Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines for Patients with Functioning Pituitary Adenomas

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

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:

Christie G Turin, MD¹, Janice M Kerr, MD¹, Kalmon D Post, MD², Gabriel Zada, MD³, Isabelle M Germano, MD, MBA⁴ D. Ryan Ormond, MD, PhD⁵

Departmental and institutional affiliations:

Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Colorado School of Medicine, Aurora, CO, United States
Mount Sinai Health System, New York, NY, United States
Department of Neurosurgery, Keck Medicine at University of Southern California, Los Angeles, CA, United States
Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, United States
Department of Neurosurgery, University of Colorado School of Medicine, Aurora, CO, United States

Corresponding Author contact information:

Christie G Turin, MD

Department of Medicine, Division of Endocrinology, Metabolism and Diabetes

University of Colorado School of Medicine – Anschutz Medical Campus

Keywords: pituitary adenoma, transsphenoidal surgery, hyponatremia, fluid restriction, growth hormone secreting pituitary adenoma, acromegaly, medical therapy, Cushing’s disease.

Abbreviations:

TSS: transsphenoidal surgery

SIADH: syndrome of inappropriate antidiuretic hormone secretion

GH: growth hormone

FPA: functioning pituitary adenomas

ACTH: adrenocorticotropic hormone

SSA: somatostatin analogue

POD: postoperative day

IGF-1: insulin-like growth factor-1

CD: Cushing’s disease

OCT: octreotide

NPV: negative predictive value

PPV: positive predictive value

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.

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: Standardized perioperative management of patients with functioning pituitary adenomas is important for optimal medical and surgical outcomes.

Objective: Review of the literature to evaluate the impacts of: 1) postoperative fluid restriction and sodium level checks to prevent delayed hyponatremia and hospital-related readmissions, 2) preoperative somatostatin analog (SSA) medical treatment in patients with growth hormone (GH) secreting tumors and its effects on surgical and medical outcomes, and 3) immediate postoperative pituitary hormone testing in patients with adrenocorticotropic hormone (ACTH)-secreting tumors to predict adrenal insufficiency and disease remission.

Methods: Systematic literature search using EMBASE and PUBMED from 1946 to June 2021.

Results: A total of 1953 abstracts were identified for review: 124 studies were selected for full text review and 44 studies were included in the analyses. Overall, based on predominantly level III evidence, the literature supported: 1) fluid restriction (1000-1500 mL/day for ~7 postoperative days), with/without a routine serum sodium check, to lower risk of delayed hyponatremia and hospital-related readmission, and 2) basal morning serum cortisol (+/- ACTH levels), within the immediate postoperative period (< 72 hours) for patients with ACTH-secreting tumors to predict adrenal insufficiency and disease remission. Conversely, perioperative treatment of patients with GH-secreting tumors with a SSA is not recommended to improve surgical or medical outcomes.

Conclusion: Limited fluid restriction is recommended for all patients after transsphenoidal surgery (without diabetes insipidus), as is routine postoperative morning cortisol testing in Cushing’s patients, but not somatostatin pre-surgical treatment in acromegalic patients.

RECOMMENDATIONS

Target Population: Adult patients with functioning pituitary adenomas (FPAs) who undergo transsphenoidal surgery (TSS)

Key Question 1: In adult patients with FPAs who undergo TSS, does postoperative fluid restriction and/or a serum sodium level check during the first postoperative week decrease complications/readmission rates for hyponatremia compared to ad libitum fluid intake?

Recommendation, Level III: In adult patients with FPAs who undergo TSS, fluid restriction after surgery is a suggested effective approach to prevent delayed hyponatremia and reduce hospital readmission for hyponatremia .There is not enough evidence to support serum sodium check without fluid restriction as a preventative strategy to reduce hyponatremia.

Target Population: Adult patients with signs/symptoms suggestive of FPAs

Key Question 2. In adult patients with signs/symptoms suggestive of FPAs, specifically GH-tumors, does the administration of preoperative medical therapy to control serum level of hyper-secreted pituitary hormones provide a better control of serum level of hyper-secreted pituitary hormones and/or extent of surgical resection and/or decreased medical co-morbidities compared to no medical therapy?

Recommendation, Level III: Preoperative medical treatment with somatostatin analogs (SSA) for patients with GH-secreting tumors is not routinely suggested, as there is insufficient evidence demonstrating a benefit to long-term biochemical remission, medical co-morbidities or surgical complications.

Target Population: Adult patients with Cushing’s disease (CD) who have undergone pituitary surgery

Key Question 3. In adult patients with CD who have undergone pituitary surgery, does the timing of the postoperative pituitary hormone(s) assessment lead to a better prediction of postoperative adrenal insufficiency, need for steroids, and/or remission?

Recommendation, Level III: Postoperative serum cortisol monitoring within the immediate postoperative period (< 72 hours) is suggested using a cut-off level of <2 ug/dl as a predictor of remission and an indicator for glucocorticoid replacement.

INTRODUCTION

Pituitary adenomas are the second most frequent type of primary intracranial neoplasms,

accounting for ~10-20% of tumors¹. Lactotroph adenomas are the most common subtype of pituitary adenomas, followed by non-functioning adenomas (NFPAs), somatotroph, corticotroph, and thyrotroph adenomas. Functional pituitary adenomas (FPAs) account for ~60% of pituitary tumors and are defined by the clinical and biochemical evidence of pituitary hormonal excess. These pituitary adenomas typically present with classic signs and symptoms specific to their target hormone excess (e.g., acromegaly with growth hormone (GH)-secreting tumors and Cushing’s disease (CD) with adrenocorticotropic hormone (ACTH)-secreting tumors). In addition, large pituitary tumors/macroadenomas may be associated with mass effects secondary to local compressive effects (e.g., headaches, visual loss from optic chiasm compression, and/or cranial nerve palsies). The optimal preoperative and postoperative management of functional tumors lack standardization but is an important consideration for optimal medical and surgical outcomes.

Goals and Rationale

This guideline has been created as an educational tool to guide qualified physicians through a series of diagnostic and treatment decisions to improve the quality and efficiency of care of patients with FPAs.

Objectives

The aim of this chapter of the guideline is to highlight 3 specific questions relevant to perioperative endocrine management of FPAs: firstly, to evaluate the impact of fluid restriction and serum sodium monitoring in TSS patients during the early postoperative period on readmission for delayed hyponatremia; secondly, to determine the potential role of pre-surgical SSA treatment to improve surgical outcomes (i.e., biochemical remission and extent of surgical resection) and medical/surgical complications in patients with GH-secreting adenomas; last, to evaluate if the timing of postoperative hormonal assessment could lead to a better prediction of postoperative adrenal insufficiency and biochemical remission. Questions were asked following a population, intervention, comparison, outcome (PICO) format and approved by the CNS Guidelines Committee prior to performing the literature search or systematic review.

