Donepezil

Donepezil

PEP Topic 
Cognitive Impairment
Description 

Donepezil is a centrally active cholinesterase inhibitor that has been used to treat dementia in patients with Alzheimer disease. It may improve the ability to think and remember in these patients, and has also been studied in patients with cancer for fatigue and cognitive impairment.

Effectiveness Not Established

Research Evidence Summaries

Jatoi, A., Kahanic, S.P., Frytak, S., Schaefer, P., Foote, R.L., Sloan, J., & Petersen, R.C. (2005). Donepezil and vitamin E for preventing cognitive dysfunction in small cell lung cancer patients: Preliminary results and suggestions for future study designs. Supportive Care in Cancer, 13(1), 66–69.

doi: 10.1007/s00520-004-0696-0
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Study Purpose:

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.

Intervention Characteristics/Basic Study Process:

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.

Sample Characteristics:

  • 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.

Setting:

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

Study Design:

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

Measurement Instruments/Methods:

  • 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. 

Results:

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.

Conclusions:

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

Limitations:

  • 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.

Shaw, E.G., Rosdhal, R., D’Agostino, R.B., Lovato, J. Naughton, M.J., Robbins, M.E., & Rapp, S.R. (2006). Phase II study of donepezil in irradiated brain tumor patients: Effect on cognitive function, mood, and quality of life. Journal of Clinical Oncology, 24(9), 1415–1420.

doi:10.1200/JCO.2005.03.3001
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Study Purpose:

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

Intervention Characteristics/Basic Study Process:

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. 

Sample Characteristics:

  • 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).

Study Design:

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

Measurement Instruments/Methods:

  • 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

Results:

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.

Conclusions:

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.

Limitations:

  • 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.

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