This memantine study is a critical first step in understanding and delaying cognitive deterioration in brain metastasis patients, noted formal discussant Vinai Gondi, MD, Associate Director of Research at the CDH Proton Center in Warrenville, Illinois, and Clinical Associate Professor at the University of Wisconsin. “Cognitive decline can be prevented with memantine, but to a fairly modest extent,” he noted.

“Only some of the cognitive domains that benefited from memantine have shown sensitivity to cranial irradiation in prior studies; importantly, some cognitive domains highly impacted by cranial irradiation were not significantly affected by memantine,” Dr. Gondi explained. “Memantine may be preventing cognitive decline in brain metastasis patients, but it remains to be determined whether this benefit is specific to the effects of cranial irradiation.”

Dr. Gondi also emphasized that almost 50% of patients in the memantine arm of the study demonstrated cognitive decline at 4 months after treatment, a modest improvement over placebo. “Thus, our efforts to prevent cognitive decline from cranial irradiation should not stop with memantine,” Dr. Gondi added. “We have much more to learn and many other neuroprotective strategies to test.”

The investigators of this trial have a large number of brain tissue specimens for translational research. They aim to identify biomarkers predictive of cognitive decline and/or memantine benefit, he said.

Other Strategies

In addition, other cognitive protection strategies for patients receiving cranial irradiation are under investigation. Potential strategies include sparing the hippocampus (ie, the memory center) from high radiation doses and use of other investigational drugs. “These are intriguing hypotheses and represent exciting opportunities to build upon the memantine study,” Dr. Gondi stated.

Dr. Gondi emphasized that this trial benefited from very rapid accrual, but suffered from poor compliance with follow-up cognitive testing. The poor compliance, while partly due to death and disease progression, may also have been due to the uniqueness of the study’s primary endpoint.

“The endpoint was not a CT scan, MRI, or survival. Rather, it was a 20-minute cognitive test that required time and effort of both patients and their health-care providers,” he continued.

“If we are to build upon the memantine study, our collective enthusiasm will need to extend beyond accrual and include an emphasis on follow-up cognitive testing,” Dr. Gondi stated. “With renewed focus on follow-up, we have the potential to identify additional neuroprotective strategies that may significantly benefit our patients.” ■

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