Importantly, in selecting the topics for review of preoperative medical therapy, this question focused exclusively on GH-secreting tumors and somatostatin presurgical treatment. This is because there was either insufficient data to support preoperative medical therapy for the other functional tumors (i.e., ACTH, thyroid stimulating hormone, and follicle stimulating hormone/ luteinizing hormone-secreting tumors) or non-standardized care (e.g., prolactinomas). A flow chart summarizing the study selection and screening process is shown in Supplemental Digital Content 3. Additional information about the methods utilized in this systematic review is provided below.

Methodology

The guidelines task force initiated a systematic review of the literature and evidence-based guideline relevant to the treatment of patients with FPAs. 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 FPAs. These guidelines were developed for educational purposes to assist practitioners in their clinical decision-making processes.

Literature Search

The task force members identified search terms/parameters and a medical librarian implemented the literature search, consistent with the literature search protocol (see Supplemental Digital Content 1: Appendix I), using the National Library of Medicine/PubMed database and Embase for the period from 1946 (inception of the database) to June 8, 2021 using the search strategies provided in Supplemental Digital Content 1: Appendix I.

RESULTS

The literature search yielded 1953 abstracts. Task force members conducted a double-blind review of the abstracts yielded from the literature search and identified 124 studies for full text review and extraction, addressing the clinical questions. Task force members identified 44 articles that met criteria for inclusion. Overall, based on predominantly level III evidence, the literature supported: 1) fluid restriction (1000-1500 mL/day for ~7 postoperative days), with/without a routine serum sodium check, to lower risk of delayed hyponatremia and hospital-related readmission, and 2) basal morning serum cortisol (+/- ACTH levels), within the immediate postoperative period (< 72 hours) for patients with ACTH-secreting tumors to predict adrenal insufficiency and disease remission. Conversely, perioperative treatment of patients with GH-secreting tumors with a SSA is not recommended to improve surgical or medical outcomes.

CONCLUSIONS

Limited fluid restriction is recommended for all patients after transsphenoidal surgery (without diabetes insipidus), as is routine postoperative morning cortisol testing in Cushing’s patients, but not somatostatin pre-surgical treatment in acromegalic patients.

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 of 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

Ostrom QT, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2014-2018. Neuro-oncology. 2021;23(12 Suppl 2):iii1-iii105.

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

View on Neurosurgery

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:

Jacqueline C. Junn, MD¹; Kalmon D. Post, MD²; Manish K. Aghi, MD, PhD, MAS³; Gabriel Zada, MD⁴; Daniel Prevedello, MD⁵; Bradley Delman, MD⁶; Puneet Belani, MD⁶; D. Ryan Ormond, MD, PhD⁷; Isabelle M Germano, MD, MBA²

Departmental and institutional affiliations:

1. Department of Radiology, Emory University, Atlanta, Georgia

2. Department of Neurosurgery, Ichan School of Medicine at Mount Sinai, New York, New York

3. Department of Neurological Surgery, University of California San Francisco, San Francisco, California

4. Department of Neurosurgery, Keck Medicine at University of Southern California, Los Angeles, California

5. Department of Neurological Surgery, The Ohio State University, Wexner Medical Center, Columbus, Ohio

6. Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, New York

7. Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado

Corresponding Author contact information:

Isabelle M. Germano, MD, MBA

Department of Neurosurgery, Ichan School of Medicine at Mount Sinai

Keywords: functioning pituitary adenoma, radiosurgery, stereotactic fractionated radiotherapy

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

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

Abbreviations

Conflicts of Interest (COI)

Functioning pituitary adenomas (FPA)

Magnetic resonance images (MRI)

Adrenocorticotrophic hormone (ACTH)

Secreting ACTH syndrome (EAS).

Positron emission tomography (PET)

Positron emission tomography (PET-CT)

Polyethylene glycol (PEG).

Corticotropin-releasing hormone (CRH)

Inferior petrosal sinus sampling (IPSS)

Bilateral inferior petrosal sinus sampling (BIPSS)

Zurich Pituitary Score (ZPS)

Three dimensional (3D)

Contrast-enhanced Constructive Interference In Steady State (CE-CISS)

Fluid-Attenuated Inversion Recovery after contrast enhancement (CE-FLAIR).

Contrast enhanced-T1 weighted images (CE-T1 WI).

Internal carotid artery (ICA)

Gradient Echo (GRE)

Disclosures

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

ABSTRACT

Background: Patients with functioning pituitary adenomas (FPA) present a diagnostic challenge with identification of microadenomas and/or invasion of the cavernous sinus.

Objective: This study aims at providing evidence-based recommendations on the use of imaging to facilitate an accurate diagnosis.

Methods: PubMed and Embase were searched from the inception of the database to June 8, 2021, using search terms and search strategies to identify pertinent abstracts. These were then screened using published exclusion/inclusion criteria to identify full-text review articles. Evidence tables were constructed using data from full-text reviews, and recommendations were made.

Results: Of the total 8,685 identified abstracts pertinent to this topic, 138 full papers met the eligibility criteria. Of these, 18 met the inclusion criteria and were included in the evidence tables. Class III evidence supported 4 Level III recommendations for adult patients with FPA.

Conclusion: This systematic review provides evidence-based recommendations to guide providers caring for adult patients with FPA when making decisions pertinent to imaging. The Congress of Neurosurgeons will continue to pursue timely updates and to further improve the care of patients with diagnosis.

RECOMMENDATIONS

Target Population: adult patients with signs/symptoms and endocrine evaluation suggestive of functioning pituitary adenomas (FPA)

Key Question 1: In adult patients with signs/symptoms and endocrine evaluation suggestive of functioning pituitary adenomas, does assessment with magnetic resonance images (MRI) or endocrine assessment alone provide a more accurate confirmation and localization of the pituitary tumor?

Recommendation, Level III: In adult patients with endocrinological suspicion of FPA, assessment with MRI is suggested as it provides a more accurate confirmation of the pituitary tumor than endocrine assessment alone. In patients with endocrinologocially suspected ectopic adrenocorticotrophic hormone (ACTH) syndrome (EAS), computed tomography (CT) of the abdomen/pelvis rather than pituitary MRI is suggested.

Target Population: Adult patients with signs/symptoms and endocrine evaluation suggestive of ACTH-secreting FPAs with MR images negative for tumor

Key Question 2: In adult patients with signs/symptoms and endocrine evaluation suggestive of ACTH-secreting FPA with MR images negative for tumor, does bilateral inferior petrosal sinus sampling (BIPSS) provide a more accurate assessment of tumor location than exploratory surgery alone?

