Despite improvements in 5-year survival, long-term survivors of childhood cancer are at four times the risk of death compared with the general, ageing population. Using the Childhood Cancer Survivor Study (CCSS) cohort, Dr. Stephanie B Dixon of the Department of Oncology, St Jude Children’s Research Hospital in Memphis, TN, US and colleagues show that excess deaths observed among survivors, previously noted to increase more than 10 years from diagnosis, accelerate in late survivorship and are highest among those at least 40 years from diagnosis at median age of 50 years.
In contrast to 5–9 years from diagnosis when most deaths are due to the primary cancer, the excess deaths beyond 10 years from diagnosis are primarily attributable to early onset of specific, health-related causes of death commonly observed in the middle-aged population including cancer, heart disease, cerebrovascular disease, influenza and pneumonia, sepsis, and kidney failure. The findings from the most comprehensive assessment of specific causes of excess late mortality and novel associations with modifiable lifestyle and cardiovascular risk factors and excess risk of death among survivors of childhood cancer are published on 5 April 2023 in The Lancet.
The authors wrote in the background that survivors of childhood cancer have the potential to live for many decades beyond cancer. Although 5-year survival now exceeds 85% in the US, long-term survivors have excess morbidity and late mortality defined as a death beyond 5 years from cancer diagnosis compared with the general population attributable to late effects of treatment. To reduce premature mortality, a better understanding of the specific causes of and risk factors for excess late mortality compared with the general population is needed as the first generation of survivors now enter their fifth, sixth, and seventh decades of life.
A previous study using the CCSS cohort identified improvements in late mortality attributable to reductions in treatment exposures and fewer deaths from recurrence among survivors diagnosed in the 1990s compared with previous decades. Although there were substantial reductions in late occurring deaths from the primary cancer, the incremental improvement in health-related late mortality (deaths not caused by the primary cancer or external and accidental causes but including chronic health conditions acquired due to cancer treatment) was only modest.
A report using data from the Surveillance, Epidemiology, and End Results programme highlighted the importance of evaluating survival among ageing survivors using the metric of excess deaths. Despite a 20% absolute increase in 5-year survival, the total number of annual excess deaths due to childhood cancer between 1985 and 2016 was largely unchanged attributable to increase in excess deaths occurring more than 10 years from diagnosis.
Although modifiable lifestyle and cardiovascular risk factors affect risk of death in the general population, their association with late mortality risk in survivors is largely unknown. A previous study documented death in the CCSS cohort through 2007, and with an additional 10 years of observation, nearly 2000 new deaths have occurred. Through using a well-characterised cohort of 5-year survivors of the most common childhood cancers diagnosed between 1970 and 1999, the investigators evaluated specific health-related causes of late mortality and excess deaths compared with the general US population and identified targets to reduce future risk.
In this multi-institutional, hospital-based, retrospective cohort study, late mortality defined as a death ≥5 years from diagnosis and specific causes of death were evaluated in 34230 5-year survivors of childhood cancer diagnosed at an age younger than 21 years from 1970 to 1999 at 31 institutions in the US and Canada. Median follow-up from diagnosis was 29 years (range, 5–48) in the CCSS. Demographic, self-reported modifiable lifestyle (smoking, alcohol, physical activity, and body mass index) and cardiovascular risk factors (hypertension, diabetes, and dyslipidaemia) associated with health-related mortality which excludes death from primary cancer and external causes and includes death from late effects of cancer therapy were evaluated.
40-year cumulative all-cause mortality was 23.3% (95% confidence interval (CI) 22.7–24.0), with 3061 of 5916 (51.2%) deaths from health-related causes. Survivors 40 years or more from diagnosis experienced 131 excess health-related deaths per 10000 person-years (95% CI 111–163), including those due to the top three causes of health-related death in the general population: cancer (absolute excess risk per 10000 person-years 54, 95% CI 41–68), heart disease (27, 18–38), and cerebrovascular disease (10, 5–17). Healthy lifestyle and absence of hypertension and diabetes were each associated with a 20–30% reduction in health-related mortality independent of other factors (all p values ≤0.002).
The authors commented that the large size of the CCSS cohort and continued follow-up into middle-adulthood and late-adulthood has allowed this study to specifically identify the causes of death within larger categories (e.g. type of cancer or heart disease related death) and include information about the relative and absolute excess risk of death by cause compared with the general population.
Even decades from diagnosis, cancer-related therapeutic exposures are significantly associated with this increased risk of death. The study team identified that healthy lifestyle and absence of cardiovascular risk factors are independently associated with a reduced risk of death among survivors. They concluded that 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 an accompanied editorial article, Emily S Tonorezos of the Division of Cancer Control and Population Sciences, National Cancer Institute in Rockville, MD, US and Valérie Marcil of the Research Center of the Centre Hospitalier Universitaire Sainte-Justine and Department of Nutrition, Faculty of Medicine, University of Montréal, QC, Canada wrote that conditional life expectancy for this population is only 48.5 years of age among survivors diagnosed in the 1970s and 57 years among those diagnosed in the 1990s.
The latest findings provide a roadmap for reducing late mortality among childhood cancer survivors and have implications for providers, researchers, and policy makers. Strategies to reduce smoking and heavy alcohol use, and improve body weight and physical activity among childhood cancer survivors are urgently needed. Research on cancer diagnosis and treatment should routinely include long-term outcome assessments. Future efforts that include well-characterised participants and a broad assessment of health behaviours (including sleep) during long-term follow-up are needed.
This work was supported by the US National Cancer Institute grant to the CCSS and additional support to St Jude Children's Research Hospital was provided by the Cancer Center Support and the American Lebanese-Syrian Associated Charities.
References
- 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: a report from the Childhood Cancer Survivor Study cohort. The Lancet; Published online 5 April 2023. DOI: https://doi.org/10.1016/S0140-6736(22)02471-0
- Tonorezos ES, Marcil V. Childhood cancer survivors: healthy beahviours and late mortality. The Lancet; Published online 5 April 2023. DOI: https://doi.org/10.1016/S0140-6736(22)02632-0