The Current Landscape of Vestibular Schwannoma Therapy: Development of Novel Targeted Therapies

May 2021

An acoustic neuroma, also known as a vestibular schwannoma, is a benign tumour that arises from Schwann cells of the vestibulocochlear nerve. In the majority of cases, these tumours occur sporadically, but the presence of bilateral tumours is pathognomonic for a genetic condition called neurofibromatosis type 2(NF2). The loss of the NF2 gene is linked to pathogenesis of acoustic neuromas, both in sporadic and genetic conditions. About 60% of sporadic unilateral acoustic neuromas have mutations in the NF2 gene. Mutations of the NF2 gene lead to deregulation of important pathways that regulate tumour growth such as RAS and mTORC1 pathway.

Regardless of the etiology, acoustic neuromas are typically located in the cerebellopontine angle (CPA) and lead to progressive hearing loss, vertigo, tinnitus, ataxia and sometimes facial nerve dysfunction.

The optimal treatment options for patients with acoustic neuromas is dependent on the size and growth of tumours, symptomology including ataxia and facial nerve dysfunction, and patient preference. Generally, the goal of treatment is to preserve neurological function as long as possible with tumour control. As such, small tumours with minimal symptomology is often treated with close observation and serial imaging.

Previous studies have identified that at the mean growth rate of these tumours is approximately 1-2 mm/year with up to 75% of tumours showing no further growth. Although observation can increase the risk of tumour progression and mass effect, it is a safe approach due to the minimal growth rate. Furthermore, studies have demonstrated that delaying surgical intervention appears to have no increased risk in mortality. However, when there is evidence of substantial growth with no compression on the brainstem, then radiotherapy or surgery is considered. When the tumour is compressing the brainstem with associated worsening of neurological symptoms, the preferred treatment is surgical resection.

Historically, the medical treatment options for vestibular schwannomas have been limited due to the tumours often benign and chronic nature. Bevacizumab, an intravenous chemotherapy, is a monoclonal antibody against the vascular endothelial growth factor (VEGF). The initial clinical trial was conducted in 10 patients with confirmed neurofibromatosis type 2 with evidence of tumour progression. The trial demonstrated 90% of patients had reduction in tumour volume and 57% patients had improvement in hearing. This landmark clinical trial led to the completion of a number of studies, which also reported decrease in tumour volume and improvement in hearing response in patients with neurofibromatosis type 2. Therefore, it is difficult to know whether the results will translate to majority of the sporadic vestibular schwannomas.

In theory, Everolimus is another promising treatment as it is an mTORC1 inhibitor. Activation of mTORC1 has been implicated in tumour growth. However, Phase II trials in NF2 patients have shown mixed results. One study showed no response to Everolimus on tumour growth or hearing improvement, while another study found a 66.5% reduction in tumour growth during Everolimus treatment. At this time, there is no strong data to support the use of Everolimus in management of vestibular schwannomas, and further long-term studies are needed to provide more robust evidence.

Vestibular schwannomas are a clinically important disease with an evolving knowledge base. Further work is needed to understand the biological alterations that are driving the tumour development, in order to better develop targeted therapies that will effectively treat this disease process.

Gelareh Zadeh
Dr Gelareh Zadeh

Gelareh Zadeh, MD, PhD, FRCS(C), FAANS is an internationally renowned neurosurgeon and neuroscientist who also happens to be chair of ANAC’s Scientific Medical Advisory Committee. Dr. Zadeh recently became the first female chair of neurosurgery at University of Toronto, which is the largest department in Canada. She is also the medical director for the Krembil Brain Institute, TWH and head of surgical oncology at the University Health Network. In addition, Dr. Zadeh holds the Wilkins Family Brain Tumour Research Chair.

Her clinical practice focuses on skull base neuro-oncology, with a dedicated brain tumour clinic and many multidisciplinary clinics that she has established including skull base, pituitary, brain metastases, gamma knife and neurofibromatosis clinic.


Suganth Suppiah
Dr Suganth Suppiah

Suganth Suppiah, MD has since 2018 provided tremendous support to ANAC. He is the Senior Neurosurgery resident at University Health Network, University of Toronto, focusing on peripheral nerve surgery. He is currently completing his PhD under the supervision of Dr. Gelareh Zadeh on the molecular profile of peripheral nerve sheath tumours.