Recommendation, Level III: In adult patients with signs/symptoms and endocrine evaluation suggestive of ACTH-secreting FPA with MR images negative for tumor, BIPSS is suggested as a diagnostic benefit.

Target Population: adult patients with signs/symptoms and endocrine evaluation suggestive of functioning pituitary microadenomas.

Key Question 3: In adult patients with signs/symptoms and endocrine evaluation suggestive of functioning pituitary microadenomas, does positron emission tomography computed tomography (PET-CT) using radioactive metabolic tracers, such as [18]fluoro-2-deoxy-D-glucose (18F-FDG), 68Gallium-DOTATATE (68Gad), and 11C-methionine (11C-met) provide a more accurate tumor localization compared to MRI alone?

Recommendation, Level III: In adult patients with signs/symptoms and endocrine evaluation suggestive of functioning pituitary microadenomas with negative MRI PET using radioactive metabolic tracers is suggested as a diagnostic benefit.

Target Population: adult patients with signs/symptoms and endocrine evaluation suggestive of FPA

Key Question 4: In adult patients with signs/symptoms and endocrine evaluation suggestive of FPA, do MRI grading systems and/or sellar imaging protocols developed since 2015 result in better prediction of post-operative biochemical control and/or complete tumor resection compared to no grading system and/or no new imaging protocols?

Recommendation, Level III: In adult patients with signs/symptoms and endocrine evaluation suggestive of FPA, MRI grading systems and/or newer sellar imaging is suggested to further predict postoperative biochemical control and/or complete tumor resection.

INTRODUCTION

Multiple disciplines are involved in managing adult patients with FPA in various clinical settings. As these patients are within a multifaceted system and approach, a clinical guideline is needed to provide treatment for these patients with appropriate information and a decision-making process. This guideline provides an educational tool for physicians with diagnostic and treatment decisions for more streamlined and improved care of FPA patients.

Pituitary adenomas or pituitary neuroendocrine tumors are considered primary tumors in the pituitary gland¹. Pituitary adenomas are the most common intracranial neoplasms. Functioning pituitary adenoma (FPA) accounts for approximately two-thirds of adenomas and they most commonly occur as micro-adenomas, less than 10mm in size.^2,3Diagnostic challenges for these tumors include confirmation and location of the tumor within the sellar region.

The aim of these guidelines was to provide an evidence-based approach on how best to use imaging techniques to diagnose and localize FPA using four key questions: 1. The role of MR images in diagnosing this disease compared to endocrine evaluation alone; 2. In those cases where the MR images fail to disclose the tumor, the aim is to provide evidence of the role of other testing; 3. In those cases where the MR images fail to disclose the tumor, provide imaging modalities to further the diagnostic yield; 4. To provide evidence of improved diagnostic yield of new MR techniques and/or MRI-based score systems to further the FPA diagnosis.

Methodology

The guidelines task force initiated a systematic review of the literature and evidence-based guidelines relevant to treating adult patients with FPA. Through objective evaluation of the evidence and transparency in making these recommendations, an evidence-based clinical practice guideline was developed for diagnosing and treating 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).

These guidelines are designed for educational purposes to assist practitioners in their clinical decision-making processes. Additional information about the methods utilized in this systematic review is provided below.

The task force members identified search terms/parameters, and a medical librarian implemented the literature search, consistent with the literature search protocol, using the National Library of Medicine/PubMed database and Embase for the period from 1946 (inception of the database) to June 8, 2021, using the search strategies provided in Supplemental Digital Content 1: Appendix I.

RESULTS

The literature search yielded 8,685 abstracts. Task force members reviewed all abstracts generated from the literature search and removed duplicates and/or abstracts only. From the remaining 5,660 abstracts, the task force selected 138 full-text articles for full-text review. Of these, 18 met the inclusion criteria outlined in the evidence tables. The extracted evidence-based data was Class III evidence supporting four Level III recommendations for adult patients with FPA. 1. In adult patients with endocrinological suspicion of FPA, assessment with MRI is suggested as it provides a more accurate confirmation of the pituitary tumor than endocrine assessment alone; 2. In adult patients with signs/symptoms and endocrine evaluation suggestive of ACTH-secreting FPA with MR images negative for tumor, bilateral inferior petrosal sinus sampling (BIPSS) is suggested as a diagnostic benefit; 3. In adult patients with suspected FPA micro-adenomas micro-adenomas with negative MRI PET-CT using radioactive metabolic tracers is suggested as a diagnostic benefit;4. MRI grading systems and/or newer sellar imaging is suggested to further predict post-operative biochemical control and/or complete tumor resection.

CONCLUSIONS

This guideline provides evidence-based recommendations for the imaging diagnosis of patients with FPA. While this guideline consisted of a thorough literature review and review by experts across neurosurgery oncology, neuro-radiology, and endocrinology disciplines, the studies included in this study were all done retrospectively. In addition, these studies were largely conducted at single institutions with limited numbers of patients. Thus, future research should incorporate prospective studies, ideally with standardized imaging sequences.

Over the years, machine learning has emerged as the next medical frontier, including imaging. Artificial intelligence (AI) and machine learning (ML) have catapulted for quantitative analysis to evaluate patients with pituitary adenomas. Mainly, radiomics and ML have been the focus of early diagnosis/screening, tumor grading, differential diagnosis, predicting outcomes, and determining the adenoma subtypes/assessing tumor consistency.^32-35 As this field is evolving, most likely new paradigms will become available to increase diagnostic accuracy.

Cavernous sinus invasion has also been a topic of interest in AI and ML studies. Even though these ML-based radiomic studies have shown high accuracy, they are still retrospective studies that need further evaluation to eliminate bias. Further research focused on providing prospective data is needed.

Disclaimer of Liability

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 of 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

