Radiosurgery to 5 or More Newly Diagnosed Brain Metastases in the Systemic Therapy Era.

2026 Background: Stereotactic radiosurgery (SRS) is an ablative modality for focal treatment of brain metastases (BM) and is standard of care for limited BM. Suitability for SRS has historically been linked to number of BM, with up to 4 BM considered amenable to SRS. JLGK0901 revealed no difference in overall survival (OS) and similar rates of adverse events for patients with 5-10 vs. 2-4 BM. Evidence supporting for SRS for >10 BM is limited. As systemic treatments have evolved to include agents with improved central nervous system (CNS) efficacy and OS, the role of SRS warrants re-evaluation. Methods: We retrospectively reviewed patients from a single institution with ≥5 BM treated with SRS with no prior history of brain radiation 2015-2022 on an IRB-approved protocol. Clinical history, including sex, histology, Karnofsky performance status (KPS), extracranial disease status and systemic regimen used before and after diagnosis of BM, was reviewed. Systemic regimens were categorized based on potential for CNS efficacy as 1) none: no evidence, 2) weak: single agent immunotherapy or known but limited data on CNS efficacy, or 3) strong: multiple agents with known CNS efficacy, single agents with strong CNS efficacy. Kaplan-Meier method was used to estimate survival with log-rank test used to evaluate differences in survival curves. Cox proportional hazards modeling was used to evaluate differences in CNS progression-free survival (CNS-PFS) and OS. Results: 558 patients (48% female) who received SRS to ≥5 BM (range 5-23) were identified. Primary histologies included: 36% non-small cell lung cancer; 22% melanoma; 14% breast; 7% renal; 5% gastrointestinal; 15% other. Median OS was 11.0 months and did not differ between patients with 5-9 (n=441) vs ≥10 BM (n=117) (median OS 11.1 vs. 10.0 months; p=0.53). Median CNS-PFS was 6.6 months and did not differ between 5-9 vs ≥ 10 BM (median CNS-PFS 6.4 vs. 7.7 p=0.86). On univariate analysis, high KPS (HR 0.96; p<0.001) was associated with improved OS. Histology ( p=0.14), BM number ( p=0.53); average BM volume ( p=0.48), and systemic disease status ( p=0.17) were not associated with OS. Change of systemic therapy at time of SRS was associated with improved OS (HR 0.58; p<0.001) and CNS-PFS (HR 0.63; p<0.001). Amongst patients with systemic therapy change, regimens with increased CNS efficacy compared to prior therapy were associated with improved OS (HR 0.59; p<0.001) and CNS-PFS (HR 0.65; p=0.002). Conclusions: In this large, retrospective analysis of patients with ≥ 5 previously untreated BM treated with SRS, we found no association between BM number and CNS-PFS or OS. Change in systemic therapy, particularly to agents with CNS efficacy, was associated with improved outcomes. While limited by biases inherent to retrospective analyses, these results suggest patients with larger number of BM (≥10) are appropriate for SRS, especially when changing to systemic therapy with CNS penetrance.