Formal discussant, Andrew B. ­Lassman, MD, of the Department of Neurology at Herbert Irving Comprehensive Cancer Center and Columbia University Medical Center in New York, congratulated Dr. Brown and his coauthors for undertaking and completing a “herculean task” that took 10 years.

To illustrate the scope of affected patients, about 25% of all cancer patients develop brain metastasis. “More patients are diagnosed with brain metastasis than with breast, lung, or prostate cancer. Treatment for these patients represents an unmet clinical need,” Dr. Lassman noted.

Dr. Lassman said that another interpretation of the results is that whole-brain radiation therapy does improve survival in appropriate patients. “Survival was not the primary endpoint of the Alliance trial, and the needed subgroup analyses have not yet been conducted to evaluate the issue of survival effectively. If you defer whole-brain radiation therapy, it leads to more recurrences, so it should be used in selected patients,” he added.

“It is reasonable to conclude that whole-brain radiation therapy leads to improved survival if brain metastases are the life-limiting site of disease such as with stable extracranial disease,” he stated. “With progressive extracranial disease, there is no difference in survival with whole-brain radiation therapy plus stereotactic radiosurgery. In the appropriate context, such as those with controlled or absent systemic disease, whole-brain radiotherapy can influence survival.… However, it is unrealistic to expect a difference in survival with whole-brain radiation therapy if patients are not appropriately selected.”

Cognitive Findings Differ From Other Studies

This is the largest trial to date studying neurocognitive effects with such a detailed battery of tests, he continued. The authors found a 12-month persistent worsening of cognitive function after whole-brain radiotherapy.

“This is discordant with other studies. This finding should be interpreted with caution. The 12-month data represent a post-hoc analysis with only 34 patients, and the numbers are too small to draw this conclusion definitively,” Dr. Lassman stated.

“The metastatic sites in the brain determine the neurologic effect. The difference of locations of metastasis in other trials could partially explain the discordant results,” he added.

“Both whole-brain radiation therapy and stereotactic radiosurgery are bad for the brain. We need alternative approaches,” Dr. Lassman continued.

Use of memantine along with whole-brain radiation therapy might be helpful, and avoiding the hippocampus as part of whole brain-radiotherapy may also reduce cognitive effects. Upcoming randomized trials by NRG Oncology will further evaluate hippocampal-sparing whole-brain radiotherapy and memantine for patients with or at risk for brain metastases. ■

Disclosure: Dr. Lassman reported a consulting or advisory role with Genentech/Roche, Midatech, Celgene, Sigma-Tau, Amgen, Agenus, Stemline Therapeutics, Novartis, Foundation Medicine, HERON, and Synapse; and research funding (institutional) from Abbvie, Novartis, Karyopharm Therapeutics, Genentech/Roche, and Novocure.