Metamemory function in chemotherapy-treated patients with breast cancer: an explanation for the dissociation between subjective and objective memory measures?

BACKGROUND: The purpose of this study was to determine if a deficit in metamemory could account for the disparity between subjective and objective measures of memory function commonly observed in patients with breast cancer (BC). Metamemory refers to the awareness and management of one's own memory function. It is considered an aspect of executive functioning, one of the most common areas of cognitive compromise associated with BC and its treatment. METHODS: Fifty-four women with early stage BC who had recently completed chemotherapy were compared with 54 healthy women matched on age and education. Cognitive function was objectively assessed with a neuropsychological test battery and subjectively assessed with the Functional Assessment of Cancer Therapy Cognitive Scale. Metamemory was assessed with a Feeling of Knowing (FOK) paradigm. RESULTS: The patients with BC scored significantly lower than the controls on both the objective and subjective cognitive measures, as well as on free recall and recognition conditions of the FOK, suggesting some decline in primary memory functions such as working memory, encoding, and retrieval. The discrepancy between the objective and subjective measures was larger in the patients with BC than in the controls, but there was no difference between the groups on the FOK metamemory index. CONCLUSIONS: Discrepancy in objective and subjective measures of cognition in patients with BC cannot be accounted for in terms of a deficit in meta-cognition. Objective and subjective measures are complementary, and a comprehensive cognitive assessment in patients with BC requires both. Copyright © 2015 John Wiley & Sons, Ltd.

Persistent cognitive changes in breast cancer patients 1 year following completion of chemotherapy.

Numerous studies have shown that there are acute cognitive side-effects of chemotherapy for breast cancer. Presumably, patients are more concerned about chronic treatment effects. This report from a prospective longitudinal study compares cognitive functioning in 56 breast cancer patients 1 year after chemotherapy to that of 56 healthy individuals. Neuropsychological test scores were combined into verbal memory, visual memory, working memory, and processing speed scores, as well as an overall summary score, and analyzed using multi-level growth modeling. Frequency of cognitive decline was assessed using regression-based change scores. There was significant rebound in the overall summary score from end of treatment to 1-year follow-up as well as a substantial reduction in the frequency of cognitive decline. However, more than one-third of the breast cancer patients who showed cognitive decline immediately following completion of chemotherapy showed persistent cognitive decline 1 year later. Furthermore, recovery was not seen in all cognitive domains. In fact, the rebound was significant only for working memory. Longer multi-site studies are recommended to explore the risk factors for and the permanence of these longer-term cognitive effects.

Cognitive effects of chemotherapy in breast cancer patients: a dose-response study.

OBJECTIVE: The purpose of this study was to determine if cognition progressively worsens with cumulative chemotherapy exposure. We reasoned that the demonstration of such a 'dose-response' relationship would help to establish whether cognitive changes are caused by neurotoxic effects of chemotherapy or whether they are due to other confounding factors such as mood and pre-treatment differences in cognition. METHODS: Sixty women with early stage breast cancer, aged 65 years or younger with no previous history of cancer or chemotherapy, were matched to 60 healthy women on age and education. Neuropsychological assessment was conducted after surgery but prior to commencing chemotherapy and then again following each chemotherapy cycle in patients and at yoked intervals in healthy controls. We used multilevel modeling to assess change over time in an overall cognitive summary score as well as domain-specific cognitive scores. RESULTS: After controlling for baseline performance, age, education, and mood, the chemotherapy group showed a significant progressive decline over time relative to a matched healthy control group in an overall cognitive summary score, as well as in working memory, processing speed, verbal memory, and visual memory scores. A linear model best fit the trajectory of cognitive change over the course of treatment in the chemotherapy group supporting a dose-response hypothesis. CONCLUSIONS: These results are in keeping with a dose-response relationship and provide the most compelling clinical evidence to date that cognitive decline is caused by chemotherapy exposure.

Clearing the air: a review of our current understanding of "chemo fog".

An increasing number of cancer survivors has led to a greater interest in the long-term side effects of cancer treatments and their impact on quality of life. In particular, cognitive impairments have been frequently reported by cancer survivors as an adverse effect which they attribute to the neurotoxicity of chemotherapy and have dubbed "chemobrain" or "chemo fog." Research within the past 15-20 years has explored the many factors thought to contribute to cancer-related cognitive decline in an attempt to determine a potential cause. In spite of many confounding factors, there is growing evidence that the neurotoxicity of chemotherapy does contribute to cognitive changes. This review examines the evolution of "chemo fog" research with a look at methodological issues, the status of our current understanding, and suggestions for future research.

Cognitive effects of chemotherapy in post-menopausal breast cancer patients 1 year after treatment.

