Endocrinopathy After Treatment for Medulloblastoma: Results From the SJMB03 Trial of Risk-Adapted Radiation Therapy

Abstract

The objective of this study was to estimate the cumulative incidence of endocrinopathy in pediatric patients treated for medulloblastoma with surgery, risk-adapted photon craniospinal irradiation, and dose-intensive chemotherapy. Children and adolescents (n=156) treated between 2003 and 2013 were evaluated for evidence of endocrinopathy. Clinical information and mean radiation dose to hypothalamus and thyroid were calculated and used to estimate cumulative incidence of growth hormone deficiency, hypothyroidism, adrenal insufficiency, hypogonadism, and precocious puberty. The 5-year cumulative incidences were estimated for growth hormone deficiency, 68.9% (60.9%, 75.6%); hypothyroidism, 48.4% (95% confidence interval (CI), 40.2%-56.1%); adrenal insufficiency, 13.0% (95% CI, 8.3%-18.9%); hypogonadism, 33.9% (95% CI, 25.2%-42.7%); and precocious puberty, 2.0% (95% CI, 0.6%-5.4%). Growth hormone deficiency was associated with increased hypothalamus dose (hazard ratio [HR], 1.035; 95% CI, 1.010-1.061; P=.0055) in average-risk patients and cerebrospinal fluid shunt (HR, 2.532; 95% CI, 1.325-4.838; P=.0049) in high-risk patients. In average-risk patients, hypothyroidism was associated with younger age (HR, 0.902; 95% CI, 0.842-0.973; P=.0070), hypothalamus dose (HR, 1.039; 95% CI, 1.004-1.075; P=.0273), and thyroid dose (HR, 1.070; 95% CI, 1.008-1.136; P=.0263). In high-risk patients, hypothyroidism was associated with increased hypothalamus dose (HR, 1.068; 95% CI, 0.995-1.147; P=.0671) and thyroid dose (HR, 1.050; 95% CI, 1.000-1.104; P=.0515). Adrenal insufficiency was associated with increased hypothalamus dose (HR, 1.112; 95% CI, 1.058-1.170; P < .0001). Growth hormone deficiency incidence was higher when comparing patients treated with cerebrospinal fluid shunt versus those not having a shunt/extraventricular drain placed during initial surgery (HR, 1.712; 95% CI, 1.109-2.643). Incidence and time to onset of clinically significant endocrinopathy after photon craniospinal irradiation for pediatric medulloblastoma is influenced by radiation dose to target organs and patient age at time of treatment. Advanced radiation therapy methods and dose-reduction strategies are needed to reduce the incidence of endocrinopathy.