Chemobrain: Is It Time to Initiate Guidelines for Assessment and Management?

Cognitive dysfunction during and following treatment for cancer, often referred to as “chemobrain,” is an adverse effect of cancer treatment that may interfere with patients’ ability to resume their precancer lifestyle, with subsequently reduced quality of life. The comprehensive review provided here by Moore on chemobrain[1] is focused primarily on the effects of systemic chemotherapy on cognitive function in patients with non–CNS-involved malignancies or treatments, highlighting areas of evolving consensus as well as some existing gaps, such as the absence of clear guidelines for the clinical assessment and management of chemobrain.

Early studies investigating the cognitive impact of chemotherapy used mostly a cross-sectional methodology and small sample sizes, and survivors were assessed after treatment completion. Because these studies observed significant deficits in cognitive performance and decreased functioning in chemotherapy-treated survivors, cognitive side effects associated with chemotherapy were thought to be long-lasting for a sizable subgroup. More recent studies have shifted to a longitudinal design and employ a prechemotherapy baseline, as well as comparisons to geographically local healthy controls and cancer controls treated without chemotherapy. Findings from these newer studies suggest that cognitive dysfunction may exist in some patients even prior to adjuvant therapies,[2-6] and that a number of factors other than chemotherapy, such as endocrine therapies,[7,8] may also contribute to cognitive dysfunction in patients with cancer.

Data from the more recent studies generally also support an adverse impact of chemotherapy treatment on cognitive functioning; however, the majority show that the effects are most pronounced in the short term, with improvement over time to be expected for most patients.[9-11] Subgroups of patients, however, may be at risk for chronically lowered cognitive functioning, and current research is aimed at identifying these subgroups. For example, older age at treatment may be a risk factor for lasting diminishment of cognitive functioning, given that patients in this population are already at risk for cognitive and functional decline. Dose and type of chemotherapy may mediate the risk; one study of long-term breast cancer survivors who had received adjuvant CMF (cyclophosphamide, methotrexate, and fluorouracil) chemotherapy an average of more than 20 years earlier reported impairment in numerous cognitive domains compared with healthy controls.[12] Correlative studies demonstrating CNS changes associated with chemotherapy treatment provide further evidence of chemotherapy effects on the CNS. For example, structural MRI studies have demonstrated a reduction in gray matter density in breast cancer patients exposed to chemotherapy; this reduction appears to improve over time after recovery from chemotherapy.[13-14]

Depression, anxiety, premorbid cognitive reserve, comorbid health conditions, and fatigue are some non–treatment-related factors that have been shown to play a role in the cognitive dysfunction identified in cancer patients.[9,15-17] The contributions of these factors vary according to whether cognitive dysfunction is assessed via patient self-report or objective tests, with psychosocial factors influencing self-perception more than objective performance. While a few studies support concordance between the two approaches, it is increasingly apparent that self-perceived cognitive dysfunction and objective cognitive dysfunction likely reflect different aspects of cognitive functioning. Traditionally, the subjective measures were felt to be less useful for research purposes[18]; however, from a clinical perspective, self-perceived cognitive dysfunction warrants monitoring and appropriate intervention similar to other self-reported symptoms in cancer patients, such as fatigue, mood, and pain.

Acceptance of self-reported cognitive dysfunction as a valid measure in clinical practice is particularly recommended when it evokes distress or interferes with a patient’s adaptive functioning. Referral for clinical neuropsychological services typically will shed light on any stressors and lifestyle factors that might contribute to the patient’s experience of changed cognitive functioning, and also inform the patient if his or her performances on standardized cognitive tests are below age-expected levels. Such information can be reassuring and/or validating of the patient’s subjective experience. Possibly due to cognitive compensation, high-functioning patients may continue to obtain performance scores on objective tests that place them in the normal range despite a change from their premorbid levels. The cognitive changes these patients experience may manifest only as subtle indicators on clinical neuropsychological assessments, yet may be experienced as detrimental by individuals who are used to performing at higher levels. The clinical assessment typically will guide the use of compensatory learning strategies to help minimize any functional impact in occupational or daily life. Clinical services also serve to facilitate coping with psychosocial factors that might function as triggers or be consequences of cognitive dysfunction.

While pharmacologic treatments to improve cognitive dysfunction generally do not appear beneficial to cancer patients, emerging intervention studies suggest that patients may benefit from cognitive rehabilitation.[19-20] Considering the available research that has identified and characterized cognitive dysfunction in cancer patients, and which now evaluates interventions to address these impairments, there appear to exist sufficient data to begin the process of formulating clinical guidelines for the assessment and management of chemotherapy-related cognitive dysfunction. An existing obstacle that will need to be addressed regarding this effort includes formulation of specific diagnostic criteria for chemotherapy-related cognitive impairment. This is a task that can be reasonably accomplished; however, consensus on the nature and extent of dysfunction that warrants clinical attention, as well as on acceptable methods of screening for and assessing dysfunction, are some of the issues that require attention.

Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Acknowledgments:Dr. Patel’s work is supported in part by American Cancer Society Research Scholar grant #12-049-01-CPPB, and Dr. Hurria’s and Dr. Mandelblatt’s work is supported in part by National Cancer Institute grant #R01CA129769.

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