Memantine was well tolerated and reduced the risk of cognitive decline, as measured by several standard screening tests, said Nadia N. I. Laack, MD, Assistant Professor of Radiation Oncology at the Mayo Clinic, reporting on behalf of the Radiation Therapy Oncology Group.
The randomized, Phase III, double-blind, placebo-controlled RTOG 0614 study just missed meeting its primary endpoint—preservation of memory at 24 weeks, as measured by the Hopkins Verbal Learning Test-Revised (HVLT-R) Delayed Recall—with a P value of 0.059, she said during her plenary talk. But that was likely because a low compliance rate weakened its power.
“More importantly, patients receiving memantine had a 17 percent relative reduced risk of cognitive decline, which was maintained even after memantine was discontinued,” she said. “In addition, patients treated with memantine had significantly delayed time to cognitive decline, and a reduction in decline in all other cognitive measures assessed, most of which were documented at multiple time points.”
Currently, there is nothing physicians can do to reduce the risk of cognitive impairment seen in as many as 60 percent of patients four months after treatment with whole-brain radiotherapy treatment—That being the case, memantine should be offered to patients “tomorrow,” she said. Additionally, memantine should be the standard of care against which experimental treatments for cognitive decline in cancer patients are compared in future clinical trials.
Brain metastases are the most common form of brain tumors in adults, with an estimated 150,000 new patients diagnosed each year in the U.S. alone. Although radiotherapy is an effective treatment to delay progression and increase survival in these patients, WBRT is associated with cognitive impairment, with memory preferentially affected, Laack explained.
Research has shown that the mechanism of radiation injury is multifactorial, with similarities to both vascular and neurodegenerative types of dementia, and that the hippocampus region appears to be particularly sensitive to radiation injury.
Glutamate, which acts through the NMDA (N-Methyl-D-aspartate) receptor and is involved in learning and memory, is the principal excitatory amino acid neurotransmitter in cortical and hippocampal neurons. Excess NMDA stimulation is neurotoxic, and research suggests that glutamate and NMDA receptors play a role in ischemic and neurodegenerative/Alzheimer's dementias.
Memantine is a unique NMDA receptor antagonist that has been shown to prevent learning decline and propagation of ischemic injury in animal models. In addition, memantine has been shown to improve cognition in mild to moderate vascular and Alzheimer's dementia in randomized, controlled clinical trials, she said.
“We thus hypothesized that memantine during and after WBRT for brain metastasis would prevent excitotoxic injury, and therefore cognitive decline, after radiotherapy.”
Why Memantine Rather than Other Neuroprotective Agents?
Asked why the researchers chose memantine over other neuroprotective agents, she said that more laboratory studies indicate that the drug can prevent the propagation and spread of vascular injury and actually prevent cognitive decline.
In the study, conducted between March 2008 and July 2010 and supported by RTOG, NCI, and Forest Pharmaceuticals, the drug's manufacturer, a total of 508 patients with newly diagnosed brain metastases were randomized to receive placebo or 20 mg memantine daily.
The whole-brain radiotherapy dose was 37.5 Gy in 15 fractions. Memantine was started within three days of initiating radiotherapy and continued for 24 weeks, even if patients experienced progressive disease.
Patient and treatment characteristics were well balanced between the groups—median age was 59; 56 percent were female, and 70 percent had non-small-cell lung cancer. Cognitive assessments were performed at baseline, and at eight, 16, 24, and 52 weeks.
The primary objective was to determine whether memantine could preserve memory as measured by the Hopkins Verbal Learning Test-Revised Delayed Recall at 24 weeks. As secondary objectives, cognitive function was assessed at other time points using a variety of other tests as well as time to neurocognitive failure.
For the purposes of the study, cognitive failure was defined as either a raw score change greater than the Reliable Change Index for that particular test, or using standardized scores, a follow-up score at least two standard deviations worse than the patient's personal baseline in any test.
Additional objectives included progression-free survival and overall survival times and toxicity, as well as quality-of-life assessments and translational studies that will be reported at a later time.
Results showed that patients who received memantine had no decline in memory (median, 0.0) at 24 weeks. Looked at another way, memantine reduced the decline in HVLT-delayed recall by 0.9, based on standardized scores, or by two points based on raw scores, Laack said. “But the results were not statistically significant, likely due to the fact that poorer than expected survival left only 149 analyzable patients at 24 weeks, resulting in only 35 percent statistical power.”
