Splitting Radiation Into Multiple Sessions Cuts Recurrence After Brain Metastasis Surgery

For the hundreds of thousands of people whose cancer spreads to the brain each year, one of the most persistent clinical challenges has just been addressed with the strongest kind of evidence available: a randomized phase 3 clinical trial. Researchers reported that delivering focused radiation therapy over three to five sessions after surgery for a large brain metastasis significantly reduced the risk of the cancer returning at the surgical site compared with delivering the same type of radiation in a single session. The trial, the first of its kind to directly compare the two approaches head to head, was presented at the American Society for Radiation Oncology (ASTRO) Annual Meeting in Boston and is poised to reshape how clinicians manage one of the most common and serious complications of cancer’s spread to the brain.

Brain metastases occur when cancer that began elsewhere in the body, most often in the lung, breast, skin or colon, travels through the bloodstream and takes hold in brain tissue. An estimated 200,000 people in the United States develop these lesions every year, and that number is climbing. Paradoxically, the rise is a consequence of progress: modern systemic therapies are helping patients with cancer live longer, and the longer patients survive their primary disease, the more time microscopic seeds of tumor have to establish themselves in the brain. The result is a growing population of patients at risk of developing lesions that can cause seizures, headaches, difficulty speaking or moving, and dangerous pressure on surrounding brain tissue.

When a metastasis grows large enough to threaten neurological function, surgery is often the first step. But removing the visible tumor is only half the battle. Microscopic cancer cells inevitably remain in the tissue surrounding the surgical cavity, and without additional treatment, these residual cells frequently give rise to recurrence. In a previous randomized trial, more than half of patients who underwent surgery without postoperative radiation therapy experienced the tumor returning at the surgical site within a single year. For that reason, radiation therapy after surgery is a standard of care for patients with a limited to moderate number of resected brain metastases.

The preferred form of that radiation has evolved considerably. Rather than irradiating the entire brain, which can impair memory and quality of life, current guidelines and randomized trial data support stereotactic radiosurgery, a technique that focuses highly precise beams of radiation on the surgical cavity while sparing healthy tissue. Yet for larger cavities, the optimal way to deliver this treatment had never been definitively established. The dose that can be safely given in one session is limited by how much surrounding healthy brain is exposed, creating a difficult tradeoff: restrict the treatment area to protect normal tissue and risk leaving tumor cells behind, or treat more comprehensively and accept a higher risk of radiation injury to the brain.

Retrospective studies had long suggested that dividing the radiation dose across several treatments, an approach known as fractionated stereotactic radiosurgery, might safely improve local control. The reasoning rests on a fundamental principle of radiation biology: healthy tissue repairs sublethal radiation damage between sessions far more effectively than tumor cells do, so splitting the dose gives normal brain time to recover while still accumulating a lethal cumulative dose in the treatment area. Until now, however, this reasoning had never been tested in a randomized phase 3 trial, the gold standard of clinical evidence.

The Alliance A071801 trial, funded by the National Cancer Institute-sponsored Alliance for Clinical Trials in Oncology, enrolled 242 patients at multiple centers between 2019 and 2022. All participants had one to four brain metastases, including at least one larger than 2 centimeters that had been surgically removed. Patients were randomly assigned to receive either a single session of postoperative radiosurgery or fractionated radiosurgery delivered in three or five sessions, with doses calibrated to the size of the treatment area. Any metastases that had not been surgically removed were treated according to the same assigned schedule, and researchers followed participants for a median of four years.

The results favored the multi-session approach. One year after treatment, 87 percent of patients who received fractionated radiosurgery remained free from recurrence at the surgical site, compared with 81 percent of those treated in a single session, a difference that was statistically significant. Fractionated treatment also showed a trend toward better control of tumors that had not been removed: treated, unresected metastases later progressed in 4 percent of the fractionated group versus 11 percent of the single-session group, though that difference did not reach statistical significance. Perhaps most strikingly, median overall survival was 29 months in the fractionated arm compared with 20 months in the single-fraction arm, corresponding to a 31 percent lower risk of death that remained significant after adjustment for other patient and treatment characteristics. Rates of adverse events were low in both groups and did not differ significantly, meaning the improved outcomes came without a measurable increase in side effects.

Paul D. Brown, MD, principal investigator of the trial and the Wilmeth Professor of Radiation Oncology at the Mayo Clinic in Rochester, Minnesota, framed the central dilemma the trial was designed to solve. After surgery for a large brain metastasis, he explained, the challenge is delivering enough radiation to eliminate microscopic cancer cells left behind without exposing too much healthy brain to a high single dose. Dividing the dose over several treatments, he said, gives healthy tissue time to recover between doses while still delivering an effective dose to the treatment area, allowing the team to improve local control while maintaining a similar safety profile. He noted that the better control at the surgical site aligned closely with the retrospective evidence that motivated the trial, but that the survival difference was surprising, and the study was not designed to determine why it occurred. Additional analyses of the well-balanced treatment groups did not identify a clear explanation, and more research is needed. As modern treatments help patients live longer with cancer, he suggested, maintaining control of disease in the brain may play an increasingly important role in long-term outcomes.

Other experts emphasized the practical significance of the findings. Ayal A. Aizer, MD, a study co-author and radiation oncologist at Mass General Brigham and Dana-Farber Cancer Institute in Boston, said the study moves fractionated radiosurgery from a reasonable practice supported by retrospective data to one backed by a randomized phase 3 trial, giving clinicians the strongest evidence to date that three to five sessions should be considered a standard postoperative treatment for patients with larger brain metastases. Lia Halasz, MD, FASTRO, chair of the ASTRO CNS Resource Panel and a radiation oncologist at Fred Hutch Cancer Center and the University of Washington in Seattle, noted that large surgical cavities have long been a challenge because the amount of radiation deliverable safely in a single session is limited: treating larger cavities at higher doses was associated with more side effects, while lower doses produced worse local control. Many clinicians, she observed, had already shifted toward fractionated approaches based on retrospective studies, and this trial now provides randomized evidence that the additional treatment visits translate into a meaningful improvement in local control without a significant increase in side effects.

The implications reach well beyond the trial itself. For patients, the finding suggests that a few extra outpatient visits for radiation could meaningfully lower the odds of their cancer returning in the brain and may extend survival, all without adding toxicity. For the health system, it validates an approach that many centers had adopted on weaker evidence and gives insurers and guideline committees a randomized basis for standardizing postoperative care. And for researchers, the unexplained survival advantage opens a compelling scientific question: whether better control of disease within the brain, an organ once considered a terminal sanctuary for metastatic cancer, can itself shape how long patients live as systemic therapies continue to improve. Larger prospective studies may yet clarify that mechanism, but for now, the message from the first rigorous comparison of these two strategies is clear. When it comes to eradicating residual disease after brain metastasis surgery, patience, in the form of fractionated radiosurgery delivered over three to five carefully planned sessions, appears to pay off.

Subject of Research: Fractionated versus single-session postoperative stereotactic radiosurgery for resected large brain metastases

Article Title: Fractionated radiosurgery reduces cancer recurrence after surgery for large brain metastases

Article References: Fractionated radiosurgery reduces cancer recurrence after surgery for large brain metastases. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: brain metastases, stereotactic radiosurgery, fractionated radiation therapy, phase 3 clinical trial, surgical cavity recurrence, radiation oncology, overall survival, local control, ASTRO, Alliance A071801, cancer, postoperative treatment