Memantine Delays Cognitive Decline in Patients With brain Metastases Treated With Whole-brain Radiation

The American Society for Radiation Oncology (ASTRO) 54th Annual Meeting, held in Boston, Massachusetts, coincided with Superstorm Sandy. Despite the havoc wreaked by the storm, Boston was largely spared, although ASTRO canceled Monday afternoon’s Plenary Session when public transportation was shut down. Below are some highlights from the meeting, including some news stories from the Plenary Session, which was available online.

Memantine delayed cognitive decline in patients treated with whole-brain radiation therapy (WBRT) for brain metastases, according to results of a randomized phase 3 trial.¹

Cognitive decline is common with WBRT, occurring in about 50% to 60% of patients by 4 months after radiation. Because the mechanism of radiation-induced cognitive decline appears to be similar to that of vascular or Alzheimer’s dementia, the researchers postulated that memantine, a drug used to treat Alzheimer’s disease, would be of benefit in patients treated with WBRT.

“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 suggest a role for further study in patients receiving radiation to the brain,” said presenter Nadia N. Laack, MD, radiation oncologist at the Mayo Clinic in Rochester, Minnesota.

Formal discussant of this trial, Vinai Gondi, MD, associate director of the Central Dupage Hospital’s Proton Center in Warrenville, Illinois, called this study “a good first step” in understanding the cognitive changes resulting from brain radiation and the role of memantine in preventing or delaying them. He said that the effect of memantine was modest in this trial and that other strategies to improve cognitive effects of radiation are being pursued by researchers.

The study included 508 patients with brain metastases who received WBRT between March 2008 and June 2010. WBRT was delivered as 37.5 Gy in 15 daily fractions. Patients were randomized to memantine 20 mg/day or placebo within 3 days of the start of radiation therapy. Six domains of cognitive function (memory, processing speed, executive function, global function, self-reported cognitive function, and quality of life) were assessed by different instruments at baseline and weeks 8, 16, 24, and 52. The primary end point was memory as assessed by the Hopkins Verbal Learning Test-Revised (HVLT-R).

Compliance with the cognitive testing protocol was suboptimal, with 32% of the patients completing drug therapy and cognitive assessments. The reasons for noncompliance appeared to be death, disease progression, and difficulty in getting patients to stay longer during a clinic visit or in physicians scheduling the extra 20 minutes to 1 hour required for cognitive testing. Of the 508 patients randomized to the 2 arms, only 149 patients were analyzable at 24 weeks.

For the primary end point of memory decline as assessed by the HVLT-R, memantine reduced the decline in HVLT-R delayed recall, with a median decline of 0 versus –2 for placebo at 24 weeks, with a statistical significance of P = .059. This result was “teetering on the edge of significance,” according to Laack, due to the small numbers of patients.
At 24 weeks, memantine reduced the relative risk of cognitive decline by 17% versus placebo (P = .01), and it reduced the rate of decline in cognitive, executive, and global function as well as processing speed (P <.01). Patients in both groups experienced similar rates of grade 3 and 4 toxicities, including alopecia, fatigue, headache, and nausea.

The investigators plan to evaluate the effect of memantine on overall survival and progression-free survival in these patients. Also, tissue specimens will be studied to identify biomarkers of cognitive decline as well as of response to memantine.

Reference

1. Brown PD, Shook S, Laack N, 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. Presented at: American Society for Radiation Oncology 54th Annual Meeting; October 29, 2012; Boston, MA. Abstract 1.