Upfront Radiosurgery vs a Wait-and-Scan Approach for Small- or Medium-Sized Vestibular Schwannoma: The V-REX Randomized Clinical Trial.

Importance: Current guidelines for treating small- to medium-sized vestibular schwannoma recommend either upfront radiosurgery or waiting to treat until tumor growth has been detected radiographically. Objective: To determine whether upfront radiosurgery provides superior tumor volume reduction to a wait-and-scan approach for small- to medium-sized vestibular schwannoma. Design, Setting, and Participants: Randomized clinical trial of 100 patients with a newly diagnosed (<6 months) unilateral vestibular schwannoma and a maximal tumor diameter of less than 2 cm in the cerebellopontine angle as measured on magnetic resonance imaging. Participants were enrolled at the Norwegian National Unit for Vestibular Schwannoma from October 28, 2014, through October 3, 2017; 4-year follow-up ended on October 20, 2021. Interventions: Participants were randomized to receive either upfront radiosurgery (n = 50) or to undergo a wait-and-scan protocol, for which treatment was given only upon radiographically documented tumor growth (n = 50). Participants underwent 5 annual study visits consisting of clinical assessment, radiological examination, audiovestibular tests, and questionnaires. Main Outcomes and Measures: The primary outcome was the ratio between tumor volume at the trial end at 4 years and baseline (V4:V0). There were 26 prespecified secondary outcomes, including patient-reported symptoms, clinical examinations, audiovestibular tests, and quality-of-life outcomes. Safety outcomes were the risk of salvage microsurgery and radiation-associated complications. Results: Of the 100 randomized patients, 98 completed the trial and were included in the primary analysis (mean age, 54 years; 42% female). In the upfront radiosurgery group, 1 participant (2%) received repeated radiosurgery upon tumor growth, 2 (4%) needed salvage microsurgery, and 45 (94%) had no additional treatment. In the wait-and-scan group, 21 patients (42%) received radiosurgery upon tumor growth, 1 (2%) underwent salvage microsurgery, and 28 (56%) remained untreated. For the primary outcome of the ratio of tumor volume at the trial end to baseline, the geometric mean V4:V0 was 0.87 (95% CI, 0.66-1.15) in the upfront radiosurgery group and 1.51 (95% CI, 1.23-1.84) in the wait-and-scan group, showing a significantly greater tumor volume reduction in patients treated with upfront radiosurgery (wait-and-scan to upfront radiosurgery ratio, 1.73; 95% CI, 1.23-2.44; P = .002). Of 26 secondary outcomes, 25 showed no significant difference. No radiation-associated complications were observed. Conclusion and relevance: Among patients with newly diagnosed small- and medium-sized vestibular schwannoma, upfront radiosurgery demonstrated a significantly greater tumor volume reduction at 4 years than a wait-and-scan approach with treatment upon tumor growth. These findings may help inform treatment decisions for patients with vestibular schwannoma, and further investigation of long-term clinical outcomes is needed. Trial Registration: ClinicalTrials.gov Identifier: NCT02249572.

Vestibular Tests Related to Tumor Volume in 137 Patients With Small to Medium-Sized Vestibular Schwannoma.

OBJECTIVE: The video head impulse test (vHIT) and cervical and ocular vestibular evoked myogenic potentials (cVEMP and oVEMP) are new methods for measuring peripheral vestibular function. The objectives of this study were to compare these tests and the traditionally used caloric test in patients with small and medium-sized untreated vestibular schwannoma (VS) and to measure the correlation between the tests' results and tumor volume. STUDY DESIGN: National cross-sectional study. SETTING: Tertiary university clinic. METHODS: Prevalence of abnormal cVEMP, oVEMP, caloric test, and 6-canal vHIT results on the tumor side and the nontumor side were compared and related to tumor volume with regression analyses in 137 consecutive VS patients assigned to a wait-and-scan protocol in the period 2017 to 2019. RESULTS: The sensitivity of 6-canal vHIT, caloric test, cVEMP, and oVEMP to detect vestibulopathy in VS patients was 51%, 47%, 39%, and 25%, respectively. Normal tests were found in 21% of the patients. The results of vHIT and caloric test were related to tumor volume, but this was not found for cVEMP and oVEMP. CONCLUSION: The caloric test and 6-canal vHIT showed the highest sensitivity in detecting vestibulopathy in untreated VS patients. vHIT, and particularly the posterior canal, was limited with a high prevalence of abnormal results on the nontumor side. A combination of cVEMP and caloric test was favorable in terms of a relatively high sensitivity and low prevalence of abnormal results on the nontumor side. Larger tumors had a higher rate of pathology on caloric testing and vHIT.

