Fractionated stereotactic radiosurgery after resection improves surgical bed control compared with single-fraction stereotactic radiosurgery for patients with large brain metastases, according to findings from a phase III trial presented at the 2026 American Society for Radiation Oncology (ASTRO) Annual Meeting (Abstract LBA 01).
“This study moves fractionated radiosurgery from a reasonable practice supported by retrospective data to one backed by a randomized phase III trial,” said study co-author Ayal A. Aizer, MD, 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.”
Background and Study Methods
Local control of brain metastases from single-fraction stereotactic radiosurgery decreases with increasing size, but fractionated radiosurgery could offer more control for larger surgical cavities.
The multicenter phase III Alliance A071801 trial enrolled 242 patients with one to four brain metastases to randomly receive either single-fraction stereotactic radiosurgery (at 12 to 20 Gy by volume) or fractionated stereotactic radiosurgery (at 27 Gy in three sessions at less than 30 cc or 30 Gy in five sessions at 30 cc or more) to intact metastases. All patients had undergone surgical resection of one lesion 2 cm or larger. Patients were stratified by age below or above 60 years, planned use of targeted therapy or immunotherapy within 4 weeks of radiotherapy, and maximal diameter of the resection cavity below or above 3 cm.
“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 principal investigator Paul D. Brown, MD, the Wilmeth Professor of Radiation Oncology at the Mayo Clinic in Rochester, Minnesota. “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.”
The primary study endpoint was time to surgical bed failure. Secondary endpoints included local control of intact brain metastases, overall survival, and radiation necrosis rates.
Key Findings
Patients were followed for a median of 48 months.
Surgical bed control was significantly improved in the fractionated arm compared with the single-fraction arm, with 1-year rates of 87% vs 81%, respectively (P = .046). The rate of failure in treated, unresected brain metastases was lower in the fractionated arm vs the single-fraction arm at 4% vs 11%, although the difference was not considered statistically significant.
Overall survival was extended with fractionated radiotherapy at a median overall survival of 29 months in the fractionated arm vs 20 months in the single-fraction arm (stratified Cox hazard ratio [HR] = 0.69; P = .035). Multivariable analysis including other baseline variables observed similar associations between the study arms in terms of overall survival (HR = 0.68; P = .032).
Toxicity rates were similar between the two arms. The rate of grade 1 or higher radiation necrosis was 14% in the fractionated arm vs 10% in the single-fraction arm, and the rates of cerebral edema were 8% and 9%, respectively.
“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.”
The study authors noted that since the study was not designed to determine the cause of the survival difference, more research is still needed.
“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 ASTRO expert Lia Halasz, MD, FASTRO, Chair of the ASTRO CNS Resource Panel and a radiation oncologist at the Fred Hutch Cancer Center and University of Washington in Seattle.
DISCLOSURES: For full disclosures of the study authors, visit elsevierdigitaledition.com.
