Fractionated radiosurgery reduces cancer recurrence after surgery for large brain metastases

ASTRO Expert Perspective: “With brain metastases, large surgical cavities present a challenge because we have been limited in the amount of radiation we can safely deliver in a single radiosurgery treatment. Treating larger cavities was associated with more side effects at higher doses and worse local control at lower doses. Many clinicians have already moved toward a fractionated radiosurgery approach based on retrospective studies, and this trial gives us randomized evidence that the additional visits translate into a meaningful improvement in local control without a significant increase in side effects,” said Lia Halasz, MD, FASTRO, Chair of the ASTRO CNS Resource Panel and radiation oncologist at the Fred Hutch Cancer Center and University of Washington in Seattle.

Delivering focused radiation therapy over three to five sessions after surgery for a large brain metastasis reduced the risk of cancer returning at the surgical site compared with delivering the radiation in a single session, according to the first randomized phase 3 clinical trial directly comparing the approaches.

Patients who received the multi-session treatment, known as fractionated stereotactic radiosurgery, also lived a median of nine months longer than those treated in a single session. There were no significant differences in side effects between the treatment groups. Results will be presented today at the American Society for Radiation Oncology (ASTRO) Annual Meeting.

“After surgery for a large brain metastasis, the challenge is giving enough radiation therapy to eliminate microscopic cancer cells left behind without exposing too much healthy brain to a high single dose,” said Paul D. Brown, MD, principal investigator of the trial and the Wilmeth Professor of Radiation Oncology at the Mayo Clinic in Rochester, Minn. “Dividing the radiation dose over several treatments gives healthy tissue time to recover between doses while still delivering an effective dose to the treatment area. By fractionating the treatment, we were able to improve local control while maintaining a similar safety profile.”

“This study moves fractionated radiosurgery from a reasonable practice supported by retrospective data to one backed by a randomized phase 3 trial,” said Ayal A. Aizer, MD, a study co-author and a radiation oncologist at Mass General Brigham/Dana-Farber Cancer Institute in Boston. “We now have the strongest evidence to date that three to five sessions should be considered a standard postoperative treatment for patients with larger brain metastases.”

Brain metastases occur when cancer that began elsewhere in the body spreads to the brain. An estimated 200,000 people develop brain metastases each year in the United States, and incidence is rising as advances in cancer treatment extended survival for many patients, contributing to a growing population of people at risk of developing these lesions.

Large metastases may require surgery when they cause pressure on the brain or symptoms such as seizures, headaches or difficulty speaking or moving. Radiation therapy is recommended after surgery because microscopic cancer cells can remain around the surgical cavity and cause the tumor to return. In a previous randomized trial, more than half of patients who had surgery without postoperative radiation therapy experienced recurrence at the surgical site within one year.

For patients with a limited to moderate number of resected brain metastases, current guidelines and randomized trial data support treating the surgical cavity with stereotactic radiation therapy rather than whole brain radiation therapy to preserve cognitive function and quality of life. But the best way to deliver postoperative radiosurgery for larger surgical cavities had not been determined definitively.

With larger treatment areas, the dose that can be delivered safely in a single session may be limited by the amount of surrounding healthy brain exposed to radiation. These dose constraints create a tradeoff between limiting the treatment area to protect healthy brain tissue or treating more comprehensively, which can increase the risk of radiation injury. Retrospective studies suggest that dividing the radiation therapy dose across several treatments may safely improve local control, but the approaches had not been compared in a randomized phase 3 trial until now.

The Alliance A071801 multi-center trial enrolled 242 patients with one to four brain metastases, including one metastasis larger than 2 centimeters that had been surgically removed. Patients were randomly assigned between 2019 and 2022 to receive either a single session of radiosurgery or fractionated radiosurgery delivered in three or five sessions, with doses based on the size of the treatment area. Any metastases that had not been surgically removed were treated according to the same assigned schedule. Researchers followed patients for a median of four years.

One year after treatment, 87% of patients who received fractionated radiosurgery remained free from recurrence at the surgical site, compared with 81% of those who received single-session radiosurgery. The difference was statistically significant.

Fractionated radiosurgery also showed a trend in controlling brain metastases that had not been removed surgically. Treated, unresected tumors later progressed in 4% of patients in the fractionated group, compared with 11% in the single-session group. That difference was not statistically significant, however.

Median overall survival was 29 months for patients treated with fractionated radiosurgery, compared with 20 months for those treated in a single session. Fractionated treatment was associated with a 31% lower risk of death, and the association remained significant after researchers adjusted for other patient and treatment characteristics. Rates of adverse events were low in both arms and did not differ significantly between the treatment groups.

The survival difference was unexpected, researchers said, and the study was not designed to determine why it occurred, so more research is needed. The treatment groups were well balanced on measured characteristics at the start of the study, and additional analyses did not identify a clear explanation for the difference.

“We were pleased to see better control at the surgical site because that finding aligns closely with the retrospective evidence that led us to undertake this trial,” Dr. Brown said. “But the survival difference was surprising, and we cannot say with certainty why it occurred. As modern treatments help patients live longer with cancer, maintaining control of disease in the brain may play an increasingly important role in long-term outcomes.”

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Attribution to the American Society for Radiation Oncology (ASTRO) Annual Meeting is requested in all coverage.

Study & Presentation Details

• Dr. Aizer will discuss this study in a news briefing on Monday, Sept. 28; register here.
• Abstract details (available after 5:00pm ET on Sept. 25; embargoed abstract available on request)
• Session details & virtual meeting link
• Dr. Aizer’s bio & disclosures; Dr. Brown’s bio & disclosures
• Funding for this study was provided by the NCI-sponsored Alliance for Clinical Trials in Oncology.
• Find more information about the meeting in our press kit.

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