Zalaquett, Nader G.

Objective: To synthesize the available evidence on medical therapies investigated for the management of NF2-related vestibular schwannomas (VS). Study design: Systematic review. Setting: Not applicable. Patients: NF2-related VS patients. Interventions: Systemic medical therapies. Main outcome measures: Tumor control and hearing outcomes. Results: Thirty studies met inclusion criteria: 18 investigated bevacizumab, 5 mTOR inhibitors, 5 tyrosine kinase inhibitors (TKIs), and 2 the vascular endothelial growth factor receptor (VEGFR) vaccine. Bevacizumab demonstrated the most consistent activity, with hearing improvement in up to 61% of patients, stable hearing in up to 84%, and tumor response in up to 60% (Level 4 evidence). Outcomes for mTOR inhibitors were variable, with 1 study stopped for futility, while others reported up to 100% hearing and tumor stability (Level 4 evidence). Five different TKIs showed hearing improvement rates ranging from 17 to 60% and tumor responses of 10 to 23.5% (Level 4 evidence). The VEGFR vaccine appeared safe and immunologically active, with radiologic and hearing improvement in one-third of patients (Level 4 evidence). Conclusions: Bevacizumab remains the most studied and clinically active systemic therapy for NF2-related VS, although evidence is largely nonrandomized. Other systemic therapies have demonstrated variable results in terms of hearing outcomes or tumor control. High-quality prospective and randomized controlled trials are needed to clarify efficacy, durability, and comparative effectiveness.

ABSTRACT Objective Management of vestibular schwannoma (VS) remains controversial. Very small VSs represent a pivotal group: on one hand, they pose the least risk to the patient from the perspective of being small; yet, not recommending treatment may result in missing a critical window for achieving the best outcome. This debate fundamentally hinges on whether treatment improves upon the natural history of the disease. There is an unproven assumption that very small tumors behave similarly to the broader observed population. To address this central question, we conducted a multicenter retrospective review to compare the natural history of tumor growth and hearing for patients with very small VS (1–3 mm) with a referent cohort with larger tumors. Methods All patients diagnosed with sporadic VS 1–3 mm were reviewed at 3 large skull base referral centers and compared with a referent cohort of patients with tumors > 3 mm. Tumor growth‐free survival rates, treatment‐free survival rates, and rates of maintenance of class A, B, or C hearing were estimated using the Kaplan–Meier method. Results In total, 123 patients with very small VS and a referent cohort of 326 patients were studied. Seventeen patients with very small VS experienced tumor growth at a median of 3.2 years after diagnosis (IQR 2.6–5.1), demonstrating a median growth rate of 1.0 mm per year (IQR 0.9–1.8). In comparison, 167 of the patients in the referent cohort experienced tumor growth at a median of 1.7 years after diagnosis (IQR 0.8–3.1). Tumor growth‐free survival rates (95% CI, number still at risk) at 5 years after diagnosis for the 2 cohorts were 84% (75–93, 39) and 45% (40–52, 100), respectively ( p < 0.001). Six patients with very small VS underwent treatment after tumor growth at a median of 3.2 years after diagnosis (IQR 3.2–3.8), compared with 138 patients in the referent cohort at a median of 2.2 years after diagnosis (IQR 1.4–3.6). Treatment‐free survival rates (95% CI, number still at risk) at 5 years after diagnosis for the 2 cohorts were 92% (86–98, 55) and 54% (49–61, 125), respectively ( p < 0.001). Among the 105 patients with very small VS and class A, B, or C hearing at diagnosis, 3 progressed to class D. Comparatively, among the 225 patients in the referent cohort with class A, B, or C hearing at diagnosis, 70 progressed to class D at a median of 2.6 years after diagnosis (IQR 1.0–4.8). Rates of maintenance of class A, B, or C hearing (95% CI, number still at risk) at 5 years after diagnosis were 96% (92–100, 28) for patients with very small VS and 65% (57–73, 70) for the referent cohort ( p < 0.001). Conclusions The natural history of tumor growth and hearing for very small VS diverges favorably from the cumulative natural history data and provides a more appropriate benchmark to compare clinical outcomes of upfront surgery or radiosurgery for this population. At 5 years after diagnosis, 96% of very small VS maintained class A, B, or C hearing and only 8% received treatment for growth within this multicenter cohort. Cumulatively, these data substantiate initial wait‐and‐scan management via size threshold surveillance in this population. Level of Evidence 3.

Objective: To systematically review studies evaluating systemic medical therapies for sporadic vestibular schwannoma (VS) and perform meta-analyses to assess associations with tumor control. Study design: Systematic review and meta-analysis. Setting: Not applicable. Patients: Sporadic VS patients. Interventions: Systemic medical therapies. Main outcome measures: Tumor growth. Results: Nine retrospective studies met criteria: 5 on nonsteroidal anti-inflammatory drugs (NSAIDs), 3 on metformin, and 1 on losartan (all level 3 evidence). A meta-analysis of ORs from 5 studies demonstrated no significant association between aspirin use and tumor growth (pooled OR: 0.77; 95% CI: 0.48-1.23; I²: 76%). Conversely, a meta-analysis of ORs from 3 studies on metformin showed significantly lower odds of tumor growth (pooled OR: 0.46; 95% CI: 0.30-0.72; I²: 0%). The study on losartan did not identify a statistically significant association of losartan with tumor growth. Less than half of the studies reported HRs to appropriately reflect the inherently time-dependent nature of tumor growth. Conclusions: Evidence for systemic therapies in sporadic VS remains preliminary. Our meta-analysis of ORs demonstrates that NSAID use is not significantly associated with tumor growth, metformin users had lower odds of tumor growth, and evidence for losartan remains limited; however, all available studies provide only level 3 evidence. At present, there is insufficient data to recommend routine use of aspirin, metformin, or losartan with the intent of mitigating VS tumor growth during wait-and-scan management. High-quality prospective studies with appropriate time-to-event methodology to assess tumor growth are required to establish the clinical utility of systemic therapies in the management of patients with sporadic VS.

Objective: Quality of life (QOL) is an important consideration in vestibular schwannoma (VS) patients when assessing management options. Understanding sex-based differences in QOL may facilitate patient counseling. Study design: Prospective cohort. Setting: Tertiary academic medical center and Acoustic Neuroma Association. Patients: Sporadic VS patients. Interventions: Observation, microsurgery, or radiation. Main outcome measures: Penn Acoustic Neuroma Quality of Life (PANQOL) scores. Results: A total of 481 patients were analyzed. In the observation group, women reported worse anxiety, facial function, and total PANQOL scores at baseline. At follow-up, men declined more in facial function (−5 vs. +3, P =0.01). For microsurgery, women reported worse facial function and balance scores at baseline. At follow-up, men declined more in facial function (−16 vs. −3, P <0.001), balance (−7 vs. +2, P =0.04), energy (−4 vs. +5, P =0.03), and total (−5 vs. +2, P =0.02) PANQOL scores. For radiation, women reported worse anxiety, balance, pain, and total scores at baseline. At follow-up, anxiety improved in women but worsened in men (+5 vs. −6, P =0.008). Sex-based differences exceeding the minimally important difference thresholds established for the PANQOL were observed for the following: anxiety at baseline in the observation group, anxiety and pain at baseline in the radiation group, and change in anxiety from baseline to follow-up in the radiation group. Conclusions: Women had worse anxiety, balance, facial function, pain, and overall QOL at baseline assessed using the PANQOL, whereas men declined more with treatment and observation. The largest difference in PANQOL change between sexes occurred after microsurgery, with men experiencing greater losses in facial function, balance, energy, and total scores.