Hypofractionated Stereotactic Radiotherapy versus Whole-Brain Radiotherapy following Brain Metastasis Resection - Results of the ESTRON Randomized Phase 2 Trial.

Background: Postoperative radiotherapy improves local control after brain metastasis (BM) resection. Whole-brain radiotherapy (WBRT) reduces recurrence risk but impairs neurocognition. Hypofractionated stereotactic radiotherapy of the cavity (HFSRT) may offer equivalent tumor control with reduced toxicity. ESTRON is the first randomized trial comparing post-operative HFSRT and WBRT.

Methods: This single-center phase 2 trial randomized 56 patients with resected BM to receive HFSRT (35 Gy in 7 fractions) or WBRT (30 Gy in 10 fractions). Patients could have ≤10 additional unresected BMs. The primary endpoint was intracranial progression-free survival (ic-PFS). Secondary endpoints included local control (LC), overall survival (OS), leptomeningeal disease (LMD), and toxicity.

Results: Fifty-four patients were evaluable (n=27 per arm). At 24.7 months median follow-up, 12-month ic-PFS was 44.4% (HFSRT) versus 59.3% (WBRT) (HR 1.72, p=0.080). Median ic-PFS was 4.7 vs. 15.0 months. LC at 24 months was 94.1% (HFSRT) vs. 85.4% (WBRT) (HR 0.41, p=0.433). One-year OS was 63.0% (HFSRT) vs. 77.8% (WBRT), with no significant difference in median OS (17.8 vs. 27.0 months; HR 1.09, p=0.336). One-year risk of LMD was 27.0% (HFSRT, predominantly outside the irradiated field) vs. 8.7% (WBRT) (log-rank p=0.03). Treatment-related adverse events were more frequent with WBRT (115 vs. 54 events), including 19% vs. 11% grade 3 events, and poorer neurocognitive performance.

Conclusions: Survival was similar for HFSRT and WBRT, while WBRT trended towards better ic-PFS. HFSRT showed substantially lower toxicity and better neurocognitive preservation, however a higher risk of LMD. Risks and benefits should be weighed individually when determining post-operative treatment for BM.