Chemotherapy and Post-traumatic Stress in the Causation of Cognitive Dysfunction in Breast Cancer Patients.

Background: Cancer-related cognitive dysfunction has mostly been attributed to chemotherapy; this explanation, however, fails to account for cognitive dysfunction observed in chemotherapy-naïve patients. In a controlled, longitudinal, multisite study, we tested the hypothesis that cognitive function in breast cancer patients is affected by cancer-related post-traumatic stress. Methods: Newly diagnosed breast cancer patients and healthy control subjects, age 65 or younger, underwent three assessments within one year, including paper-and-pencil and computerized neuropsychological tests, clinical diagnostics of post-traumatic stress disorder (PTSD), and self-reported cognitive function. Analysis of variance was used to compare three groups of participants-patients who did or did not receive chemotherapy and healthy control subjects-on age- and education-corrected cognitive performance and cognitive change. Differences that were statistically significant after correction for false discovery rate were investigated with linear mixed-effects models and mediation models. All statistical tests were two-sided. Results: Of 226 participants (166 patients and 60 control subjects), 206 completed all assessment sessions (attrition: 8.8%). Patients demonstrated overall cognitive decline (group*time effect on composite z -score: -0.13, P = .04) and scored consistently worse on Go/Nogo errors. The latter effect was mediated by PTSD symptoms (mediation effect: B = 0.15, 95% confidence interval = 0.02 to 0.38). Only chemotherapy patients showed declined reaction time on a computerized alertness test. Overall cognitive performance correlated with self-reported cognitive problems at one year ( T = -0.11, P = .02). Conclusions: Largely irrespective of chemotherapy, breast cancer patients may encounter very subtle cognitive dysfunction, part of which is mediated by cancer-related post-traumatic stress. Further factors other than treatment side effects remain to be investigated.

Elucidating pretreatment cognitive impairment in breast cancer patients: the impact of cancer-related post-traumatic stress.

BACKGROUND: Pretreatment cognitive impairment in cancer patients is well established but unexplained. Similar cognitive compromise has been observed in post-traumatic stress disorder (PTSD) patients, and PTSD symptoms are a frequent concomitant of cancer diagnosis. We tested the hypothesis that pretreatment cognitive impairment is attributable to cancer-related post-traumatic stress. METHODS: Women aged 65 years or younger who were diagnosed with breast cancer (case patients) or had undergone negative routine breast imaging (control patients) at one of six participating breast centers underwent traditional and computerized neuropsychological testing, clinician-administered diagnostic assessment of stress disorders, and self-report assessments of cognitive function and depression. To minimize confounding, case patients were evaluated prior to any local or systemic treatment. Cognitive indices of case patients, control patients, and normative samples were compared. The patients' risk of overall cognitive impairment was determined. Linear regression and a mediation model were used to test the study hypothesis. All statistical tests were two-sided. RESULTS: The 166 case patients and 60 well-matched control patients showed near-identical deviations from population norms. Case patients scored worse than control patients on two of 20 cognitive indices (Go/Nogo commission errors, Go/Nogo omission errors). Self-reported cognitive problems were associated with Go/Nogo omission errors and more pronounced in case patients. Only PTSD symptoms (Beta = 0.27, P = .004) and age (Beta = 0.22, P = .04) statistically significantly predicted Go/Nogo errors. The effect of having cancer on Go/Nogo errors was mediated by PTSD symptoms. Case patients did not have an increased risk of overall cognitive impairment. CONCLUSION: Prior to any treatment, breast cancer patients may show limited cognitive impairment that is apparently largely caused by cancer-related post-traumatic stress.

Two different sides of 'chemobrain': determinants and nondeterminants of self-perceived cognitive dysfunction in a prospective, randomized, multicenter study.

