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Adult brain tumor survivors taking donepezil, a drug approved for the treatment of Alzheimer’s disease, showed significant improvements in the cognitive functions of memory, motor speed, and dexterity, compared with those taking a placebo. However, improvements in the primary outcome of composite cognitive function were similar for the two arms, investigators reported.
The study results were published online April 20 in the Journal of Clinical Oncology.
Patients with greater pretreatment deficits saw greater improvements in cognitive functioning with donepezil treatment, reported Stephen Rapp, Ph.D., professor of psychiatry and behavioral medicine at Wake Forest School of Medicine, Winston-Salem, N.C., and associates.
“This suggests that treatment with a daily dose of donepezil can provide benefit to some adult long-term brain tumor survivors after PBI or WBI [partial- or whole-brain irradiation], particularly those with greater pretreatment cognitive impairment,” they wrote (J. Clin. Oncol. 2015 Apr. 20 [doi: 10.1200/JCO.2014.58.4508]).
The phase III trial enrolled 198 primary or metastatic brain tumor survivors who underwent fractionated PBI or WBI at least 6 months previously. Patients received either donepezil at 5 mg daily for 6 weeks, followed by 10 mg daily for 18 weeks if well tolerated, or placebo for 24 weeks. Composite cognitive scores improved for both arms and did not differ significantly. Donepezil treatment resulted in significantly greater improvements in memory (recognition, P = .027; discrimination, P = .007) and motor speed and dexterity (P = .016).
Donepezil was generally well tolerated, except for diarrhea in 25% of the active arm vs. 9% in the placebo arm (P = .005). The study retention rate was 74% at 24 weeks for both groups.
Although enrolled patients had a high level of cognitive impairment relative to noncancer controls, with 91% having at least one test score at least 1.5 standard deviations below the normal comparison group, scores across most measures varied widely from significantly lower to higher than the comparison group. This heterogeneity may underlie the less than significant improvement observed with the study treatment. Patients with greater cognitive deficits saw greater benefits.
“This indicates that brain tumors and their treatments, including cranial irradiation, are associated with clinically significant cognitive impairment among some but not all patients. In future studies, demonstrable cognitive impairment should be an inclusion criterion for enrollment,” Dr. Rapp and associates wrote.
The study by Rapp et al. suggests that for brain tumor survivors experiencing cognitive difficulties, intervention with donepezil, a drug approved for use in Alzheimer’s disease (AD), may be helpful. Although average improvements were small, the trial indicates clear benefit for some patients, especially those most impaired. The study followed patients taking the drug for 6 months, but patients who responded to treatment likely will continue with lifelong therapy, based on experience with donepezil in AD. After cessation of the agent, neurocognitive function of treated AD patients declined to the level of untreated patients.
The results of the current study justify administering the drug to affected patients and monitoring for effects. In the absence of evidence of clinical benefit, the data do not support continuing treatment. Donepezil use in AD is continued for some patients even without signs of improvement, on the basis of slowing expected decline. However, cognitive declines due to tumor and treatment injury do not progress over time, and donepezil use in this population is supported only with evidence of benefit.
Optimal dosing for cancer patients requires further study, but studies with AD patients showed no clear benefit of dose escalation that outweighed GI adverse effects.
Maintaining maximal cognitive functioning in patients who often begin treatment with brain injury due to the tumor and unrelated illnesses, requires first the prevention of further damage. Strategies include functional image-guided surgery, limiting daily radiation fraction size, improved image-guided radiotherapy target definition, highly conformal radiotherapy administration techniques, and highly focused stereotactic radiosurgery in place of whole-brain radiotherapy for many patients with brain metastasis. Research on improvements in imaging of tumor and functional brain to better guide surgery and radiation is worthwhile.
Neurocognitive rehabilitation is recommended for patients with cognitive deficits that persist after therapy had ended. A recent randomized study showed clear benefit of rehabilitation for attention, verbal memory, and mental fatigue.
By taking steps to prevent injury, rehabilitate patients with deficits, and administer drug therapies while monitoring for benefit, improvements to cognitive function in brain tumor survivors may begin to increase. To best employ these strategies, a validated, easy-to-use instrument that measures mild to moderate impairment is needed for routine oncology practice.
Dr. Lawrence Kleinberg is associate professor of radiation oncology and molecular radiation sciences at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore. These comments were excerpted from the editorial accompanying the report by Dr. Rapp et al. (J. Clin. Oncol. 2015 April 20 [doi: 10.1200/JCO.2014.60.2805]).
