Phase III randomized, double-blind, placebo-controlled trial of donepezil in irradiated brain tumor survivors.

Abstract

2006 Background: This RCT assessed the effect of 24 weeks of 5-10 mg per day of donepezil, an acetyl cholinesterase inhibitor, on cognitive functioning (primary endpoint) and fatigue, mood and QOL in long-term brain tumor survivors following partial or whole-brain irradiation. Cognitive results are reported herein. Methods: From 2/08-12/11,198 adult primary and metastatic brain tumor survivors > 6 months post radiation treatment (>30 Gray) recruited at 24 sites affiliated with the Wake Forest Community Clinical Oncology Program Research Base, 3 CTSU sites and M.D. Anderson Cancer Center were randomly assigned to receive donepezil (n=99) or placebo (n=99). Cognitive function was assessed at baseline, 12 and 24 weeks with Hopkins Verbal Learning Test-Revised, Rey-Osterreith Complex Figure, Trail Making Test, Digit Span, Controlled Oral Word Association, and Grooved Pegboard. A Cognitive Composite (CC) score was the primary outcome. Results: The sample was 91% White, 54% female, and median age was 55 yrs. 66% had primary tumors, 27% brain metastases and 8% PCI. Median time since diagnosis: 38 mos. 95% had 0-1 ECOG performance status scores. 74% completed the study. CC score improved significantly by 24 weeks in both arms (p < .01); however, there was not a statistically significant difference between groups (p = .57). Donepezil group performed better than placebo on HVLT Recognition (p = .03) and Discrimination (p = .01) and GP-Dominant Hand (p = 0.02). Significant interactions were found between treatment arm and baseline cognitive scores for: CC (p = .01), HVLT Immed. Recall (p = .03), HVLT %Savings (p < .01), Digit Span Forward (p = .01), ROCF Copy (p = .03), TMT-B (p = .05) and GP-Dominant (p < .01). In all cases, the benefit of donepezil, relative to placebo, was greater for those with worse baseline scores. Conclusions: Long-term brain tumor survivors treated with brain irradiation who have cognitive impairment can benefit from 5-10mg of donepezil for 24 weeks. Improvements in verbal memory, working memory, visuo- and psychomotor performance and executive functioning were observed in this group. (Study supported by NIH/NINR grant 5R01NR009675-04, NIH/NCI grant 2 U10 CA 81851-09-13 and Eisai, Inc.) Clinical trial information: NCT00369785.

Medical management of brain tumors and the sequelae of treatment

“…194 A double blind, placebo-controlled phase III trial of donepezil (5 -10 mg/day) was conducted in long-term brain tumor survivors to confirm these favorable results. 195 Although the neurocognitive composite score was not improved in the donepezil arm, there was improvement in verbal memory, working memory, visuomotor and psychomotor performance, and executive functioning, especially in patients with more severe baseline neurocognitive impairment. These results suggest that some long-term brain tumor survivors may benefit from treatment with donepezil, especially if they have severe neurocognitive impairment.…”

Treatment of Brain Metastases in Lung Cancer: Strategies to Avoid/Reduce Late Complications of Whole Brain Radiation Therapy

“…Donepezil administration for 24 weeks, in a group of patients with primary brain tumours who had survived ≥6 months post radiation, was shown to improve cognitive function, mood and health related QOL [65]. Based on these positive findings a randomised phase III, placebo controlled, double blinded trial of donepezil and partial or whole brain radiotherapy was conducted, completed and presented in abstract form at ASCO 2013 [66].…”

Cognitive Deficits in Primary Brain Tumours: A Framework for Management and Rehabilitation

“…This multicentre study used donepezil at 5 -10 mg for 6 months and compared with placebo. There were some improved scores on selected assessments, but no overall benefit in a combined cognitive function score [21].…”