Late mortality among 5‐year survivors of childhood cancer: A systematic review and meta‐analysis

Background Childhood cancer survivors are at increased risk of late mortality (death ≥5 years after diagnosis) from cancer recurrence and treatment‐related late effects. The authors conducted a systematic review and meta‐analysis to provide comprehensive estimates of late mortality risk among survivors internationally and to investigate differences in risk across world regions. Methods Health sciences databases were searched for cohort studies comprised of 5‐year childhood cancer survivors in which the risk of mortality was evaluated across multiple cancer types. Eligible studies assessed all‐cause mortality risk in survivors relative to the general population using the standardized mortality ratio (SMR). The absolute excess risk (AER) was assessed as a secondary measure to examine excess deaths. Cause‐specific mortality risk was also assessed, if reported. SMRs from nonoverlapping cohorts were combined in subgroup meta‐analysis, and the effect of world region was tested in univariate meta‐regression. Results Nineteen studies were included, and cohort sizes ranged from 314 to 77,423 survivors. Throughout survivorship, SMRs for all‐cause mortality generally declined, whereas AERs increased after 15–20 years from diagnosis in several cohorts. All‐cause SMRs were significantly lower overall in North American studies than in European studies (relative SMR, 0.63; 95% confidence interval, 0.49–0.80). SMRs for subsequent malignant neoplasms and for cardiovascular, respiratory, and external causes did not vary significantly between world regions. Conclusions The current findings suggest that late mortality risk may differ significantly between world regions, but these conclusions are based on a limited number of studies with considerable heterogeneity. Reasons for regional differences remain unclear but may be better elucidated through future analyses of individual‐level data. This systematic review and meta‐analysis demonstrated that, across international settings, childhood cancer survivors remain at an increased risk of all‐cause and cause‐specific mortality for decades after their cancer diagnosis. These findings suggest that late mortality risk might differ significantly between world regions, but these conclusions are based on a limited number of studies with considerable heterogeneity.