Memantine Provides Modest Improvement in Cognition after Cranial Irradiation

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Memantine, a drug used to treat Alzheimer’s disease, slowed cognitive decline in patients with brain cancer treated with whole-brain radiation therapy in a phase III trial reported at the 54th Annual Meeting of the American Society for Radiation Oncology (ASTRO), held recently in Boston.

Cognitive decline commonly occurs after whole-brain radiotherapy; 4 months after radiation, about 60% of patients experience a decline in at least one cognitive domain, and the mechanism of cognitive impairment is similar to that of Alzheimer’s disease, explained lead author Nadia N.I. Laack, MD, the Mayo Clinic, Rochester, Minnesota. Dr. Laack and her colleagues evaluated memantine in the setting of radiation-induced cognitive decline.

“We are excited to see that adding memantine to the treatment plan for brain tumor patients helps preserve their cognitive function after whole-brain radiotherapy even 6 months after treatment. Our findings suggest that memantine may prevent the changes that occur in the brain following radiation therapy, impacting future treatment practices for these patients and suggesting a role for further study in patients receiving radiation to the brain,” she said.

Key Data

The study enrolled 508 patients with brain metastases who received whole-brain radiotherapy between March 2008 and June 2010. Whole-brain radiotherapy was delivered as 37.5 Gy in 15 daily fractions. Patients were randomly assigned to memantine at 20 mg/d or placebo within 3 days of the start of radiation therapy. 

Specific instruments were used to assess six domains of cognitive function (memory, processing speed, executive function, global function, self-reported cognitive function, and quality of life). Assessments were done at baseline and at 8, 16, 24, and 52 weeks. The primary endpoint was memory, as assessed by the Hopkins Verbal Learning Test–Revised, Delayed Recall (HVLT-R). 

Compliance with the cognitive testing protocol was poorer than expected. Only 32% of patients completed the drug therapy and cognitive assessments for various reasons, and only 149 patients were analyzable at 24 weeks. For the primary endpoint, memantine reduced the decline in HVLT-R delayed recall by 0.9 at 24 weeks. The P value for this finding was .059, “teetering on the edge of significance,” according to Dr. Laack, due to small numbers of patients. At 24 weeks, memantine reduced the relative risk of cognitive decline by 17% vs placebo (P = .01), and reduced the rate of decline in cognitive, executive, and global function as well as processing speed (P < .01).

Patients in both groups reported similar levels of grade 3 and 4 toxicities, including alopecia, fatigue, headache, and nausea. There was no difference between the groups in progression-free and overall survival.

Disclosure: Dr. Laack reported no potential conflicts of interest.


1. Brown PD, Shook S, Laack NN, et al: Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiation therapy (WBRT): First report of RTOG 0614, a placebo-controlled, double-blind, randomized trial. 54th ASTRO Annual Meeting. Abstract 2. Presented October 29, 2012.

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