Preoperative Stereotactic Radiosurgery for Brain Metastases: A Phase 1 Dose Escalation Study Demonstrating Reduced...

Preoperative stereotactic radiosurgery (SRS) has been proposed as a strategy to reduce nodular leptomeningeal disease (nLMD) after resection of brain metastases by devitalizing tumor cells before surgical manipulation. This study aimed to determine the safety of preoperative SRS via a phase 1 dose escalation trial and compare outcomes-including nLMD, classical LMD, local control, and overall survival (OS)-between preoperative and postoperative treatment cohorts.

A phase 1 trial evaluated the safety of single-fraction preoperative SRS at escalating doses (12 and 15 Gy) in patients with tumors 2 to 6 cm. Adverse events were assessed per National Cancer Institute Common Terminology Criteria for Adverse Events v4.0, with dose-limiting toxicity (DLT) defined as high-grade neurologic or wound complications. Retrospective analysis included an expanded preoperative cohort (n = 95) and a historical postoperative cohort (n = 107). Outcomes were analyzed with Kaplan-Meier and Cox proportional hazards models.

Fifteen Gy was well tolerated in the phase 1 cohort, with no DLTs in larger tumors (4-6 cm) and 3 DLTs in smaller tumors, not meeting thresholds for dose de-escalation. In the expanded analysis, preoperative SRS significantly reduced rates of nLMD (7.4% vs 27.1%, P = .002), while rates of classical LMD (4.2% vs 4.5%) and local failure (14.6% vs 18.7%) were similar between groups. OS was also similar (median 12.8 vs 12.3 months). Multivariable analysis confirmed preoperative SRS as protective against nLMD (hazard ratio = 0.18, 95% CI, 0.07-0.43, P < .001).

Preoperative SRS to 15 Gy is safe for tumors 2 to 6 cm and significantly reduces nLMD without compromising local control or OS. These findings support preoperative SRS as a viable treatment strategy and justify further investigation into optimal dosing and patient selection.