Toxicity and efficacy of the acetylcholinesterase (AChe) inhibitor donepezil in childhood brain tumor survivors: A pilot study

Abstract

Background Neurocognitive deficits are a recognized late effect of curative brain tumor therapy. We evaluated the feasibility, tolerance, and impact of a pilot pharmacologic intervention with the acetylcholinesterase (AChe) inhibitor, donepezil, in pediatric brain tumor (BT) survivors at risk for neurocognitive dysfunction. Procedure A single institution open-label pilot study was conducted in childhood BT survivors: ≥ 1 year from cancer treatment; and who received > 23.5 Gy cranial radiation therapy (RT). Toxicity, adherence and neurocognitive outcomes were evaluated at baseline and serially during 24 weeks of donepezil, and following a 12-week washout period off drug. Results From a pool of subjects, 13 were successfully contacted and screened, and 11 met all eligibility criteria to initiate donepezil at a median of 4.7 (1.9–11.9) years from RT. Seventy-two percent of patients completed the 24-week drug study visit. Despite transient gastrointestinal toxicity (vomiting and diarrhea) in 30% of patients there was no weight loss on donepezil. Significant improvement in performance was noted at 24 weeks on the Dellis-Kaplan Executive Function (D-KEF) Tower test (p<=0.001), the Wide Range Assessment of Memory and Learning, 2nd Edition (WRAML-2) Visual memory (p= 0.007), and the Number/Letter task (p= 0.018). Conclusions Donepezil was well tolerated among childhood BT survivors who had received substantial prior therapy. Based on improved executive function and memory performance in this pilot trial, a randomized placebo controlled trial of this pharmacologic agent is warranted to fully evaluate its efficacy in remediating neurocognitive dysfunction.

Monitoring and Assessment of Neuropsychological Outcomes as a Standard of Care in Pediatric Oncology

“…Studies involving survivors of brain tumor and ALL demonstrate significant improvement on parent report ratings. Higher baseline IQ, males, and older age at treatment predicted better response to 0.60 mg/kg dose of methylphenidate in the cohort …”

“…Pharmacotherapy approaches to improve attention dysfunction have included psychostimulant medications (e.g., methylphenidate) and acetylcholinesterase inhibitors (e.g., donepezil) . Studies involving survivors of brain tumor and ALL demonstrate significant improvement on parent report ratings.…”

Cognitive Effects of Chemotherapy and Cancer-Related Treatments in Older Adults

“…109–114 Other pharmacologic treatment studies have evaluated donepezil, an acetylcholinesterase inhibitor, approved to treat mild to severe AD. 115,116 Both open-label and placebo controlled studies in glioma patients suggested statistically significant improvements in cognitive performance. 115,116 Additionally, a study in breast cancer survivors suggested improved verbal memory in those who had poorer cognitive functioning at baseline.…”

“…115,116 Both open-label and placebo controlled studies in glioma patients suggested statistically significant improvements in cognitive performance. 115,116 Additionally, a study in breast cancer survivors suggested improved verbal memory in those who had poorer cognitive functioning at baseline. 117 Cholinesterase inhibitor studies provide support for the cholinergic system as a therapeutic target for improving cognitive functioning in CRCI.…”

Neuro-cognitive sequelae of the treatment of brain tumors among children and adolescents, and the possibilities for neuro-rehabilitation with a case report

“…U nekoliko studija je ispitivana efikasnost farmakoloških stimulansa u unapređenju neurokognitivnih funkcija kod dece lečene od tumora CNS-a. Kastelino i Smitson su dokazali napredak u pažnji, brzini obrade i kognitivnoj fleksibilnosti kod dece koja su lečena od tumora CNS-a korišćenjem psihostimulansa methylphenidate [49,50].…”