2012 - Dose-Escalated WBRT Independently Improves Survival In NSCLC Leptomeningeal Metastases: A Multimodal Analysis of Local and Systemic Therapies

Purpose/Objective(s):

Leptomeningeal metastases (LM) from non-small cell lung cancer (NSCLC) carry a poor prognosis. Modern management combines systemic therapies (targeted therapy [TT], chemotherapy, and immunotherapy) with local therapies (whole-brain radiotherapy [WBRT] and intrathecal chemotherapy [IT]). While most centers use 30Gy/10 fractions WBRT, whether dose escalation provides additive benefit when combined with effective systemic therapies remains unclear. We evaluated survival outcomes across WBRT fractionation regimens in the context of contemporary multimodal local and systemic treatment strategies.

Materials/Methods:

We performed a retrospective analysis of 160 NSCLC patients with LM treated with WBRT-based multimodal therapy at Sanjiu Brain Hospital between December 2019 and March 2024. The primary endpoint was overall survival from WBRT completion. Patients received one of three WBRT regimens: 30Gy/10 fractions, 36Gy/18 fractions, or 40Gy/20 fractions. Systemic therapies included TT, chemotherapy, immunotherapy, and VEGF inhibitors. Local therapies included WBRT and IT. Univariate and multivariate Cox proportional hazards models assessed the independent impact of WBRT dose, along with clinical factors including age, sex, mutation status, IT, and systemic therapy, on overall survival.

Results:

Among 160 patients (82 males, 78 females), 13 (8%) received 30Gy/10f, 56 (35%) received 36Gy/18f, and 91 (57%) received 40Gy/20f; 91% received systemic TT (predominantly EGFR/ALK inhibitors) and 73% received IT, reflecting modern practice patterns. With a median follow-up of 259 days, 119 deaths occurred. Median OS was 325 days (95% CI: 258-387) for 40Gy/20f vs. 298 days (95% CI: 242-607) for 36Gy/18f vs. 120 days (95% CI: 80-NA) for 30Gy/10f (log-rank p = 0.011). On univariate Cox analysis, both higher-dose WBRT regimens significantly reduced mortality risk compared to 30Gy/10f: 36Gy/18f (HR 0.38, 95% CI: 0.20–0.73, p = 0.004) and 40Gy/20f (HR 0.44, 95% CI: 0.24–0.81, p = 0.009). Similarly, systemic TT (325 vs. 173 days without TT; HR 0.39, 95% CI: 0.21–0.70, p = 0.002) and IT (346 vs. 199 days without IT; HR 0.62, 95% CI: 0.42–0.92, p = 0.016) each demonstrated significant survival benefit. On multivariate analysis, all components retained independent significance: 36Gy/18f WBRT (HR 0.29, 95% CI: 0.15-0.57, p < 0.001), 40Gy/20f WBRT (HR 0.37, 95% CI: 0.20-0.70, p = 0.002), TT (HR 0.35, 95% CI: 0.19-0.65, p < 0.001), and IT (HR 0.57, 95% CI: 0.38-0.84, p = 0.005).

Conclusion:

In NSCLC patients with LM, dose-escalated WBRT (36Gy/18f and 40Gy/20f), IT, and systemic TT each appeared to independently contribute to survival, suggesting potential benefit from a comprehensive multimodal approach. Higher-dose WBRT may retain survival benefit even alongside effective TT, though these findings should be interpreted cautiously given the retrospective design, and prospective validation is needed to define optimal treatment integration in this poor-prognosis population.