BACKGROUND: Stereotactic radiosurgery (SRS) is an emerging alternative to whole-brain radiotherapy (WBRT) for treating multiple brain metastases (BM), reducing toxicity, and improving tumor control. The CYBER-SPACE trial compared SRS based on either SPACE or MPRAGE MRI sequence for avoiding or delaying WBRT in patients with 1-10 BM. METHODS: Patients with 1-10 untreated BM were randomized 1:1 to receive SRS of all lesions based on either SPACE or MPRAGE MRI sequences. If subsequently new BM occurred, SRS was repeated. WBRT was indicated upon occurrence of >
10 new BM, leptomeningeal disease, or exhausted SRS-radiotolerance. The primary outcome was freedom from WBRT indication (WBRTi). Secondary outcomes included overall survival (OS), safety, and quality of life. RESULTS: A total of 202 patients were randomized
SPACE n = 99, MPRAGE n = 103. Twelve-month WBRTi-free survival was 77.1% (95% CI: 69.5%-83.1%) overall, 78.5% (95% CI: 66.7%-86.5%) for SPACE, and 76.0% (95% CI: 65.2%-83.9%) for MPRAGE (hazard ratio [HR] = 0.84, 95% CI: 0.43-1.63, P = .590). Patients with 5-10 BM had shorter WBRTi-free survival (HR = 3.13, 95% CI: 1.53-6.40, P = .002). Median OS was 13.1 months overall, 10.5 months for SPACE, and 15.2 months for MPRAGE (HR = 1.10, 95% CI: 0.78-1.56, P = .585). Neurologic death rate was 10.1%. Predictors for longer OS included Karnofsky Performance Status >
80% (HR = 0.51, 95% CI: 0.33-0.77, P = .002) and concurrent immunotherapy (HR = 0.34, 95% CI: 0.23-0.52, P <
.001). CONCLUSIONS: The more sensitive SPACE sequence did not improve outcomes over MPRAGE. SRS with thorough monitoring and immediate re-treatment for new lesions decreases the need for WBRT and achieves low neurologic death rates. SRS should be considered a favorable alternative to WBRT for patients with 1-10 BM.