Nick Mulcahy

November 01, 2012

BOSTON, Massachusetts — A drug approved to treat Alzheimer's disease should be administered to cancer patients who receive whole-brain radiation therapy, according to a randomized controlled phase 3 trial.

When the drug, memantine (Namenda, Forest), is taken at the same time as radiation therapy, it helps preserve cognitive function in patients who are irradiated for brain metastases, said study coauthor Nadia N. Laack, MD, from the Mayo Clinic in Rochester, Minnesota.

Memantine appears to protect the brain from radiation injury and is no more toxic than placebo, she explained during a press conference here at the American Society for Radiation Oncology 54th Annual Meeting.

We feel that this is going to impact practice tomorrow. Dr. Nadia Laack

"We feel that this is going to impact practice tomorrow," Dr. Laack said about the drug's effect.

In future clinical trials, memantine should become the standard against which experimental treatments for radiation-induced cognitive decline are measured, she added.

Another expert also endorsed the use of the drug in this setting.

"Should we recommend memantine for our brain metastasis patients? I would say yes," said Vanai Gondi, MD, from the University of Wisconsin in Madison, who acted as discussant at the plenary session when the study was presented.

"The study demonstrates that cognitive deterioration in brain metastasis patients can, in fact, be prevented," he said, calling it a "critical first step" to improving cognitive outcomes in these patients.

However, Dr. Gondi is not certain whether the drug's mechanism acted on the effects of radiation or the "broader effects" from brain metastases.

Memory Assessment Was Primary Objective

Memantine is an NMDA-receptor antagonist that blocks a type of neurotransmission that, when excessive, is neurotoxic, Dr. Laack explained.

Because memory is the cognitive function that is most likely to be affected by whole-brain radiation, it was the primary focus of the study, she said. However, the study, known as RTOG (Radiation Therapy Oncology Group) 0614, showed that memantine did not appear to have a robust effect on memory.

Patients randomized to receive memantine (20 mg/day for 24 weeks) had no decline in delayed recall (measured on the Hopkins Verbal Learning Test-Revised) at 24 weeks (median, 0.0), which was the primary objective of the study. This compares favorably to patients randomized to placebo, who had a median decline in delayed recall of 0.9.

This difference translated into a 17% relative reduction in cognitive decline for memantine over placebo. However, this difference was not statistically significant (P = .059). Still, because there was no decline in delayed recall in the memantine-treated patients, this could be construed as a positive outcome, Dr. Laack suggested.

The statistical power of the results was weaker than planned because only 149 of 508 patients were analyzable at 24 weeks, she explained.

Memantine had more robust effects on other aspects of cognition, which is even more encouraging, she noted.

Relative to placebo, the drug was associated with significant improvements in a number of secondary measures, including delayed recognition at 24 weeks (P = .0149), time to cognitive decline (P = .0145), and cognitive function failure at 24 weeks (P = .01)

Patients in the memantine group also had less decline in executive function at 16 weeks (P = .004), global function at 24 weeks (P = .009), and processing speed (P < .01), compared with those in the placebo group.

There was one especially "intriguing" result related to cognitive function, said Dr. Laack.

A smaller percentage of patients in the memantine group had cognitive function failure at 6 months than in the placebo group (53.8% vs 64.9%). Notably, this difference in cognitive function continued out to the 1-year mark, which was the end of the study, even though memantine was discontinued at 6 months.

Memantine may be preventing radiation injury, rather than simply treating cognitive dysfunction. Dr. Nadia Laack

In other words, the effect of taking the drug during radiotherapy might be lasting with regard to cognitive function. The results suggest that "memantine may be preventing radiation injury, rather than simply treating cognitive dysfunction," said Dr. Laack. However, the number of patients who were followed for this time period was small, she acknowledged.

The study actually accrued more than 500 patients who had received whole-brain radiation (37.5 Gy in 15 fractions), some of whom had undergone previous radiosurgery or surgical resection. However, the compliance rate (only 32% completed the 24-week per-protocol drug therapy) was among the lowest of any RTOG study, observed Dr. Gondi, who is a member of the cooperative group.

He said the low compliance was related to death and progressive disease, but also, importantly, to study design. Participants were required, with the help of a clinician, to fill out a prohibitively long questionnaire that takes 20 minutes, he said.

The study was supported by the RTOG, the National Cancer Institute, and Forest Pharmaceuticals. Several coauthors report ties to industry, but none relevant to the study. Dr. Gondi has disclosed no relevant financial relationships.

American Society for Radiation Oncology (ASTRO) 54th Annual Meeting. Abstract 2. Presented October 30, 2012.