Congress of Neurological Surgeons Evidence-Based Clinical Practice Guidelines for the Treatment of Adults with Vestibular Schwannoma:  Introduction and Methods Update

1. Introduction And Methods: Update

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

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

(CNS)

Author: Jeffrey J. Olson, MD¹

Departmental and institutional affiliations:

1. Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia, USA

Corresponding Author contact information:

Keywords:  vestibular schwannoma, acoustic neuroma, guideline

Abbreviations:  AANS:  American Association of Neurological Surgeons, Akt: protein kinase B, CNS: Congress of Neurological Surgeons, DNA:  deoxyribonucleic acid, ErbB:  erythroblastic leukemia viral oncogene,  ERK:  extracellular signal regulated kinase, MEK:  mitogen-activated extracellular signal-regulated kinase, NF2: neurofibromatosis type 2, mTORC1:  mammalian target of rapamycin complex 1, PDGFR:  platelet derived growth factor receptor, PI3K:  phosphoinositide 3-kinase , Raf:  rapidly accelerated fibrosarcoma, Ras: rat sarcoma, RNA:  ribonucleic acid, VS:  vestibular schwannoma

ABSTRACT

Background:  The management of vestibular schwannomas is an important facet of physicians practicing neurosurgery, neuro-otology, and an important diagnosis to keep in mind for audiologists, radiologists, and pathologists.  

Objective:  This is an update of the evidence-based guidelines for management of vestibular schwannomas published by the Congress of Neurological Surgeons in 2018. 

Methods:  The questions from the previously published guideline were updated to PICO format.  The medical literature from 1/1/2015 through 5/20/2022 was searched with these reformatted questions serving as guidance to determine if information was available to update, modify or create new recommendations in the context of the prior guidelines related to audiologic screening, imaging, surgery, intraoperative cranial nerve monitoring, hearing preservation and radiation therapy.

Results:  The writing group utilized the information from the updated literature search to modify old recommendations or formulate new recommendations based on this evidence.  Across all six sections of the guideline, 31 questions were utilized to direct a search of the literature ultimately yielding 27 recommendations. 

Conclusion:  This series of guideline documents provides an update and addition to the information and recommendations provided in the 2018 version. It now serves as this organization’s most up to date and current recommendations on the management of vestibular schwannoma.  It also sets a point of reference for treatment development and topics for research going forward to improve management of this difficult disease. 

INTRODUCTION

Background and Rationale

The guidelines for the management of vestibular schwannomas was sponsored by the Congress of Neurological Surgeons (CNS) were published in 2018.[1-9]  As suggested by the Institute of Medicine, now the National Academy of Medicine, guidelines should be updated in the range of every 5 years.[10]  That interval allows for a reasonable time to assess new methods of diagnosis and treatment including audiologic screening, imaging, surgery, intraoperative cranial nerve monitoring, hearing preservation and radiation therapy that have developed since the time of the publication in 2018.[11-20]  A set of guideline documents representing each of these management topics have been produced.  They were produced using the evidence-based methodology supported by the Joint Guidelines Review Committee of the American Association of Neurological Surgeons (AANS) and Congress of Neurological Surgeons (CNS) which can be found at https://www.cns.org/guidelines/guideline-development-methodology.  

Objectives and Guideline Panel Development

The objectives of these guidelines are to update the evidence-based management of vestibular schwannomas published in 2018.  The writing group was recruited from those who had written the original version of this guideline and new writers from the neurosurgical, neuro-otology and radiation oncology communities.  The authors were screened for professional conflicts, and this was documented as outlined under the Conflicts of Interest section below. 

Topic Range of this Systematic Review and Evidence-Based Clinical Practice Guideline

The subjects of this guideline update include initial otologic evaluation, imaging diagnosis, use of surgical techniques, intraoperative monitoring, and the administration of radiation therapy.  The initial set of publications in 2018 included sections on pathology and emerging therapies.  However, the ability to make strong recommendations regarding those topics was limited.  Upon review of the literature published since the close of the searches for the initial publication new publications provided negative or contradictory class III information at best and did not warrant an update in those areas. 