Louis DN, Perry A, Wesseling P, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro-oncology. 2021;23(8):1231-1251.
Pisaneschi M, Kapoor G. Imaging the sella and parasellar region. Neuroimaging Clin N Am. 2005;15(1):203-219.
Zamora C, Castillo M. Sellar and parasellar imaging. Neurosurgery. 2017;80(1):17-38.
Institute of Medicine Committee on Standards for Developing Trustworthy Clinical Practice G. In: Graham R, Mancher M, Miller Wolman D, Greenfield S, Steinberg E, eds. Clinical Practice Guidelines We Can Trust. Washington (DC): National Academies Press (US). Copyright 2011 by the National Academy of Sciences. All rights reserved.; 2011.
Sherazi NA, Baig MZ, Khan AH. Frequency of Macroprolactin in Hyperprolactinemia. Journal of the College of Physicians and Surgeons–Pakistan : JCPSP. 2018;28(2):93-97.
Kakade HR, Kasaliwal R, Jagtap VS, et al. Ectopic ACTH-secreting syndrome: a single-center experience. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2013;19(6):1007-1014.
Testa RM, Albiger N, Occhi G, et al. The usefulness of combined biochemical tests in the diagnosis of Cushing’s disease with negative pituitary magnetic resonance imaging. European journal of endocrinology. 2007;156(2):241-248.
Bayrak A, Saadat P, Mor E, Chong L, Paulson RJ, Sokol RZ. Pituitary imaging is indicated for the evaluation of hyperprolactinemia. Fertility and sterility. 2005;84(1):181-185.
Strachan MWJ, Teoh WL, Don-Wauchope AC, Seth J, Stoddart M, Beckett GJ. Clinical and radiological features of patients with macroprolactinaemia. Clinical endocrinology. 2003;59(3):339-346.
Dwyer AJ, Frank JA, Doppman JL, et al. Pituitary adenomas in patients with Cushing disease: initial experience with Gd-DTPA-enhanced MR imaging. Radiology. 1987;163(2):421-426.
Gupta R, Gambhir M, Ammini AC. Imaging of the pituitary gland in Cushing’s disease. Medical Principles and Practice. 1998;7(4):246-250.
Alexandraki KI, Grossman AB. Management of hypopituitarism. Journal of Clinical Medicine. 2019;8(12).
Potts MB, Shah JK, Molinaro AM, et al. Cavernous and inferior petrosal sinus sampling and dynamic magnetic resonance imaging in the preoperative evaluation of Cushing’s disease. Journal of neuro-oncology. 2014;116(3):593-600.
Erickson D, Erickson B, Watson R, et al. 3 Tesla magnetic resonance imaging with and without corticotropin releasing hormone stimulation for the detection of microadenomas in Cushing’s syndrome. Clinical endocrinology. 2010;72(6):793-799.
Harker P, Feo-Lee O, Giraldo-Grueso M, Puentes JC. Effectiveness of Bilateral Inferior Petrosal Sinuses Sampling in Tumor Lateralization: Intraoperative Findings and Postoperative Results. Journal of neurological surgery Part B, Skull base. 2017;78(6):506-511.
Jehle S, Walsh JE, Freda PU, Post KD. Selective use of bilateral inferior petrosal sinus sampling in patients with adrenocorticotropin-dependent Cushing’s syndrome prior to transsphenoidal surgery. Journal of Clinical Endocrinology and Metabolism. 2008;93(12):4624-4632.
Zampetti B, Grossrubatscher E, Dalino Ciaramella P, Boccardi E, Loli P. Bilateral inferior petrosal sinus sampling. Endocrine connections. 2016;5(4):R12-25.
Rahmani F, Mahdavi M, Edraki K, Valizadeh M. A case series of bilateral inferior petrosal sinus sampling with desmopressin in evaluation of ACTH-dependent Cushing’s syndrome in Iran. Hormones (Athens, Greece). 2021;20(2):299-304.
Swearingen B, Katznelson L, Miller K, et al. Diagnostic errors after inferior petrosal sinus sampling. The Journal of clinical endocrinology and metabolism. 2004;89(8):3752-3763.
Gandhi CD, Meyer SA, Patel AB, Johnson DM, Post KD. Neurologic complications of inferior petrosal sinus sampling. AJNR American journal of neuroradiology. 2008;29(4):760-765.
Walia R, Gupta R, Bhansali A, et al. Molecular Imaging Targeting Corticotropin-releasing Hormone Receptor for Corticotropinoma: A Changing Paradigm. The Journal of clinical endocrinology and metabolism. 2021;106(4):e1816-e1826.
Bashari WA, Senanayake R, Koulouri O, et al. PET-guided repeat transsphenoidal surgery for previously deemed unresectable lateral disease in acromegaly. Neurosurgical focus. 2020;48(6):E8.
Xin C, Rui-xue C, Hui P, Tao Y, Hui-Juan Z, Fang L. Value of [18F] fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography in diagnosis and localization of Cushing’s disease. Zhongguo yi xue ke xue yuan xue bao Acta Academiae Medicinae Sinicae. 2011;33(2):107-110.
Alzahrani AS, Farhat R, Al-Arifi A, Al-Kahtani N, Kanaan I, Abouzied M. The diagnostic value of fused positron emission tomography/computed tomography in the localization of adrenocorticotropin-secreting pituitary adenoma in Cushing’s disease. Pituitary. 2009;12(4):309-314.
Kim M, Kim HS, Kim HJ, et al. Thin-Slice Pituitary MRI with Deep Learning-based Reconstruction: Diagnostic Performance in a Postoperative Setting. Radiology. 2021;298(1):114-122.
Staartjes VE, Serra C, Zoli M, et al. Multicenter external validation of the Zurich Pituitary Score. Acta neurochirurgica. 2020;162(6):1287-1295.
Braileanu M, Hu R, Hoch MJ, et al. Pre-operative MRI predictors of hormonal remission status post pituitary adenoma resection. Clinical imaging. 2019;55:29-34.
Chatain GP, Patronas N, Smirniotopoulos JG, et al. Potential utility of FLAIR in MRI-negative Cushing’s disease. Journal of neurosurgery. 2018;129(3):620-628.
Masopust V, Netuka D, Beneš V, et al. Magnetic resonance imaging and histology correlation in Cushing’s disease. Neurologia i neurochirurgia polska. 2017;51(1):45-52.
Heck A, Ringstad G, Fougner SL, et al. Intensity of pituitary adenoma on T2-weighted magnetic resonance imaging predicts the response to octreotide treatment in newly diagnosed acromegaly. Clinical endocrinology. 2012;77(1):72-78.
Knosp E, Steiner E, Kitz K, Matula C. Pituitary adenomas with invasion of the cavernous sinus space: a magnetic resonance imaging classification compared with surgical findings. Neurosurgery. 1993;33(4):610-617; discussion 617-618.
Fan Y, Liu Z, Hou B, et al. Development and validation of an MRI-based radiomic signature for the preoperative prediction of treatment response in patients with invasive functional pituitary adenoma. European journal of radiology. 2019;121:108647.
Dai C, Feng M, Liu X, et al. Refractory pituitary adenoma: a novel classification for pituitary tumors. Oncotarget. 2016;7(50):83657-83668.
Fan Y, Feng M, Wang R. Application of Radiomics in Central Nervous System Diseases: a Systematic literature review. Clinical neurology and neurosurgery. 2019;187:105565.
Soldozy S, Farzad F, Young S, et al. Pituitary Tumors in the Computational Era, Exploring Novel Approaches to Diagnosis, and Outcome Prediction with Machine Learning. World neurosurgery. 2021;146:315-321.e311.

