Integrating CNS-active therapy with stereotactic radiotherapy for brain metastases: comparative outcomes of PULSAR and FSRT

IntroductionBrain metastases (BMs) affect an increasing number of cancer patients and are typically managed with stereotactic radiosurgery (SRS). Our institution advocates the use of Personalized Ultrafractionated Stereotactic Adaptive Radiotherapy (PULSAR), where radiation is delivered in high-dose pulses at extended intervals allowing for treatment adaptation and easy concurrent systemic therapy integration. We explore the integration of PULSAR with central nervous system (CNS)-active drugs (CNS-aDs) compared to traditional fractionated stereotactic radiotherapy (FSRT). MethodsThis study involved a retrospective evaluation of patients treated with either PULSAR or FSRT using Gamma Knife from 2018-2024. We collected demographic, clinical, and specific treatment details, outcomes such as local failure (LF) and toxicity rates. Cumulative incidence analysis for local failure and toxicity, considering death a competing risk, and Kaplan-Meier survival analysis for overall survival (OS) were conducted. Multivariate (MV) Cox proportional hazard models assessed failure and toxicity rates. ResultsAnalysis included 166 lesions treated with FSRT and 109 with PULSAR, predominantly in patients with lung and breast cancer. The median follow-up and OS were 1.88 and 1.48 years. 1- and 2-year LF rates were similar; 5%/8.9% vs 8.2%/12.3% for PULSAR and FSRT and 3.4%/5.5% vs 10.1%/12.3% with concurrent CNS-aDs (cCNS-aDs). BMs > 2 cm LF rates were 9.4% and 17.3% at two years for PULSAR and FSRT (p=0.1). No LFs were observed in BMs > 2 cm treated with PULSAR+CNS-aDs at 2.5 years. The two-year grade 3+ toxicity rate for PULSAR (8.7%) and FSRT (11.7%), without an increase in toxicity when combined with cCNS-aDs. BMs treated with PULSAR+cCNS-aDs were less likely to fail (HR 0.15, p=0.048) on MV analysis (MVA). ConclusionThe integration of PULSAR with cCNS-aDs appears to offer excellent local control for larger brain metastases without increased toxicity. These promising results merit further prospective investigation to validate the findings and potentially establish new treatment protocols.