Linac-based stereotactic radiosurgery for brain metastases: Survival and salvage treatment in a contemporary cohort of 3893 patients

Abstract

Abstract Background Real-world outcomes after stereotactic radiosurgery (SRS) for brain metastases across the full burden spectrum are limited. We tested whether overall survival (OS) in higher-burden lesion groups is non-inferior to a 5-10 lesion reference and characterized salvage patterns, including whole-brain radiotherapy (WBRT). Methods A total of 3893 consecutive patients received linac-based SRS (1-5 fractions) at seven sites of an NCI-designated cancer center network (2017-2026), stratified by lesion count (1, 2-4, 5-10, 11-20, >20). Multivariable Cox regression used 5-10 as reference; pre-specified non-inferiority testing (margin HR 1.30, one-sided α = 0.025) compared higher-burden groups. Cumulative incidences of salvage interventions used death as the competing event. Results Median age 65 years; median follow-up 41.2 months. 77% had 1-4, 17% had 5-10, and 6% had >10 lesions (maximum 140). Median OS was 16.2, 11.0, 8.2, 8.7, and 6.5 months for the 1, 2-4, 5-10, 11-20, and >20 groups. OS was significantly better for 1 (HR 0.62, 0.55-0.69) and 2-4 (HR 0.81, 0.73-0.90) versus 5-10; non-inferiority was met for 11-20 (P < .001) but not >20 (n = 41, P = .20). CNS-directed systemic therapy was strongly protective (HR 0.62, 0.57-0.68); 21.7% of patients with ≤20 lesions survived ≥30 months. 12-month salvage WBRT incidence was 2.9%-6.3%; 24-month incidence was 6.7% versus 41.7% for a third SRS course. Conclusions OS plateaued from 5 through 20 lesions, with non-inferiority to the 5-10 reference established for 11-20; the >20 group (n = 41) was underpowered and showed a directionally worse estimate that could not exclude a clinically meaningful decrement. Salvage WBRT was uncommon across all lesion-count groups (24-month cumulative incidence ≤7.3%; >90% of patients received no salvage WBRT), even after multiple SRS courses. These data support an SRS-first strategy guided by clinical factors rather than fixed lesion-count thresholds.