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

Reporter: Annemarie Fernandes, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 29, 2012

Presenter: Nadia Laack, MS, MD
Presenter's Affiliation: Radiation Therapy Oncology Group


  • Brain metastases is the most common form of intracranial malignancy with about 150,000 patients diagnosed with brain metastases each year
  • Whole-brain Radiation Therapy (WBRT) is an effective therapy for patients with metastatic disease to the brain
  • Cognitive deterioration after WBRT is a potential adverse effect of this treatment
    • At 4 months after WBRT, 60% of patients experience declines in >1 cognitive domain. Memory appears to be preferentially affected
    • The mechanism appears to be multifactorial, involving vascular and neuroglial etiologies
  • Memantine is a NMDA receptor antagonist that has been shown to be beneficial for vascular and Alzheimer's dementia
  • The purpose of this phase III trial was to evaluate the potential protective cognitive effects of memantine in patients receiving WBRT

Materials and Methods

  • Patients with newly diagnosed intracranial brain metastases were included and stratified by recursive partitioning analysis (RPA) and prior radiosurgery or surgical resection
  • All patients received WBRT (37.5 Gy in 15 fractions)
  • Patients were randomized to receive placebo or memantine
  • Memantine was administered as an oral pill: 20 mg/day for 24 weeks and started within 3 days of initiating radiotherapy. All patients were to continue the medication for 24 weeks despite progressive disease
  • Standardized tests of cognitive function were performed at baseline, 8, 16, 24 and 52 weeks
  • The primary endpoint was memory decline at 24 weeks. Secondary endpoints were time to cognitive decline, overall survival and progression-free survival
    • Memory decline (primary endpoint) was determined by Hopkins Verbal Learning Test-Revised Delayed Recall (HVLT-DR).
    • Processing speed was determined by the Trail Making Test, Part A. Executive function was assessed by Trail Making Test Part B and Controlled Oral Work Association (COWA).
    • Global function was assessed by the mini-mental status examination (MMSE).
    • Cognitive function was assessed by self-report using the medical outcomes scale.
    • Quality of life was assessed by FACT-Br (not reported)


  • 554 patients were accrued between March 2008-July 2010, of whom 508 were eligible
  • The median follow-up was 12.4 months
  • Patient characteristics were well balanced between the 2 arms (median age 59, 56% female, 70% NSCLC)
  • Toxicity: 28% of patients experienced grade 3-4 toxicities; 14% were attributed to therapy (usually RT: alopecia, fatigue, headache, nausea)
    • There were no differences in toxicity between the 2 arms
  • There was no difference in overall survival or progression-free survival
  • Study compliance was similar between the 2 arms. 52% of patients completed cognitive testing. Only 32% of patients completed drug therapy per protocol, mainly due to death, progressive disease or noncompliance. Therefore 149 patients were analyzable at 24 weeks
  • Memantine resulted in a non-significant reduction in memory decline (p=0.059)
    • The authors attribute this to the poor study compliance due to early deaths resulting in only 35% statistical power
  • Memantine resulted in fewer declines in delayed recognition at 24 weeks (p=0.015), less cognitive function failure at 24 weeks (p=0.01) and increased the time to cognitive decline (HR 0.78, p=0.015).
  • At 24 weeks, the rate of cognitive function failure was 64.9% in the placebo arm vs. 53.8% in the memantine arm. Both of these curves plateaued around 6-9 months
  • Memantine improved executive function with less decline in COWA at 8 weeks (2% vs. 13%, p=0.0015) and 15 weeks.
  • Memantine improved global function with less decline in MMSE at 24 weeks (p=0.0093) and better processing speed (p=0.0038).

Author's Conclusions

  • Memantine reduces the decline in memory at 24 weeks (though this not statistically significant, this endpoint was likely underpowered)
  • Memantine reduces the relative risk of cognitive decline, which was maintained even after memantine was discontinued (at 6-9 months)
  • Memantine delays the time to cognitive decline and reduces decline in memory, cognitive, executive and global function, as well as processing speed.
  • In summary, memantine helps to preserve cognitive function after WBRT in patients with brain metastases

Clinical Implications

  • Whole brain radiation therapy is an effective treatment for patients with brain metastases.
  • Patients are often apprehensive to undergo whole brain radiation treatment, particularly due to the potential cognitive side effects of treatment that have been demonstrated in prior studies.
  • While the exact etiology of these effects is not clear, cognitive decline is likely related to vascular and neuroglial effects. It is possible that these mechanisms are related to the mechanisms associated with Alzheimer's disease.
  • As such, the authors conducted a well-designed study to test the effect of a medication known to benefit Alzheimer's disease on patients undergoing whole brain radiation therapy for brain metastases.
  • The study is prospective, randomized, double-blind and placebo controlled, however, the authors did not appropriately take into account the poor 2-year survival in patients with brain metastases when performing their power calculation.
    • Due to the 35% power in their final analysis, their primary endpoint of memory decline was not statistically significant
  • Despite the lack of statistical significance of their primary endpoint, memantine clearly has an advantage in preventing cognitive decline based on their secondary endpoints and rate of cognitive function failure. The rates of cognitive function failure appear to plateau at 6-9 months, which indicates that memantine may be help to prevent cognitive decline rather than reverse cognitive dysfunction. As such, this study is potentially practice changing.
  • Given the rate of cognitive function failure (53.8%) even with memantine, further developments in preventing cognitive decline after treatment of brain metastases are necessary. Gamma knife and stereotactic treatments are commonly administered to patients with few brain metastases in hopes of sparing patients from the side effects of whole brain radiation therapy.
  • In order to improve the side effects associated with whole brain radiation therapy, the mechanism of cognitive decline needs to be further researched and better understood. Studies are underway to identify predictive biomarkers for cognitive decline in order to select for patients who are at higher risk of developing these adverse effects. While the overall survival rates of patients with brain metastases are low, there are subgroups of patients who have favorable survival rates and are at increased risk of developing neurocognitive decline after whole brain radiation. Additionally, RTOG 0933 is a phase II trial assessing the effect of hippocampus avoidance.
  • Due to the difficulty in assessing objective outcomes and the poor understanding of mechanisms related to cognitive decline, cognitive preservation studies present unique challenges that require creative solutions.