS, and co-authors believe that the findings highlight the importance of continued surveillance and risk-based screening for late effects in survivors of childhood cancer, even as they age, as well as timely intervention to improve outcomes.
Rusha Bhandari, MD, MS
“We highlight the need for ongoing surveillance and early intervention for chronic health conditions, in addition to risk-based screening for subsequent malignant neoplasms, frailty, and adverse health status in survivors in this older age range [ie, 50 and older],” Bhandari et al wrote in their published report. Dr. Bhandari is a pediatric hematologist-oncologist at City of Hope in Duarte, California. “We also provide early evidence suggesting that the overall risk of subsequent malignant neoplasms and chronic health conditions in older survivors treated without radiotherapy is comparable with the general population, which is reassuring and supports the need to continue reducing radiotherapy exposure to improve long-term morbidity and mortality.”
Background
Survivors of cancer represent a growing population. A recent report indicated that there are about 18.6 million people living with a history of cancer in the United States, and that number is expected to grow to more than 22 million by 2035.2
Survivors of childhood cancer, specifically, are also expected to live longer,3 despite an increased risk for mortality beyond cancer relapse. Most data to date, however, have focused on outcomes of survivors of childhood cancers in earlier years.
The Childhood Cancer Survivor Study is a retrospective, multi-institution cohort study of 37,577 5-year survivors of childhood cancer.4,5 All participants in the study were diagnosed with childhood cancer before the age of 21 between 1970 and 1999. Of these participants, 7,490 had survived to 50 years or older. In the study, participants were asked to complete questionnaires at baseline and throughout follow-up.
Study Methods
The researchers explored data from the 7,490 eligible older survivors, including the 2,920 individuals who had completed a follow-up questionnaire at the age of 50 or beyond.1
They compared overall and cause-specific mortality as well as the development of subsequent malignancies in survivors older than 50 years with the general population. They also looked at chronic health conditions and health status in survivors in comparison with their siblings older than 50.
In addition, they explored the population with subsequent malignancies that could be attributed to radiation exposure.
Study Findings
A total of 897 (12%) of the 7,490 survivors died after age 50. Mortality risk was 8.6% over 5 subsequent years (95% confidence interval [CI] = 7.8%–9.3%); 18.4% over 10 years (95% CI = 17.0%–19.7%); and 32.7% over 15 years (95% CI = 30.0%–35.4%). By 15 years after age 50, about one-third of these survivors had died, which is a higher proportion than would be expected in the general population of the same age and sex.
The most common cause of death was a subsequent malignancy, with respiratory cancers being the most common (6%).
The overall standardized mortality ratio was 3.2 (95% CI = 3.0–3.4), but survivors of childhood Hodgkin lymphoma had greater risks (standardized mortality ratio = 5.5; 95% CI = 5.0–6.1; absolute excess risk = 30.2; 95% CI = 26.7–33.9) across all ages. Standardized mortality ratios were highest for deaths due to subsequent malignant neoplasms overall; however, the highest standardized mortality ratio differed by sex, with subsequent malignant neoplasms highest among males and cardiovascular disease highest among females.
Among the 2,920 older survivors who completed the questionnaires, 7.6% developed a subsequent malignant neoplasm after age 50. The risk for a subsequent malignant neoplasm exceeded that of the general population across all age groups. Survivors of childhood cancers were more likely to develop subsequent bone and soft tissue, thyroid, hematologic, breast, gastrointestinal, and pulmonary cancers compared with the general population.
There was a statistically significant greater risk for a secondary malignancy among those who had received radiotherapy as part of their cancer treatment. Forty percent of all subsequent malignant neoplasms occurring in survivors at or after age 50 were attributable to prior radiation therapy. Both standardized incidence ratios and absolute excess risks indicated a significantly increased risk of subsequent malignant neoplasms among survivors who received radiotherapy, whereas survivors without radiotherapy exposure had risks comparable to the general population. Notably, no subsequent lung or bronchus malignancies were reported among survivors without a history of radiation exposure.
No significant associations were observed between the development of subsequent malignancies and exposure to chemotherapy.
