Patterns of failure after Stereotactic Radiosurgery for Patients with 15 or more Brain Metastases

Purpose: Current standard of care treatment for patients with ≥15 brain metastases(BM) is whole brain radiation therapy(WBRT), despite poor neurocognitive outcomes. We analyzed our institutional experience of treating these patients with stereotactic radiosurgery(SRS), with the aim of evaluating safety, cognitive outcomes, and survival metrics.

Methodology: Patients who received SRS for ≥15 BMs in 1-5 fractions from 2014-2022 were included. Patients were typically treated with a single isocenter multi-target VMAT technique (SIMT) which has been previously described. Our primary endpoint was grade 3 or higher toxicity, while the secondary end points were overall survival (OS) and intracranial progression free survival (PFS). Cognitive outcomes were objectively evaluated using serial Patient-Reported Outcome Measurement Information System(PROMIS) scores. Kaplan-Meier method was used for survival analysis and log-rank test was used for intergroup comparisons. All statistical analyses were performed using SPSS v23.0.

Results: Overall, 118 patients underwent 124 courses of LINAC-based SRS. The median number of lesions treated per course was 20(range 15–94) to a median SRS dose of 24 Gy(range 18–30 Gy). Median age of patients at RT was 61.6 years (IQR 51.4 – 69.5). Most common primary tumor histologies were lung (47.6%), followed by melanoma (21.0%) and breast (14.5%). At the time of SRS, 19.4% patients had received prior WBRT and 24.2% had received prior SRS, with 79 patients not receiving any prior brain RT (“Brain RT naïve”). The rate of any grade radiation necrosis (RN) and ≥grade 3 RN were 15.3% and 3.2% respectively. 81% patients had a stable PROMIS score. At last follow-up, 22.6% patients were alive, 2.4% had local failure of treated metastases and 50.0% had distant intracranial progression. Brain RT naïve patients had a significantly higher median OS (7.4 months vs 4.6 months, p = 0.034). Overall, median OS from BM diagnosis was 11.3m. No prior WBRT or SRS (p = 0.038), higher KPS (p = 0.002) and systemic therapy after SRS (p < 0.001) predicted for improved OS. There was no impact of number of lesions, GTV volume, or PTV volume on survival outcomes. The 12-month local control was 97.6%, while the cumulative incidence of distant intracranial failure, with death as a competing event, was 46% (95% CI 36%, 55%). On Fine and Gray competing risk analyses, 12-month freedom from neurological death, leptomeningeal disease, and salvage WBRT were 89%, 94.6% and 84% respectively.

Conclusions: We present the largest study evaluating SRS for patients with ≥15 BMs. SRS was safe, had favorable cognitive outcomes, and comparable survival outcomes to contemporary studies evaluating WBRT in this population. Treatment-naïve patients had a median survival of > 6 months, long enough to benefit from cognitive sparing with SRS. Our study supports randomized studies comparing SRS and hippocampal avoidance WBRT approaches for these patients.

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