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 38 ICNS Innovations in Clinical Neuroscience • January–February 2018 • Volume 15 • Number 1–2 early stages of cancer and is triggered by cancer chemotherapy as well, possibly contributing to the emerging cognitive impairments. 43 Increased cytokine levels (e.g., interleukin [IL]6, IL8, and IL10) have been associated with chemotherapy drugs such as paclitaxel and docetaxel. 51–54 Longitudinal studies on interferon-α and IL-2 treatments in cancer populations have shown cognitive impairments in information processing speed, executive function, spatial ability, and reaction time that were independent of depressive symptoms. 55–57 The chemotherapeutic agents used to treat cancer-induced tumor cell apoptosis through DNA damage 43,58,59 can also impact normal cells. Cytokine neurotoxicity might be triggered by the DNA damage, setting up a cycle of increasing DNA damage and increased cytokine activity. 60 Oxidative DNA damage has been identified in peripheral blood lymphocytes following chemotherapy for breast cancer, 61,62 and an increased number of point mutations in mitochondrial DNA has been detected following cancer chemotherapy with or without radiation. 63 Chemotherapy also has been associated with increased oxidative stress, and DNA damage increased levels of nonprotein-bound iron, 64 increased free radicals, 65 and reduced antioxidant activity. 65–67 Oxidative DNA damage has also been found in patients with breast cancer prior to receiving chemotherapy, 61,62 suggesting that deficits in DNA-repair mechanisms are associated with an increased risk of cancer 68,69 and might also contribute to the cognitive symptoms noted prior to treatment. Both brain atrophy and white matter pathology have been observed after chemotherapy in patients with breast cancer. Longitudinal studies have shown reductions in gray matter, primarily in bilateral frontal regions and the hippocampus. 70 Only partial gray matter recovery has been found within one-year post-chemotherapy compared to cancer patients who did not receive chemotherapy and compared to healthy controls. 70 Changes in overall gray matter volume equivalent to four additional years of aging have also been observed in survivors of breast cancer after more than 20 years. 29 Evidence of reduced white matter integrity, believed to reflect axonal degeneration and demyelination, has been reported using diffusion tensor imaging. 8 Specifically, decreased frontal, parietal, and occipital white matter integrity have been found in patients treated with chemotherapy compared to cancer patients who had not received chemotherapy and compared to healthy controls. 45 Several imaging studies suggest that the pattern of treatment-related cognitive impairment seen in patients with cancer and those in remission is related to functional and structural changes in the brain. 44–47 For instance, hypoactivation in the prefrontal cortex has been observed during memory encoding and executive function tasks in patients with breast cancer during chemotherapy. 71 Furthermore, a prospective, longitudinal treatment study on patients with breast cancer tracked alterations in frontal activation during a working memory task. The authors reported evidence of hyperactivation at baseline, a relative decrease at one month post-completion of chemotherapy, and a return to hyperactivation after one year, which was interpreted as reflecting a compensatory recruitment of neural circuitry. 72 Altered resting-state functional brain network activity characterized by disrupted frontal, striatal, and temporal areas has been observed in patients with breast cancer treated with chemotherapy compared to typical controls. 73,74 Patterns of disrupted default mode network (DMN) that were distinct from DMN connectivity patterns seen in patients with breast cancer who were not treated with chemotherapy or in typical controls have been reported in imaging studies of patients with breast cancer treated with chemotherapy. 75 Kessler et al 75 reported that the alterations in DMN connectivity were associated with patient- reported disturbances in memory. EFFECTS OF ADJUNCTIVE TREATMENTS ON COGNITION Adjunctive treatments, such as endocrine therapy, can induce cognitive impairment in patients with cancer. 2,36,44,76,77 A longitudinal study of cognitive performance in breast cancer found that use of adjuvant endocrine therapy was associated with slowed processing speed and verbal memory. 37 Patients with breast cancer who received combined chemotherapy and endocrine therapies have been reported to exhibit poorer scores on a working memory task compared to patients receiving either chemotherapy or endocrine therapy alone. 78 Furthermore, a longitudinal study reported that treatment- induced menopause was associated with cognitive impairment following chemotherapy in patients with early stage breast cancer. 79 EFFECTS OF RADIATION TREATMENTS ON COGNITION Patients receiving brain radiation treatments often experience radiation-induced fatigue and headache, in addition to possible cognitive impairment. Whole brain radiotherapy (WBRT) has been shown to worsen fatigue in patients with cancer. 80,81 The European Organization for Research and Treatment of Cancer (EORTC) reported that patients who received WBRT had measurable cognitive decline that they attributed to fatigue, as well as clinically significant higher fatigue scores, compared to patients with surgical or radiosurgical management. 80 Chang et al 82 found that adding WBRT to stereotactic radiosurgery increased the risk of learning and memory impairment at four months post- treatment, compared to patients who were treated only with stereotactic radiosurgery. Patients who have received radiotherapy are at risk of developing subacute toxicity approximately 1 to 6 months after completion of radiotherapy. This effect has been associated with impairment in processing information, attention, verbal memory, executive functioning, and fine motor dexterity. 8 White matter changes have been associated with these cognitive changes, and post-radiotherapy white matter recovery might result in cognitive recovery over time. 8 Numerous risk factors for developing radiation- induced cognitive impairment include age (under 5 years or older than 60 years), greater than 2-Gy dose per fraction, higher total dose, hyperfractionated schedules, shorter overall treatment time, the presence of comorbid vascular risk factors, concomitant or subsequent treatment with chemotherapy, and a greater total volume of brain irradiated. 83,84 Long-term memory impairment has been associated with increased exposure of radiation to the bilateral hippocampi. 85 Late-delayed toxicity from radiotherapy can occur months to years after completion of treatment and can include severe, irreversible memory loss. 8,86 Consequently, monitoring of cognitive and daily functioning in patients with cancer who receive radiotherapy is necessary long-term and in the immediate post- treatment period. ASSESSMENT OF COGNITIVE FUNCTIONING IN PATIENTS WITH CANCER AND THOSE IN REMISSION The assessment of cognitive functioning in patients with cancer and those in remission

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