Among survivors who answered additional health outcome questionnaires at age 50 or beyond (n = 2,723), 60.7%and 79.2% showed chronic health conditions of grade 3 to 5 at age 50 and age 65, respectively. Comparatively, the cumulative incidence rates of grade 3 to 5 chronic health conditions among siblings were 23.0% and 41.7% at ages 50 and 65, respectively. By age 55, 39.5% of survivors of childhood cancer had a cumulative incidence of multiple grade 3 to 5 chronic health conditions, which exceeded the 28.3% incidence rate among siblings at age 70.
Adjusted models showed a relative risk of 2.6 (95% CI = 2.2–3.1) for a survivor developing any grade 3 to 5 chronic health condition, and of 3.3 (95% CI = 2.5–4.4) for developing multiple conditions compared with siblings. The risk for developing a chronic health condition was statistically significantly greater among survivors treated with radiation therapy.
Survivors were also more likely than siblings to report frailty, poor general health, physical limitations, and functional impairment (P < .001). However, they were not more likely than siblings to report poor mental health. Only chest radiation therapy was associated with an increased risk for frailty among survivors in adjusted analyses.
Greater Context
“Even decades after cancer treatment, these survivors continue to have a higher risk of morbidity and mortality attributable to radiotherapy compared with the general population. The overall burden of these late outcomes more closely approximates the general population, with relative magnitudes of risk less than what has been reported for younger survivor cohorts as these survivors enter the life stage when age-related health problems increase for all people,” the study authors noted. They indicated that the survivors of childhood cancer who reached 50 years or older, with a median of 44 years from their initial cancer diagnosis, had a threefold relative risk of mortality; younger survivors who had a median of 29 years from their diagnosis had a sixfold risk for mortality.1,5
“This likely reflects the increased background risk of mortality, subsequent malignant neoplasms, and other chronic comorbidities in the general aging population, which may contribute to lower relative risks, or reflect more resilient host, disease, and treatment characteristics of cancer survivors who survived to 50 years and were included in these analyses,” Bhandari et al commented.
Older survivors without prior radiation therapy had comparable rates of subsequent malignancies as the general population, meaning that the risk for secondary cancers can normalize over time. The association between radiation exposure and subsequent malignancies has led to changes in childhood cancer treatment approaches, where possible, to reduce these long-term risks. Risks for subsequent malignancies related to chemotherapy exposure, on the other hand, seem to be restricted to earlier years in a survivor’s lifetime.
Future studies are still needed to evaluate the later morbidity burden in more contemporary survivors of childhood cancer who received more modern treatment strategies and to incorporate a wider variety of childhood cancer diagnoses.
DISCLOSURE: The study was supported by grants from the National Cancer Institute, Cancer Center Support, and the American Lebanese Syrian Associated Charities. For full study author disclosures, visit ascopubs.org.
REFERENCES
1. Bhandari R, et al: Health outcomes beyond age 50 years in survivors of childhood cancer. J Clin Oncol 43:2998-3010, 2025.
2. Wagle NS, et al: 2025. CA Cancer J Clin 75:308-340, 2025.
3. Armstrong GT, et al: N Engl J Med 374:833-842, 2016.
4. Robison LL, et al: J Clin Oncol 27:2308-2318, 2009.
5. Dixon SB, Liu Q, Chow EJ, et al: Specific causes of excess late mortality and association with modifiable risk factors among survivors of childhood cancer. Lancet 401:1447-1457, 2023.
EXPERT POINT OF VIEW
Laura Tenner, MD, MPH, Medical Director of the Cancer Survivorship Program, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, shared these comments on the findings from the Childhood Cancer Survivor Study reported by Bhandari et al.1
“This study highlights the importance of giving as much therapy as is needed for the treatment and cure of cancer but no more. As we continue to see the number of cancer survivors rise with improved screening strategies and new treatments across the globe, the study and understanding of the long-term effects of those therapies continue to play a significant role in better informing not only long-term cancer survivorship care, but also the initial treatment of [patients with] those cancers. Because of efforts like the Childhood Cancer Survivor Study, treatment for childhood cancer has been modified over time in an effort to reduce subsequent neoplasm risks as well as other health risks. Radiation dosing and usage in childhood cancers has continued to decline over the last 5 decades.2-4
Laura Tenner, MD, MPH
“This study reports long-term health effects data from childhood survivors who were treated in the 1970s through the 1990s and are now over 50 years. Radiation therapy continues to play a statistically significant role in the increased risk of subsequent malignant neoplasms in patients over 50, while there was no significant association with specific chemotherapies, which played a role in increased risk of subsequent malignant neoplasms earlier in the survivorship period.
