Chemotherapy can improve prospects for long-term survival after a cancer diagnosis, but it may also be associated with long-term toxicity, including the possibility of cognitive dysfunction. While a variety of factors may contribute to cognitive impairment in cancer survivors, there is increasing evidence that chemotherapy contributes to both subjective and objective changes in cognition. These effects appear to be most pronounced in the short-term, with improvement over time expected for most patients. Pharmacologic treatments do not have proven value in the management of chemotherapy-related cognitive dysfunction, but patients may benefit from cognitive rehabilitation. Clinical guidelines are needed for assessment and management of chemotherapy-related cognitive dysfunction.
Chemotherapy-associated cognitive dysfunction, often referred to as “chemobrain,” includes subjectively reported and objectively measured problems with cognition following chemotherapy. The American Cancer Society estimates there will be close to 14.5 million cancer survivors in the United States by 2015. Increasingly, individuals with cancer are experiencing long-term survival following initial treatment, leading to an ever greater need to understand, manage, and prevent lasting adverse effects of cancer treatment. Reflecting this need, the American Society of Clinical Oncology has recently issued a set of new Survivorship Guidelines addressing fatigue, mood disorders, and peripheral neuropathy. Currently there are no clear guidelines for the clinical assessment and management of chemobrain.
The recognition that a variety of factors other than chemotherapy may contribute to cognitive decline in cancer patients has led to use of the broader term, “cancer treatment–related cognitive impairment.” This review, however, will focus largely on the effects of systemic cytotoxic treatment on cognitive function, reflecting what has been most extensively studied in the literature. It should also be noted that much of the research on this topic has been conducted in breast cancer patients, as they represent the largest group of long-term cancer survivors who have had frequent exposure to chemotherapy. This review does not address cognitive effects of central nervous system (CNS) malignancies or CNS-directed treatments.
In a sampling of participants in the National Health and Nutrition Examination Survey, individuals with and without a history of cancer were surveyed about whether they felt they were limited by difficulty with memory or periods of confusion. Approximately 14% of cancer survivors reported memory problems, compared with 8% of participants without a prior cancer diagnosis, representing an approximately 40% increase in the likelihood of cancer survivors reporting cognitive concerns. Similarly, studies assessing cognitive function with objective cognitive tests have suggested a higher likelihood of impairment among individuals who have received chemotherapy. In one study of breast cancer survivors who had, on average, completed treatment with adjuvant cyclophosphamide, methotrexane, and fluorouracil (CMF) chemotherapy more than 20 years prior to enrollment, cognitive deficits were observed compared with a control group who underwent the same neuropsychological tests as part of a population-based assessment.
Factors Other Than Chemotherapy That Have an Impact on Cognitive Function
Studies that only address cognitive performance in a cross-sectional manner after patients have completed chemotherapy do not account for other effects of the cancer diagnosis and treatment or possible baseline differences between patients who get cancer and those who do not. To get around these limitations, investigators have begun to conduct studies that perform baseline cognitive assessments and include, in addition to healthy control groups, control groups of patients with cancer types similar to those under investigation but treated without systemic therapy. In some studies, formal testing of cancer patients after initial diagnosis and surgery but prior to any systemic therapy has demonstrated higher-than-expected baseline rates of cognitive dysfunction. Among breast cancer patients who had completed surgery but had not yet initiated planned chemotherapy, cognitive dysfunction rates upwards of 20% have been reported in several studies.[4-6] In a study of colon cancer patients evaluated prior to adjuvant chemotherapy, 37% demonstrated cognitive impairment prior to systemic treatment, and among testicular cancer patients evaluated after surgery but prior to chemotherapy, the incidence of cognitive impairment was 46%. Among studies looking at specific cognitive domains affected in newly diagnosed cancer patients, abnormalities have been seen in psychomotor function, verbal learning and ability, executive function, language, visual-spatial skill, and memory.[4-6,8,9]
There is evidence that surgery and anesthesia contribute to cognitive impairment, particularly in older patients, those with cardiovascular disease, and patients who undergo more extensive surgical procedures or have post-surgery complications. In general, postoperative cognitive dysfunction, believed to be due in part to inflammatory and immune responses to surgery, appears to resolve within days to months.
It is unclear to what extent baseline cognitive impairment is related to anxiety and depression. Certainly learning of a cancer diagnosis can affect mood, which may in turn affect sleep and other physiologic functions. In a small study of breast cancer patients who were to receive either chemotherapy or radiation treatment, pretreatment worry was associated with alterations in brain function measured by functional magnetic resonance imaging (MRI), and with subjective and objective measures of cognitive function in both treatment groups, with the prechemotherapy group reporting significantly more worry. However, in several studies of women undergoing adjuvant or neoadjuvant chemotherapy for breast cancer, the authors reported that anxiety, distress, or poor quality of life correlated with self-perceived cognitive concerns but not with neuropsychological test results.[6,9,12] In another study of breast cancer patients, cognitive impairment observed prior to systemic treatment was associated with certain comorbidities but not with anxiety, depression, or type of surgery.
In addition to any modest effects on baseline test performance, mood may influence cognitive function assessment during or after chemotherapy treatment. However, these effects seem to be predominantly in subjective rather than objective performance. In a multicenter study of 101 breast cancer patients undergoing chemotherapy, negative affectivity and depression correlated with self-reported cognitive dysfunction. In another study of 53 breast cancer survivors at least 2 years out from diagnosis, subjective cognitive complaints were associated with measures of fatigue and psychological distress but not with objective performance on cognitive testing. Similarly, as discussed above, in a study of 40 women receiving adjuvant or neoadjuvant chemotherapy for breast cancer, the authors found anxiety, depression, and poor quality of life correlated with self-perceived cognitive concerns but not with neuropsychological test results.
Endocrine factors may influence objective neuropsychological testing performance after chemotherapy; however, results have been mixed. In a longitudinal study of breast cancer patients undergoing chemotherapy for early-stage breast cancer, treatment-induced menopause was associated with some decline in cognitive performance following chemotherapy. In another longitudinal study of cognitive effects of chemotherapy for breast cancer, use of adjuvant endocrine therapy was associated with worse performance on measures of processing speed and verbal memory. In a prospective study of women receiving adjuvant chemotherapy for breast cancer, fatigue and menopausal symptoms correlated with quality-of-life scores but not with cognitive impairment as determined by a High-Sensitivity Cognitive Screen.
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