Salvage radiosurgery following subtotal resection of vestibular schwannomas: does timing influence tumor control?

OBJECTIVE: The goal of microsurgical resection of vestibular schwannoma (VS) is gross-total resection (GTR) to provide oncological cure. However, a popular strategy is to halt the resection if the surgical team feels the risk of cranial nerve injury is imminent, achieving a maximally safe subtotal resection (STR) instead. The tumor remnant can then be treated with stereotactic radiosurgery (SRS) once the patient has recovered from the immediate postoperative period, or it can be followed with serial imaging and treated with SRS in a delayed fashion if residual tumor growth is seen. In this study, the authors evaluated the efficacy of this multimodality approach, particularly the influence of timing and dose of SRS on radiological tumor control, need for salvage treatment, and cranial nerve function. METHODS: VS patients treated with initial microsurgery and subsequent radiosurgery were retrospectively included from two tertiary treatment centers and dichotomized depending on whether SRS was given upfront (defined as before 12 months) or later. Radiological tumor control was defined as less than 20% tumor volume expansion and oncological tumor control as an absence of salvage treatment. Facial and cochlear nerve functions were assessed after surgery, at the time of SRS, and at last follow-up. Finally, a systematic literature review was conducted according to PRISMA guidelines. RESULTS: A total of 110 VS patients underwent SRS following microsurgical resection, with a mean preradiosurgical tumor volume of 2.2 cm3 (SD 2.5 cm3) and mean post-SRS follow-up time of 5.8 years (SD 4.1 years). The overall radiological tumor control and oncological tumor control were 77.3% and 90.9%, respectively. Thirty-five patients (31.8%) received upfront SRS, while 75 patients (68.2%) were observed for a minimum of 12 months prior to SRS. The timing of SRS did not influence the radiological tumor control (p = 0.869), the oncological tumor control (p = 0.560), or facial nerve (p = 0.413) or cochlear nerve (p = 0.954) function. An escalated marginal dose (> 12 Gy) was associated with greater tumor shrinkage (p = 0.020) and superior radiological tumor control (p = 0.020), but it did not influence the risk of salvage treatment (p = 0.904) or facial (p = 0.351) or cochlear (p = 0.601) nerve deterioration. CONCLUSIONS: Delayed SRS after close observation of residuals following STR is a safe alternative to upfront SRS regarding tumor control and cranial nerve preservation in selected patients.

Comparing the impact of upfront radiosurgery versus expectation in vestibular schwannoma (the V-REX study): protocol for a randomised, observer-blinded, 4-year, parallel-group, single-centre, superiority study.

INTRODUCTION: The optimal management of small-sized to medium-sized vestibular schwannoma (VS) is a matter of controversy. Clinical results of the prevailing treatment modalities (microsurgery, stereotactic radiosurgery (SRS), and conservative management (CM)) are documented, but comparative studies are few, and none are randomised or blinded. Upfront radiosurgery, or a careful follow-up by MRI with subsequent treatment on growth, are two strategies used at many centres. The present study aims at comparing these strategies by randomising individuals with newly diagnosed tumours to either upfront SRS or initial CM. METHODS AND ANALYSIS: The Vestibular Schwannoma: Radiosurgery or Expectation study is designed as a randomised, controlled, observer-blinded, single-centre superiority trial with two parallel groups. Eligible patients will be randomised using sequentially numbered opaque sealed envelopes, and the radiosurgery group will undergo standard Gamma Knife Radiosurgery (GKRS) within 2 months following randomisation. The primary endpoint is tumour growth measured as volume ratio V4years/Vbaseline and volume doubling time, evaluated by annual T1 contrast MRI volumetric analysis. Secondary endpoints include symptom and sign development measured by clinical examination, audiovestibular tests, and by patient's responses to standardised validated questionnaires. In addition, the patient's working status, and the health economics involved with both strategies will be evaluated and compared. All outcome assessments will be performed by blinded observers. Power analysis indicates that 100 patients is sufficient to demonstrate the effect of GKRS on tumour volume. ETHICS AND DISSEMINATION: The trial has ethical approval from the Regional Ethical Committee (23503) and funding from The Western Norway Regional Health Authority. Trial methods and results will be reported according to the Consolidated Standards of Reporting Trials 2010 guidelines in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: Clinical trials: NCT02249572. Haukeland University Hospital record: 2014/314. Regional Ethical Committee (REC West): 23 503. The Western Norway Regional Health Authority: 912 281.

Postural Sway Predicts Growth in Untreated Vestibular Schwannoma: A Retrospective Volumetric Study.