To elaborate on why the pathology and emerging therapies have no updates, targeted therapy for either sporadic vestibular schwannomas or those related to neurofibromatosis type 2 (NF2) certainly is an area of interest.  However, the following data regarding these interventions are both positive and negative, precluding development of a coherent recommendation.  In a small study of everolimus in ten NF2 subjects, no reduction in vestibular schwannoma volume was noted over 12 months of therapy, though the rate of tumor growth was observed in four individuals.[21]  In a later phase 0 study looking at the effect of everolimus on its commonly understood targets in theses tumors, it was observed that the drug incompletely inhibited mTORC1 and its downstream signaling, thus explaining this lack of substantial tumor controlling effect.[22]  In a small carefully monitored 14 subject cohort of NF2 associated VS, treated with bevacizumab for nearly a year, 35% of subjects had measurable hearing improvement and 43% had a partial radiographic response.[23]  Contrary to that experience, in another study, assessing 9 individuals with 16 surgically debulked tumors, bevacizumab induced no evidence of tumor growth control or measurable improvements in speech discrimination scores or pure tone audiometry.[24]  In a prospective study of fourteen individuals with NF2 related vestibular schwannomas, half the subjects reported self-assessed reductions in hearing difficulty with over a 48 week course of bevacizumab , 7.5 mg/kg every three weeks.  This improvement correlated with objective word recognition scores but not with pure tone audiometry.[25]  When used, higher doses of bevacizumab to not seem to increase rates of hearing response or radiographic response in the short term.[26]  In the studies using bevacizumab, varying proportions of subjects, usually in the range of 25%, had to stop or substantially modify therapy because of toxicity, generally manifest as fatigue, hypertension, proteinuria, skin and mucous membrane dryness, and infection.[24, 27]  Based on these findings, the authors chose against making a recommendation for bevacizumab at this time.  Interestingly, and in spite of these reported experiences from the interval of the search for this guideline update not being uniformly positive, the use of bevacizumab has been adopted an established treatment option for NF2 associated schwannomas based on previous experience and publications.[1-8] 

METHODOLOGY

As first step the guidelines task force reviewed the questions from the 2018 publications and modified them to PICO (patient/intervention/comparison/outcome) format.  With these as guidance the guidelines task force initiated a systematic review of the literature and evidence-based guideline relevant to the treatment of patients with vestibular schwannomas. Through objective evaluation of the evidence and transparency in the process of making recommendations, this evidence-based clinical practice guideline update was developed for the diagnosis and treatment of adult patients with vestibular schwannomas. These guidelines are developed 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.

Literature Examination Approach

A thorough literature search strategy was undertaken to identify all citations relevant to the management of vestibular schwannomas in regard to the set of chosen topics. The PubMed and Embase electronic databases were searched, with guidance of a reference librarian, from January 1, 2015, through May 20, 2022 using the search strategies provided in Appendix I.  The search strategies used a combination of controlled vocabulary and text words. The specifics of the searches for a given topic are outlined in each respective guideline section. The writing groups used the citations from these databases that were pertinent to answering the questions they had developed. In addition, important articles from before this interval were reviewed and included if deemed to be critical evidence by the writing group. For completeness, reference lists of the publications chosen for full-text review were also screened for potentially relevant studies. 

Study Selection, Quality Assessment and Statistical Methods

The searches of the bibliographic databases identified possibly relevant citations for a given topic, and often these were large in number.  The eligibility (inclusion/exclusion) criteria to screen the citations for each of the questions were determined ahead of time for each section by the respective writing group.  These are documented in the individual clinical practice guideline sections in this series to assist the reader in understanding the development process.  At least two authors evaluated the titles and abstracts using the inclusion and exclusion criteria. Cases of disagreement about pertinence were resolved by a third author when needed. Full text articles of the selected abstracts were then collected and the same process of applying the eligibility criteria was carried out again with the more in depth information available.  Articles that met the eligibility criteria were grouped according to the questions they addressed and used to create the evidence tables and scientific foundation sections. Reasons for exclusion for papers were also documented so as to be able to discuss pertinent problem citations in the scientific foundation as needed. 

The method by which evidence was assessed and reported is expanded upon in the CNS Guideline Development Methodology document (https://www.cns.org/guidelines/guideline-development-methodology).  The qualifying evidence derived from the searches was then collected and compared to the evidence already present in the 2018 publications, i.e., through the end of 2014, to determine if the recommendations could remain unchanged, needed updating, or if whole new recommendations were warranted.  Internal drafts of the tables and manuscripts were developed by sharing them between writers electronically, by telephone, and in face-to-face meetings.  Summary and conclusion statements were included for each section, with comments on key issues for future investigation being added where pertinent.  

No question resulted in a collection of studies that warranted a meta-analysis. 

Rating Quality of Evidence

The quality of evidence was rated using an evidence hierarchy for each of four different study types; therapeutic, prognostic, diagnostic, and decision modeling. These hierarchies are shown in Appendix II: Rating Evidence Quality. Additional information regarding the hierarchy classification of evidence can be located here: https://www.cns.org/guidelines/guideline-procedures-policies/guideline-development-methodology.

