Donepezil Helps Some Patients Treated With Brain Irradiation

Veronica Hackethal, MD

April 30, 2015

Donepezil (multiple brands), a drug commonly used for Alzheimer's disease, improved some measures of cognitive functioning in patients with brain tumors treated with brain irradiation, according to results from a phase 3 clinical trial published April 20 in the Journal of Clinical Oncology.

"This study demonstrates that an acetylcholine esterase inhibitor, specifically, donepezil, can be beneficial to brain tumor survivors following brain irradiation," commented first author Stephen Rapp, PhD, a professor at Wake Forest University School of Medicine, in Winston-Salem, North Carolina.

"[W]hile not a 'silver bullet' ― it did not improve the overall cognitive functioning of all the patients ― donepezil did improve key cognitive functions, like memory and motor function, especially among survivors with greater cognitive impairment," Dr Rapp added. "And this treatment was very well tolerated."

About 50% to 90% of patients who receive brain irradiation experience cognitive impairment, according to background information in the article.

Patients who receive cranial irradiation often report problems with cognition and mood. Brain irradiation affects the hippocampus in particular, which plays an important role in learning, memory, and mood regulation.

Donepezil works as a reversible acetylcholinesterase inhibitor, which slows degradation of acetylcholine in synapses and increases signaling.

"Memory is a key function of the hippocampus, which is rich in acetylcholine receptors. Hence, donepezil is likely to show an effect on this function," explained Dr Rapp. "In addition to affecting the central nervous system, acetylcholine also activates peripheral skeletal muscles, which may explain the observed improvement in motor performance."

The randomized, double-blind, placebo-controlled study looked at 198 adult brain tumor survivors, of whom 66% had primary brain tumors, 27% had brain metastases, and 8% had undergone prophylactic cranial irradiation.

Participants had completed partial- or whole-brain irradiation 6 months before starting the study. They came from two academic medical centers, 21 community cancer programs, and three cancer trial support sites. Researchers assigned participants to placebo or donepezil, starting at 5 mg per day for 6 weeks and increasing the dosage to 10 mg per day for 18 weeks, depending on tolerability. The patients performed a battery of cognitive tests before randomization, at 12 weeks, and at 24 weeks.

Results at 24 weeks showed that the two groups did not differ significantly on composite scores of cognitive functioning (P = .48). However, the drug significantly improved individual scores for memory (recognition, P = .027; discrimination, P = .007), as well as motor speed and dexterity (P = .016).

Compared with patients receiving placebo, participants with greater cognitive impairment before starting donepezil experienced more improvement in overall cognitive functioning, memory, working memory, motor speed and dexterity, and executive functioning (cognitive composite score, P = .01; immediate recall, P = .05; delayed recall, P = .004; attention, P = .01; visuomotor skills, P = .02; and motor speed and dexterity, P < .001).

Participants most commonly experienced fatigue (donepezil group, 58%; placebo group, 67%; P = .24). Diarrhea accounted for the only significant difference between groups in side effects (donepezil group, 25%; placebo group, 9%; P = .005).

"The main clinical significance of our findings is that oncologists now have the choice of prescribing a well-tolerated drug for a growing patient population where few treatment options exist," Dr Rapp emphasized.

Much more research is needed, he added, and his team at Wake Forest School of Medicine will continue to study interventions to treat cognitive dysfunction in cancer patients.

Greatest Response in Most Impaired Patients

"[T]his trial confirms that the drug [donepezil] clearly helps some patients, with the greatest response in the most impaired patients," wrote Lawrence Kleinberg, MD, an associate professor at Johns Hopkins University, in Baltimore, Maryland, in a linked editorial.

"Given that the drug is generally well tolerated..., the results of this study provide appropriate justification to administer donepezil to affected patients and assess them for an effect over at least several months," he added.

As survival rates for patients with brain tumors continue to improve, preventing treatment-related brain injury will take on greater importance, Dr Kleinberg commented. He emphasized the "significant" cognitive issues that result from treatment for brain tumors. To highlight the issue, he quoted well-known brain tumor survivor Susan Sontag.

Sixteen years after receiving combined modality therapy, Sontag described her symptoms in a speech given at the Society for Neuro-Oncology Meeting, in 2004:

"Everything I do is slow. I walk, talk, and think slowly.... I still have no short-term memory.... Much of the time I can't even remember the names of relatives and close friends.... I am always confused.... Because I look normal and often sound normal, people assume I am normal. But I'm not.... I get depressed a lot knowing that I will never have my competence back," she said.

Dr Kleinberg suggested that donepezil could potentially treat brain deterioration by stabilizing hippocampal volume, inhibiting inflammatory processes, and improving brain perfusion. He also emphasized that patients who experience cognitive problems beyond the acute period should receive rehabilitation.

"With these steps — prevention of injury, rehabilitation, and use of these drug therapies while monitoring for benefit — there is now reason for cautious optimism that the proportion of patients who find themselves in the challenging situation described by Sontag will begin to grow smaller, even as long-term survival improves," Dr Kleinberg concluded.

Dr Chan has provided expert testimony for Cooney, Scully, Dowling, attorneys at law. Dr Edenfield has served on the speakers' bureaus for Astellas Pharma and Medivation. The other authors and Dr Kleinberg have disclosed no relevant financial relationships.

J Clin Oncol. Published 20 April 2015, Abstract, Editorial


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