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

Abstract

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.

Figure 1.. Participant Flow in the V-REX Randomized Clinical Trial

^aStratified for age and whether the tumor was extracanalicular or intracanalicular at the time of recruitment. ^bA multidisciplinary team, independent from the blinded study investigators, evaluated the participants annually, and chose either radiosurgery or salvage microsurgery in the case of tumor growth.

Figure 2.. Changes in Tumor Volume in Patients Treated With Upfront Radiosurgery vs the Wait-and-Scan Protocol With Treatment Upon Tumor Growth

The parallel line plot contains a vertical line for each patient that extends from the baseline tumor volume to the 4-year volume. Descending lines indicate a shrinking tumor. Baseline values are placed in ascending order for the upfront radiosurgery group and descending order for the wait-and-scan group. The ends of the boxes in the box plots are located at the first and third quartiles, with the solid line indicating the median and the diamond indicating the mean. Whiskers extend to the upper and lower adjacent values, the location of the furthest point within a distance of 1.5 interquartile ranges from the first and third. Dots indicate more extreme values.

Figure 3.. Development of Tumor Volume and Clinical Outcomes From Baseline to Year 4

Shown are the development of outcomes from baseline to 4-year follow-up. The estimates are geometric means in Panel A and arithmetic means in the other panels, all with 95% CIs, indicated with whiskers. They are based on longitudinal models with adjustments for random baseline imbalance and missing data. A, Shows volumetric tumor growth curves for each group. The increase in tumor volume seen during the first year following radiosurgery may reflect pseudoprogression, a transient volumetric tumor enlargement caused by ischemic infarction and central necrosis. B and C, Pure-tone average and the word recognition score show a reduction in hearing acuity in both groups. D, The composite-equilibrium score showed some increase over time for both groups indicating improved vestibular function. E, The caloric asymmetry slightly increased over time in both groups indicating worsening of canal paresis over time. F, The Penn Acoustic Neuroma Quality-of-Life (PANQOL) total score appeared fairly stable throughout the study period, except for a small dip at year 1 in both groups. Details of changes in continuous outcomes from baseline to trial end are in eTable 2 in Supplement 2. ^aThe average hearing sensitivity at 500 Hz, 1000 Hz, 2000 Hz, and 4000 Hz. ^bA 10-step scale reporting the percentage of words correctly repeated by the patient. ^cFor equilibrium score and range definitions, see the footnotes in Table 1. ^dFor calculation and measures of caloric asymmetry see the footnotes in Table 1. ^eFor the PANQOL score ranges and measures, see the footnotes in Table 1.