Introduction: Post-operative radiotherapy has been shown to improve tumor control and recurrence-free survival in patients with pituitary adenomas. However, due to the potential for complications and long-term side effects, the role of adjuvant radiotherapy in this setting remains unclear. This study aims to address this gap in the clinical management of patients with pituitary adenomas, and to determine the efficacy and safety of post-operative radiotherapy.

Methods: PubMed, MEDLINE and Cochrane databases were searched, with no language or publication date restrictions. Studies were included if they reported on patients treated post-operatively with any form of radiation therapy. Studies reporting on both functioning and non-functioning pituitary adenomas were included. Forest plots were generated to determine a pooled event rate and 95% confidence interval (CI) for each outcome using a random effect model analysis.

Results: A total of 89 studies from 1986-2017 met the inclusion criteria, consisting of 7679 cumulative patients. Studies included patients with functioning adenomas only (n=24), non-functioning adenomas only (n=31) or both (n=36). The median age of all patients was 50 years, with a median follow-up duration of 60 months across all studies. The cumulative 5- and 10-year progression-free survival rates were 90.8% (95% CI 86-94%) and 88.6% (95% CI 81-93%), respectively. The overall adverse events rate was 8% (95% CI 5-12%). All outcomes were associated with significant heterogeneity (I2 = 70%). There were no differences in survival rates or adverse events in relation to study date, tumor pathology, radiosurgery system used or dose of radiation.

Conclusions: This study is one of the largest and most comprehensive surveys of the literature pertaining to adjuvant radiotherapy for pituitary adenomas. Our findings demonstrate that post-operative radiotherapy for pituitary adenomas is effective and safe. Further prospective studies are needed to delineate specific rates of adverse outcomes, as well as the optimal timing of administration of post-operative radiotherapy.

Patient Care: This systematic review and meta-analysis is one of the largest and most inclusive analyses in the literature. We have synthesized existing data across multiple international patient cohorts to gain a better understanding of the efficacy and safety of radiotherapy for pituitary adenomas in the post-operative setting. Our findings highlight the efficacy of all radiotherapy modalities in achieving high rates of progression-free survival and tumor control. This is an important consideration for the use of adjuvant treatments in resource-limited settings. We further demonstrate that radiosurgical modalities such as SRS and FSRT are tools that neurosurgeons can utilize in this setting to achieve high rates of tumor control with lower overall rates of adverse effects, such as visual deficits and pituitary insufficiency. These findings also identify important gaps in the clinical management of patients with pituitary adenomas, particularly in relation to the optimal timing of radiation administration. The results from this study support an individualized approach to adjuvant therapy, while providing evidence for a benefit of early post-operative radiotherapy in the setting of partial and subtotal resections. Taken together, the findings from this study will improve patient care by providing a refined analysis to the overall neurosurgical approach to patients with pituitary adenomas.

Learning Objectives: 1. Gain an understanding of the neurosurgical management of functioning and non-functioning pituitary adenomas and basic surgical approaches 2. Learn about the various radiation therapy modalities available as tools to neurosurgeons for the use of adjuvant therapy in the setting of pituitary adenomas 3. Gain an understanding of the indications and limitations to various radiotherapy modalities, including patient-specific considerations and adverse effects 4. Learn about the current landscape of literature surrounding the use of adjuvant radiation in the post-operative setting 5. Develop a framework for treating patients with functioning and non-functioning pituitary adenomas, with a multi-disciplinary approach to adjuvant therapies to achieve optimal long-term tumor control rates

