A new study offers hope of longer survival to a subset of patients who suffer from malignant melanoma that has spread to the brain. The study found that patients whose cancer includes a mutated gene had longer survival when treated with a combination of stereotactic radiosurgery and a targeted medication known as an inhibitor. Survival was further enhanced when the inhibitor, a form of chemotherapy, was delivered at least one week following radiosurgery.
Malignant melanoma, the most aggressive form of skin cancer, accounts for three-fourths of all skin cancer deaths. It spreads (metastasizes) to the brain in 70 percent of patients, the highest frequency of metastasis of any cancer.
In the retrospective study, recently published online in the journal Neurosurgery, researchers studied the survival rates of 198 patients who were treated for 710 brain metastases between 2011 and 2015. Thirteen patients were treated at the Gamma Knife® Center at The Jewish Hospital – Mercy Health, an integral component of The Jewish Hospital’s Brain Tumor Center. Gamma Knife radiosurgery was delivered in a single, high dose that targeted the brain metastases while sparing nearby healthy tissue.
“Patients with melanoma can be divided into two types,” says Ronald Warnick, MD, Co-Director of the Gamma Knife Center and a study co-investigator. “Those who had a special feature on their tumor did better with radiosurgery and did even better when treated with an inhibitor following radiosurgery.”
“The finding is very important,” continues Dr. Warnick, a neurosurgeon with Mayfield Brain & Spine. “We have identified a subset of patients with melanoma who respond exceedingly well to sequential treatment with Gamma Knife radiosurgery and an oral inhibitor.”
The “special feature” that extends life is a mutation of BRAF, a gene that encodes a protein known as B-Raf. The mutation appears in approximately 50 percent of patients with malignant melanoma. Previous research has shown the mutation to be an important predictor of survival and a promising target for inhibitor therapies. The Neurosurgery study found that after being diagnosed with a brain metastasis, 56.7 percent of patients with the BRAF mutation survived one year when treated with radiosurgery and the inhibitor. Among those without the BRAF mutation, 31.5 percent survived one year following diagnosis and radiosurgery treatment.
The study was a multi-site effort involving the International Radiosurgery Research Foundation, a consortium of academic and clinical centers of excellence that perform brain stereotactic radiosurgery with the Leksell Gamma Knife. The consortium’s 32 centers are committed to performing clinical research that will establish best practices and lead to improved outcomes for patients.
The study also evaluated survival among patients with the BRAF mutation who received inhibitors prior to, on the day of, and at least one week following radiosurgery. Patients who received inhibitors following surgery had a median survival of 24 months, compared to 8 months for those who received inhibitors prior to radiosurgery and 10.1 months for those who received them on the day of radiosurgery.
“It may be that stereotactic radiosurgery enhances the ability of the BRAF inhibitor to cross the blood brain barrier into the tumor,” Dr. Warnick says. He adds that while the longest-surviving group received inhibitors one week following radiosurgery, the optimal time point for delivering the inhibitors is not yet known.
The study also found that:
- Patients who do not carry the beneficial BRAF mutation are not candidates for BRAF inhibitors but can be treated with immunotherapy agents. Patients receiving radiosurgery and PD-1 inhibitors (a form of immunotherapy) survived an average of 32 months following a diagnosis of brain metastasis, while those treated with radiosurgery alone survived an average of 7.6 months.
- Targeted radiosurgery was so effective that only about 10 percent of patients required whole-brain radiation as a follow-up treatment. Whole brain radiation, once a first-line treatment for brain metastasis, can cause severe side effects, including cognitive decline.
- 62.5 percent of females enrolled in the study carried the favorable BRAF mutation, compared to 37.3 percent of males.
Researchers acknowledged the risk of intracranial hemorrhage, which increased when patients were treated with BRAF inhibitors. But the finding was not associated with any significant neurological deterioration or need for hospitalization.
“The tumor vessels within melanoma are friable and can bleed,” Dr. Warnick says. “We think bleeding happens more frequently in patients who receive a BRAF inhibitor after radiosurgery because the inhibitor is getting into the tumor and disrupting it.”
Principal investigator of the study was Jason Sheehan, MD, PhD, of the University of Virginia. In addition to Virginia and The Jewish Hospital - Mercy Health, there were two study sites: Yale University School of Medicine and New York University. The co-investigators have no personal, financial, or institutional interest in any of the drugs or technologies described in the study.