Rapp, S.R., Case, L.D., Peiffer, A., Naughton, M.M., Chan, M.D., Stieber, V.W., . . . Shaw, E.G. (2015). Donepezil for irradiated brain tumor survivors: A phase III randomized placebo-controlled clinical trial. Journal of Clinical Oncology, 33, 1653–1659. 

To evaluate the effects of 24 weeks of donepezil versus placebo on objectively measured cognitive function starting at least six months after whole- or partial-brain irradiation

This clinical trial tested donepezil at 5 mg daily for six weeks followed by 10 mg daily for 18 weeks compared to a placebo. Study outcome measurements were collected before randomization, and 12 and 24 weeks after randomization.

• N = 146
• MEDIAN AGE = 55 years (range = 20–84 years)
• MALES: 50%, FEMALES: 50%
• KEY DISEASE CHARACTERISTICS: 68% primary brain tumor (primary diagnosis was glioblastoma multiforme); 26% brain metastases from other primary tumor (primary diagnosis was lung cancer); 6% prophylactic cranial irradiation; 35% primarily frontal lobe involvement; median time since diagnosis was 40 months
• OTHER KEY SAMPLE CHARACTERISTICS: Pretreatment sample characteristics did not differ between groups. Most participants were married, white, had some college education, and had Eastern Cooperative Oncology Group scores of 0–1. Retention at the end of the trial was 74%, which did not differ between groups. Participants who dropped out had less education, lower income, smaller brain volume, and more hippocampal involvement.

• SITE: Multi-site
• SETTING TYPE: Outpatient
• LOCATION: Winston-Salem, NC, and Houston, TX

PHASE OF CARE: Late effects and survivorship

Randomized, double-blinded, placebo-controlled trial

• Hopkins Verbal Learning Test–Revised (HVLT-R)
• Modified Rey-Osterrieth Complex Figure
• Trail Making Test (TMT) parts A and B
• Controlled Oral Word Association Test (COWAT)
• Digit Span Test
• Grooved Pegboard Test

Self-reported adherence to the dose was approximately 92%, which did not differ between groups. The donepezil group reported more diarrhea (25%, p = 0.005) than the control. At baseline, both groups had poorer verbal memory, motor speed and dexterity, attention, and executive function compared to population norms. There was no improvement in overall cognitive function with 24 weeks of donepezil, but improvements were found for individual measures of memory (p = 0.007, 0.027) and motor speed and dexterity (p = 0.016). Donepezil showed greater improvement in overall cognitive function for patients with poorer cognitive function at baseline (p = 0.01).

For patients who received whole or partial brain irradiation, 24 weeks of donepezil improved memory and motor and speed dexterity. Greater improvements in multiple cognitive domains, including significant improvement in overall cognitive function, were found for patients with poorer cognitive function at baseline.

• Subject withdrawals ≥ 10%
• Most participants were white.

For patients who receive partial- or whole-brain irradiation for primary brain tumors or brain metastases, donepezil may improve memory and motor speed and dexterity. Patients with poorer cognitive function may have greater benefit, including improvement in overall cognitive function. Educate patients about the risk for diarrhea and appropriate management.