Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the Role of Radiosurgery for Patients With Functioning Pituitary Adenomas

NEUROSURGERY, 2025

Sponsored by: Congress of Neurological Surgeons (CNS) and the AANS/CNS Section on Tumors

Endorsement: Reviewed for evidence-based integrity and endorsed by the Congress of Neurological Surgeons (CNS), American Association of Neurological Surgeons (AANS)

Authors:

Sheryl Green, MBBCh¹, Eric J. Lehrer, MD², Christopher P. Cifarelli, MD, PhD³, Pablo F. Recinos, MD⁴, Jason P. Sheehan, MD⁵, Mateo Ziu, MD, MBA⁶, D. Ryan Ormond, MD, PhD⁷, Isabelle M. Germano, MD, MBA⁸

Departmental and institutional affiliations:

1. Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York
2. Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
3. Department of Neurosurgery & Radiation Oncology, West Virginia University
4. Department of Neurosurgery, Cleveland Clinic, Cleveland, Ohio
5. Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia
6. Department of Neuro-oncology at Inova Schar Cancer Institute, Fairfax, Virginia
7. Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado
8. Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Corresponding Author contact information:

Sheryl Green, MBBCh

Department of Radiation Oncology

Icahn School of Medicine at Mount Sinai

Abbreviations: adrenocorticotropic hormone (ACTH), conflicts of interest (COIs), , functioning pituitary adenomas (FPA), fractionated (>5fractions) stereotactic radiotherapy (FSRT), growth hormone (GH), gamma knife radiosurgery (GKRS), insulin like growth factor (IGF), pituitary neuroendocrine tumors (PitNET’s), radiation therapy (RT) stereotactic radiosurgery (SRS), World Health Organization (WHO)

Conflicts of Interest

All Guideline Task Force members were required to disclose all potential conflicts of interest (COIs) prior to beginning work on the guideline, using the COI disclosure form of the AANS/CNS Joint Guidelines Review Committee. The CNS Guidelines Committee and Guideline Task Force Chair reviewed the disclosures and either approved or disapproved the nomination and participation on the task force. The CNS Guidelines Committee and Guideline Task Force Chair may approve nominations of task force members with possible conflicts and restrict the writing, reviewing, and/or voting privileges of that person to topics that are unrelated to the possible COIs.

Funding 

These evidence-based clinical practice guidelines were funded exclusively by the Congress of Neurological Surgeons, which received no funding from outside commercial sources to support the development of this document.

The AANS/CNS Section on Tumors funded the cost of publication for the supplement. 

Disclosure

See Supplemental Digital Content 5 for a complete list of disclosures.

ABSTRACT

Background: Patients with functioning pituitary adenomas (FPA) require a multi-disciplinary team-based approach to select best medical, surgical and radiation treatments, including stereotactic radiosurgery (SRS).

Objective: The aim of this study is to provide evidence-based recommendations on the use of SRS for adult patients with FPA.

Methods: PubMed and Embase were searched from data base inception to June 8, 2021.Full text articles were then  screened using published exclusion/inclusion criteria. Evidence tables were developing based on data extraction from the full-text reviews and evidence based recommendations were finalized.

Results: Of the total 1842 abstracts pertinent to this topic, 343 full papers met eligibility. Of these 21 met entry criteria and were included in the evidence tables. They provided Class III evidence supported two Level III recommendations: 1. SRS, hypo-fractionated SRS, fractionated (>5fractions) radiotherapy and conventional radiation therapy provide excellent radiographic control with variable hormonal reduction and endocrine remission rates. For SRS and fractionated radiotherapy hormonal reduction may continue for up to 10 years after treatment. 2. Clinicians may continue to administer endocrine suppressive medical treatment before SRS as this may not affect radiographic control.

Conclusion: This systematic review provides evidence-based recommendations to guide providers caring for adult patients with FPA when making decisions pertinent to radiosurgery.

The CNS Guidelines Committee will continue to pursue timely updates to further improve the care of patients with this diagnosis.

Keywords: functioning pituitary adenoma, radiosurgery, stereotactic fractionated radiotherapy

RECOMMENDATIONS

Target Population: adult patients with signs/symptoms, endocrine evaluation and imaging supportive of progressive/recurrent FPA

Key Question 1. In adult patients with signs/symptoms, endocrine evaluation and imaging supportive of progressive/recurrent FPA, does single fraction radiosurgery provide better radiographic control and/or biochemical normalization and/or result in lower incidence of  hypopituitarism requiring hormonal replacement compared to 1) external beam radiation OR 2) FSRT) OR 3) hypo-fractionated (2-5 fractions) SRS or 4) proton beam therapy?

