Exploratory Evaluation of Personalized Ultra-Fractionated Stereotactic Adaptive Radiotherapy (PULSAR) with CNS-Active Drugs in Brain Metastases Treatment.

Introduction: Brain 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).

Methods: This study involved a retrospective evaluation of patients treated with PULSAR 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.

Results: Analysis included 109 lesions treated with PULSAR, predominantly in patients with lung and breast cancer. The median follow-up was 1.72. Median OS was not reached. The 1- and 2-year LF rates were 5% and 8.9%, respectively, and 3.4% and 5.5% with concurrent CNS-aDs (cCNS-aDs). BMs > 2 cm had LF rates of 9.4% at two years. No LFs were observed in BMs > 2 cm treated with the combined PULSAR+CNS-aDs approach at 2.5 years. Univariate analysis indicated CNS-aD and radioresponsive histologies were associated with decreased LR rates. The two-year grade 3+ toxicity rate for PULSAR was 8.7%, with no increase in toxicity with cCNS-aDs.

Conclusion: The integration of PULSAR with CNS-aDs appears to offer excellent local control for larger brain metastases with limited toxicity. These promising results merit further prospective investigation to validate the findings and potentially establish new treatment protocols.