The study by Rapp et al. suggests that for brain tumor survivors experiencing cognitive difficulties, intervention with donepezil, a drug approved for use in Alzheimer’s disease (AD), may be helpful. Although average improvements were small, the trial indicates clear benefit for some patients, especially those most impaired. The study followed patients taking the drug for 6 months, but patients who responded to treatment likely will continue with lifelong therapy, based on experience with donepezil in AD. After cessation of the agent, neurocognitive function of treated AD patients declined to the level of untreated patients.
The results of the current study justify administering the drug to affected patients and monitoring for effects. In the absence of evidence of clinical benefit, the data do not support continuing treatment. Donepezil use in AD is continued for some patients even without signs of improvement, on the basis of slowing expected decline. However, cognitive declines due to tumor and treatment injury do not progress over time, and donepezil use in this population is supported only with evidence of benefit.
Optimal dosing for cancer patients requires further study, but studies with AD patients showed no clear benefit of dose escalation that outweighed GI adverse effects.
Maintaining maximal cognitive functioning in patients who often begin treatment with brain injury due to the tumor and unrelated illnesses, requires first the prevention of further damage. Strategies include functional image-guided surgery, limiting daily radiation fraction size, improved image-guided radiotherapy target definition, highly conformal radiotherapy administration techniques, and highly focused stereotactic radiosurgery in place of whole-brain radiotherapy for many patients with brain metastasis. Research on improvements in imaging of tumor and functional brain to better guide surgery and radiation is worthwhile.
Neurocognitive rehabilitation is recommended for patients with cognitive deficits that persist after therapy had ended. A recent randomized study showed clear benefit of rehabilitation for attention, verbal memory, and mental fatigue.
By taking steps to prevent injury, rehabilitate patients with deficits, and administer drug therapies while monitoring for benefit, improvements to cognitive function in brain tumor survivors may begin to increase. To best employ these strategies, a validated, easy-to-use instrument that measures mild to moderate impairment is needed for routine oncology practice.
Dr. Lawrence Kleinberg is associate professor of radiation oncology and molecular radiation sciences at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore. These comments were excerpted from the editorial accompanying the report by Dr. Rapp et al. (J. Clin. Oncol. 2015 April 20 [doi: 10.1200/JCO.2014.60.2805]).
The study by Rapp et al. suggests that for brain tumor survivors experiencing cognitive difficulties, intervention with donepezil, a drug approved for use in Alzheimer’s disease (AD), may be helpful. Although average improvements were small, the trial indicates clear benefit for some patients, especially those most impaired. The study followed patients taking the drug for 6 months, but patients who responded to treatment likely will continue with lifelong therapy, based on experience with donepezil in AD. After cessation of the agent, neurocognitive function of treated AD patients declined to the level of untreated patients.
The results of the current study justify administering the drug to affected patients and monitoring for effects. In the absence of evidence of clinical benefit, the data do not support continuing treatment. Donepezil use in AD is continued for some patients even without signs of improvement, on the basis of slowing expected decline. However, cognitive declines due to tumor and treatment injury do not progress over time, and donepezil use in this population is supported only with evidence of benefit.
Optimal dosing for cancer patients requires further study, but studies with AD patients showed no clear benefit of dose escalation that outweighed GI adverse effects.
Maintaining maximal cognitive functioning in patients who often begin treatment with brain injury due to the tumor and unrelated illnesses, requires first the prevention of further damage. Strategies include functional image-guided surgery, limiting daily radiation fraction size, improved image-guided radiotherapy target definition, highly conformal radiotherapy administration techniques, and highly focused stereotactic radiosurgery in place of whole-brain radiotherapy for many patients with brain metastasis. Research on improvements in imaging of tumor and functional brain to better guide surgery and radiation is worthwhile.
Neurocognitive rehabilitation is recommended for patients with cognitive deficits that persist after therapy had ended. A recent randomized study showed clear benefit of rehabilitation for attention, verbal memory, and mental fatigue.
By taking steps to prevent injury, rehabilitate patients with deficits, and administer drug therapies while monitoring for benefit, improvements to cognitive function in brain tumor survivors may begin to increase. To best employ these strategies, a validated, easy-to-use instrument that measures mild to moderate impairment is needed for routine oncology practice.
Dr. Lawrence Kleinberg is associate professor of radiation oncology and molecular radiation sciences at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore. These comments were excerpted from the editorial accompanying the report by Dr. Rapp et al. (J. Clin. Oncol. 2015 April 20 [doi: 10.1200/JCO.2014.60.2805]).
Adult brain tumor survivors taking donepezil, a drug approved for the treatment of Alzheimer’s disease, showed significant improvements in the cognitive functions of memory, motor speed, and dexterity, compared with those taking a placebo. However, improvements in the primary outcome of composite cognitive function were similar for the two arms, investigators reported.
The study results were published online April 20 in the Journal of Clinical Oncology.