Recommendation, Level III: In adult patients with signs/symptoms, endocrine evaluation and imaging supportive of progressive/recurrent FPAs, it is suggested clinicians use SRS, hypo-fractionated SRS, FRT and conventional radiation therapy (RT) to provide improved radiographic control with variable rates of hormonal reduction.

Target Population: Adult patients with signs/symptoms, endocrine evaluation and imaging indicative of FPA requiring radiosurgery treatment

Key Question 2.  In adult patients with signs/symptoms, endocrine evaluation and imaging indicative of FPA requiring radiosurgery treatment, does stopping endocrine suppressive medical treatment prior to radiosurgery or continuing medical treatment provide a better radiographic control and/or biochemical normalization?

Recommendation, Level III: In adult patients with signs/symptoms, endocrine evaluation and imaging indicative of FPA requiring radiosurgery treatment, clinicians may continue to administer endocrine suppressive medical treatment prior to SRS as this may not affect radiographic control.

Recommendation, Insufficient Evidence: There is insufficient evidence to make a recommendation about the effects of stopping the endocrine suppressive medications prior to radiosurgery on biochemical normalization.

INTRODUCTION

Goals and Rationale

Pituitary tumors have been considered as benign tumors of the sella turcica. Their expected prevalence in the US in 2023 is 13,900, representing approximately 17% of all primary brain tumors.¹ However, since these tumors are often clinically inactive, their reported prevalence in autopsy studies is significantly higher as only about 0.5% will come to medical attention.²

Approximately 66-75% of pituitary adenomas secrete excessive hormones and have been defined as FPA.³ The most commonly secreted excess hormones include prolactin, growth hormone (GH), or adrenocorticotropic hormone (ACTH).⁴

More recently, the World Health Organization (WHO) reclassified pituitary adenomas as pituitary neuroendocrine tumors (PitNET). This new classification provides detailed histologic subtyping of a PitNET based on tumor cell lineage, cell type and related characteristics. The  routine use of immunohistochemistry for pituitary transcription factors  (PIT1, TPIT, SF1, GATA3, and ERα) is endorsed in this classification. The major PIT1, TPIT, and SF1 lineage-defned PitNET types and subtypes feature distinct morphologic, molecular, and clinical differences.⁵ The literature reviewed for guideline development did not utilize the new classification and hence the term pituitary adenoma will be utilized for this report. 

Treatment options for FPA include medical, surgical and radiation therapies. The latter is usually reserved for refractory and/or biochemical disease after exhaustion of medical and surgical therapies. Compared to non-functioning pituitary adenomas, FPA require a higher dose of radiation to achieve endocrine control.^6,7 Stereotactic radiosurgery (SRS) has successfully been used to treat FPA for over 5 decades.⁷

Introduction

Radiation therapy (RT) has been shown to control excess hormonal secretion in FPAs in 28-36% of patients with Cushing’s Disease. Although disease recurrence seems to be more frequent following conventional RT than SRS, there are limited supporting data.⁸ In addition,  variability in side effects, such as hypopituitarism and visual field deficits between the different radiation treatment modalities are not well documented.

The aim of these guidelines is to provide evidence-based recommendations on two important topics focused on the use of SRS in adults with FPA. First, the authors aimed to compare the role of single fraction SRS in FPA patients assessing radiographic control, endocrine remission and new onset of side effects compared to the following other radiation modalities:  hypofractionated SRS (2-5 fractions), fractionated radiotherapy (>5 fractions, SRT) and proton beam therapy. Second, the authors aimed to assess the role of cessation versus continuing medical treatment prior to SRS on radiographic control and biochemical normalization.

Methodology

The guidelines task force initiated a systematic review of the literature and evidence-based guideline relevant to the treatment of adult patients with FPA. The Guidelines Task Force used DistillerSR (which utilizes artificial intelligence) to cull, narrow and aid its review of the relevant literature.  All abstracts were reviewed and relevant full text articles were retrieved and graded (by individuals of the guideline task force).  Through objective evaluation of the evidence and transparency in the process of making recommendations, this evidence-based clinical practice guideline was developed for the diagnosis and treatment of adult patients with FPA. These guidelines are developed for educational purposes to assist practitioners in their clinical decision-making processes.  

RESULTS

The literature search yielded 1842 abstracts.  Task force members reviewed all abstracts yielded from the literature search and identified the literature for full text review and extraction, addressing the clinical questions, in accordance with the Literature Search Protocol (Supplemental Digital Content 1). Task force members identified the best research evidence available to answer the targeted clinical questions.