Additionally, the fact that patients did not experience the anticipated decline in memory after WBRT makes this a positive outcome of sorts, Laack said. Patients given placebo had a median decline in recall of 0.9.
* Memantine was associated with a statistically significant, 17 percent relative reduction in delayed recognition, another measure of memory, compared with placebo at 24 weeks.
* Memantine significantly increased the time to cognitive decline by 22 percent versus placebo: (3.9 vs. 2.6 months).
* Memantine significantly reduced the incidence of cognitive dysfunction at 24 weeks, to 53.8 percent from 64.9 percent in the placebo arm.
* Memantine significantly improved executive function, as evidenced by a lower rate of decline in controlled-oral word association test results at eight weeks: two vs. 13 percent deterioration in the placebo group. The improvement was maintained at 16 weeks.
* Memantine was associated with significantly improved global function, as measured by less decline and higher scores on the Mini-Mental Status Examination at 24 weeks and improved processing speed, as measured by the Trail Making Test, Part A.
* And finally, linear regression models performed only on patients with complete data confirmed improved global function and processing speed in patients receiving memantine.
Showing a graph of the results, Laack said, “Although the numbers of patients are small, the area in the box between six and 12 months highlights an intriguing result. Although memantine was discontinued at six months, the effect on cognitive function was maintained for the duration of the 12-month trial, suggesting that memantine may be preventing radiation injury rather than simply treating cognitive dysfunction.”
Memantine was well tolerated. Although 28 percent of patients had Grade 3 or 4 toxicities, only 14 percent were attributed to therapy. “These were usually the expected toxicities of whole-brain radiotherapy—alopecia, fatigue, headache, nausea —and there were no differences in toxicity between the two arms,” Laack said.
She said the researchers did not expect to see a difference in survival or progression rates between the two arms, and they did not. With a median follow-up of 12.4 months for surviving patients, the median overall survival and progression-free survival times were 7.7 and 5.3 months, respectively, in both groups.
The biggest problem with the study was compliance. “The compliance rates were similar between the two arms, but poorer than expected survival resulted in poor protocol compliance,” she said. “Cognitive testing compliance was similar between arms, with 52 percent of surviving patients completing cognitive testing. Overall, 32 percent of patients completed protocol therapy, leaving 149 analyzable patients at 24 weeks.”
That makes the compliance rate among the lowest of all the RTOG studies, said the study's Discussant, Vinai Gondi, MD, Clinical Assistant Professor of Radiation Oncology at the University of Wisconsin Comprehensive Cancer Center.
While Laack blamed the high mortality rate, Gondi said the study design played a major role in compliance. “This was one of the fastest accruing studies, testament to our radiation oncology community's commitment to finding better treatments for our patients and improving their quality of life,” he said, adding, though, that the study required that patients and health care workers fill out long, excruciatingly detailed questionnaires that take 20 minutes—at five different time points.
Still, Gondi agreed with Laack that memantine should be offered—immediately—to brain metastasis patients. That said, the improvement in cognition in the memantine arm was quote modest, he said.
“This is a critical first step” toward preventing or at least slowing early cognitive side effects in these patients. “The study demonstrates proof of principle that cognitive deterioration in brain metastasis patients can be prevented.”
Many questions remain, Gondi continued. It is unclear, for example, whether memantine's cognitive benefits “are specific to the effects of cranial radiation,” or if the drug is “more broadly impacting” cognitive function in patients with brain metastases.
To that end, he said, the planned translational analyses may help to tease out which patients benefit most from the drug. And the analyses will hopefully identify biomarkers predictive of cognitive decline and memantine benefit.
In the meantime, the RTOG 0933 trial is exploring another strategy—hippocampal avoidance—to prevent cognitive decline in patients undergoing whole-brain radiotherapy for brain metastases.
The Phase II trial, which has the same hypothesis and same primary endpoint as the memantine trial, just finished enrolling patients; early results may be available next spring.
Since the hippocampus is central to memory and is particularly sensitive to the effects of radiation, the idea is that avoiding the region—quite literally, by shielding it from radiation—will help prevent cognitive decline.© 2012 Lippincott Williams & Wilkins, Inc.
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