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The acetylcholinesterase inhibitor donepezil (Aricept) failed to improve chemotherapy-related cognitive impairment (CRCI) in breast cancer survivors, a placebo-controlled trial showed.

After 24 weeks of treatment, performance on a standardized battery of neurocognitive tests showed no significant improvement in immediate recall, the primary endpoint, compared with the placebo group. Assessments performed at 12, 24, and 36 weeks showed no significant differences on any measurements of cognitive function, reported Stephen Rapp, PhD, of Wake Forest University in Winston-Salem, North Carolina, and co-authors in the (JCO).

"Early preclinical and clinical studies suggested that donepezil, an acetyl cholinesterase inhibitor used effectively in patients with Alzheimer's disease, might also benefit BCS [breast cancer survivors] with CRCI," the authors stated. "Contrary to our hypothesis ... we found that among BCS who were 1-5 years post-chemotherapy and who demonstrated reported CRCI ... [treatment for] 24 weeks produced no significant benefit for memory or other cognitive domains or self-reported cognitive problems compared with a placebo."

The results raised several questions, they acknowledged. Was donepezil a reasonable treatment choice? Were the dose and timing of administration appropriate? Might certain subgroups of patients benefit from donepezil? Why did the study fail to replicate results of a that showed a benefit with donepezil on the same memory test?

In an interpretation of the findings, JCO associate editor Camilla Zimmermann, MD, PhD, of the University of Toronto, said donepezil is not ready for prime time to improve cognitive function after chemotherapy for cancer.

"Donepezil cannot be recommended as a treatment to improve CRCI in BCS 1-5 years after completing chemotherapy," she stated. "Further trials with a different timing of administration, different medications or medication combinations, or non-pharmacological interventions are warranted."

The for mild-to-moderate Alzheimer's disease. Multiple studies have suggested a benefit of donepezil on cognitive function in several other conditions, including , , and . In a placebo-controlled trial in treated with radiotherapy, donepezil improved performance on selected tests of neurocognitive function, but not global cognitive function.

Favorable results from the previously mentioned pilot study provided additional support for the current study, a phase III placebo-controlled trial involving breast cancer survivors with documented cognitive impairment 1-5 years after completion of chemotherapy. Investigators at 87 sites affiliated with the Wake Forest National Cancer Institute Community Oncology Research Program enrolled 276 breast cancer survivors who were at a mean of 29.6 months after completion of chemotherapy.

Patients were randomized to donepezil or placebo for 24 weeks. Objectively measured and self-reported cognitive function were assessed at baseline, 12, 24, and 36 weeks. The primary outcome was immediate recall on the (HVLT-R) at 24 weeks, and secondary outcomes were other cognitive domains, also as assessed at 24 weeks.

At 24 weeks, mean scores on the HVLT-R were 25.98 for the donepezil group and 26.50 for the placebo group. The data showed no statistically significant differences between donepezil and placebo at 12, 24, or 36 weeks for attention, executive function, verbal fluency, processing speed, or self-reported cognitive function. Neither endocrine status nor menopausal status changed the results.

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