BRAIN METASTASES ARE BEING DIAGNOSED in greater numbers thanks to more effective methods of detection. But even if they’re found early, treatments are limited. Surgery isn’t an option unless only a single metastasis is found, which rules out 80% of patients. Targeted therapies have shown some promise, but they accumulate in the brain at lower concentrations than elsewhere in the body, which can limit their efficacy. Whole-brain radiation therapy, which affects the entire brain, and stereotactic radiosurgery, which can be targeted more precisely, are the most common forms of treatment, as well as surgery when appropriate.

The blood-brain barrier is a semipermeable border of cells that prevents circulating toxins from entering the brain or pathogens from causing infections in the brain, without preventing nutrients from reaching the brain. Immunotherapy drugs were at one point considered unsuitable for treating brain metastases because of concerns that they wouldn’t be able to cross the blood-brain barrier, or that even if they did, they wouldn’t have the capacity to induce an immune response. But doctors treating brain metastases are now embracing systemic options like immunotherapy that target the whole body, rather than relying solely on local treatments like whole-brain radiation therapy or radiosurgery, says Antonio Omuro, chief of neuro-oncology at Yale Cancer Center in New Haven, Connecticut.

“Many traditional cytotoxic chemotherapy agents have shown limited activity in the nervous system due to [their] inability to cross the blood-brain barrier, which could be due to the molecular size and structure of those agents,” says Chi Lin, a radiation oncologist at the University of Nebraska Medical Center in Omaha. “The discovery of … new immunotherapeutic agents such as immune checkpoint inhibitors has changed the treatment landscape, since they are found to cross the blood-brain barrier and have activity in the central nervous system.”

“Immunotherapies have become an important part of the treatment, with many patients displaying responses in the brain metastases,” says Omuro, adding that sometimes these responses are comparable to those seen elsewhere in the body. This shift has brought a desire for more clinical research into the effect of immunotherapy on brain metastases. People with brain metastases have historically been excluded from most immunotherapy clinical trials due to concerns about immunotherapy causing toxicity in the brain. Researchers also worried that including patients with brain metastases, who have less favorable prognoses than patients without these metastases, would lead to worse overall results for the drugs being tested, says Lin.

Lin contributed to two recent papers that looked at how immunotherapy affected survival for two different cohorts of patients with brain metastases: those who had previously had a primary tumor removed surgically and those who had not. The researchers looked at these two groups of patients separately because they have different median survival lengths.

The researchers investigated the effect of immunotherapy combined with other treatments on people who had surgery to remove a primary tumor using data from the National Cancer Database (NCDB) for a paper published in the September 2020 JAMA Network Open. Among 3,112 adult patients diagnosed with non-small cell lung cancer, melanoma, breast cancer, colorectal cancer or kidney cancer between 2010 and 2016, people who received radiation therapy and immunotherapy lived longer after diagnosis than those who received radiation therapy alone. This benefit was not seen in patients who received immunotherapy alongside chemoradiation or chemotherapy compared with those who received chemoradiation or chemotherapy alone.

The second paper studied patients who did not receive surgery for their primary tumor and was published in the July 2020 Journal of the National Comprehensive Cancer Network. Data from the NCDB recorded the experiences of 94,215 patients diagnosed with the same cancer types as the patients in the first study. Among this cohort, people who received immunotherapy in combination with chemotherapy, radiation therapy or chemoradiation lived longer after diagnosis than those who received any of these therapies alone.

The authors of both papers suggest further study into the benefits of immunotherapy administered in combination with other treatments for patients with brain metastases is needed. “The challenges [of treating brain metastases with immunotherapy] are the same as in systemic therapies,” says Omuro, who was not involved in either study. “Not all patients respond, and much research is needed to elucidate the reasons.”