Browse by Medical Category
Monday, May 17, 2010
Neurofibromatosis type 2 (NF2) is a genetic condition associated with bilateral vestibular schwannomas. It is rare, affecting only about one in 25,000 people.
The benign tumors that characterize NF2 originate from the eighth cranial nerve, which carries signals from the ear to the brain.
As these benign tumors grow, most patients with NF2 will develop complications that can severely impact their quality of life. For some, that can mean near total hearing loss by young adulthood. In addition, growing tumors may press on the brainstem and cause headaches, facial weakness, difficulty swallowing, and other neurological complications.
NF2 Treatments Can Damage Hearing
In the past, physicians have had two primary treatments for vestibular schwannomas associated with NF2: surgery or radiation. However, both treatments can damage the nerve, leading to significant or complete hearing loss. Yet untreated tumors can lead to progressive brain-stem compression, resulting in severe neurological complications.
For this reason, researchers at the Massachusetts General Hospital Cancer Center wanted to explore medical therapies that might provide a less invasive approach to managing vestibular schwannomas and their complications. Their first step was bench research to understand the nature of tumor growth in NF2 patients.
Finding What Feeds Schwannomas
Massachusetts General Hospital is home to the country’s second oldest clinic for neurofibromatosis patients. Today, the clinic works in collaboration with Mass General experts from audiology, neurology, neuropathology, neurosurgery, radiation oncology, and other disciplines to promote a greater understanding of NF2, with the hope that better therapies will become available for this hard-to-treat disease.
Physician-researchers at the Cancer Center have sought to understand what fuels the growth of these benign tumors. Benign cells are often difficult to study using in vitro tests and mouse models, the standards for testing malignant disease processes. Instead, the team—led by Emmanuelle di Tomaso, PhD, and Rakesh Jain, PhD, of the Edwin Steele Laboratory and by Anat Stemmer-Rachamimov, MD, of Neuropathology—studied human tumor samples using immunohistochemical analyses and found increased density of blood vessels in tumors, as well as strong expression of the protein vascular endothelial growth factor (VEGF) in the tumors. It is believed that VEGF drives tumor growth by stimulating angiogenesis, the proliferation of blood vessels.
Based on these findings, the physicians sought to test an anti-VEGF therapy to inhibit the angiogenesis that spurs tumor growth. By interfering with this process, physicians aimed to stall the progress of the disease.
Choosing an Established Anti-VEGF Antibody
Led by Scott R. Plotkin, MD, PhD, director of the Neurofibromatosis Clinic, researchers at the Massachusetts General Hospital Cancer Center decided to test the effectiveness of an FDA-approved agent at slowing vestibular schwannoma growth in NF2 patients. They selected bevacizumab, a biological therapy approved by the FDA to treat various cancers. Developed from research by Harvard researcher Judah Folkman, MD, this monoclonal antibody binds to and blocks VEGF. Bevacizumab, an injectable, is sold under the brand name Avastin and is currently marketed as a combination chemotherapy agent for metastatic colorectal cancer and as monotherapy for brain cancer. It is also used to treat breast, kidney, and lung cancer. Patients in the study were not considered candidates for surgery or radiation because they were at high risk for complete hearing loss or because they refused surgery.
Dr. Plotkin and his team gave bevacizumab to 10 patients with progressive vestibular schwannomas associated with NF2. After a median treatment time of 12 months, bevacizumab shrank tumors in nine patients, and six patients had shrinkage of 20 percent or more. That response was maintained in four patients during 11 to 16 months of follow-up. Magnetic resonance imaging studies showed the median best response to treatment was a tumor volume reduction of 26 percent. Although modest, the reduction is considered clinically significant. Of the seven patients measured for hearing response, four had improved hearing. Two had stable hearing, while one had progressive hearing loss.
Of the patients who had improved hearing, some reported significant increases in word recognition. For example, “patient 2,” a 22-year-old student, had a word-recognition score that increased from 8 percent to 98 percent and was able to regain enough hearing to resume school and complete a master’s degree in deaf education.
In general, hearing improved about eight weeks after treatment and continued to improve for as long as 16 months. The results were published in the July 23, 2009, issue of the New England Journal of Medicine. This was the first study to investigate a chemotherapy agent in NF2 patients. Although it is not yet proven, the researchers believe that bevacizumab may improve hearing by reducing tumor volume as well as intraneural edema.
Future Research Directions
Dr. Plotkin and his colleagues will continue to test bevacizumab in the NF2 population. One trial, in development with the National Cancer Institute, will further examine the drug in 14 adult and pediatric NF2 patients who are at risk for complete hearing loss or who have brain stem compression. Researchers hope the trial will offer a better understanding of how the drug might improve hearing loss.
Another multicenter trial is planned, in partnership with the Radiation Therapy Oncology Group (RTOG). The study, expected to begin in late 2010 or early 2011, will enroll 60 NF2 patients in North America, Canada, and Israel. The primary goal will be to determine the durability of bevacizumab response in NF2 patients.
In addition, research is under way to test an experimental oral agent for NF2. The Cancer Center has enrolled 11 patients for a phase 2 trial of PTC299, which has been shown to decrease production of VEGF in animal models of human cancer. The phase 2 study is designed to test if the drug shows evidence of VEGF reduction, antitumor activity, and hearing improvement when administered orally to patients with NF2.
Researchers at Mass General hope they can apply their findings from the NF2 population to patients affected by other types of brain tumors. Future therapies could also target patients with other types of neurofibromatosis as a result of this early but promising research.
Plotkin S, Stemmer-Rachamimov A, Barker F, Halpin C, Padera T, Tyrrell A, Sorensen G, Jain R, di Tomaso E. (2009). Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. New Engl J Med, 361(4): 358-67.
Massachusetts General Hospital Cancer Center
The Massachusetts General Hospital Cancer Center is among the leading cancer care providers in the United States. Known for providing customized, innovative treatments to both adults and children, the Cancer Center comprises 20 fully integrated, multidisciplinary clinical programs and a vast array of support and educational services. The Cancer Center’s commitment to eradicating cancer is fueled by scientific investigation in all phases of cancer research conducted as part of one of the largest hospital-based research programs in the nation. Physician investigators conduct more than 350 clinical trials annually. The Massachusetts General Hospital Cancer Center is proud to be a founding member of the DF/HCC, a Harvard Medical School consortium designated by the National Cancer Institute as a comprehensive cancer center.
Back to Top