Randomized placebo-controlled trial of memantine for prevention of radiation-induced cognitive decline in brain metastases

A prospective, double-blind, randomized placebo-controlled trial at Amrita Institute or Medical Sciences (Kerala, India) evaluated the role of memantine in preventing cognitive decline following radiotherapy for brain metastases (BM). Patients with BM undergoing stereotactic radiosurgery (SRS) of whole-brain radiotherapy with or without hippocampal avoidance (HA/WBRT) were randomized to receive memantine (20 mg/day) or placebo for 6 months post-radiotherapy. Primary outcomes included cognitive function (Addenbrookes Cognitive Examination, ACE), quality of life (QOL; EORTC QLQ-C30 and BN20), white matter volume changes (MRI T2 FLAIR), and adverse events (CTCAE v5.0). A total of 130 patients were enrolled (memantine n=66; placebo n=64; SRS n=75; HA/WBRT n=55). At 6 months post-radiotherapy, cognitive decline was significantly higher in the placebo group than in the memantine group (mean ACE 72.9 ± 20.2 versus 83.9 ± 10.8; p=0.005). Memantine improved memory, delayed recall, and verbal fluency, with better domain-specific cognitive preservation in the SRS subgroup (p<0.001). Global health status improved in the memantine group and was unchanged with placebo. Common toxicities were appetite loss (25.7% versus 12.5%) and gastric irritation (7.5% versus 0). White matter volume correlated negatively with cognitive decline (r=-0.544; p=0.055). The authors conclude that 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.