Memantine Prevents Radiation-Induced Cognitive Decline in Brain Metastases - A Randomized Placebo-Controlled Trial.
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Surendran Haripriya Parapparambil, Dutta Debnarayan, Sruthi Kalavagunta, Unnikrishnan Mazhuvancherry Kesavan, Chandran Dhanya, Bhaskaran Renjitha, Poornachary Narmadha Mukunthu, Ayiramuthu Parasuraman, Mangalathillam Sabitha, Sasidharan Ajay, Nair Anoop Remesan, Ullattil Pushpaja Kuttassery, Nair Haridas M, Philip Megha, Haridas Annex, Nottamkandath Vidya, S Sheejamol V, Kannan Rajesh, Jose Wesley Mannirathil, Pavithran Keechilat, Haridas Nikhil Krishna, Radhakrishnan Sourabh, P Rakesh M, Menon Sajesh, Udayakumaran Suhas, R Sreehari N, Thomas Dalvin
Аннотация
METHODS: 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).
RESULTS: 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.
CONCLUSION: 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.