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PurposeTo test the hypotheses that (1) the increased risk of stroke conferred by childhood cranial radiation therapy (CRT) persists into adulthood; and (2) atherosclerotic risk factors further increase the stroke risk in cancer survivors.Methods and materialsThe Childhood Cancer Survivor Study is a multi-institutional retrospective cohort study of 14,358 5-year survivors of childhood cancer and 4023 randomly selected sibling controls with longitudinal follow-up. Age-adjusted incidence rates of self-reported late-occurring (≥5 years after diagnosis) first stroke were calculated. Multivariable Cox proportional hazards models were used to identify independent stroke predictors.ResultsDuring a mean follow-up of 23.3 years, 292 survivors reported a late-occurring stroke. The age-adjusted stroke rate per 100,000 person-years was 77 (95% confidence interval [CI] 62-96), compared with 9.3 (95% CI 4-23) for siblings. Treatment with CRT increased stroke risk in a dose-dependent manner: hazard ratio 5.9 (95% CI 3.5-9.9) for 30-49 Gy CRT and 11.0 (7.4-17.0) for 50+ Gy CRT. The cumulative stroke incidence in survivors treated with 50+ Gy CRT was 1.1% (95% CI 0.4-1.8%) at 10 years after diagnosis and 12% (95% CI 8.9-15.0%) at 30 years. Hypertension increased stroke hazard by 4-fold (95% CI 2.8-5.5) and in black survivors by 16-fold (95% CI 6.9-36.6).ConclusionYoung adult pediatric cancer survivors have an increased stroke risk that is associated with CRT in a dose-dependent manner. Atherosclerotic risk factors enhanced this risk and should be treated aggressively.