OBJECTIVE: Complaints of cognitive dysfunction are frequent among cancer patients. Many studies have identified neuropsychological compromise associated with cancer and cancer therapy; however, the neuropsychological compromise was not related to self-reported cognitive dysfunction. In this prospective study, the authors examined if confounding factors masked an underlying association of self-perceived cognitive function with actual cognitive performance. Determinants of self-perceived cognitive dysfunction were investigated. METHODS: Self-perceived cognitive function and cognitive performance were assessed before treatment, at the end of treatment, and 1 year after baseline in 101 breast cancer patients randomized to standard versus intensified chemotherapy. Linear mixed-effects models were applied to test the relationships of performance on neuropsychological tests, patient characteristics, and treatment variables to self-reported cognitive function. Change of cognitive performance was tested as a predictor of change in self-reports. RESULTS: Self-perceived cognitive function deteriorated during chemotherapy and had partially recovered 1 year after diagnosis. The personality trait negative affectivity, current depression, and chemotherapy regimen were consistently related to cognitive self-reports. No significant associations with performance in any of the 12 cognitive tests emerged. Change of cognitive performance was not reflected in self-reports of cognitive function. CONCLUSIONS: Neuropsychological compromise and self-perceived cognitive dysfunction are independent phenomena in cancer patients. Generally, cancer-associated neuropsychological compromise is not noticed by affected patients, but negative affectivity and treatment burden induce pessimistic self-appraisals of cognitive functioning regardless of the presence of neuropsychological compromise. Clinicians should consider this when determining adequate therapy for patients who complain of 'chemobrain'.

Short-term effects of treatment-induced hormonal changes on cognitive function in breast cancer patients: results of a multicenter, prospective, longitudinal study.

BACKGROUND: It is suspected that estrogen depletion resulting from treatment may contribute to cognitive compromise in patients with breast cancer. However, the evidence for estrogen effects on cognition is inconclusive, and the consequences of hormonal changes for cognitive function in patients with cancer rarely have been investigated. In this study, the authors investigated the effects of treatment-induced menopause and antiestrogen therapy with tamoxifen and aromatase inhibitors (AIs) on cognitive function. METHODS: Cognitive performance was assessed in 101 patients with breast cancer before the start of cancer therapy (T1), toward the end of neoadjuvant chemotherapy (T2), and 1 year after baseline (T3) using 12 cognitive tests. Menopause occurred in a subgroup of patients, and an overlapping subgroup started antiestrogen therapy with tamoxifen or AIs. Linear mixed-effects models that made it possible to determine effects at group levels and individual levels simultaneously were used for statistical analysis. RESULTS: At the group level, a significant favorable effect of induced menopause emerged in a test of executive function (P= .0035). Two additional group-level effects of induced menopause, both favorable, and 2 individual-level effects that were positive in some patients and negative in others were not significant when multiple testing was taken into account. No significant effects of tamoxifen or AIs on cognitive function were observed. CONCLUSIONS: Hormonal changes did not appear to contribute to cognitive compromise in patients with breast cancer during the first year after diagnosis. Antiestrogen treatment with tamoxifen or AIs did not affect cognition, and the effects of induced menopause were more likely to be favorable. However, the possibility that some cognitive decline occurs in individual patients could not be excluded.

Cognitive function during neoadjuvant chemotherapy for breast cancer: results of a prospective, multicenter, longitudinal study.

BACKGROUND: It is believed widely that chemotherapy-induced cognitive impairment occurs in a subgroup of patients with breast cancer. However, recent reports have provided no evidence that chemotherapy affects cognition. In this study, the authors questioned whether cognitive compromise in patients with breast cancer is attributable to chemotherapy. In addition, the effects of therapy-induced menopause and of the erythropoiesis-stimulating factor darbepoetin alpha on cognitive performance were assessed. METHODS: A battery of neuropsychological tests was used to assess cognitive performance in 101 patients with breast cancer before neoadjuvant chemotherapy (T1) and toward the end of neoadjuvant chemotherapy (T2) with combined epirubicin, paclitaxel, and cyclophosphamide with concomitant darbepoetin alpha. Repeated-measures multiple analyses of variance and a reliable-change approach were used for statistical analyses. RESULTS: At T1, the group means ranged below the test norms in 5 of 12 cognitive tests. At T2, multiple analyses of variance (MANOVA) indicated a significant overall improvement in the test results (P<.001). After correcting for practice effects, cognitive decline predominated in 27% of patients, whereas improvement predominated in 28% of patients. Cognitive performance was not related significantly to self-reported cognitive problems, anxiety and depression, menopause, or darbepoetin alpha administration. CONCLUSIONS: Even before chemotherapy, a subgroup of patients with breast cancer showed cognitive compromise that was unrelated to anxiety or depression. During chemotherapy, cognitive function remained stable in most patients, improved in a subgroup, and deteriorated in another subgroup. The deterioration may have been caused by side effects of chemotherapy, but it also may have been related to currently unidentified factors that cause prechemotherapy cognitive compromise. Therapy-induced menopause and darbepoetin alpha did not appear to influence cognition.