Bevacizumab (Avastin), a therapy federally approved to inhibit the formation of new blood vessels that feed tumors and used to treat advanced forms of cancer — helped shrink tumors in and improve hearing in a small group of patients with neurofibromatosis type 2 (NF-2), an autosomal dominant disorder characterized by bilateral tumors on the eighth cranial nerve.
The story of how a handful of NF-2 patients regained hearing and had a reversal of genetic misfortune when their tumors shrank is a reminder of how surprising laboratory findings can quickly pave the way to clinical advances, said Scott Plotkin, MD, PhD, a neuro-oncologist at Massachusetts General Hospital who led the study that was published in the July 23 New England of Journal of Medicine.
Dr. Plotkin had been looking for a medical option for his NF-2 patients with bilateral acoustic neuromas. Hearing loss can result from the tumors compressing the eighth cranial nerve, as well as from surgery and localized radiation.
BASIC SCIENCE, CLINICAL FINDINGS
The study was triggered by new evidence from Dr. Plotkin's colleagues in basic science that suggested that the blood supply for NF2 tumors was fueled by vascular endothelial growth factor (VEGF) and that blocking this expression could reduce the tumor volume.
Before this study, doctors had not considered the use of VEGF inhibitors because it was thought that benign tumors do not have the same tumor-feeding blood vessels as did malignant tissue.
Emmanuelle di Tomaso, PhD, who conducted the original lab work while she was at Massachusetts General Hospital, examined 44 NF2 specimens from the Massachusetts General Hospital Tumor Bank and found “quite a bit of VEGF,” she said. “We were all fascinated by what we were seeing in the patients,” she added. Dr. di Tomaso is now a biomarker project leader at Novartis in Cambridge, MA.
Dr. Plotkin and his colleagues tested the treatment in six men and four women who had NF2 with progressive vestibular schwannomas and who were not candidates for surgery (or radiation.) They received IV bevacizumab at a dose of 5 mg per kilogram of body weight every two weeks; the median duration of treatment was 12 months (three to 19 months). Six of the patients were followed for at least one year. The patients in the trial received the medication under a compassion use provision from the US FDA.
The tumor shrank 20 percent or more in six of 10 patients. At the end of the 16 month follow-up, four of the tumors remained stable. What's more, seven of the 10 patients had continuous testing for hearing improvement during the study and four of them showed improved hearing. Three of the 10 patients were not eligible for hearing improvement; one had no auditory nerves and two had normal hearing.
The improved hearing may be the result of the tumor shrinking and taking pressure off the nerve or in a reduction of swelling within the tumors, Dr. Plotkin said, adding: “No one has ever seen this preservation of hearing before. This opens the door to new ways to treat these very complex cases.”
It is not yet clear precisely how the VEGF inhibitor works to reclaim hearing and reduce the volume of the benign tumors. It is also not clear how long patients will have to stay on the infusion treatment or whether they will require the same high doses that patients with malignant tumors receive
“These patients are young and we know that any treatment will be used for a long time,” Dr. Plotkin said. “We are now testing to see how effective the treatment will be at lower doses.”
‘A NOVEL APPROACH’
“This experimental treatment is indeed a novel approach,” said Bruce Korf, MD, PhD, professor and chair of the department of genetics at the University of Alabama in Birmingham and an expert of neurofibromatosis. “That it helped some of these 10 people is more than can be said for any other treatment tried for NF2,” said Dr. Korf, who was not involved with the study.
There is enough encouraging evidence to lead to a larger study of this treatment for NF patients,” added Dr. Korf. “It is really exciting but will require a lot of follow-up research. It did not work for everybody.”
A New Jersey biotech company called PTC Therapeutics received a Department of Defense grant through its NF program to test a new oral VEGF inhibitor. The phase I safety studies in normal volunteers and cancer patients looks promising, Dr. Plotkin said. “It is well tolerated with minimal side effects.”
Meanwhile, the Mass General team is expanding their study on NF2 patients to confirm the response rate and see whether they can reduce or discontinue the treatment and maintain the effect on the size of the tumor and hearing.
• Plotkin SR, Stemmer-Rachamimov AO, di Tomaso E, et al. Hearing improvement after bevacizumab in patients with neurofibromatosis Type 2. N Engl J Med 2009;361:358–367.