Unilateral vs Bilateral Hippocampal Avoidance During WBRT With Memantine for Brain Metastases: A Randomized Single-Blind Phase 2 Clinical Trial

Background Hippocampal avoidance whole-brain radiotherapy (HA-WBRT) with memantine reduces, but does not eliminate, cognitive decline. Left hippocampal dose may be more closely associated with cognitive outcomes. We investigated whether unilateral (left) HA-WBRT is equivalent to bilateral HA-WBRT for neurocognitive function. Methods In this randomized, single-blind, phase 2 equivalence trial, patients with brain metastases were assigned 1:1 to unilateral (left) or bilateral HA-WBRT (30 Gy in 10 fractions) with concurrent memantine. The primary endpoint was relative decline in Hopkins Verbal Learning Test-Revised (HVLT-R) memory score from baseline to 6 months; equivalence required the 90% CI for the between-arm difference to fall within ±15 percentage points. Results Among 73 patients (unilateral, n = 36; bilateral, n = 37; median follow-up, 13.2 months), mean 6-month relative HVLT-R decline was 4.75% versus 5.05% (difference, -0.31%; 90% CI, -12.02% to 11.40%; TOST P = .02), meeting the equivalence criterion. Brain progression-free survival (10.3 vs 10.8 months; P = .96), overall survival (17.8 vs 12.8 months; P = .94), acute toxicity (≥ grade 2, 44.4% vs 35.1%; P = .43), and 6-month neurocognitive failure (61.1% vs 56.8%; Gray test P = .78) were similar. Global health status appeared more stable with unilateral HA-WBRT (interaction, P < .001). Exploratory plasma BDNF trajectories varied by neurocognitive failure status (FDR q = .09). Conclusions Unilateral (left) HA-WBRT with memantine met the prespecified equivalence criterion for verbal memory, with comparable oncologic outcomes and safety; non-verbal memory was not assessed. These findings warrant validation, particularly when bilateral avoidance is challenging.