Innovations In Clinical Neuroscience

JAN-FEB 2018

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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R E V I E W 37 ICNS Innovations in Clinical Neuroscience • January–February 2018 • Volume 15 • Number 1–2 varied cognitive tests used, and the definition of cognitive impairment that was applied. 16 In a retrospective study of 68 patients with brain tumors, Lageman et al 17 found that 58.8 percent of the patients exhibited cognitive impairment as defined by standard deviations of 2 or greater below the published normative means on at least one subtest of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). In this study, 90 percent of the cognitive impairment occurred within the domains of visuoconstruction, processing speed, and verbal memory. 17 Of the domains listed by the authors, processing speed is better considered an outcome metric than a cognitive domain, as slowing is caused by deficits in attention, working memory, and executive function deficits. Cancer-related cognitive changes and impairment also have been documented in patients with non-central nervous system (non-CNS) cancer prior to exposure to treatment interventions. Several studies have identified cognitive impairment in newly diagnosed patients with cancer across several cognitive domains, including verbal memory, language, visual spatial skills, executive function, and psychomotor function. 18–23 Approximately 11 to 35 percent of women with breast cancer are reported to have cognitive impairment prior to treatment, with specific difficulties on measures of learning and memory. 24–26 Patients with newly diagnosed large or locally advanced breast cancer demonstrated a range of significant impairments in attention, immediate and delayed word recall, and word and picture recognition on a computerized assessment (Cognitive Drug Research [CDR] system) prior to initiating primary chemotherapy, with notable large impairments in the speed of picture recognition (30%) and delayed word recall (25%). 24 EFFECTS OF COMORBID FACTORS ON COGNITION Several comorbid factors can impact cognitive functioning in patients with cancer and those in remission. Depression, anxiety, and fatigue can adversely affect cognitive functioning in healthy and ill patient populations. These symptoms are common and are particularly important comorbid conditions in patients with cancer. Berman et al 27 found that pretreatment worry was associated with subjective and objective measures of cognitive impairment, and alterations in brain function, as measured by functional magnetic resonance imaging (fMRI), were also observed in patients with breast cancer about to receive either chemotherapy or radiation treatment. Other studies have found a relationship between reported mood symptoms and subjective reports of cognitive impairment in patients with cancer. 20,28,29 One study of 40 patients with breast cancer found that anxiety, depression, and poor quality of life correlated with self-reported cognitive concerns but not with impaired cognitive performance. 30 Subjective cognitive complaints were associated with measures of fatigue and distress but not with objective performance on cognitive testing in a study of 53 survivors of breast cancer at least two years out from diagnosis. 31 In one study examining the cognitive functioning of lymphoma survivors using the CNS Vital Signs (Chapel Hill, North Carolina) computerized assessment, fatigue and anxiety were related to subjective reports of cognitive difficulties, whereas pain was associated with performance deficits on objective cognitive measures. 32 Fatigue can significantly impact daily functioning and quality of life in patients with cancer. 33,34 This is perhaps unsurprising given the importance of cognition in the execution and initiation of many activities of daily living. Treatment expectations might also influence cognitive function in some patients with cancer. One recent study found that patients treated with chemotherapy who were informed of the possible cognitive side effects performed worse on cognitive testing and were more likely to report problems compared to comparable patients who were not informed about the possible cognitive side effects. 35 DIRECT EFFECTS OF CANCER MEDICATION TREATMENTS ON COGNITION It is well established that cancer chemotherapy can induce cognitive impairment. 6 It has been estimated that 13 to 70 percent of patients receiving cancer chemotherapy have measurable cognitive impairment. 3,20,25,26,36 As noted earlier, the wide range of cognitive impairment that has been reported relates to the diversity of definitions and tests that are used. The observed cognitive impairment might or might not resolve for some patients following treatment, and consequently, some patients might experience persistent, long-term cognitive problems. 5 Several recent meta-analyses examining cognitive impairment following oncological treatments have shown that patients with cancer and those in remission have impairment in the domains of memory, attention, executive function, "processing speed," visual and verbal memory, and language relative to people without cancer. 2,11,26,37–40 One study observed moderate-to-severe cognitive impairment in 16 percent of patients receiving adjuvant or neoadjuvant chemotherapy for breast cancer compared to only four percent of typical controls. 41 Cognitive function was examined in 196 long-term survivors of breast cancer treated with cyclophosphamide, methotrexate, and fluorouracil (CMF) who were, on average, 21 years out from diagnosis. The researchers found that the chemotherapy group performed significantly worse on several cognitive tests, including immediate and delayed verbal memory, executive functioning, and psychomotor speed compared to 1,509 control patients with no history of cancer. 29 A separate study of 189 survivors of breast cancer found that memory and executive function complaints were present in approximately 20 percent of the cohort and showed a statistically significant association with results of domain- specific cognitive tests. 42 It is noteworthy that age was not a moderating factor of cognitive impairment in the reported meta-analyses. 2,39,40 This observation suggests that aged individuals are not more susceptible to the negative impacts on cognition of cancer treatments. PUTATATIVE MECHANISMS AFFECTING COGNITION DURING CHEMOTHERAPY Elevated levels of cytokines, deoxyribonucleic acid (DNA) damage, or white matter damage might contribute to cognitive deficits, 43–47 and the risk of developing chemotherapy-associated neurotoxicity might be related to exposure to higher doses, 48 additive and synergistic effects of multi-agent chemotherapy, 8 and administration of chemotherapy via intra-arterial and/or intrathecal methods. 49 Several articles by Ahles and colleagues have been published discussing different proposed mechanisms for cancer- associated cognitive impairments, including recent research exploring the relationship between cognitive changes in cancer patients with the aging process and genetic factors. 43,44,50 Cytokines have important roles in normal CNS function, including the modulation of neuronal and glial cell functioning and neural repair and the metabolism of dopamine and serotonin. 43 Cytokine neurotoxicity has been found during

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