BEVACIZUMAB EVERYWHERE

Bevacizumab May Improve Hearing in Neurofibromatosis Type 2

Allison Gandey

July 29, 2009 — Blocking vascular endothelial growth factor with bevacizumab (Avastin, Genentech) may reduce vestibular schwannomas, report investigators. The preliminary work suggests there may be an alternative to surgery and radiation for patients with neurofibromatosis type 2. Their findings are published in the July 23 issue of the New England Journal of Medicine.

"Bevacizumab showed good activity in a selected group of patients," lead author Scott Plotkin, MD, from Massachusetts General Hospital, in Boston, told Medscape Neurology. His team found that blocking vascular endothelial growth factor improved hearing in some, but not all, patients and was associated with a reduction in the volume of most growing vestibular schwannomas.

"People have been really surprised by how much we saw hearing improve," Dr. Plotkin said. "This offers hope where previously there wasn't any." The study proposes a possible new indication for bevacizumab, but Genentech was not involved in this work.

Alternative to Surgery and Radiation

Investigators studied 10 consecutive patients with neurofibromatosis type 2 and progressive vestibular schwannomas who were not candidates for standard treatment. They were treated instead with bevacizumab.

Researchers defined an imaging response as a decrease of at least 20% in tumor volume compared with baseline. They defined a hearing response as a significant increase in word-recognition score.

Investigators determined the expression pattern of vascular endothelial growth factor and 3 of its receptors — VEGFR-2, neuropilin-1, and neuropilin-2 — in paraffin-embedded samples from 21 vestibular schwannomas and 22 sporadic schwannomas.

After immunohistochemical analysis, they found that VEGF was expressed in 100% of vestibular schwannomas and VEGFR-2 in 32% of tumor vessels.

Before treatment, the median annual volumetric growth rate for 10 index tumors was 62%. After bevacizumab, tumors shrank in 9 patients, and 6 patients had an imaging response. This response 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%. In all, 3 patients were not eligible for a hearing response. Of the remaining 7 patients, 4 had a hearing response, 2 had stable hearing, and 1 had progressive hearing loss. There were 21 adverse events of grade 1 or 2.

"Although the need for an effective medical therapy for patients with neurofibromatosis type 2 is clear, the risk of toxic effects deserves careful consideration," the researchers emphasize.

"In our preliminary experience, toxic effects were limited to grade 1 or 2 adverse events during follow-up of up to 16 months, which is not long in comparison with the expected survival of these young patients. The absence of many common toxic effects of bevacizumab in our patients may have reflected their relative youth, the lack of other medical conditions, and the small number of patients who were treated."

Bevacizumab has been linked to an increased risk for venous thromboembolism. A meta-analysis published in November 2008 in the Journal of the American Medical Association called on clinicians to remain vigilant about the potential risk (Nalluri SR et al. JAMA. 2008;300:2277-2285).

Study authors, led by Shobha Rani Nalluri, MD, from Stony Brook University, in New York, recommended anticoagulation in the event of venous thromboembolism and suggested that bevacizumab be continued, if the benefits outweigh the risk.

Increased Venous Thromboembolism Risk

Speaking to Medscape Oncology when the study was first published, Herbert Hurwitz, MD, from Duke University Medical Center, in Durham, North Carolina, said, "The most important issue for clinicians remains prompt and careful management of venous thromboembolism if and when it occurs."

Dr. Hurwitz was the senior author of a previous smaller meta-analysis that found no increased risk. In the newer study, researchers observed 3 deaths — 2 in the bevacizumab group and 1 in the control group.

Dr. Plotkin and his team conclude that additional research will be necessary to determine the optimal drug regimen, duration and adverse-effect profile for long-term therapy for vestibular schwannomas associated with neurofibromatosis type 2.

"One of the remarkable things about this study," Dr. Plotkin said during an interview, "is we saw longer response rates than what is typically observed with malignant gliomas. This suggests that there is something different about these benign tumors, and some of the drugs we already have available might prove to be even more effective in this setting."