Brown, P.D., Pugh, S., Laack, N.N., Wefel, J.S., Khuntia, D., Meyers, C., . . . for the Radiation Therapy Oncology Group (RTOG). (2013). Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: A randomized, double-blind, placebo-controlled trial. Neuro-Oncology, 15, 1429–1437 

To determine the protective effects of memantine on cognitive function in patients receiving whole brain radiotherapy (WBRT)

Patients received a total of 37.5 Gy WBRT over 15 fractions. Patients were randomized to receive escalating doses of memantine or placebo orally for 24 weeks beginning within three days of WBRT initiation. Weekly escalation was: Week 1: 5 mg every morning; Week 2: 5 mg twice daily; Week 3: 10 mg every morning, 5 mg every evening; Weeks 4–24: 10 mg twice daily.  Five neuropsychological assessments were performed at baseline, 8 weeks, 16 weeks, 24 weeks, and 52 weeks.

• N = 256 (study drug arm) and 252 (placebo arm)    
• MEDIAN AGE = 59 years
• MALES: 44%, FEMALES: 56%
• KEY DISEASE CHARACTERISTICS:
  • Adults with a pathologically proven solid malignancy and visible brain metastases on MRI or CT scan: lung = 355, breast = 75, colon = 5, other sites = 73 
  • Neurologic function: fully active, no symptoms = 40%; some symptoms, fully active = 53%; not active with symptom = 7% 
  • 71% had no prior radiosurgery or surgical resection for brain lesions; 45% had received prior chemotherapy; 65% were receiving steroid therapy at baseline assessment; and 27% were receiving WBRT at time of baseline assessment.
• OTHER KEY SAMPLE CHARACTERISTICS:
  • Primarily Caucasian = 84%, non-Hispanic/Latino = 93% 
  • Education status: grades 0–12 = 65%, some college/technical school = 18%, bachelor’s degree = 17%

• SITE: Multi-site (143 centers participating in Radiation Therapy Oncology Group studies)  
• SETTING TYPE: Outpatient    
• LOCATION: United States of America and Canada

• PHASE OF CARE: Multiple phases of care

• Longitudinal randomized double-blind placebo-controlled clinical trial; pre-post test design involving multiple longitudinal neuropsychological assessments (baseline up to one-year post intervention)

• Hopkins Verbal Learning Test (HVLT)-Revised Total Recall, Delayed Recall, and Delayed Recognition subscales: memory
• Trails Making Test Part A (TMT-A): speed of processing
• Trails Making Test Part B (TMT-B): executive control function 
• Controlled Oral Word Association Test (COWA): verbal fluency
• Clinical Trials Battery Composite (mean of the z scores of all the instruments)
• Mini-Mental Status Examination (MMSE): global cognitive function

Overall, trends of less cognitive decline were observed over time for those receiving memantine versus those receiving placebo. Significant differences (p < 0.05) between groups for cognitive decline were (1) raw scores and standardized scores for memory recognition (HVLT-Recognition) at 24 weeks, (2) raw scores for global cognitive function (MMSE) at 24 weeks, and (3) fewer individuals experiencing a change of 2 SD in verbal fluency (COWA) at eight weeks. The probability of cognitive failure was greater for the memantine arm (53.5%) than for the placebo arm (64.9%). Likewise, the time to cognitive failure was significantly longer in the memantine arm. Significant differences (p < 0.05) were observed in the memantine arm for COWA scores at 8 weeks and 16 weeks and for TMT-A and MMSE at 24 weeks. There were no differences between groups in progression-free survival, overall survival, use of steroids, or side effects experienced for memantine or placebo.

Use of memantine during and after WBRT was well tolerated and resulted in trends of better cognitive function over time, delays in cognitive failure, and reduced rates of decline for specific cognitive functions involving memory, executive control function, and processing speed. However, generalization of these results is limited due to the small sample size at study conclusion, which resulted in a lack of statistically significant findings.

• Subject withdrawals ≥ 10%  
• Other limitations/explanation: Number of subjects completing intervention and longitudinal assessments did not meet power analysis quota.

This study demonstrates the potential application of administering prophylactic memantine during WBRT to reduce cognitive decline observed in individuals with brain metastasis. These results are limited and warrant further study with a larger sample size enrolled throughout study conclusion.