The task force selected 343 full-text articles for full text review .  Of these, 21^9-30  met criteria  for inclusion as specified in methods in the evidence tables (Supplemental Digital Content 4). The provided Class III evidence supported two Level III recommendations: SRS, hypo-fractionated SRS, fractionated (>5fractions) radiotherapy (FSRT) and conventional radiation therapy (RT) provide improved radiographic control with variable hormonal reduction and endocrine remission rates. For SRS and FRT hormonal reduction may continue for up to 10 years after treatment. There is insufficient evidence to make a recommendation about the effects of stopping the endocrine suppressive medications prior to radiosurgery on biochemical normalization. Temporary cessation of suppressive medications may be considered.

CONCLUSIONS

Radiosurgery remains a successful therapeutic approach for tumor control and endocrine remission in patients with FPAs. This systematic review provides evidence-based recommendations to guide providers caring for adult patients with FPA when making decisions pertinent to radiosurgery.

Conflicts of Interest

All Guideline Task Force members were required to disclose all potential COIs prior to beginning work on the guideline, using the COI disclosure form of the AANS/CNS Joint Guidelines Review Committee. The CNS Guidelines Committee and Guideline Task Force Chair reviewed the disclosures and either approved or disapproved the nomination and participation on the task force. The CNS Guidelines Committee and Guideline Task Force Chair may approve nominations of task force members with possible conflicts and restrict the writing, reviewing, and/or voting privileges of that person to topics that are unrelated to the possible COIs. See Appendix V for a complete list of disclosures.

Disclaimer of Liability

          This clinical systematic review and evidence-based guideline was developed by a physician volunteer task force as an educational tool that reflects the current state of knowledge at the time of completion. Each chapter is designed to provide an accurate review of the subject matter covered. This guideline is disseminated with the understanding that the recommendations by the authors and consultants who have collaborated in their development are not meant to replace the individualized care and treatment advice from a patient's physician(s). If medical advice or assistance is required, the services of a competent physician should be sought. The proposals contained in these guidelines may not be suitable for use in all circumstances. The choice to implement any particular recommendation contained in these guidelines must be made by a managing physician in light of the situation in each particular patient and on the basis of existing resources.

Acknowledgments:

                    The guidelines task force would like to acknowledge the CNS Guidelines Committee for their contributions throughout the development of the guideline, the AANS/CNS Joint Guidelines Review Committee, as well as the contributions Trish Rehring, MPH, Director for Evidence-Based Practice Initiatives for the CNS, and Janet Waters, MLS, BSN, RN, for assistance with the literature searches. Throughout the review process, the reviewers and authors were blinded from one another. At this time the guidelines task force would like to acknowledge the following individual peer reviewers for their contributions: Brandon Lucke-Wold, MD, Koji Ebersole, MD, Andrew Carlson, MD, MS, Andrew Ryu, MD, Vincent Alentado, MD and Jeffrey Olson, MD.

