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Donepezil displays some cognitive benefit for patients with irradiated brain tumors
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Donepezil was not associated with significant improvements in cognitive functioning among survivors of brain tumors who underwent irradiation, according to the results of a phase 3 clinical trial.
However, donepezil was associated with significant improvements in individual cognitive functions, including memory and motor speed and dexterity, especially among patients with larger deficits before treatment, results showed.
“This study was born of a desire to help patients with one of the most common and vexing problems following brain cancer and its treatments, including radiation,” Stephen R. Rapp, PhD, of the department of psychiatry and behavioral medicine at Wake Forest University School of Medicine, told HemOnc Today. “At the time, there were few options for treating cancer-related cognitive impairment. We chose donepezil because it had proven to be helpful to patients with Alzheimer’s disease and the biological mechanisms underlying its effect were plausible in our patient population.”
Stephen R. Rapp
Further, a phase 2 pilot study displayed positive outcomes in patients with irradiated brain tumors and warranted a phase 3, placebo-controlled clinical trial, Rapp said.
Rapp and colleagues evaluated data from 198 survivors of brain tumors. All participants previously underwent partial- or whole-brain irradiation for at least 6 months. Two-thirds of the population had primary brain tumors, 27% had brain metastases and 8% underwent prophylactic cranial irradiation.
Researchers randomly assigned patients to donepezil or placebo in daily doses of 5 mg for 6 weeks or 10 mg for 18 weeks.
Researchers administered a series of cognitive tests evaluating memory, attention, language and verbal fluency, visuomotor skill and executive functions at baseline, week 12 and week 24.
The study’s primary outcome was a cognitive composite score based on results of the cognitive tests after 24 weeks of therapy.
Overall, there was no significant difference in cognitive function between the study arms at 24 weeks. However, patients who received donepezil demonstrated significant improvements in memory recognition (P = .027), memory discrimination (P = .007) and motor speed and dexterity (P = .004).
Researchers noted pretreatment neurocognitive function was significantly associated with treatment for cognitive composite (P = .01), immediate recall (P = .05), delayed recall (P = .004), attention (P = .01), visuomotor skills (P = .02) and motor speed and dexterity (P < .001). Patients who displayed more severe cognitive impairment at baseline appeared to derive greater benefit from treatment with donepezil.
Researchers noted the treatment was well tolerated. Diarrhea was the only adverse event to occur significantly more frequently among patients assigned donepezil (25% vs. 9%; P = .005).
The researchers acknowledged the use of prior studies of patients with Alzheimer’s disease to determine medication dose and treatment duration may be a limitation to the study’s design. The study also was not designed to account for underlying disease properties or tumor types and locations. Further, the evaluation of multiple cognitive outcomes could result in false-positive results.
“For physicians treating brain tumor survivors, there is now available a well-tolerated medication that can improve cognitive functioning, especially among survivors with greater deficits,” Rapp said. “The next step in our research will be to examine other drugs, combinations of drugs and nonpharmacological interventions to see if we can provide greater relief to our patients.”
Despite insignificant outcomes across the entire study population, the positive outcomes associated with donepezil in certain subsets should be considered by physicians for appropriate patients, Lawrence Kleinberg, MD, of the Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins University, wrote in an accompanying editorial.
“Given that the drug is generally well tolerated, except for reversible nausea, vomiting and diarrhea in less than 20% of patients, 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,” Kleinberg wrote. “Routine or prophylactic use of this drug in patients or continuation without clinical benefit is not sufficiently supported or addressed by these data. Before such use can be recommended, a long-term benefit for patients without significant decline at the time of drug therapy, superior to the benefit of initiating treatment at the time of symptom development, would need to be demonstrated.” – by Cameron Kelsall
For more information:
Stephen R. Rapp, PhD, can be reached at Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157; e-mail: srapp@wakehealth.edu.
Disclosure: Rapp reports no relevant financial disclosures. Other researchers report speakers bureau roles with Astellas Pharma and Medivation and providing expert testimony for Cooney, Scully and Dowling: Attorneys at Law.
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