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

View on Neurosurgery

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:

Kevin O. Lillehei, MD¹, Sarah Travers, MD¹, Garni Barkhoudarian, MD², Nelson M. Oyesiku, MD, MSc (Lond), PhD, FACS³, Isabelle M Germano, MD, MBA⁴ D. Ryan Ormond, MD, PhD¹

Departmental and institutional affiliations:

Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado
Pacific Neuroscience Institute, Santa Monica, California
Department of Neurological Surgery, University of North Carolina, Chapel Hill, North Carolina
Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York

Corresponding Author contact information:

Kevin O. Lillehei, MD

Department of Neurological Surgery

UC Health Neurosciences Center

Anschutz Medical Campus

Keywords: endoscopic surgery, functioning pituitary adenomas, microscopic surgery, surgery, transsphenoidal

Abbreviations:

conflicts of interest (COIs)

extent of surgical resection (EOR)

length of stay (LOS)

Adrenocorticotropic hormone (ACTH)

growth hormone (GH)

Thyroid-Stimulating Hormone (TSH)

cerebrospinal fluid (CSF)

Transsphenoidal Surgery (TSS)

microscopic transsphenoidal surgery (mTSS)

dopamine-agonist (DA)

somatostatin analogs (SA)

slow-release lanreotide (SRL)

upper limit of normal (ULN)

insulin-like growth factor (IGF)

pituitary adenomas (PA)

intraoperative magnetic resonance imaging (iMRI)

magnetic resonance imaging (MRI)

transsphenoidal resection (TSA)

Cushing Disease (CD)

Gamma Knife stereotactic radiosurgery (GKRS)

Conflicts of Interest

Funding

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: With recent improvements in surgery, along with our ability to manage many pituitary tumors medically, the exact role of surgery for the treatment of functioning pituitary adenomas remains unclear.

Objective: The purpose of this evidence-based clinical practice guideline is to determine the role of surgery in the treatment of functioning pituitary adenomas.

Methods: A systematic review of the literature was performed using the National Library of Medicine/PubMed database and Embase for studies relevant to the role of surgery in the treatment of patients with functioning pituitary adenomas. Clinical studies evaluating the role of surgery were selected for review.

Results: The literature search yielded to 7073 abstracts. Of these, 60 studies met inclusion criteria, and evidence-based guidelines were formulated

Conclusions: Class III evidence suggests a benefit to surgery over medical management for GH-secreting adenomas without evidence to support pre-treatment with a somatostatin analogue before surgery. Class III evidence suggests a benefit to medical management over surgery in the treatment of patients with prolactinomas at primary diagnosis. There are insufficient data to support the benefit of endoscopic surgery compared to microscopic surgery, with or without additional adjuvant surgical techniques, for the extent of surgical resection, hormone remission, length of stay, or complication rate, in the treatment of functioning pituitary adenomas. There is a suggestion, however, that the endoscopic technique may be superior to the microscopic technique, for a shorter operative time and for extent of surgical resection and hormone remission rates for noninvasive pituitary microadenomas. EOR and hormone remission rates for non-invasive pituitary macroadenomas. Similarly, there are insufficient data to support the use of reoperation for recurrent tumor compared to radiation and/or medical treatment.

Keywords: endoscopic surgery, functioning pituitary adenomas, microscopic surgery, surgery, transsphenoidal

RECOMMENDATIONS

Target Population: These recommendations apply to adult patients with functioning pituitary adenomas.

Key Question 1: In adult patients with signs/symptoms, endocrine evaluation, and imaging supportive of functioning pituitary microadenomas secreting prolactin, ACTH, GH or TSH, does transsphenoidal surgical resection, compared to medical management alone provide a better clinical outcome?

Recommendation, Level III: In adult patients with signs/symptoms, endocrine evaluation and imaging supportive of functioning pituitary microadenomas secreting prolactin, medical management is suggested over surgery for the treatment at primary diagnosis for providing a better clinical outcome.

Recommendation, Insufficient evidence: Due to the lack of any class I, II, or III studies meeting inclusion criteria in this analysis, no evidence-based recommendation could be made concerning the treatment of ACTH secreting PAs. (See note at end of this Recommendations section*.)

Recommendation, Level III: In adult patients with signs/symptoms, endocrine evaluation and imaging supportive of functioning pituitary microadenomas secreting GH, surgery is suggested over medical management to provide a better clinical outcome and biochemical remission. There is insufficient evidence to support pretreatment with a somatostatin analog (SA).

Recommendation, Insufficient evidence: In adult patients with signs/symptoms, endocrine evaluation, and imaging supportive of functioning pituitary microadenomas secreting TSH, there is insufficient evidence to favor surgery over medical management in providing a better clinical outcome.

Key Question 2: In adult patients with signs/symptoms, endocrine evaluation, and imaging supportive of functioning pituitary requiring surgical resection, do endoscopic techniques, compared to transsphenoidal micro-surgery alone provide an increased surgical resection?

Recommendation, Insufficient evidence: In adult patients with signs/symptoms, endocrine evaluation, and imaging supportive of FPA requiring surgical resection, endoscopic techniques are not superior to microscopic techniques for EOR, hormone remission, LOS, or complication rates, in the treatment of functioning pituitary adenomas. There is a suggestion, however, that the endoscopic technique may be superior to the microscopic technique, for a shorter operative time and for EOR and hormone remission rates for pituitary macroadenomas without cavernous sinus invasion.

Key Question 3. In adult patients with signs/symptoms, endocrine evaluation, and imaging supportive of FPA requiring surgical resection, do other adjuvant surgical techniques (neuronavigation, cerebrospinal fluid (CSF) diversion, intrathecal injection, dural closure techniques), compared to standard transsphenoidal micro-surgery techniques provide a better outcome?

Recommendation, Insufficient evidence: There is insufficient evidence to make recommendations regarding adjuvant surgical techniques for transsphenoidal surgery (TSS) for functioning pituitary adenomas compared with standard TSS techniques regarding outcome improvement.

Key Question 4: In adult patients with signs/symptoms, endocrine evaluation, and imaging supportive of residual FPA, does a second surgery, compared to medical management and or radiotherapy, provide a better outcome?

Recommendation, Insufficient evidence: In adult patients with recurrent Cushing Disease, or recurrent acromegaly, there is insufficient evidence to recommend that a second operation provides improved radiographic or biochemical control compared to medical treatment or radiotherapy.

*NOTE: Absent class I, II, or III evidence-based studies concerning the treatment of ACTH secreting PAs, expert opinion favors the strong consideration of operative intervention as the first line of therapy.

INTRODUCTION

With the recent improvements in surgery, along with our ability to manage many pituitary tumors medically, the exact role of surgery for the treatment of functioning pituitary adenomas remains unclear. The purpose of this evidence-based clinical practice guideline is to determine the role of surgery in the treatment of functioning pituitary adenomas. Neurosurgical intervention in patients with functioning pituitary adenomas is evolving and the role of endoscopic transsphenoidal techniques versus microsurgery, surgery versus medical management, and the beneficial role of adjuvant surgical techniques, along with second surgery on patient outcomes remains unclear.

