Donepezil

• 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.

The study was conducted to test oral donepezil and oral vitamin E in patients with small-cell lung cancer after completion of all cancer therapy and prophylactic cranial irradiation.

A randomization procedure was conducted after participant stratification in the following ways.

• Baseline cognitive function on the Mini-Mental State Examination (MMSE) placed participants in three impairment groups: normal, mild to moderate, and severe.  
• Participants were categorized by age into two groups, 60 years or younger or older than 60 years.

The treatment group received 5 mg/day of oral donepezil, which increased to 10 mg/day after one month of therapy if tolerated well. Treatment group participants also received 1000 IU/day of oral vitamin E. The control group was given an identical oral placebo. Assessments were performed at study enrollment, one month, and every three months until cancer recurrence or treatment failure.

• The total number of participants enrolled over 15 months was 9.
• There were 4 participants in the treatment group and 5 participants in the control group.  
• All participants had a diagnosis of small-cell lung cancer.
• All participants had a limited disease status and similar prophylatic carnial irradiation.  
• All participants had an Eastern Cooperative Oncology Group (ECOG) performance status of ≥ 2.
• The mean age of the treatment group was 67, with a range of 65–69.
• The mean age of the control group mean was 67, with a range of 60–76.
• The treatment group was 100% male; the control group was 80% male and 20% female.

The study took place at the North Central Cancer Treatment Group and the Mayo Clinic.

The study was a double-blind, placebo-controlled trial.

• The Mini-Mental State Examination (MMSE) was used to measure global cognitive functioning. A three-point drop indicated treatment failure.
• A five-point drop on the Blessed Dementia Scale indicated treatment failure.
• The Common Terminology Criteria for Adverse Version 2.0 was also used. 

There were no notable differences in cognitive stability, adverse events, or quality of life between treatment arms. Only one patient, who received donepezil and vitamin E, manifested a three-point drop in cognitive scores as measured by the MMSE. There was a slight trend of increased gastrointestinal side effects among patients treated with donepezil and vitamin E.

The median time spent in the study was 42 or 69 days for the treatment or control group, respectively.

Due to low enrollment and retention, the effect of oral doses of vitamin E and donepezil on cognitive function could not be determined. 

• The study had a small sample size.
• Inclusion criteria seriously limited eligibility and enrollment.
• Participant withdrawal tended to occur sooner in the study for those receiving the medication intervention than among those in the control group. No explanation for subject withdrawals was provided.

To evaluate the feasibility of taking daily donepezil, an acetylcholinesterase inhibitor, to improve cognitive function in women who report cognitive impairment one to five years after completing adjuvant chemotherapy for breast cancer

This study evaluated the feasibility of a randomized, controlled trial of 24 weeks of donepezil (5 mg/day for 6 weeks, then 10 mg/day for 18 weeks) versus placebo. Potential participants were prescreened for moderate-to-severe self-reported cognitive impairment, and those enrolled were stratified by menopausal status and time since chemotherapy. Self-reported cognitive function, co-occurring symptoms, and quality of life were measured before the trial, halfway through the trial (i.e., 12 weeks), and at the completion of the trial (i.e., 24 weeks). Neuropsychological testing was conducted at baseline and 24 weeks.

• N = 47   
• MEDIAN AGE = 56 years
• AGE RANGE = 39–79 years
• FEMALES: 100%
• CURRENT TREATMENT: Other
• KEY DISEASE CHARACTERISTICS: Nonmetastatic invasive breast cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Of the patients, 90% were Caucasian, 71% were married, 98% had completed high school, 95% were perimenopausal or postmenopausal, and 68% were on hormonal therapy (primarily an aromatase inhibitor). All patients had completed adjuvant chemotherapy one to five years (X = 2.5 years) before enrollment. Excluded current poor performance status, severe fatigue, and untreated major depressive disorder, as well as a history of major neurological or psychological disorders

• SITE: Multi-site   
• SETTING TYPE: Outpatient    
• LOCATION: A university medical center and 15 community clinical oncology programs in the Southeastern United States

• PHASE OF CARE: Late effects and survivorship
• APPLICATIONS: Elder care

Double-blind, randomized, controlled trial of donepezil versus placebo with repeated measures

Donepezil may have some benefit for patients related to changes in cognitive function. Further research is needed to provide strong evidence.

• Small sample (< 100)
• Findings not generalizable
• Subject withdrawals ≥ 10%  
• This feasibility study of a randomized, controlled trial was not powered to detect group differences.

This study primarily showed that future large studies of donepezil in women with breast cancer are feasible. The findings suggest that donepezil may improve memory in breast cancer survivors who report moderate-to-severe cognitive problems. Executive function may improve for some women. Anxiety and insomnia are potential side effects.

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.

The study was conducted to determine whether donepezil improved cognitive functioning, mood, and quality of life in patients who had irradiated brain tumors.

All participants received 5 mg/day of donepezil for 6 weeks, then 10 mg/day of donepezil for 18 weeks, followed by a washout period of 6 weeks where no treatment was administered. 

• The total number of enrolled participants was 35, with 24 completing all outcome assessments.
• The participants were 54% male and 46% female.
• The participants were 92% Caucasian and 8% black.
• 23 participants had glioma (about half low-grade), 4 participants had meningioma, 7 patients had other primary brain tumors, and 1 patient had metastatic disease).

This was a prospective, open-label, phase II study.

• Mini-Mental State Examination (MMSE) for global cognitive functioning
• Trail Making Test Parts A and B (TMT-A and TMT-B) for visual attention, motor speed, and cognitive flexibility
• Digit Span Test for attention and concentration
• Revised Rey-Osterrieth Complex Figure Test for visual construction skills and figural memory
• Controlled Oral Word Association Test for verbal fluency
• California Verbal Learning Test-II for verbal memory
• Health-Related Quality of Life (HRQOL) measures for health-related quality of life
• Karnofsky Performance Status Scale (KPS) for general well-being; scores range from 0 (death) to 100 (perfect health with no complaints or signs of disease)
• Functional Assessment of Cancer Therapy-Brain (FACT-Br) for cancer-related quality of life for patients with brain tumors
• Profile of Mood States assessment for subscales in depression, anxiety, anger, subjective confusion, fatigue, and vigor, as well as an overall mood score for distress

Significant improvement was noted between the pre-treatment baseline  and week 24 on measures of attention/concentration, verbal memory, figural memory, and a trend for verbal fluency (all p < 0.05). Confused mood was also improved from baseline to 24 weeks (p = 0.03). Health-related quality of life improved from baseline to 24 weeks in brain-specific concerns (p = 0.003), emotional functioning (p = 0.04), and social functioning (p = 0.02), with a trend for improvement in total health-related quality of life (p = 0.07).

Ten of 21 participants, or 48% of those who completed the study through the 30-week assessment, chose to go back on donepezil. A total of 63 toxicities ranging from grade 1 to grade 3 were reported.

Mood, health-related quality of life, and cognitive functioning (attention/concentration, verbal memory, and figural memory) were significantly improved following a 24-week course of donepezil.

• The study had a small sample size.
• The study had no control group for comparison. 
• Participants who completed the entire study differed significantly from those who dropped out in terms of age (p = 0.04). No control comparison.
• The repeated measures study did not address practice effects.
• Other co-occurring events may explain improvements in cognitive functioning. These events include concurrent tumor shrinkage, resolution of radiation-induced fatigue, and repair and recovery from radiation-induced brain damage.