OBJECTIVE: Studies in breast cancer patients indicate that chemotherapy may cause subtle cognitive disturbances in some women, but the course is unclear. The current study evaluated the cognitive effects of adjuvant chemotherapy in post-menopausal breast cancer patients 1 year following completion of treatment. PATIENTS AND METHODS: Breast cancer patients scheduled to receive adjuvant chemotherapy (n=53) completed comprehensive neuropsychological testing before commencing chemotherapy (T1), 1 month after completing chemotherapy (T2), and again 1 year later (T3). A control group of women receiving adjuvant hormonal therapy (n=40) was tested at comparable intervals. A standardized regression-based approach was used to identify cognitive decline, and incidence of decline was compared across treatment groups. RESULTS: Whereas at T2, chemotherapy patients were more likely to show cognitive decline than hormonal patients, by T3, the frequency of reliable cognitive decline was the same in both groups (11 and 10%, respectively). However, those chemotherapy patients receiving hormonal therapy at T3 were inferior to the chemotherapy patients not receiving hormonal treatment on composite measures of processing speed and verbal memory. CONCLUSION: These data suggest that there is a subtle negative impact of chemotherapy on cognitive function in breast cancer patients shortly following completion of treatment, but that this resolves within 1 year. However, given that our control group comprises breast cancer patients receiving hormonal therapy, and indications that hormonal therapy may also adversely affect cognition, such conclusions must be considered tentative.

Cognitive effects of hormonal therapy in early stage breast cancer patients: a prospective study.

OBJECTIVE: The primary purpose of this study was to evaluate the cognitive effects of adjuvant hormonal therapies in breast cancer patients. PARTICIPANTS AND METHODS: Post-menopausal breast cancer patients scheduled to receive tamoxifen (n=31) or anastrozole (n=14) completed neuropsychological testing around the time of commencement of treatment (T1), and again 5-6 months later (T2). A sample of healthy female volunteers (n=28) was tested at comparable intervals. A standardized regression-based approach was used to assess cognitive change. This method uses test/retest scores of the healthy control group to generate an equation that predicts T2 scores from T1 scores. The difference between the predicted and obtained T2 scores divided by the standard error of the estimate produces a deviation score that reflects the discrepancy from the T1-T2 difference scores that would be expected on the basis of practice and error alone. RESULTS: Analysis of individual deviation scores revealed that both the patients taking tamoxifen and those taking anastrozole were more likely than healthy controls to show reliable cognitive decline from T1 to T2 (39, 64, and 7%, respectively). Processing speed and verbal memory were the cognitive domains most affected. CONCLUSION: These data suggest that hormonal therapies exert a subtle negative influence on cognition in breast cancer patients. Further analyses indicated that this effect was not fully accounted for by demographic factors or fatigue. Methodological limitations of the current study are addressed, along with recommendations for future studies in this area.

A prospective study of grey matter and cognitive function alterations in chemotherapy-treated breast cancer patients.

PURPOSE: Subsequent to chemotherapy treatment, breast cancer patients often report a decline in cognitive functioning that can adversely impact many aspects of their lives. Evidence has mounted in recent years indicating that a portion of breast cancer survivors who have undergone chemotherapy display reduced performance on objective measures of cognitive functioning relative to comparison groups. Neurophysiological support for chemotherapy-related cognitive impairment has been accumulating due to an increase in neuroimaging studies in this field; however, longitudinal studies are limited and have not examined the relationship between structural grey matter alterations and neuropsychological performance. The aim of this study was to extend the cancer-cognition literature by investigating the association between grey matter attenuation and objectively measured cognitive functioning in chemotherapy-treated breast cancer patients. METHODS: Female breast cancer patients (n = 19) underwent magnetic resonance imaging after surgery but before commencing chemotherapy, one month following treatment, and one year after treatment completion. Individually matched controls (n = 19) underwent imaging at similar intervals. All participants underwent a comprehensive neuropsychological battery comprising four cognitive domains at these same time points. Longitudinal grey matter changes were investigated using voxel-based morphometry. RESULTS: One month following chemotherapy, patients had distributed grey matter volume reductions. One year after treatment, a partial recovery was observed with alterations persisting predominantly in frontal and temporal regions. This course was not observed in the healthy comparison group. Processing speed followed a similar trajectory within the patient group, with poorest scores obtained one month following treatment and some improvement evident one year post-treatment. CONCLUSION: This study provides further credence to patient claims of altered cognitive functioning subsequent to chemotherapy treatment.

Study of the cognitive effects of chemotherapy: considerations in selection of a control group.

Neuropsychological data collected in 28 breast cancer patients before and after chemotherapy were compared to those of a local healthy control group, a local disease control group, and published norms, respectively, in order to determine whether the nature of the control group influenced outcome. The frequency of decline in the chemotherapy group was 21% and significantly higher than that of the control group whether referenced to the healthy controls, disease controls, or published norms. These results suggest that published norms may be adequate to demonstrate cancer-related cognitive impairment provided that cognitive function is measured adequately, practice effects and base rates are taken into account, and demographic factors that might influence practice effects are considered.

Differences in verbal memory retrieval in breast cancer chemotherapy patients compared to healthy controls: a prospective fMRI study.

