Donepezil Provides Modest Improvement in Cognitive Function Domains in Irradiated Brain Tumor Survivors


Key Points

  • Among all patients, donepezil did not improve the cognitive composite score but was associated with improvements in memory and in motor speed and dexterity.
  • Donepezil was associated with significant improvement in the cognitive composite score and several domains in patients with poorer cognitive function at baseline.

In a phase III trial reported in the Journal of Clinical Oncology, Rapp et al found that the neurotransmitter modulator donepezil may modestly improve some cognitive function domains in patients undergoing cranial irradiation for brain tumors. Improvements were greater in patients with greater baseline cognitive impairment.

Donepezil is a reversible inhibitor of acetylcholinesterase that has direct effects on neuronal function and increases perfusion in brain regions involved in cognitive processing.

Study Details

In the double-blind study, 198 adult patients who had undergone partial- or whole-brain irradiation ≥ 6 months prior to enrollment were randomly assigned to receive donepezil at 5 mg for 6 weeks and 10 mg for 18 weeks (n = 99) or placebo (n = 99). A cognitive test battery was used to assess memory, attention, language, visuomotor, verbal fluency, and executive function at baseline and at 12 and 24 weeks.

The donepezil and placebo groups were generally balanced for age (median 56 and 54 years), sex (57% and 51% female), race/ethnicity (91% white in both), marital status (67% and 74% married), Eastern Cooperative Oncology Group performance status (0 or 1 for 96% and 94%), primary brain tumor (66% in both) or brain metastases (27% and 26%), and tumor location (eg, frontal in 32% and 39%, temporal in 21% and 16%, parietal in 19% and 13%).


After 24 weeks of treatment, composite cognitive scores did not differ significantly between the groups (P = .48). Patients in the donepezil group had significantly better scores in the domains of memory (P = .027 for recognition, P = .007 for discrimination) and motor speed and dexterity (P = .016). Significant interactions between pretreatment function and treatment, indicating increased benefit of donepezil in patients with greater cognitive impairment prior to treatment, were observed in the cognitive composite score (P = .01) and in the domains of immediate recall (P = .05), delayed recall (P = .004), attention (P = .01), visuomotor skills (P = .02), and motor speed and dexterity (P < .001).

Self-reported adherence to treatment was 92% in the donepezil group and 91% in the placebo group. The most common adverse event of any grade was fatigue, reported in 58% of the donepezil group and 67% of the placebo group. Diarrhea, which occurred in 25% vs 9% of patients, was the only adverse event that differed significantly in frequency between the groups (P = .005).

The investigators concluded: “Treatment with donepezil did not significantly improve the overall composite score, but it did result in modest improvements in several cognitive functions, especially among patients with greater pretreatment impairments.”

Stephen R. Rapp, PhD, of Wake Forest University School of Medicine, is the corresponding author of the Journal of Clinical Oncology article.

The study was supported by grants from the National Institute of Nursing Research and National Cancer Institute and by Eisai. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.