Endocrine Deficiency As A Function Of Proton Radiation Dose To The Hypothalamus In Children With Brain Tumors

A relationship between RT dose and risk of endocrine dysfunction has been described for children treated with photon RT, however, this has not been examined thoroughly in children treated with proton RT, with some expressing concerns about a higher relative biological effect of proton RT on normal brain tissue. We examined the effect of RT dose to the hypothalamus on development of endocrine dysfunction in children with brain tumors treated with proton RT, and evaluated other factors that affect the risk of endocrine dysfunction. Dosimetric and clinical data was collected from pediatric patients with brain tumors treated with proton RT on 3 prospective single institution clinical trials (2010-2014) and a retrospective registry from 2002-2014 with a minimum of 2 years of follow up. Patients had a pre-treatment endocrine evaluation and were followed yearly by a pediatric endocrinologist, and monitored for clinical and serological evidence of thyroid, growth hormone (GH), cortisol, and sex hormone dysfunction. Hypothalamus and pituitary were contoured on all planning CT scans and dose statistics, including D90, D10, median, and mean dose were collected at the time of treatment planning. Incidence of endocrine deficiency over time was estimated using the Kaplan-Meier method, and multivariate analysis was conducted using a binary logistic regression model. One hundred eighteen patients were evaluable (60% male; 40% female) with a median follow up of 3.4 yrs (range, 2-11 yrs). Medulloblastoma (73%, n = 86) was the most common diagnosis, with all receiving CSI and boost. All other patients received partial brain RT (n = 32), with the most common diagnoses of ependymoma (9.3%, n = 11), glioma (7.6%, n = 9), and craniopharyngioma (3.4%, n = 4). GH deficiency was the most common endocrinopathy (48%), followed by cortisol (21%), thyroid (20%), and sex hormone deficiency (16%). For patients receiving partial brain RT, median hypothalamic dose ≥50 GyE was associated with a rate of 64% for GH deficiency and 45% for thyroid deficiency. Patients with a median hypothalamic dose <50 GyE did not develop GH or thyroid deficiency. Patients with a diagnosis of medulloblastoma who received CSI and concurrent chemotherapy developed higher rates of endocrine deficiency with a hypothalamic dose of 35-40 GyE associated with a higher risk. D90, D10, mean hypothalamic dose, and median pituitary dose correlated with median hypothalamic dose and were not independent predictors of outcome. Hypothalamic tolerance to proton RT is comparable to previously reported values for photons. In addition to RT dose, a diagnosis of medulloblastoma with CSI and concurrent chemotherapy were associated with an increase in risk for endocrine dysfunction in children treated with proton RT for brain tumors.