References

1. Oncology ASoC. Cancer.Net. Pituitary Gland Tumor: Statistics 2023; https://www.cancer.net/cancer-types/pituitary-gland-tumor/statistics#. Accessed 7/26/2023, 2023.
2. Dekkers OM, Karavitaki N, Pereira AM. The epidemiology of aggressive pituitary tumors (and its challenges). Rev Endocr Metab Disord. 2020;21(2):209-212.
3. Mehta GU, Lonser RR. Management of hormone-secreting pituitary adenomas. Neuro Oncol. 2017;19(6):762-773.
4. Molitch ME. Diagnosis and Treatment of Pituitary Adenomas: A Review. Jama. 2017;317(5):516-524.
5. Asa SL, Mete O, Perry A, Osamura RY. Overview of the 2022 WHO Classification of Pituitary Tumors. Endocrine pathology. 2022;33(1):6-26.
6. Albano L, Losa M, Barzaghi LR, et al. Gamma Knife Radiosurgery for Pituitary Tumors: A Systematic Review and Meta-Analysis. Cancers (Basel). 2021;13(19).
7. Heringer LC, Machado de Lima M, Rotta JM, Botelho RV. Effect of Stereotactic Radiosurgery on Residual or Relapsed Pituitary Adenoma: A Systematic Review and Meta-Analysis. World neurosurgery. 2020;136:374-381.e374.
8. Khattab MH, Sherry AD, Xu MC, et al. Stereotactic Radiosurgery and Hypofractionated Stereotactic Radiotherapy for Nonfunctioning Pituitary Adenoma. J Neurol Surg B Skull Base. 2021;82(Suppl 3):e51-e58.
9. Ransohoff DF, Pignone M, Sox HC. How to decide whether a clinical practice guideline is trustworthy. JAMA. 2013;309(2):139-140.
10. Apaydin T, Ozkaya HM, Durmaz SM, Meral R, Kadioglu P. Efficacy and Safety of Stereotactic Radiotherapy in Cushing's Disease: A Single Center Experience. Exp Clin Endocrinol Diabetes. 2021;129(7):482-491.
11. Knappe UJ, Petroff D, Quinkler M, et al. Fractionated radiotherapy and radiosurgery in acromegaly: analysis of 352 patients from the German Acromegaly Registry. Eur J Endocrinol. 2020;182(3):275-284.
12. Sherry AD, Khattab MH, Xu MC, et al. Outcomes of stereotactic radiosurgery and hypofractionated stereotactic radiotherapy for refractory Cushing's disease. Pituitary. 2019;22(6):607-613.
13. Wilson PJ, Williams JR, Smee RI. Single-centre experience of stereotactic radiosurgery and fractionated stereotactic radiotherapy for prolactinomas with the linear accelerator. Journal of medical imaging and radiation oncology. 2015;59(3):371-378.
14. Wilson PJ, Williams JR, Smee RI. Cushing's disease: a single centre's experience using the linear accelerator (LINAC) for stereotactic radiosurgery and fractionated stereotactic radiotherapy. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2014;21(1):100-106.
15. Wilson PJ, De-Loyde KJ, Williams JR, Smee RI. Acromegaly: A single centre's experience of stereotactic radiosurgery and radiotherapy for growth hormone secreting pituitary tumours with the linear accelerator. Journal of Clinical Neuroscience. 2013;20(11):1506-1513.
16. Jallad RS, Musolino NR, Salgado LR, Bronstein MD. Treatment of acromegaly: is there still a place for radiotherapy? Pituitary. 2007;10(1):53-59.
17. Kong DS, Lee JI, Lim DH, et al. The efficacy of fractionated radiotherapy and stereotactic radiosurgery for pituitary adenomas: long-term results of 125 consecutive patients treated in a single institution. Cancer. 2007;110(4):854-860.
18. Powell JS, Wardlaw SL, Post KD, Freda PU. Outcome of radiotherapy for acromegaly using normalization of insulin-like growth factor I to define cure. Journal of Clinical Endocrinology and Metabolism. 2000;85(5):2068-2071.
19. Milker-Zabel S, Debus J, Thilmann C, Schlegel W, Wannenmacher M. Fractionated stereotactically guided radiotherapy and radiosurgery in the treatment of functional and nonfunctional adenomas of the pituitary gland. International journal of radiation oncology, biology, physics. 2001;50(5):1279-1286.
20. Mitsumori M, Shrieve DC, Alexander E, 3rd, et al. Initial clinical results of LINAC-based stereotactic radiosurgery and stereotactic radiotherapy for pituitary adenomas. International journal of radiation oncology, biology, physics. 1998;42(3):573-580.
21. Ding D, Mehta GU, Patibandla MR, et al. Stereotactic Radiosurgery for Acromegaly: An International Multicenter Retrospective Cohort Study. Neurosurgery. 2019;84(3):717-725.
22. Kong DS, Kim YH, Kim YH, et al. Long-Term Efficacy and Tolerability of Gamma Knife Radiosurgery for Growth Hormone-Secreting Adenoma: A Retrospective Multicenter Study (MERGE-001). World neurosurgery. 2019;122:e1291-e1299.
23. Ježková J, Hána V, Kosák M, et al. Role of gamma knife radiosurgery in the treatment of prolactinomas. Pituitary. 2019;22(4):411-421.
24. Liu X, Kano H, Kondziolka D, et al. Gamma knife radiosurgery for clinically persistent acromegaly. Journal of neuro-oncology. 2012;109(1):71-79.
25. Iwai Y, Yamanaka K, Yoshimura M, Kawasaki I, Yamagami K, Yoshioka K. Gamma knife radiosurgery for growth hormone-producing adenomas. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2010;17(3):299-304.
26. Jagannathan J, Sheehan JP, Pouratian N, Laws ER, Jr., Steiner L, Vance ML. Gamma knife radiosurgery for acromegaly: outcomes after failed transsphenoidal surgery. Neurosurgery. 2008;62(6):1262-1269; discussion 1269-1270.
27. Vik-Mo EO, Oksnes M, Pedersen PH, et al. Gamma knife stereotactic radiosurgery for acromegaly. European journal of endocrinology. 2007;157(3):255-263.
28. Pollock BE, Jacob JT, Brown PD, Nippoldt TB. Radiosurgery of growth hormone-producing pituitary adenomas: factors associated with biochemical remission. Journal of neurosurgery. 2007;106(5):833-838.
29. Pollock BE, Nippoldt TB, Stafford SL, Foote RL, Abboud CF. Results of stereotactic radiosurgery in patients with hormone-producing pituitary adenomas: factors associated with endocrine normalization. Journal of neurosurgery. 2002;97(3):525-530.
30. Landolt AM, Haller D, Lomax N, et al. Octreotide may act as a radioprotective agent in acromegaly. The Journal of clinical endocrinology and metabolism. 2000;85(3):1287-1289.