Hearing Improvement after Bevacizumab in Patients with Neurofibromatosis Type 2

Abstract

BACKGROUND Profound hearing loss is a serious complication of neurofibromatosis type 2, a genetic condition associated with bilateral vestibular schwannomas, benign tumors that arise from the eighth cranial nerve. There is no medical treatment for such tumors. METHODS We determined the expression pattern of vascular endothelial growth factor (VEGF) and three of its receptors, VEGFR-2, neuropilin-1, and neuropilin-2, in paraffin-embedded samples from 21 vestibular schwannomas associated with neurofibromatosis type 2 and from 22 sporadic schwannomas. Ten consecutive patients with neurofibromatosis type 2 and progressive vestibular schwannomas who were not candidates for standard treatment were treated with bevacizumab, an anti-VEGF monoclonal antibody. An imaging response was defined as a decrease of at least 20% in tumor volume, as compared with baseline. A hearing response was defined as a significant increase in the word-recognition score, as compared with baseline. RESULTS VEGF was expressed in 100% of vestibular schwannomas and VEGFR-2 in 32% of tumor vessels on immunohistochemical analysis. Before treatment, the median annual volumetric growth rate for 10 index tumors was 62%. After bevacizumab treatment in the 10 patients, tumors shrank in 9 patients, and 6 patients had an imaging response, which was maintained in 4 patients during 11 to 16 months of follow-up. The median best response to treatment was a volumetric reduction of 26%. Three patients were not eligible for a hearing response; of the remaining seven patients, four had a hearing response, two had stable hearing, and one had progressive hearing loss. There were 21 adverse events of grade 1 or 2. CONCLUSIONS VEGF blockade with bevacizumab improved hearing in some, but not all, patients with neurofibromatosis type 2 and was associated with a reduction in the volume of most growing vestibular schwannomas.

Vascular Normalization as a Therapeutic Strategy for Malignant and Nonmalignant Disease

“…Neurofibromatosis 2, a rare genetic disease defined by a defect in a single allele of the Nf2 gene (and hence loss of its product, the tumor suppressor merlin) often presents with bilateral acoustic neuromata, which compress the vestibular nerve causing deafness and other complications relating to their expansion in the cerebellopontine angle (Lu-Emerson and Plotkin 2009). Vessel tortuosity Bullitt et al 2007 Vestibular schwannomas are known to express VEGF and VEGFRs, and the VEGF level within these tumors correlates with their growth rate (Brieger et al 2003;CayeThomasen et al 2003CayeThomasen et al , 2005Plotkin et al 2009). Interestingly, the mechanism of heightened VEGF activity in these tumors is not hypoxia-driven VEGF overexpression, but rather a loss of factors that attenuate VEGF function.…”

An allograft mouse model for the study of hearing loss secondary to vestibular schwannoma growth

“…The report of a favorable impact of an anti-angiogenic treatment on hearing in NF2 VS patients compels the need to understand the relationship between VS growth and hearing loss [16]. As a result, hearing outcome during treatment has became the primary endpoint for clinical trials investigating antiangiogenic compounds such as bevacizumab.…”

“…Moreover, the use of anti-angiogenic drug therapy has suggested a beneficial effect on hearing, an endpoint that is overlooked in the preclinical field [16]. Thus, a better understanding of the process underlying hearing loss requires specific models.…”

Anti-Angiogenic Agents for Non-Malignant Brain Tumors

“…16 Several studies have also indicated that VEGF and VEGFR antagonists have roles in the treatments of other brain tumors, including vestibular schwannomas, meningiomas, and low-grade astrocytomas. 5,[7][8][9]11,12,17,18 Despite being nonmalignant brain tumors, vestibular schwannomas and meningiomas carry significant morbidity and risk of mortality for certain patients. Many but not all of these tumors can be treated with surgery or radiotherapy.…”