References: Ayuk J, Stewart PM. Mortality following pituitary radiotherapy, Pituitary 12 (2009) 35–39. Brochier S, Galland F, Kujas M, Parker F, Gaillard S, Raftopoulos C, et al: Factors predicting relapse of nonfunctioning pituitary macroadenomas after neurosurgery: a study of 142 patients. Eur J Endocrinol. 2010 Aug;163(2):193-200. doi: 10.1530/EJE-10-0255. Dallapiazza RF, Grober Y, Starke RM, Laws ER Jr, Jane JA Jr: Long-term results of endonasal endoscopic transsphenoidal resection of nonfunctioning pituitary macroadenomas. Neurosurgery 76:42–53, 2015. El-Shehaby AM, Reda WA, Tawadros SR, Abdel Karim KM: Low-dose Gamma Knife surgery for nonfunctioning pituitary adenomas. J Neurosurg 117 Suppl:84–88, 2012. Ezzat S, Asa SL, Couldwell WT, Barr CE, Dodge WE, Vance ML, et al: The prevalence of pituitary adenomas: a systematic review. Cancer 101:613–619, 2004. Feigl GC, Pistracher K, Berghold A, Mokry M: Pituitary insufficiency as a side effect after radiosurgery for pituitary adenomas: the role of the hypothalamus. J Neurosurg 113 Suppl:153–159, 2010. Gopalan R, Schlesinger D, Vance ML, Laws E, Sheehan J: Long-term outcomes after Gamma Knife radiosurgery for patients with a nonfunctioning pituitary adenoma. Neurosurgery 69:284–293, 2011. Fernández-Balsells MM, Murad MH, Barwise A, Gallegos-Orozco JF, Paul A, Lane MA, et al: Natural history of nonfunctioning pituitary adenomas and incidentalomas: a systematic review and metaanalysis. J Clin Endocrinol Metab 96:905–912, 2011. Höybye C, Rähn T: Adjuvant Gamma Knife radiosurgery in non-functioning pituitary adenomas; low risk of long-term complications in selected patients. Pituitary 12:211–216, 2009. Kajiwara K, Saito K, Yoshikawa M, Ideguchi S, Nomura M, Fujii M. Suzuki M. Stereotactic radiosurgery/radiotherapy for pituitary adenomas: a review of recent literature, Neurol. Med. Chir. (Tokyo) 50 (2010) 749–755. Li X, Li Y, Cao Y, Li P, Liang B, Sun J, Feng E. Safety and efficacy of fractionated stereotactic radiotherapy and stereotactic radiosurgery for treatment of pituitary adenomas: A systematic review and meta-analysis. J Neurol Sci. 2017 Jan 15;372:110-116. doi: 10.1016/j.jns.2016.11.024. Epub 2016 Nov 15. Loeffler JS, Shih HA. Radiation therapy in the management of pituitary adenomas, J. Clin. Endocrinol. Metab. 96 (2011) 1992–2003. Minniti G, Gilbert DC & Brada M. Modern techniques for pituitary radiotherapy. Reviews in Endocrine & Metabolic Disorders 2009 10 135–144. doi:10.1007/s11154-008-9106-0. Minniti G, Scaringi C, Amelio D, Maurizi Enrici R. Stereotactic irradiation of GH-secreting pituitary adenomas, Int. J. Endocrinol. 2012 (2012) 482861. Mortini P, Losa M, Barzaghi R, Boari N & Giovanelli M. Results of transsphenoidal surgery in a large series of patients with pituitary adenoma. Neurosurgery 2005 56 1222–1233. (doi:10.1227/01.NEU.0000159647.64275.9D) Murad MH, Ferna´ndez-Balsells MM, Barwise A, Gallegos-Orozco JF, Paul A, Lane MA, Lampropulos JF, Natividad I, Perestelo-Pe´rez L, Ponce de Leo´n-Lovato´n PG et al. Outcomes of surgical treatment for nonfunctioning pituitary adenomas: a systematic review and metaanalysis. Clinical Endocrinology 2010 73 777–791. doi:10.1111/j.1365-2265.2010.03875.x. Sheehan JP, Niranjan A, Sheehan JM, J.A. Jane Jr., E.R. Laws, D. Kondziolka, J. Flickinger, A.M. Landolt, J.S. Loeffler, L.D. Lunsford, Stereotactic radiosurgery for pituitary adenomas: an intermediate review of its safety, efficacy, and role in the neurosurgical treatment armamentarium, J. Neurosurg. 102 (2005) 678–691. Sheehan JP, Jagannathan N, Pouratian L, Steiner L. Stereotactic radiosurgery for pituitary adenomas: a review of the literature and our experience, Front. Horm. Res. 34 (2006) 185–205. Sheehan JP, Starke RM, Mathieu D, Young B, Sneed PK, Chiang VL, Lee JY, Kano H, Park KJ, Niranjan A, Kondziolka D, Barnett GH, Rush S, Golfinos JG, Lunsford LD. Gamma Knife radiosurgery for the management of nonfunctioning pituitary adenomas: a multicenter study, J. Neurosurg. 119 (2013) 446–456. Voges J, Kocher M, Runge M, Poggenborg J, Lehrke R, Lenartz D, Maarouf M, Gouni-Berthold I, Krone W, Muller RP, Sturm V. Linear accelerator radiosurgery for pituitary macroadenomas: a 7-year follow-up study, Cancer 107 (2006) 1355–1364.