Presenter: Stephen R. Rapp, MD Presenter's Affiliation: Wake Forest University, Winston Salem, NC Abstract #: 2006
Cognitive impairment associated with brain tumors, both primary and metastatic tumors, is common, with >50% of patients demonstrating objective declines in cognitive function following treatment and ~10% of patients becoming debilitated secondary to dementia.
Objective declines in cognitive function, including but not limited to short term memory, verbal expression, attention, and motor speed, have been documented following brain radiation. Additionally, patients reported decreased quality of life secondary to increased fatigue, poor concentration, and loss of short term memory.
Currently, no treatments have demonstrated prevention or improvements in neurocognitive function following treatment for brain tumors.
Previous attempts to treat neurocognitive changes, including methylphenidate and modafinil, have proven unsuccessful.
Initial Phase II studies of 24 weeks of donepezil demonstrated improvements in attention/concentration, verbal memory, and figural memory, confused mood, and a trend for verbal fluency and fatigue and anger. Overall, health-related QOL improved as well with minimal toxicity noted.
Donepezil is an FDA approved acetylcholinesterase inhibitors, currently in use for the treatment of Alzheimer’s patients.
This randomized trial (DIBS) was undertaken to evaluate the effect of 24 weeks of donepezil on cognitive functioning (primary endpoint) and fatigue, mood and QOL (secondary endpoints) in long-term brain tumor survivors following partial or whole-brain irradiation.
Materials and Methods
From 2/08-12/11,adult primary and metastatic brain tumor survivors at least 6 months post-treatment were enrolled at Wake Forest, M.D. Anderson Cancer Center, and 22 community sites.
Patients were required to be >18 years old with KPS >60 and ECOG 0-2.
Radiation treatment must have consisted of >30 Gy
Recent imaging with stable disease demonstrated on MRI was required.
Patients were randomly assigned to receive donepezil (5 mg for 6 weeks followed by 10 mg for 18 weeks) or placebo for 24 weeks
Cognitive function was assessed at baseline, 12 and 24 weeks with Hopkins Verbal Learning Test-Revised, Rey-Osterreith Complex Figure, Trail Making Test, Digit Span, Controlled Oral Word Association, and Grooved Pegboard.
Cognitive Composite (CC) score was the primary outcome.
The patient population was 91% Caucasian, 54% female, and median age was 57 years.
Patient characteristics were well balanced.
66% had primary tumors, 27% brain metastases and 8% PCI.
Median time since diagnosis was 38 months.
95% had 0-1 ECOG performance status scores. 74% completed the study with >90% adherence to the medication.
Cognitive Composite score improved significantly by 24 weeks in both arms; however, there was not a statistically significant difference between groups.
The donepezil group showed a trend for improvement in motor speed/dexterity, and verbal memory but no change in learning or attention/concentration.
In all cases, the benefit of donepezil, relative to placebo, was greater for those with worse baseline scores.
For patients with self-reported cognitive deficits below the median, there was a non-significant trend for improvement with donepezil for global cognitive function, memory tasks, and motor speed/dexterity.
The drug was well tolerated with fatigue being the most common complaint and headache following. In total, 14 patients stopped donepezil vs. 5 in the placebo group.
Long-term brain tumor survivors treated with brain irradiation who have cognitive impairment did not benefit from 5-10mg of donepezil for 24 weeks.
Although trends for improved motor speed/dexterity and memory were noted, no significant improvements were seen.
The authors presented a well-performed phase III multi-center double-blind placebo-controlled study evaluating the efficacy of donzepezil on cognitive functioning in long-term brain tumor survivors.
Neurocognitive decline is an active area of enormous research. Three areas of neurocognitive decline, motor, cognitive, and language, have all been shown to significantly decline on validated and FDA approved neurocognitive function tests following treatment for brain tumors.
The results of this study were disappointing with no significant findings to demonstrate improvements in outcomes for this patient population.
The investigators decision to wait for 6 months to initiate the drug is interesting and an area of debate. The authors reported the rationale was to ensure stable disease as the issue of cognitive decline is of particular interest in long term survivors; however, earlier use of the drug could potentially result in different outcomes.
Future studies must continue to search for a potential treatment to decrease neurocognitive decline in patients with brain tumors following radiation treatments. Additionally, studies should seek to identify groups at particular risk for decline that may benefit from treatments such as this.
Aug 7, 2013 - Cellular immunotherapy and gene therapy alone or in combination are effective in reducing tumor size and improving survival in a mouse model of breast cancers that have metastasized to the brain, according to a study published in the Aug. 1 issue of Clinical Cancer Research.