This clinical guideline was created to improve patient care by outlining the appropriate information gathering and decision-making processes involved in the treatment of patients with functioning pituitary adenomas. This guideline has been created as an educational tool to guide qualified physicians through a series of diagnostic and treatment decisions to improve the quality and efficiency of care.

Methodology

The guidelines task force initiated a systematic review of the literature and evidence-based guideline relevant to the treatment of patients with functioning pituitary adenomas. 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 functioning pituitary adenomas. 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). These guidelines are developed for educational purposes to assist practitioners in their clinical decision-making processes.

The task force members identified search terms/parameters and a medical librarian implemented the literature search, consistent with the literature search protocol using the National Library of Medicine/PubMed database and Embase for the period from 1946 to June 8, 2021 using the search strategies and methodology provided in Supplemental Digital Content 1.

RESULTS

The literature search yielded 7073 abstracts. Of these, 60 met criteria and were used to provide evidence-based recommendations (Supplemental Digital Content 3). With respect to treatment for prolactin-producing pituitary adenomas, medical management appears to be safe and effective at reducing the tumor size and controlling the prolactin level and is suggested over surgical treatment at the time of primary diagnosis. In GH secreting tumors, surgery is favored over medical management to provide better clinical outcomes at the time of initial presentation. There was contradictory or insufficient evidence for other tumor types. In evaluating the superiority of endoscopic vs microscopic techniques, studies are contradictory whether there is a significant difference between either technique concerning complication rates, LOS, and intra-operative blood loss. Overall, there appeared to be no advantage to either technique in EOR or hormonal remission rates. There was a suggestion, however, that the endoscopic technique may be superior to the microscopic technique, for EOR and hormone remission rates, for non-invasive pituitary macroadenomas. This recommendation does not hold for microadenomas or invasive adenomas with extension into the cavernous sinus. The data also suggests that the endoscopic technique is associated with a shorter operative time. Regarding adjuvant techniques, given insufficient evidence, no specific recommendations for adjuvant surgical techniques could be made for functioning pituitary adenomas compared to standard transphenoidal techniques to improve outcomes. All the data available on reoperation were related to Cushing’s disease. These data provided level III evidence, showed significant heterogeneity and had contradictory results, precluding any ability to recommend one treatment modality over another.

Conclusions

This guideline relied on a significant literature for review and ultimate Guidelines recommendations. However, despite this, very few studies met inclusion criteria, and most were of low quality. For this reason, there was often insufficient evidence to draw conclusions and make recommendations, or data was contradictory and not of high quality. Future studies of higher quality are needed to address these questions, many of which remain unanswered.

Conflicts of Interest

Disclaimer of Liability

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, Kirsten Aquino, contracted project manager 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

