Phase III Clinical Trial Compares Fractionated SRS to Single-Fraction Treatment
Fractionated stereotactic radiosurgery significantly improves surgical-bed control and overall survival compared with single-fraction treatment for patients with large resected brain metastases, according to results from the phase III Alliance A071801 trial presented at the 2026 ASTRO Annual Meeting. Data from the multicenter study show that delivering radiation across multiple sessions reduces local recurrence without increasing treatment-related toxicity.
Trial Eligibility Requires Adults with Specific Brain Metastases
Investigators designed the Alliance A071801 trial to evaluate postoperative radiation approaches in adults with brain metastases. Patients aged 18 years or older were eligible if they had one to four brain metastases, including at least one completely resected metastasis measuring 2 cm or larger within 30 days of registration. Resection cavities were required to be smaller than 5.0 cm, and participants could have up to three unresected brain metastases smaller than 4 cm, alongside a Karnofsky performance status of at least 60.
The trial excluded individuals with small cell carcinoma, germ cell tumors, lymphoma, leptomeningeal disease, peri-optic or peri-brainstem lesions within 5 mm, prior whole-brain radiotherapy, or an inability to tolerate contrast-enhanced brain MRI. Between October 2019 and October 2022, researchers pre-registered 254 patients and randomly assigned 242 participants to receive either single-fraction SRS or fractionated SRS. The median age was 65.0 years in the single-fraction arm and 63.0 years in the fractionated arm, with lung cancer serving as the most common primary tumor site across both cohorts.
Dosing Protocols Vary by Treatment Arm and Cavity Volume
Patients in the single-fraction arm received a resection cavity dose ranging from 12 Gy to 20 Gy based on cavity volume. Participants assigned to the fractionated SRS arm received treatment delivered in three to five fractions. Cavities smaller than 30 cc received 27 Gy in three fractions, while those measuring 30 cc or larger received 30 Gy in five fractions. Central radiotherapy quality assurance and site-based SRS credentialing were maintained throughout the trial.
Prior randomized trials published in 2017 established single-fraction SRS as a standard of care but produced 1-year surgical-bed recurrence rates of 40% and 28%. Data from those earlier studies also linked larger preoperative tumor sizes to greater recurrence risks. In contrast, retrospective series evaluating fractionated SRS reported 1-year surgical bed control rates ranging from 84% to 93%.
Survival Outcomes and Local Control Rates at One Year
Primary endpoint analysis demonstrated that fractionated stereotactic radiosurgery improved 1-year surgical-bed control compared with single-fraction treatment. Surgical-bed control at 1 year rose from 81% with single-fraction SRS to 87% with fractionated SRS. Ayal Aizer, MD, of Mass General Brigham and Dana-Farber Cancer Institute, stated at the ASTRO meeting that the improvement in surgical-bed control was achieved without an apparent increase in toxicity.
Secondary outcomes revealed additional clinical benefits. Overall survival improved from a median of 20.2 months with single-fraction SRS to 28.6 months with fractionated SRS. The 1-year rate of freedom from salvage whole-brain radiotherapy was 94% with fractionated SRS versus 84% with single-fraction treatment, though this difference showed a stratified log-rank $P$ value of .06.
Recurrence Rates and Adverse Events Remain Comparable
Intracranial recurrence rates outside the surgical bed remained comparable between the two treatment arms at 1 year. Rates of local failure in unresected metastases were 3% for fractionated SRS versus 7% for single-fraction SRS, while new brain metastases occurred in 34% versus 38% of patients, respectively. Nodular meningeal disease was observed in 7% of the fractionated cohort and 5% of the single-fraction cohort, and classical leptomeningeal disease occurred in 3% versus 4% of patients.
Adverse event profiles remained balanced across both treatment groups. Radiation necrosis occurred in 13% of patients receiving fractionated SRS and 11% of those receiving single-fraction SRS, while cerebral edema rates were 8% and 9%, respectively. Patient-reported outcomes, including functional independence and cognitive function scores, showed no statistically significant differences between the two cohorts.
Trial investigators concluded that fractionated stereotactic radiosurgery establishes a preferred postoperative approach for patients undergoing resection of a brain metastasis measuring 2 cm or larger. Rupesh Kotecha, MD, of Baptist Health Herbert Wertheim Cancer Institute, acting as an ASTRO discussant, noted that if postoperative external beam radiotherapy is selected after upfront resection, fractionated radiosurgery serves as the new standard of care, though the observed overall survival differences warrant additional investigation.
Related reading