Dose Escalation With Intensity-Modulated Proton Therapy for Patients with High-Risk Meningiomas – Results From a Phase 1 Trial

BACKGROUND: Outcomes for grade 2 and 3 meningiomas are poor. A few studies suggest a benefit from radiation therapy dose escalation. This trial evaluates the safety and efficacy of dose escalation with intensity-modulated proton therapy (IMPT) for grade 2 and 3 meningiomas. METHODS: This prospective single-arm phase 1 trial enrolled patients with grade 2 meningioma with residual disease or recurrence, or patients with grade 3 meningioma after gross total resection. Patients underwent dose-escalated IMPT to 66 Gy (relative biological effectiveness, RBE) for grade 2 gross disease and 63 Gy(RBE) for grade 3 tumor beds. The primary endpoint was acute dose-limiting toxicity (DLT). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and late toxicity. RESULTS: Twenty-one patients with 16 grade 2 and five grade 3 meningiomas were enrolled and treated between 2016 and 2023. The median clinical and radiographic follow-up periods were 3.4 and 3.2 years, respectively. No DLT was observed. Five new late grade 3 toxicities occurred in four patients. Three treatment failures were observed in two grade 2 and one grade 3 tumors. Two deaths occurred in patients with grade 2 meningiomas. The 1-, 2-, and 3-year PFS rates were 100%, 95.0%, and 88.2%, respectively. The corresponding OS rates were 100%, 95.0%, and 95.0%, respectively. CONCLUSIONS: This first prospective trial investigating dose-escalated IMPT for high-grade meningiomas demonstrated a favorable early safety profile and clinical outcomes. Phase 2 and 3 studies are warranted to confirm the superiority of dose escalation for high-grade meningiomas.