Ransohoff DF, M. Pignone, and H.C. Sox, . How to decide whether a clinical practice guideline is trustworthy. . JAMA. 2013;309(2):139-140.
Andereggen L, Frey J, Andres RH, et al. 10-year follow-up study comparing primary medical vs. surgical therapy in women with prolactinomas. Endocrine. 2017;55(1):223-230.
Berinder K, Stackenäs I, Akre O, Hirschberg AL, Hulting AL. Hyperprolactinaemia in 271 women: up to three decades of clinical follow-up. Clinical endocrinology. 2005;63(4):450-455.
Asano S, Ueki K, Suzuki I, Kirino T. Clinical features and medical treatment of male prolactinomas. Acta neurochirurgica. 2001;143(5):465-470.
Acquati S, Pizzocaro A, Tomei G, et al. A comparative evaluation of effectiveness of medical and surgical therapy in patients with macroprolactinoma. Journal of neurosurgical sciences. 2001;45(2):65-69.
Elston MS, Conaglen JV. Clinical and biochemical characteristics of patients with thyroid-stimulating hormone-secreting pituitary adenomas from one New Zealand centre. Internal medicine journal. 2010;40(3):214-219.
Macchia E, Gasperi M, Lombardi M, et al. Clinical aspects and therapeutic outcome in thyrotropin-secreting pituitary adenomas: a single center experience. Journal of endocrinological investigation. 2009;32(9):773-779.
Căpraru OM, Gaillard C, Vasiljevic A, et al. Diagnosis, pathology, and management of TSH-secreting pituitary tumors. A single-center retrospective study of 20 patients from 1981 to 2014. Annales d’endocrinologie. 2019;80(4):216-224.
Van Varsseveld NC, Bisschop PHLT, Biermasz NR, Pereira AM, Fliers E, Drent ML. A long-term follow-up study of eighteen patients with thyrotrophin- secreting pituitary adenomas. Clinical endocrinology. 2014;80(3):395-402.
Karaca Z, Tanriverdi F, Elbuken G, et al. Comparison of primary octreotide-lar and surgical treatment in newly diagnosed patients with acromegaly. Clinical endocrinology. 2011;75(5):678-684.
Biermasz NR, van Dulken H, Roelfsema F. Direct postoperative and follow-up results of transsphenoidal surgery in 19 acromegalic patients pretreated with octreotide compared to those in untreated matched controls. The Journal of clinical endocrinology and metabolism. 1999;84(10):3551-3555.
Shen M, Shou X, Wang Y, et al. Effect of presurgical long-acting octreotide treatment in acromegaly patients with invasive pituitary macroadenomas: a prospective randomized study. Endocrine journal. 2010;57(12):1035-1044.
Cannavò S, Squadrito S, Curtò L, Almoto B, Trimarchi F. Effectiveness of slow-release lanreotide in previously operated and untreated patients with GH-secreting pituitary macroadenoma. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2001;33(10):618-624.
Evran M, Sert M, Tetiker T. Clinical experiences and success rates of acromegaly treatment: the single center results of 62 patients. BMC endocrine disorders. 2014;14:97.
Colao A, Pivonello R, Galderisi M, et al. Impact of treating acromegaly first with surgery or somatostatin analogs on cardiomyopathy. The Journal of clinical endocrinology and metabolism. 2008;93(7):2639-2646.
Portocarrero-Ortiz LA, Vergara-Lopez A, Vidrio-Velazquez M, et al. The Mexican Acromegaly Registry: Clinical and Biochemical Characteristics at Diagnosis and Therapeutic Outcomes. The Journal of clinical endocrinology and metabolism. 2016;101(11):3997-4004.
Mercado M, Abreu C, Vergara-López A, et al. Surgical and Pharmacological Outcomes in Acromegaly: Real-Life Data From the Mexican Acromegaly Registry. The Journal of clinical endocrinology and metabolism. 2020;105(12).
Kristof RA, Stoffel-Wagner B, Klingmüller D, Schramm J. Does octreotide treatment improve the surgical results of macro-adenomas in acromegaly? A randomized study. Acta neurochirurgica. 1999;141(4):399-405.
Colao A, Ferone D, Cappabianca P, et al. Effect of octreotide pretreatment on surgical outcome in acromegaly. Journal of Clinical Endocrinology and Metabolism. 1997;82(10):3308-3314.
Eseonu CI, ReFaey K, Garcia O, Salvatori R, Quinones-Hinojosa A. Comparative Cost Analysis of Endoscopic versus Microscopic Endonasal Transsphenoidal Surgery for Pituitary Adenomas. Journal of neurological surgery Part B, Skull base. 2018;79(2):131-138.
Cho DY, Liau WR. Comparison of endonasal endoscopic surgery and sublabial microsurgery for prolactinomas. Surgical neurology. 2002;58(6):371-375; discussion 375-376.
Wong EH, Al-Witri A, Chong J, Brown SJ, Dexter MAJ, Singh N. An alternative technique for pituitary tumour removal: Sequential endoscopic-microscopic pituitary procedure (SEMPP). Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2019;64:94-97.
O’Malley BW, Jr., Grady MS, Gabel BC, et al. Comparison of endoscopic and microscopic removal of pituitary adenomas: single-surgeon experience and the learning curve. Neurosurgical focus. 2008;25(6):E10.
Choe JH, Lee KS, Jeun SS, Cho JH, Hong YK. Endocrine outcome of endoscopic endonasal transsphenoidal surgery in functioning pituitary adenomas. Journal of Korean Neurosurgical Society. 2008;44(3):151-155.
Sarkar S, Chacko AG, Chacko G. An analysis of granulation patterns, MIB-1 proliferation indices and p53 expression in 101 patients with acromegaly. Acta neurochirurgica. 2014;156(12):2221-2230; discussion 2230.
Bokhari AR, Davies MA, Diamond T. Endoscopic transsphenoidal pituitary surgery: a single surgeon experience and the learning curve. British journal of neurosurgery. 2013;27(1):44-49.
Pablo A, Sofia B, Maximiliano T, et al. Endoscopic versus Microscopic Pituitary Adenoma Surgery: A Single-center Study. Neurology India. 2019;67(4):1015-1021.
Eseonu CI, ReFaey K, Rincon-Torroella J, et al. Endoscopic Versus Microscopic Transsphenoidal Approach for Pituitary Adenomas: Comparison of Outcomes During the Transition of Methods of a Single Surgeon. World neurosurgery. 2017;97:317-325.
Guo-Dong H, Tao J, Ji-Hu Y, et al. Endoscopic Versus Microscopic Transsphenoidal Surgery for Pituitary Tumors. The Journal of craniofacial surgery. 2016;27(7):e648-e655.
Jain AK, Gupta AK, Pathak A, Bhansali A, Bapuraj JR. Excision of pituitary adenomas: randomized comparison of surgical modalities. British journal of neurosurgery. 2007;21(4):328-331.
Ogawa T, Matsumoto K, Nakashima T, et al. Hypophysis surgery with or without endoscopy. Auris, nasus, larynx. 2001;28(2):143-149.
Dehdashti AR, Ganna A, Karabatsou K, Gentili F. Pure endoscopic endonasal approach for pituitary adenomas: early surgical results in 200 patients and comparison with previous microsurgical series. Neurosurgery. 2008;62(5):1006-1015; discussion 1015-1007.
Wang AC, Shah AH, Sidani C, et al. Volumetry in the Assessment of Pituitary Adenoma Resection: Endoscopy versus Microscopy. Journal of neurological surgery Part B, Skull base. 2018;79(6):538-544.
Kawamata T, Iseki H, Ishizaki R, Hori T. Minimally invasive endoscope-assisted endonasal trans-sphenoidal microsurgery for pituitary tumors: experience with 215 cases comparing with sublabial trans-sphenoidal approach. Neurological research. 2002;24(3):259-265.
Kartal I, Üzüm AK, Mert M, Tamer G, Özbey N, Aral F. Outcomes of endoscopic endonasal transsphenoidal surgery in Cushing’s disease. Nobel Medicus. 2011;7(2):45-49.
Popov D, Hadzhiyanev A, Bussarsky A, Ferdinandov D. Short-term outcome of endoscopic versus microscopic pituitary adenoma surgery in a single center. Biomedical Research (India). 2018;29(14):2971-2974.
Kalinin PL, Sharipov OI, Pronin IN, et al. Endoscopic transsphenoidal resection of pituitary adenomas invading the cavernous sinus. Zhurnal voprosy neirokhirurgii imeni N N Burdenko. 2016;80(4):63-74.
McLaughlin N, Eisenberg AA, Cohan P, Chaloner CB, Kelly DF. Value of endoscopy for maximizing tumor removal in endonasal transsphenoidal pituitary adenoma surgery. Journal of neurosurgery. 2013;118(3):613-620.
Razak AA, Horridge M, Connolly DJ, et al. Comparison of endoscopic and microscopic trans-sphenoidal pituitary surgery: early results in a single centre. British journal of neurosurgery. 2013;27(1):40-43.
Kabil MS, Eby JB, Shahinian HK. Fully endoscopic endonasal vs. transseptal transsphenoidal pituitary surgery. Minimally invasive neurosurgery : MIN. 2005;48(6):348-354.
Cappabianca P, Alfieri A, Colao A, Ferone D, Lombardi G, de Divitiis E. Endoscopic endonasal transsphenoidal approach: an additional reason in support of surgery in the management of pituitary lesions. Skull base surgery. 1999;9(2):109-117.
Lenzi J, Lapadula G, D’Amico T, et al. Evaluation of trans-sphenoidal surgery in pituitary GH-secreting micro- and macroadenomas: a comparison between microsurgical and endoscopic approach. Journal of neurosurgical sciences. 2015;59(1):11-18.
Bora SK, Suri A, Khadgawat R, et al. Management of Cushing’s Disease: Changing Trend from Microscopic to Endoscopic Surgery. World neurosurgery. 2020;134:e46-e54.
D’Haens J, Van Rompaey K, Stadnik T, Haentjens P, Poppe K, Velkeniers B. Fully endoscopic transsphenoidal surgery for functioning pituitary adenomas: a retrospective comparison with traditional transsphenoidal microsurgery in the same institution. Surgical neurology. 2009;72(4):336-340.
Strange F, Remonda L, Schütz P, Fandino J, Berkmann S. 10 Years’ Experience of Using Low-Field Intraoperative MRI in Transsphenoidal Surgery for Pituitary Adenoma: Results of the Swiss Pituitary Registry (SwissPit). World neurosurgery. 2020;136:e284-e293.
Kim EH, Oh MC, Kim SH. Application of low-field intraoperative magnetic resonance imaging in transsphenoidal surgery for pituitary adenomas: technical points to improve the visibility of the tumor resection margin. Acta neurochirurgica. 2013;155(3):485-493.
. Determining the utility of intraoperative magnetic resonance imaging for transsphenoidal surgery: a retrospective study. Journal of neurosurgery. 2014;120(2):346-356.
Dusick JR, Esposito F, Mattozo CA, Chaloner C, McArthur DL, Kelly DF. Endonasal transsphenoidal surgery: the patient’s perspective-survey results from 259 patients. Surgical neurology. 2006;65(4):332-341, discussion 341-332.
Kim EH, Roh TH, Park HH, Moon JH, Hong JB, Kim SH. Direct suture technique of normal gland edge on the incised dura margin to repair the intraoperative cerebrospinal fluid leakage from the arachnoid recess during transsphenoidal pituitary tumor surgery. Neurosurgery. 2015;11 Suppl 2:26-31; discussion 31.
Nishioka H, Izawa H, Ikeda Y, Namatame H, Fukami S, Haraoka J. Dural suturing for repair of cerebrospinal fluid leak in transnasal transsphenoidal surgery. Acta neurochirurgica. 2009;151(11):1427-1430.
Esposito F, Dusick JR, Fatemi N, Kelly DF. Graded repair of cranial base defects and cerebrospinal fluid leaks in transsphenoidal surgery. Operative neurosurgery (Hagerstown, Md). 2007;60(4 Suppl 2):295-303; discussion 303-294.
Sherman JH, Pouratian N, Okonkwo DO, Jane JA, Jr., Laws ER. Reconstruction of the sellar dura in transsphenoidal surgery using an expanded polytetrafluoroethylene dural substitute. Surgical neurology. 2008;69(1):73-76; discussion 76.
Charalampaki P, Reisch R, Ayad A, Welschehold S, Conrad J, Wüster C. Image-guided endonasal transsphenoidal microsurgical treatment of recurrent microadenomas of the pituitary gland. Minimally invasive neurosurgery : MIN. 2006;49(2):93-97.
Achey RL, Karsy M, Azab MA, et al. Improved Surgical Safety via Intraoperative Navigation for Transnasal Transsphenoidal Resection of Pituitary Adenomas. Journal of neurological surgery Part B, Skull base. 2019;80(6):626-631.
Mehta GU, Oldfield EH. Prevention of intraoperative cerebrospinal fluid leaks by lumbar cerebrospinal fluid drainage during surgery for pituitary macroadenomas. Journal of neurosurgery. 2012;116(6):1299-1303.
Bodaghabadi M, Riazi H, Aran S, et al. Repeated transsphenoidal surgery or gamma knife radiosurgery in recurrent cushing disease after transsphenoidal surgery. Journal of neurological surgery Part A, Central European neurosurgery. 2014;75(2):91-97.
Aghi MK, Petit J, Chapman P, et al. Management of recurrent and refractory Cushing’s disease with reoperation and/or proton beam radiosurgery. Clinical neurosurgery. 2008;55:141-144.
Prevedello DM, Pouratian N, Sherman J, et al. Management of Cushing’s disease: outcome in patients with microadenoma detected on pituitary magnetic resonance imaging. Journal of neurosurgery. 2008;109(4):751-759.
Espinosa-de-Los-Monteros AL, Sosa-Eroza E, Espinosa E, Mendoza V, Arreola R, Mercado M. LONG-TERM OUTCOME OF THE DIFFERENT TREATMENT ALTERNATIVES FOR RECURRENT AND PERSISTENT CUSHING DISEASE. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2017;23(7):759-767.
Martínez Ortega AJ, Venegas-Moreno E, Dios E, et al. Surgical Outcomes and Comorbidities in Cushing Disease: 30 Years of Experience in a Referral Center. World neurosurgery. 2019;122:e436-e442.
Ross DA, Wilson CB. Results of transsphenoidal microsurgery for growth hormone-secreting pituitary adenoma in a series of 214 patients. Journal of neurosurgery. 1988;68(6):854-867.

