Methodological extensions of meta-analysis with excess relative risk estimates: application to risk of second malignant neoplasms among childhood cancer survivors treated with radiotherapy

Although radiotherapy is recognized as an established risk factor for second malignant neoplasms (SMNs), the dose response of SMNs following radiotherapy has not been well characterized. In our previous meta-analysis of the risks of SMNs occurring among children who have received radiotherapy, the small number of eligible studies precluded a detailed evaluation. Therefore, to increase the number of eligible studies, we developed a method of calculating excess relative risk (ERR) per Gy estimates from studies for which the relative risk estimates for several dose categories were available. Comparing the calculated ERR with that described in several original papers validated the proposed method. This enabled us to increase the number of studies, which we used to conduct a meta-analysis. The overall ERR per Gy estimate of radiotherapy over 26 relevant studies was 0.60 (95%CI: 0.30–1.20), which is smaller than the corresponding estimate for atomic bomb survivors exposed to radiation as young children (1.7; 95% CI: 1.1–2.5). A significant decrease in ERR per Gy with increase in age at exposure (0.85 times per annual increase) was observed in the meta-regression. Heterogeneity was suggested by Cochran's Q statistic (P < 0.001), which may be partly accounted for by age at exposure.