Memantine delayed cognitive decline in patients undergoing WBRT

Issue: November 25, 2012

Memantine slows cognitive function decline in patients with brain cancer who received whole-brain radiation therapy, according to results of a phase 3 study presented at the 2012 American Society for Radiation Oncology Annual Meeting in Boston.

Brain metastases are the most common form of brain tumor in adults, with an estimated 150,000 new patients diagnosed each year in the United States.

Although radiation therapy is an effective treatment for patients with brain tumors, whole-brain radiation therapy (WBRT) is associated with cognitive impairment, documented in as many as 60% of patients as early as 4 months after treatment, according to background information provided by researchers.

Radiation injury appears similar to vascular and Alzheimer’s-type dementia, prompting the prescription of Alzheimer’s-type medications for the treatment of radiation-induced brain injury.

Memantine is an N-Methyl-D-aspartate receptor antagonist that has been shown to be beneficial for vascular and Alzheimer’s dementias.

In this study, Nadia N. Laack, MD, radiation oncologist at Mayo Clinic in Rochester, Minn., and colleagues hypothesized that patients treated with memantine during and after WBRT for brain metastases would not experience cognitive decline.

Laack and colleagues enrolled 554 patients between March 2008 and July 2010. Of them, 508 were eligible for the study. The patients had newly diagnosed brain metastases and were treated with WBRT (37.5 Gy in 15 fractions).

Researchers randomly assigned the patients to 20 mg memantine daily or placebo.

Researchers gave patients memantine within 3 days of initiating radiation therapy. Patients repeated the protocol for 6 months.

Laack and colleagues assessed patients for cognitive function at 8, 16, 24 and 52 weeks. Tests examined different types of brain function, including memory decline, at 24 weeks. Researchers defined the primary endpoint as memory decline at 24 weeks as measured by the Hopkins Verbal Learning Test-Revised Delayed (HVLT-R DR).

Secondary objectives included OS, PFS and time to cognitive decline.

Median follow-up was 12.4 months.

As they expected, the researchers found no statistical differences in OS and PFS between the treatment arms.

Researchers examined 149 analyzable patients (32%) at 24 weeks. Many patients were ill at the time of the study, resulting in poor protocol compliance.

Results of the study showed memantine significantly increased the time to cognitive decline (P=.02), Laack said. Memantine also reduced the incidence of cognitive dysfunction at 24 weeks.

Patients in the memantine arm experienced a 17% RR reduction in cognitive dysfunction at 24 weeks (P=.01) compared with the placebo group, the researchers found.

The results showed no statistical significance in delayed-recall. Still, patients treated with memantine had better cognitive function over time, according to researchers.

Although the numbers of patients were small, researchers said they discovered an intriguing result in the time between 6 and 12 months of treatment.

“Memantine was discontinued at 6 months, but its effect on cognitive function was maintained for the duration of the trial, suggesting memantine may be preventing radiation injury rather than simply treating cognitive function,” Laack said.

Patients in the memantine arm had slower memory decline at 24 weeks compared with the placebo arm (P=.015).

“Overall, we feel that the weight of evidence supports our conclusion that memantine helps preserve cognitive function after WBRT in patients with brain metastases,” Laack concluded.

For more information:

Laack NN. Abstract #2. Presented at: 2012 ASTRO Annual Meeting; Oct. 28-31, 2012; Boston.

Disclosure: Laack reports no relevant financial disclosures. Another researcher involved with the study reports serving as a speaker, advisory board member and consultant for Abbott, ASCO, BioStrategies, Bristol-Myers-Squibb, Cleveland Clinic, Merck, Novartis and other pharmaceutical companies.