Donepezil for cancer-related cognitive impairment: systematic review and meta-analysis

Cancer-related cognitive impairment (CRCI) affects a significant proportion of cancer patients and survivors, impacting their memory, focus, mood, and quality of life. While non-pharmacological interventions have shown effectiveness in managing this condition, some studies have also explored various pharmacological agents, including donepezil, a reversible acetylcholinesterase inhibitor. This compound demonstrated beneficial effects on cognition in Alzheimer's disease; however, its effectiveness in CRCI remains unknown. This systematic review and meta-analysis aims to evaluate the efficacy of donepezil in improving cognitive outcomes in cancer patients. We conducted a search of PubMed/Medline, Embase, Cochrane Library, ClinicalTrials.gov, and the International Clinical Trials Registry Platform. Both randomized controlled trials and observational studies were included. We extracted data on cognitive outcomes of donepezil treatment, including the Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test (TMT), and Controlled Oral Word Association Test (COWA), as well as reported adverse events (AEs). Out of 896 identified records, nine studies involving 837 patients met the inclusion criteria, including five RCTs and four observational studies. Donepezil failed to demonstrate significant improvements in cognitive outcomes in HVLT-R, TMT, and COWA. Fatigue, measured as a secondary outcome, also showed no significant improvement. AEs, such as insomnia and headache, were more prevalent in adults than children. Donepezil did not increase the risk of AEs compared to placebo. This meta-analysis found that donepezil does not provide cognitive improvements for CRCI patients. Given the complex and multifactorial nature of CRCI, the lack of efficacy suggests that donepezil may not address the underlying mechanisms of the condition.