Revision Plans

In accordance with the National Academy of Medicine’s standards for developing clinical practice guidelines and criteria specified by the former National Guideline Clearinghouse, the task force will monitor related publications following the release of this document and will revise the entire document and/or specific sections “if new evidence shows that a recommended intervention causes previously unknown substantial harm; that a new intervention is significantly superior to a previously recommended intervention from an efficacy or harms perspective; or that a recommendation can be applied to new populations.[28]”  In addition, the task force will confirm within five years from the date of publication that the content reflects current clinical practice and the available technologies for the evaluation and treatment for patients with vestibular schwannomas.

SUMMARY

This series of guidelines assessed new literature from 2015 to 2022 in the context of the data already abstracted for the prior version to update and make current and clinically relevant evidence for management of vestibular schwannomas.  They serve to  set a point of reference for patient care while also highlighting important key areas for future research.  This will allow design of future investigations in a manner that overcomes prior weaknesses noted in these guidelines.  Secondarily, the suggestions provided are set forth for conscientious use by the practicing physician who must account for all the unique individual conditions in the therapy of a given person during his or her illness. 

Fortunately, new research is constantly underway.  This includes clinical trials currently pursuing the potential value of systemic brigatinib, aspirin, losartan, axitinib and local doxycycline.[29] 

Application of advanced RNA profiling and DNA methylation analysis of vestibular schwannomas that have been banked for analysis by Landry et al resulted in identification of two main subgroups of tumor, they term “immunogenic” and “proliferative”.  The immune checkpoint pathway and MEK pathway integrity is very different in these subgroups may provide an avenue to application of gene network analysis and computational drug repurposing.[30]  In another analysis of banked NF2 vestibular schwannomas Amit et al correlated rate of tumor progession after resection with immune cell profiles showing a distinct difference from those that recur more slowly.[31]  In respect to the possibility of using immunologically directed therapies, a clinical trial using aVEGFR-1/2 peptide vaccine was also conducted in patients with progressive NF2-derived tumors, showing hearing improvement and tumor volume reduction.[32]

Merlin, the protein lost in NF2 related schwannomas, and many sporadic vestibular schwannomas inhibits the signaling of various tyrosine kinases and their downstream proliferative signals.  This naturally leads to the consideration of several protein kinase inhibitors that can prevent tumor progression by inhibtion of these tyrosine kinases or members of their downstream pathways.  This includes the including retrovirus-associated DNA sequences(Ras)/rapidly accelerated fibrosarcoma (Raf)/mitogen extracellular signal-regulated kinase(MEK)/extracellular-signal-regulated kinases (ERK) pathways and mammalian target of rapamycin complex 1 (mTORC1)/phosphoinositide 3-kinase (PI3K)/Akt pathways.[33, 34  Though of scientific interest clinical trials of inhibitors of ErbB and PDGFR pathway function in vestibular schwannomas have been without positive effect.[35, 36] Although a phase II study has shown that everolimus is ineffective in progressive NF2-related VS patients, another study has shown that everolimus reduced the tumor volume in 55.6% of patients with NF2-related VS.[21, 37, 38]. Thus, the effect of everolimus is still debatable and warrants additional study. 

Wider afield is the preclinical development of therapy with dietary supplements such as sulforane from broccoli, bacteriotherapy (direct injection of Salmonella typhimurium followed by administration of enrofloxacin, and adeno-associated virus mediated gene therapy to restore the NF2 gene to merlin deficient cells.[29, 39, 40, 41]  The result of this work on immunologic, targeted and alternative therapies will eventually result in the modification of these guidelines as updates are published. 

The data analyzed for this set of guidelines has been collected through May 20, 2022.  It is estimated that the updated iteration of this guideline overall will be written in approximately five years with modification of this time-line dependent on emergence of important scientific and therapeutic advances. 

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 III for a complete list of disclosures.

Disclosure of 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.

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: Patti Raksin, Tjoumakaris, Andrew Carlson,  Neil Majmundar, Jeff Mullin and Koji Ebersole.

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Appendix I: Literature Searches

See individual chapters

Appendix II: Rating Evidence Quality

Classification of Evidence on Therapeutic Effectiveness and Levels of Recommendation

Classification of Evidence on Prognosis and Levels of Recommendation

Classification of Evidence on Diagnosis and Levels of Recommendation

Classification of Evidence on Clinical Assessment and Levels of Recommendation

Appendix III. Conflicts of Interest