Treatment with the angiogenesis inhibitor bevacizumab (Avastin®) improved hearing and alleviated other symptoms in patients with neurofibromatosis type 2 (NF2), a genetic tumor disorder, according to a new study conducted at the Massachusetts General Hospital (MGH) in Boston. Bevacizumab treatment successfully shrank tumors in a group of NF2 patients, which makes the antiangiogenic approach the first successful NF2 treatment not involving surgery or radiation. The findings are published in the July 23, 2009 issue of the New England Journal of Medicine.

NF2 is an uncommon inherited disorder in which benign tumors develop throughout the nervous system. The most common tumor is the vestibular schwannoma, which forms in the inner ear. Although it is slow growing, patients with these tumors often lose all or most of their hearing by young adulthood or middle age. The tumors can be removed surgically or treated with radiation, but such treatment usually leads to complete hearing loss, especially when tumors grow in both ears. Growing vestibular schwannomas can also press on the brainstem, leading to headaches, difficulty swallowing and other serious neurologic symptoms.

Although vestibular schwannomas are benign, they also rely on the growth of new blood vessels for oxygen and micronutrients, as do malignant tumors. Researchers studying tissue samples from both NF2-related schwannomas and sporadic vestibular schwannomas (tumors not caused by NF2) documented the presence of tumor blood vessels, as well as the increased expression of the angiogenic protein VEGF (vascular endothelial growth factor). The finding of tumor angiogenesis formed the rationale for treating NF2 patients in danger of complete hearing loss or other significant neurological damage with an antiangiogenic drug. The researchers chose bevacizumab, an anti-VEGF antibody therapy, already approved for treating advanced cancers of the colon, lung, breast, and brain.

Among the first 10 NF2 patients to receive bevacizumab, 9 patients experienced tumor shrinkage, and 6 patients had at least a 20% reduction in the size of their tumors. In those patients, tumor shrinkage lasted from 11 to 16 months—longer in duration of benefit than the 4 months of tumor shrinkage typically seen with bevacizumab treatment for glioblastoma, a highly malignant brain tumor. Of 7 patients who had started to lose their hearing before treatment, 4 experienced some hearing restoration (2 returned to work or school), the benefits of which also lasted for up to 16 months. In one patient who had no significant tumor shrinkage or hearing improvement, bevacizumab treatment alleviated his headaches and nausea caused by brainstem compression by tumors. No serious side effects were observed in this study.

“This kind of treatment response is unprecedented,” said Scott Plotkin, MD, PhD, of the Pappas Center for Neuro-Oncology in the MGH Cancer Center and lead author of the NEJM paper. “Our study is the first to provide evidence that a drug can shrink vestibular schwannomas, and the first to show that patients’ hearing can be improved.”
Emmanuelle di Tomaso, PhD, the study’s senior author, formerly with the Steele Laboratory of Tumor Biology in the MGH Department of Radiation Oncology, added: “This study has opened a new approach to research and understanding of these tumors.”

Separately, researchers at MGH will be initiating a phase 2 clinical trial for NF2 using another antiangiogenic agent, PTC299. PTC299 is an orally administered experimental drug that also inhibits the VEGF protein, but by a different mechanism of action than bevacizumab. In this study, 25 NF2 patients will receive up to 48 weeks of treatment with PTC299, and will be evaluated for tumor shrinkage and improvement in hearing and word recognition.

“This is another landmark for the angiogenesis field,” says William W. Li, M.D., president and medical director of the Angiogenesis Foundation. “It demonstrates that benign as well as cancerous tumors can respond to antiangiogenic therapy, and that important symptoms that impact quality of life, such as hearing loss, may be ameliorated or even reversed by treating abnormal blood vessel growth.”