Cognitive complaints by breast cancer survivors receiving chemotherapy have led to an increasing interest in elucidating the possible causes of such impairment. Although a number of neuroimaging studies have been conducted, only a handful of them have taken into account cognitive status pre-chemotherapy. The current study included pre-chemotherapy and post-chemotherapy assessment. In addition, various factors such as depression, anxiety, fatigue and days since surgery were considered during analyses. Breast cancer patients performed an fMRI verbal recall task before and an average of 1 month after chemotherapy. Well matched controls also performed the task with a similar timeline. Pre-chemotherapy analyses revealed that patients activated the anterior cingulate less than controls during memory retrieval when anxiety and fatigue scores were added as covariates during group comparisons. In addition, there were also changes in brain activation from pre- to post-chemotherapy in patients but not in controls. Post-chemotherapy, patients had less activation in the bilateral insula, the left inferior orbitofrontal cortex and the left middle temporal gyrus. Finally, patients also showed significantly less activation when compared to controls. Brain regions included: the right middle and superior temporal gyrus, the right medial frontal gyrus, the right inferior orbitofrontal cortex, the left insula and left superior temporal pole. Importantly, depression, anxiety, and particularly fatigue accounted for some of brain activation differences. Our results suggest that chemotherapy in part plays a role in brain activation differences and it also highlights the importance of rigorously controlling for confounding variables. Only by controlling such factors can we understand the role that chemotherapy may play on cognition.

Prechemotherapy differences in response inhibition in breast cancer patients compared to controls: a functional magnetic resonance imaging study.

Prechemotherapy neuroimaging data are lacking in posttreatment cognitive impairment studies. Breast cancer patients and noncancer controls were scanned prior to chemotherapy during a response inhibition task. Task reaction times and error rates, as well as neuropsychological tests, hospital records, and salivary biomarkers, were investigated, yielding no significant group differences. Significant group differences observed for the functional magnetic resonance imaging (fMRI) data depended on the type of analysis performed, most consistently implicating widespread attenuated activations in patients. The patient group also revealed considerable variability in task-related brain activity. These pretreatment differences highlight the need to understand the effects of confounding variables before considering posttreatment effects. Role of the funding source: The Canadian Breast Cancer Foundation has funded this project. Their contribution was solely financial support.

Pre-chemotherapy differences in visuospatial working memory in breast cancer patients compared to controls: an FMRI study.

INTRODUCTION: Cognitive deficits are a side-effect of chemotherapy, however pre-treatment research is limited. This study examines neurofunctional differences during working memory between breast cancer (BC) patients and controls, prior to chemotherapy. METHODS: Early stage BC females (23), scanned after surgery but before chemotherapy, were individually matched to non-cancer controls. Participants underwent functional magnetic resonance imaging (fMRI) while performing a Visuospatial N-back task and data was analyzed by multiple group comparisons. fMRI task performance, neuropsychological tests, hospital records, and salivary biomarkers were also collected. RESULTS: There were no significant group differences on neuropsychological tests, estrogen, or cortisol. Patients made significantly fewer commission errors but had less overall correct responses and were slower than controls during the task. Significant group differences were observed for the fMRI data, yet results depended on the type of analysis. BC patients presented with increased activations during working memory compared to controls in areas such as the inferior frontal gyrus, insula, thalamus, and midbrain. Individual group regressions revealed a reverse relationship between brain activity and commission errors. CONCLUSION: This is the first fMRI investigation to reveal neurophysiological differences during visuospatial working memory between BC patients pre-chemotherapy and controls. These results also increase the knowledge about the effects of BC and related factors on the working memory network. SIGNIFICANCE: This highlights the need to better understand the pre-chemotherapy BC patient and the effects of associated confounding variables.

The cognitive effects of adjuvant chemotherapy in early stage breast cancer: a prospective study.

PURPOSE: The primary purpose of this study was to evaluate the cognitive effects of adjuvant chemotherapy in post-menopausal breast cancer patients. PATIENTS AND METHODS: Breast cancer patients scheduled to receive adjuvant chemotherapy (n = 61) completed comprehensive cognitive testing before and after treatment. A control group of women receiving adjuvant hormonal therapy (n = 51) was tested at comparable intervals. RESULTS: Mean scores for both patient groups were within the normal range relative to published norms on all cognitive tests at both time points, and generally inclined or stayed the same from baseline to retest in both groups. However, in an analysis of individual change scores, the chemotherapy patients were 3.3 times more likely than the hormonal patients to show reliable cognitive decline (31 and 12%, respectively). Chemotherapy subjects showing decline were less educated and had higher baseline depression scores than their counterparts who did not decline. Working memory was the cognitive domain most vulnerable to the effects of chemotherapy. CONCLUSION: These data support previous findings of a subtle negative influence of chemotherapy on cognitive function in a subgroup of breast cancer patients. The results are discussed in terms of the importance of study design.