Patients with greater pretreatment deficits saw greater improvements in cognitive functioning with donepezil treatment, reported Stephen Rapp, Ph.D., professor of psychiatry and behavioral medicine at Wake Forest School of Medicine, Winston-Salem, N.C., and associates.
“This suggests that treatment with a daily dose of donepezil can provide benefit to some adult long-term brain tumor survivors after PBI or WBI [partial- or whole-brain irradiation], particularly those with greater pretreatment cognitive impairment,” they wrote (J. Clin. Oncol. 2015 Apr. 20 [doi: 10.1200/JCO.2014.58.4508]).
The phase III trial enrolled 198 primary or metastatic brain tumor survivors who underwent fractionated PBI or WBI at least 6 months previously. Patients received either donepezil at 5 mg daily for 6 weeks, followed by 10 mg daily for 18 weeks if well tolerated, or placebo for 24 weeks. Composite cognitive scores improved for both arms and did not differ significantly. Donepezil treatment resulted in significantly greater improvements in memory (recognition, P = .027; discrimination, P = .007) and motor speed and dexterity (P = .016).
Donepezil was generally well tolerated, except for diarrhea in 25% of the active arm vs. 9% in the placebo arm (P = .005). The study retention rate was 74% at 24 weeks for both groups.
Although enrolled patients had a high level of cognitive impairment relative to noncancer controls, with 91% having at least one test score at least 1.5 standard deviations below the normal comparison group, scores across most measures varied widely from significantly lower to higher than the comparison group. This heterogeneity may underlie the less than significant improvement observed with the study treatment. Patients with greater cognitive deficits saw greater benefits.
“This indicates that brain tumors and their treatments, including cranial irradiation, are associated with clinically significant cognitive impairment among some but not all patients. In future studies, demonstrable cognitive impairment should be an inclusion criterion for enrollment,” Dr. Rapp and associates wrote.
Adult brain tumor survivors taking donepezil, a drug approved for the treatment of Alzheimer’s disease, showed significant improvements in the cognitive functions of memory, motor speed, and dexterity, compared with those taking a placebo. However, improvements in the primary outcome of composite cognitive function were similar for the two arms, investigators reported.
The study results were published online April 20 in the Journal of Clinical Oncology.
Patients with greater pretreatment deficits saw greater improvements in cognitive functioning with donepezil treatment, reported Stephen Rapp, Ph.D., professor of psychiatry and behavioral medicine at Wake Forest School of Medicine, Winston-Salem, N.C., and associates.
“This suggests that treatment with a daily dose of donepezil can provide benefit to some adult long-term brain tumor survivors after PBI or WBI [partial- or whole-brain irradiation], particularly those with greater pretreatment cognitive impairment,” they wrote (J. Clin. Oncol. 2015 Apr. 20 [doi: 10.1200/JCO.2014.58.4508]).
The phase III trial enrolled 198 primary or metastatic brain tumor survivors who underwent fractionated PBI or WBI at least 6 months previously. Patients received either donepezil at 5 mg daily for 6 weeks, followed by 10 mg daily for 18 weeks if well tolerated, or placebo for 24 weeks. Composite cognitive scores improved for both arms and did not differ significantly. Donepezil treatment resulted in significantly greater improvements in memory (recognition, P = .027; discrimination, P = .007) and motor speed and dexterity (P = .016).
Donepezil was generally well tolerated, except for diarrhea in 25% of the active arm vs. 9% in the placebo arm (P = .005). The study retention rate was 74% at 24 weeks for both groups.
Although enrolled patients had a high level of cognitive impairment relative to noncancer controls, with 91% having at least one test score at least 1.5 standard deviations below the normal comparison group, scores across most measures varied widely from significantly lower to higher than the comparison group. This heterogeneity may underlie the less than significant improvement observed with the study treatment. Patients with greater cognitive deficits saw greater benefits.
“This indicates that brain tumors and their treatments, including cranial irradiation, are associated with clinically significant cognitive impairment among some but not all patients. In future studies, demonstrable cognitive impairment should be an inclusion criterion for enrollment,” Dr. Rapp and associates wrote.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Among adult brain tumor survivors who underwent partial- or whole-brain irradiation, treatment with donepezil compared with placebo was associated with significant improvements in memory and motor speed and dexterity, but composite cognitive scores were similar.
Major finding: After 24 weeks of treatment, patients taking donepezil (vs. placebo) had significantly more improvement in memory (recognition, P = .027; discrimination, P = .007) and motor speed and dexterity (P = .016).
Data source: A double-blind phase III trial that randomized 198 patients who had undergone irradiation at least 6 months previously to receive donepezil (5 mg for 6 weeks followed by 10 mg for 18 weeks) or placebo (24 weeks).
Disclosures: Dr. Rapp reported having no financial disclosures.
