Memantine Prevents Radiation-Induced Cognitive Decline in Brain Metastases - A Randomized Placebo-Controlled Trial

This prospective, double-blind, placebo-controlled, randomized clinical trial evaluated the role of memantine in preventing cognitive decline following radiotherapy (RT) for brain metastases (BM).

Patients with BM undergoing either stereotactic radiosurgery (SRS) or whole-brain radiotherapy with or without hippocampal avoidance (HA/WBRT) were randomized to receive memantine (20 mg/day) or placebo for 6 months post-RT. Primary outcomes included cognitive function (Addenbrooke's Cognitive Examination [ACE]), quality of life (QoL; EORTC QLQ-C30 and BN20), white matter volume changes (MRI T2 FLAIR), plasma memantine levels (LC-MS/MS), and adverse events (CTCAE v5.0).

130 patients were enrolled (memantine n=66; placebo n=64; SRS n=75; HA/WBRT n=55). At 6 months post-RT, cognitive decline was significantly higher in the placebo group (mean ACE: 72.9 ± 20.2) than in the memantine group (83.9 ± 10.8; p=0.005). Memantine improved memory (p<0.001), delayed recall (p<0.001), and verbal fluency (p=0.007), with better domain-specific cognitive preservation in the SRS subgroup (p<0.001). Memantine was associated with improved cognitive function in both HA/WBRT and SRS cohorts; the effect was statistically significant in HA/WBRT patients, whereas in the SRS subgroup better domain-specific cognitive preservation was observed but the global cognitive effect estimate was underpowered. Global health status improved with memantine (median change +33.3 points) but was unchanged with placebo (between-arm difference +33.3 points, 95% CI +16.7 to +41.7; p<0.001). Common toxicities included appetite loss (25.7% vs. 12.5%) and gastric irritation (7.5% vs. 0%). White matter volume correlated negatively with cognitive decline (r = -0.544; p = 0.055). The optimal trough concentration (118.06 ng/mL) was achieved at 5 mg BID; while levels exceeded the alert threshold (300 ng/mL) at 10 mg BID for 6.25% patients.

Memantine preserved cognitive function relative to placebo and improved QOL in patients receiving radiotherapy for BM, with benefits observed in both SRS and HA/WBRT cohorts.