Radiation Dementia Treatment

Motivation: Dementia is a dreadful word - a terminal cognitive decline ending in dependence and ultimately death.  Among the many causes, prior history of whole brain radiation is a risk factor.  Recently, a friend in radiation oncology told me that there was a trial for this kind of dementia with memantine.  How good is it?

Paper: Brown, PD, Pugh, S, Laack, NN et. al. "Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial." Neuro-Oncol (2013); 15 (10): 1429-37.

Method: Eligible patients were adults with metastatic solid cancer to the brain receiving whole brain radiation with good performance status without renal failure and mini-mental status exam score > 18.  Patients were randomized to placebo or memantine (titrated up to 10 mg twice daily for length of 24 weeks).  Primary end-point was cognitive function (as measured by Hopkins Verbal Learning Test-Revised) at 24 weeks.

Results:
Cohort: Total of 508 patients randomized with 56% female.  Most common malignancy is lung cancer (70%).  256 were randomized to memantine while 252 were randomized to placebo. There were no differences in baseline age, gender, neurological functional status, education, prior history of radiation, or baseline neurocognitive score.

Compliance: Study compliance for the drug was 31% for memantine arm and 33% for placebo arm.  The most common reasons for discontinuation were patient refusal and patient death followed by disease progression or adverse event (similar in both groups).

Outcome: Compared to the placebo group, there was decreased decline in Hopkins Verbal Learning Test-Revised scale (0 for memantine vs. -0.9 for placebo, p = 0.059).  There was a statistical benefit in terms of Mini Mental Status Exam (0 vs -1, p = 0.0093).  There were no differences in progression-free survival or overall survival.

Adverse Effect: No statistical difference in adverse effect between groups.

Discussion: This trial seeks to hint that memantine may have some cognitive benefit in whole brain radiation, but the trial is seriously hampered by the very poor study compliance (2/3 or more of the patients did not comply with study assignment).  Also, the statistically significant Mini-Mental Status Exam improvement by one point is likely not clinically meaningful.  At present, I would say that the efficacy of memantine remains unanswered awaiting further testing.