Radiation-Induced Hypopituitarism in Cranial Base Malignancies: Clinical Outcomes, Screening, and Dosimetric Analysis

Background Management of sinonasal and cranial base malignancies requires a comprehensive multimodal approach. High-dose radiation, often exceeding 60 Gy, is required to provide therapeutic effects to the skull base. Sequelae of radiation are well described for head and neck cancer patients; however, the effects of high-dose radiation on the pituitary function in this patient population remain poorly described, with no widely accepted screening protocols. We aim to describe a comprehensive screening protocol and characterize the clinical effects of pituitary dysfunction after cranial base irradiation while detailing the radiation profiles of these patients.

Methods A retrospective review of patients prospectively enrolled in a skull base registry from June 2012 to June 2015 at an academic tertiary care center was performed. All patients had a history of ventral skull base malignancy and external beam radiation to the primary site. Exclusion criteria were the absence of comprehensive posttreatment pituitary serologies and less than 1 year of postradiation follow-up. Routine yearly pituitary screening was initiated at our institution during the study period for all patients with ventral skull base irradiation for malignancies. Serologies were reviewed by the senior endocrinologist to identify clinical hypopituitarism. Dosimetric analysis for all patients treated with radiation at the primary study center was then performed to quantify dosing patterns to the sella and correlate with clinical disease.

Results A total of 103 patients with anterior cranial base malignancies who received radiation enrolled in the registry during this time period, with 81 patients having comprehensive post-treatment pituitary laboratories. Thirty patients (37%) demonstrated evidence of hypopituitarism. Twenty-four (29%) of patients screened showed evidence of central hypogonadism, and 16% of patients showed central hypothyroidism. Ten patients (12%) had evidence of central adrenal insufficiency with six patients demonstrating panhypopituitarism. A statistically significant relationship was seen when evaluating primary tumor subsite and incidence of hypopituitarism. Tumors of both sphenoid and ethmoid origin were statistically more likely to display dysfunction compared with tumors of orbital or maxillary origin (p = 0.04). Dosimetric analysis revealed a linear correlation of dosing to the sella and incidence of hypopituitarism approaching statistical significance (p = 0.07).

Conclusion Radiation for malignancies of the anterior skull base resulted in a 37% incidence of hypopituitarism in our population and can be strongly correlated to tumor subsite and radiation dose delivered to the sella. Given the potential morbidity and delayed effects of radiation, we recommend routine post-treatment pituitary function screening in these patients, such as the protocol described. Subsite and dosing data can help predict patients at highest risk, though further studies will be needed to better define risk factors. We recommend updating clinical guidelines to reflect the necessity of this screening.