Dose to neuroanatomical structures surrounding pituitary adenomas and the effect of stereotactic radiosurgery on neuroendocrine function: an international multicenter study
Authors: Pomeraniec I. Jonathan , Xu Zhiyuan , Lee Cheng-Chia , Yang Huai-Che , Chytka Tomas , Liscak Roman , Martinez-Alvarez Roberto , Martinez-Moreno Nuria , Attuati Luca , Picozzi Piero , Kondziolka Douglas , Mureb Monica , Bernstein Kenneth , Mathieu David , Maillet Michel , Ogino Akiyoshi , Long Hao , Kano Hideyuki , Lunsford L. Dade , Zacharia Brad E. , Mau Christine , Tuanquin Leonard C. , Cifarelli Christopher , Arsanious David , Hack Joshua , Warnick Ronald E. , Strickland Ben A. , Zada Gabriel , Chang Eric L. , Speckter Herwin , Patel Samir , Ding Dale , Sheehan Darrah , Sheehan Kimball , Kvint Svetlana , Buch Love Y. , Haber Alexander R. , Shteinhart Jacob , Vance Mary Lee , Sheehan Jason P. 
Published: September 2021

OBJECTIVE
Stereotactic radiosurgery (SRS) provides a safe and effective therapeutic modality for patients with pituitary adenomas. The mechanism of delayed endocrine deficits based on targeted radiation to the hypothalamic-pituitary axis remains unclear. Radiation to normal neuroendocrine structures likely plays a role in delayed hypopituitarism after SRS. In this multicenter study by the International Radiosurgery Research Foundation (IRRF), the authors aimed to evaluate radiation tolerance of structures surrounding pituitary adenomas and identify predictors of delayed hypopituitarism after SRS for these tumors.

METHODS
This is a retrospective review of patients with pituitary adenomas who underwent single-fraction SRS from 1997 to 2019 at 16 institutions within the IRRF. Dosimetric point measurements of 14 predefined neuroanatomical structures along the hypothalamus, pituitary stalk, and normal pituitary gland were made. Statistical analyses were performed to determine the impact of doses to critical structures on clinical, radiographic, and endocrine outcomes.

RESULTS
The study cohort comprised 521 pituitary adenomas treated with SRS. Tumor control was achieved in 93.9% of patients over a median follow-up period of 60.1 months, and 22.5% of patients developed new loss of pituitary function with a median treatment volume of 3.2 cm3. Median maximal radiosurgical doses to the hypothalamus, pituitary stalk, and normal pituitary gland were 1.4, 7.2, and 11.3 Gy, respectively. Nonfunctioning adenoma status, younger age, higher margin dose, and higher doses to the pituitary stalk and normal pituitary gland were independent predictors of new or worsening hypopituitarism. Neither the dose to the hypothalamus nor the ratio between doses to the pituitary stalk and gland were significant predictors. The threshold of the median dose to the pituitary stalk for new endocrinopathy was 10.7 Gy in a single fraction (OR 1.77, 95% CI 1.17–2.68, p = 0.006).

CONCLUSIONS
SRS for the treatment of pituitary adenomas affords a high tumor control rate with an acceptable risk of new or worsening endocrinopathy. This evaluation of point dosimetry to adjacent neuroanatomical structures revealed that doses to the pituitary stalk, with a threshold of 10.7 Gy, and doses to the normal gland significantly increased the risk of post-SRS hypopituitarism. In patients with preserved pre-SRS neuroendocrine function, limiting the dose to the pituitary stalk and gland while still delivering an optimal dose to the tumor appears prudent.