Primary Hypothyroidism in Childhood Cancer Survivors Treated With Radiation Therapy: A PENTEC Comprehensive Review

Purpose: From the Pediatric Normal Tissue Effects in the Clinic (PENTEC) initiative, a systematic review and meta-analysis of publications reporting on radiation dose -volume effects for risk of primary hypothyroidism after radiation therapy for pediatric malignancies was performed. Methods and Materials: All studies included childhood cancer survivors, diagnosed at age <21 years, whose radiation therapy fields exposed the thyroid gland and who were followed for primary hypothyroidism. Children who received pituitaryhypothalamic or total -body irradiation were excluded. PubMed and the Cochrane Library were searched for studies published from 1970 to 2017. Data on age at treatment, patient sex, radiation dose to neck or thyroid gland, specific endpoints for hypothyroidism that were used in the studies, and reported risks of hypothyroidism were collected. Radiation dose -volume effects were modeled using logistic dose response. Relative excess risk of hypothyroidism as a function of age at treatment and sex was assessed by meta-analysis of reported relative risks (RR) and odds ratios. Results: Fifteen publications (of 1709 identified) were included for systematic review. Eight studies reported data amenable for dose-response analysis. At mean thyroid doses of 10, 20, and 30 Gy, predicted rates of uncompensated (clinical) hypothyroidism were 4%, 7%, and 13%, respectively. Predicted rates of compensated (subclinical) hypothyroidism were 12%, 25%, and 44% after thyroid doses of 10, 20, and 30 Gy, respectively. Female sex (RR = 1.7, P < .0001) and age >15 years at radiation therapy (RR = 1.3, P = .005) were associated with higher risks of hypothyroidism. After a mean thyroid dose of 20 Gy, predicted risks of hypothyroidism were 13% for males <14 years of age, increasing to 29% for females >15 years of age. Conclusion: A radiation dose response for risk of hypothyroidism is evident; a threshold radiation dose associated with no risk is not observed. Thyroid dose exposure should be minimized when feasible. Data on hypothyroidism after radiation therapy should be better reported to facilitate pooled analyses.