Safety and Efficacy of Sonodynamic Therapy Combined with Stupp Regimen in Controlling Postoperative Residual Lesions of Glioblastoma: A Prospective Pilot Phase I Study.

BACKGROUND: Postoperative residual disease in glioblastoma (GBM) drives early recurrence due to the blood-brain barrier (BBB), local hypoxia, and normal brain tissue dose constraints. Sonodynamic therapy (SDT) utilizes transcranial low-intensity ultrasound to selectively activate sonosensitizers (e.g., hematoporphyrin), inducing non-invasive oxidative tumor ablation, BBB permeabilization, and hypoxia alleviation. We evaluated the safety, feasibility, and preliminary efficacy of multi-session transcranial SDT combined with standard chemoradiotherapy in newly diagnosed GBM patients with MRI-confirmed residual lesions. METHODS: In this prospective, open-label Phase I trial (Ethics Approval No. 2024-KY-0621-002), 18 newly diagnosed IDH-wildtype GBM patients received a three-phase regimen: (1) Induction: pre-radiotherapy SDT (hematoporphyrin 3 mg/kg, 0.84 MHz, 1.5 W/cm², 50% duty cycle, twice daily for 5 days) with temozolomide (TMZ, 75 mg/m² daily); (2) Concurrent: intensity-modulated radiotherapy (60 Gy in 30 fractions) with daily TMZ (75 mg/m² for 6 weeks); and (3) Maintenance: adjuvant TMZ with optional concurrent SDT (hematoporphyrin 5 mg/kg, n = 9) or TMZ alone (n = 9). Primary endpoints were safety (NCI-CTCAE v5.0) and feasibility. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) via RANO criteria. RESULTS: Over a median follow-up of 26.23 months (95% CI: 21.97-27.47), primary safety and feasibility endpoints were met. No treatment-related deaths or grade 4/5 toxicities occurred. Treatment-related adverse events were mostly mild-to-moderate (grade 1/2) and transient, including 1 grade 1 photosensitivity reaction and 2 grade 1 cerebral edema events managed with osmotic therapy. For the entire cohort (n = 18), median OS was 19.00 months (95% CI: 17.27-23.97; 12-month OS rate: 88.9%), median PFS was 10.53 months (95% CI: 8.67-18.23), ORR was 66.7% (12 PR, 6 SD), and Disease Control Rate was 100%. In maintenance subgroup analysis, patients receiving SDT + TMZ showed a higher ORR (88.9% vs. 44.4%) and extended median PFS (11.80 vs. 9.27 months; P = 0.599) compared with TMZ alone, with comparable OS (19.00 vs. 20.10 months; P = 0.740). CONCLUSIONS: Integrating transcranial SDT with standard chemoradiotherapy and maintenance temozolomide is safe, feasible, and well tolerated in newly diagnosed GBM with residual disease. Encouraging preliminary efficacy signals warrant further evaluation in multi-center Phase II trials.