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

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:

Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York
Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota
Department of Neurosurgery & Radiation Oncology, West Virginia University
Department of Neurosurgery, Cleveland Clinic, Cleveland, Ohio
Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia
Department of Neuro-oncology at Inova Schar Cancer Institute, Fairfax, Virginia
Department of Neurosurgery, University of Colorado Anschutz Medical Campus, Aurora, Colorado
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

Funding

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

Disclaimer of Liability

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

Oncology ASoC. Cancer.Net. Pituitary Gland Tumor: Statistics 2023; https://www.cancer.net/cancer-types/pituitary-gland-tumor/statistics#. Accessed 7/26/2023, 2023.
Dekkers OM, Karavitaki N, Pereira AM. The epidemiology of aggressive pituitary tumors (and its challenges). Rev Endocr Metab Disord. 2020;21(2):209-212.
Mehta GU, Lonser RR. Management of hormone-secreting pituitary adenomas. Neuro Oncol. 2017;19(6):762-773.
Molitch ME. Diagnosis and Treatment of Pituitary Adenomas: A Review. Jama. 2017;317(5):516-524.
Asa SL, Mete O, Perry A, Osamura RY. Overview of the 2022 WHO Classification of Pituitary Tumors. Endocrine pathology. 2022;33(1):6-26.
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).
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.
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.
Ransohoff DF, Pignone M, Sox HC. How to decide whether a clinical practice guideline is trustworthy. JAMA. 2013;309(2):139-140.
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.
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.
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.
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.
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.
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.
Jallad RS, Musolino NR, Salgado LR, Bronstein MD. Treatment of acromegaly: is there still a place for radiotherapy? Pituitary. 2007;10(1):53-59.
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.
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.
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.
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.
Ding D, Mehta GU, Patibandla MR, et al. Stereotactic Radiosurgery for Acromegaly: An International Multicenter Retrospective Cohort Study. Neurosurgery. 2019;84(3):717-725.
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.
Ježková J, Hána V, Kosák M, et al. Role of gamma knife radiosurgery in the treatment of prolactinomas. Pituitary. 2019;22(4):411-421.
Liu X, Kano H, Kondziolka D, et al. Gamma knife radiosurgery for clinically persistent acromegaly. Journal of neuro-oncology. 2012;109(1):71-79.
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.
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.
Vik-Mo EO, Oksnes M, Pedersen PH, et al. Gamma knife stereotactic radiosurgery for acromegaly. European journal of endocrinology. 2007;157(3):255-263.
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.
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.
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.

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Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines for Patients with Functioning Pituitary Adenomas

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