Memantine

• FINAL NUMBER STUDIES INCLUDED = 6
• TOTAL PATIENTS INCLUDED IN REVIEW = 550 (prevention intervention); 169 (amelioration intervention)
• KEY SAMPLE CHARACTERISTICS: In both intervention groups, adults aged ≥ 18 years, received radiotherapy for the treatment of brain metastasis, primary or secondary brain tumors, or prophylaxis for other cancer. For amelioration, intervention group documented cognitive impairment in at least one cognitive domain at baseline. At least 80% of the sample had to receive radiotherapy, and radiotherapy may have been provided during childhood, but the cognitive intervention performed in adulthood.

PHASE OF CARE: Multiple phases of care

Three cognitive interventions aimed at preventing cognitive decline during radiation therapy were reported. Two were pharmacologic. One tested memantine versus a placebo and found significant improvement in overall cognitive function, and one tested methylphenidate versus a placebo but failed to detect any significant differences between groups. The third study was nonpharmacologic and investigated the use of a rehabilitation program to prevent cognitive decline but did not statistically compare differences between groups. Three cognitive interventions aimed at ameliorating cognitive decline were reported. All three were pharmacologic studies. Two studies compared methylphenidate versus modafinil and one study examined donepezil versus a placebo. Both methylphenidate and modafinil interventions resulted in improved cognitive function. Combination therapy resulted in greater adverse events. Donepezil was found to improve the domain of memory after radiotherapy.

The authors reported that there was evidence for the use of memantine for preventing cognitive decline in patients receiving radiotherapy for brain metastasis. Likewise, there was supporting evidence for the use of donepezil in improving memory after radiotherapy for primary or metastatic brain tumors. There was limited evidence for cognitive behavioral or training interventions in preventing cognitive decline.

• Small sample sizes of less than 30 subjects
• High risk of bias, particularly for nonpharmacologic interventions
• Large number of patient withdrawals

Patients who receive cranial radiation therapy for primary brain tumors or metastatic lesions are at risk for declining cognitive function. The use of memantine during radiation therapy may aid in preventing cognitive decline. Those who develop cognitive decline after the completion of radiation therapy, even years afterwards, may benefit from donepezil administration. Additional exploration of interventions that may prevent or ameliorate cognitive decline related to cranial radiation therapy is warranted.

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.