“More evidence is needed over time to see if the trends in decreasing radiation dosages and therapy over the last 5 decades will significantly impact the increased risk of subsequent malignant neoplasms for survivors [of childhood cancer] once they reach their sixth decade of life and beyond. As this study relied on the participation of patients to complete a follow-up questionnaire, the authors recognize the participation bias inherent in this study. As we move into the era of big data, real-time analysis of subsequent malignant neoplasms and chronic health conditions of all childhood cancer survivors may be made more accessible. Furthermore, diagnosis in younger children, such as those with Wilms tumors and leukemias, were underrepresented in this study as they had not yet reached the appropriate age to participate in the study. Further follow-up data should be collected on these populations.
“In terms of other health outcomes, survivors of childhood cancer had accumulated an incidence of more severe chronic health conditions at the age of 55 years than the incidence rate of their 70-year-old siblings. Survivors were more likely to report frailty, poor general health, physical limitations, and functional impairment, but not poor mental health. This highlights the need for further interventional childhood cancer survivorship studies focused on physical fitness and improvement of general health screenings in this population.
“Finally, females had a higher magnitude of risk of all-cause and cause-specific mortality than males, with higher standardized mortality ratios for cardiovascular causes of death. Additional studies are needed to evaluate primary ovarian insufficiency and cardiovascular risk, as well as other biological or care delivery causes. Studies have shown women are less likely to receive bystander cardiopulmonary resuscitation or receive cardiac intervention post–cardiac arrest.5 As women in the general population have a considerably lower incidence of sudden cardiac death than men, the vast majority of data are predominantly male-derived. Health-care providers should be aware that female childhood cancer survivors over the age of 50 are at a much higher risk than the general population of dying from cardiac events, so appropriate screenings and treatments for this population should be further studied and identified.”
Additional Perspectives
“This article underscores one of the key strengths of the Childhood Cancer Survivorship Study, namely its ability to provide a comprehensive and robust longitudinal framework through which the long-term morbidity and mortality of pediatric and adolescent cancer survivors can be systematically evaluated,” commented Jill P. Ginsberg, MD, Director of the Cancer Survivorship Program at Children’s Hospital of Philadelphia. “By leveraging decades of follow-up data from a large, diverse cohort, the study enables researchers to identify patterns of late effects, assess risk factors that contribute to adverse outcomes, and generate evidence that directly informs clinical guidelines and survivorship care strategies.
Jill P. Ginsberg, MD
“Radiation exposure continues to play a substantial role in the development of secondary malignancies among survivors over the age of 50. This persistent risk underscores not only the importance of minimizing radiation use, whenever clinically feasible, but also the urgency of advancing and implementing alternative anticancer strategies—such as targeted therapies, immunotherapies, and precision-based modalities—that can achieve durable disease control while mitigating long-term toxicity associated with radiation therapy.”
DISCLOSURE: Dr. Tenner has served as a consultant or advisor for Curio Science and has received travel expenses from Curio Science. Dr. Ginsberg reported no conflicts of interest.
REFERENCES
1. Bhandari R, Chen Y, Chow EJ, et al: Health outcomes beyond age 50 years in survivors of childhood cancer: A report from the childhood cancer survivor study. J Clin Oncol 43:2998-3010, 2025.
2. Jairam V, Roberts KB, Yu JB: Historical trends in the use of radiation therapy for pediatric cancers: 1973-2008. Int J Radiat Oncol Biol Phys 85:e151-e155, 2012.
3. Turcotte LM, Liu Q, Yasui Y, et al: Temporal trends in treatment and subsequent neoplasm risk among 5-year survivors of childhood cancer, 1970-2015. JAMA 317:814-824, 2017.
4. Bryant AK, Banegas MP, Martinez ME, et al: Trends in radiation therapy among cancer survivors in the United States, 2000–2030. Cancer Epidemiol Biomarkers Prev 26:963-970, 2017.
5. Butters A, Arnott C, Sweeting J, et al: Sex disparities in sudden cardiac death. Circ Arrhythm Electrophysiol. 14:e009834, 2021.