BACKGROUND: One in three vestibular schwannomas (VS) will grow within 3 years after diagnosis, but no reliable baseline parameter has been found to predict such growth. OBJECTIVE: To determine if postural sway is associated with growth of untreated VS. METHODS: Patients with newly diagnosed sporadic VS assigned to a wait-and-scan protocol were identified from a prospectively maintained database. Postural sway was measured by posturography at baseline and patients were classified as steady or unsteady. Observer-blinded volumetric tumor measurements were performed on the diagnostic MRI and a 3-year control MRI. Tumor growth quantified as relative growth (%) and volume-doubling time (VDT and VDT-1) were investigated as dependent variables against baseline parameters. RESULTS: Out of 204 VS patients, 53 (26%) were classified as unsteady on the platform at baseline. Median tumor volume was 0.32 cm3 (range 0.02-4.79), and 51% demonstrated significant growth within 3 years. Unsteady patients had significantly faster-growing tumors, with a mean relative growth of 172.5% compared to 79.5% in steady patients (p < 0.006). Seventy-seven percent of unsteady patients had >20% volume increase, compared to 42% in steady patients (p < 0.001). Mean VDT-1 was 0.65 doublings per year for unsteady patients, and 0.22 for steady patients (p < 0.001). Multivariate regression analysis including demographic and clinical parameters showed an OR of 5.6 (95% CI 2.6, 11.8) for growth in unsteady patients. CONCLUSIONS: This is the first demonstrated association between a measurable parameter and future growth in untreated VS. Our findings may help clinicians identify patients with a higher risk for tumor growth and provide closer monitoring or early treatment.

Gamma Knife Radiosurgery does not alter the copy number aberration profile in sporadic vestibular schwannoma.

INTRODUCTION: Ionizing radiation is a known etiologic factor in tumorigenesis and its role in inducing malignancy in the treatment of vestibular schwannoma has been debated. The purpose of this study was to identify a copy number aberration (CNA) profile or specific CNAs associated with radiation exposure which could either implicate an increased risk of malignancy or elucidate a mechanism of treatment resistance. METHODS: 55 sporadic VS, including 18 treated with Gamma Knife Radiosurgery (GKRS), were subjected to DNA whole-genome microarray and/or whole-exome sequencing. CNAs were called and statistical tests were performed to identify any association with radiation exposure. Hierarchical clustering was used to identify CNA profiles associated with radiation exposure. RESULTS: A median of 7 (0-58) CNAs were identified across the 55 VS. Chromosome 22 aberration was the only recurrent event. A median aberrant cell fraction of 0.59 (0.25-0.94) was observed, indicating several genetic clones in VS. No CNA or CNA profile was associated with GKRS. CONCLUSION: GKRS is not associated with an increase in CNAs or alteration of the CNA profile in VS, lending support to its low risk. This also implies that there is no major issue with GKRS treatment failure being due to CNAs. In agreement with previous studies, chromosome 22 aberration is the only recurrent CNA. VS consist of several genetic clones, addressing the need for further studies on the composition of cells in this tumor.

Fatigue in patients with vestibular schwannoma.

BACKGROUND: Patients with vestibular schwannoma (VS) often complain about tiredness, exhaustion, lack of energy, and strength, but such symptoms of fatigue have scarcely been objectified and analyzed in a VS population. We aimed to characterize fatigue in a cohort of patients with VS and compare such symptoms with a control group. METHODS: All patients who attended an educational course for patients with VS were surveyed with validated tools for assessment of fatigue (fatigue severity scale), anxiety and depression (hospital anxiety and depression scale), sleepiness (Epworth sleepiness scale), and apathy (Starkstein apathy scale). Quality of Life was assessed with the disease-specific Penn Acoustic Neuroma Quality of Life (PANQOL). Symptom severity was estimated with a visual analog scale (VAS). The results have been compared to a control group consisting of patient companions. RESULTS: Data from 88 VS patients and 49 controls were analyzed. The controls had similar age and sex distribution as patients. Fifty-seven percent of VS patients had significant fatigue, compared to 25% in the control group. The mean fatigue score was 4.1 for the patients, and 2.8 for controls. Patients with fatigue were more likely to have depression, anxiety, sleepiness, and apathy. No correlation of fatigue was found with age, gender, or treatment modality. Regression analyses revealed depression, apathy, and vertigo to be predictors of fatigue. Fatigue was strongly correlated to QoL. CONCLUSION: Almost six out of ten VS patients had fatigue, significantly higher than the control group. Interest and focus on fatigue in VS patients can improve the patient's QoL.