Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial.

TLDR: Overall, patients treated with memantine had better cognitive function over time; specifically, memantine delayed time to cognitive decline and reduced the rate of decline in memory, executive function, and processing speed in patients receiving WBRT.

Abstract: Radiotherapy is a proven curative and palliative therapeutic tool in the treatment of a wide variety of primary and metastatic brain tumors in adults, and recent advances in multimodality therapy have led to improvements in survival. As survival has improved, more attention has been directed toward long-term treatment-related morbidity. Specifically, the effect of cerebral radiotherapy on long-term cognitive performance is a major concern.1 The vascular hypothesis of radiation injury attributes radiation-induced accelerated atherosclerosis and mineralizing microangiopathy to the vascular insufficiency and infarction that can develop after radiotherapy.2 Therefore, the mechanisms of radiation-induced injury are similar to the small vessel disease seen with vascular dementia.3,4 For this reason, there is great interest in studying vascular dementia treatments to prevent or reduce radiation-induced cognitive injury. Additionally, because treatment of cognitive decline after radiation is limited, new approaches aimed at preventing the detrimental cognitive effect of whole-brain radiotherapy (WBRT) should be developed. Glutamate is the principal excitatory amino acid neurotransmitter in cortical and hippocampal neurons.5 One of the receptors activated by glutamate is the N-methyl-D-aspartate (NMDA) receptor, which is involved in learning and memory.6 Ischemia can induce excessive NMDA stimulation and lead to excitotoxicity, suggesting that agents that block pathologic stimulation of NMDA receptors may protect against further damage in patients with vascular dementia.7 One such agent is memantine, an NMDA receptor antagonist. Memantine is a noncompetitive, low-affinity, open-channel blocker that has been shown to be neuroprotective in preclinical models.8–10 In 2 placebo-controlled phase III trials, memantine was well tolerated and effective in treating vascular dementia, especially in patients with small vessel disease.11,12 The Radiation Therapy Oncology Group (RTOG) therefore initiated a placebo-controlled, double-blind, randomized trial to evaluate the potential protective effect of memantine on neurocognitive function in patients receiving WBRT.