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Cognitive Function in Breast Cancer Patients Receiving Adjuvant Chemotherapy

By Christine B. Brezden, Kelly-Anne Phillips, Mohamed Abdolell, Terry Bunston, Ian F. Tannock

From the Department of Medical Oncology and Hematology, Department of Biostatistics, Department of Psychosocial Oncology, Princess Margaret Hospital; and University of Toronto, Toronto, Ontario, Canada.
Deceased.

Address reprint requests to Ian F. Tannock, MD, PhD, Department of Medical Oncology, Princess Margaret Hospital, 610 University Ave, Toronto, ON M5G 2M9; email ian.tannock{at}uhn.on.ca

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Breast cancer patients receiving chemotherapy have complained of difficulties in their ability to remember, think, and concentrate. This study assessed whether there are differences in cognitive function between breast cancer patients treated with standard-dose adjuvant chemotherapy compared with healthy controls.

PATIENTS AND METHODS: The High Sensitivity Cognitive Screen and the Profile of Mood States (POMS) were used to assess cognitive function and mood in a group of 107 women. The women consisted of 31 breast cancer patients receiving adjuvant chemotherapy (group A), 40 breast cancer patients who had completed adjuvant chemotherapy a median of 2 years earlier (group B), and 36 healthy controls (group C).

RESULTS: Univariate analysis showed statistically significant differences (P = .009) in overall cognitive function scores between groups A and C, with poorer function in patients receiving adjuvant chemotherapy. These differences remained significant (P = .046) when controlling for age, education level, and menopausal status. More patients had moderate or severe cognitive impairment in groups A and B than in controls (P .002). There were no significant differences in POMS scores between the groups, suggesting that the differences seen in cognitive scores were unlikely to be because of mood disturbance.

CONCLUSION: Cognitive differences were observed in breast cancer patients receiving adjuvant chemotherapy compared with healthy controls. These differences did not seem to be caused by significant differences in mood disturbance between the two groups. If confirmed, these results have substantial implications for informed consent, counseling, and psychosocial support of patients receiving adjuvant chemotherapy for breast cancer.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
BREAST CANCER affects approximately 200,000 women in North America each year,^1,2 most of whom are diagnosed with potentially curable early-stage disease. Adjuvant combination chemotherapy has been used since the 1970s for subgroups of women with early-stage breast cancer³ and has been shown to reduce mortality from this disease.⁴ Criteria for the use of adjuvant chemotherapy have broadened substantially so that the majority of women with early-stage breast cancer now receive chemotherapy as part of their treatment.⁵ Many of the side effects of adjuvant chemotherapy (both short- and long-term) are well documented in the literature.^6-8 However, more subtle side effects, such as possible changes in memory or cognitive ability, have received little attention, even though many women complain of subjective changes in memory and the ability to think clearly during and after chemotherapy. Even mild cognitive impairment may be expected to influence a patient’s quality of life and ability to function, but subtle changes are difficult to identify because of lack of appropriate measures.

There are several reports of the effects of cancer and its treatment on cognition in cancer patients.^9-21 Some of these reports suggest that cognitive impairment may occur after treatment with some of the commonly used chemotherapeutic agents. Most of these studies examined the effect of therapy on the cognitive function of patients with advanced malignancies, so that confounding disease-related factors might have been responsible for some of the findings. However, three studies have addressed cognitive function in women who have completed adjuvant chemotherapy for breast cancer.^19,22,23

Wieneke and Dienst¹⁹ examined cognitive function in patients with early-stage breast cancer who had completed between 3 and 18 months of cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy (cyclophosphamide 100 mg/m² orally days 1 to 14, methotrexate 40 mg/m² intravenously [IV] days 1 and 8, and fluorouracil 600 mg/m² days 1 and 8; cycles repeated every 4 weeks). They found a decrease in cognitive function when compared with published test norms of healthy individuals. Decreased cognitive function was positively correlated with duration of chemotherapy treatment but was unrelated to other treatment variables or depression. A major criticism of this study has been the use of published test norms of healthy individuals as controls.

A pivotal article by van Dam et al²² reported a randomized trial that compared cognitive functioning and quality of life after different chemotherapy regimens. They reported that breast cancer patients receiving high-dose adjuvant chemotherapy (four cycles of standard-dose fluorouracil [500 mg/m² IV], epidoxorubicin [90 to 120 mg/m² IV], and cyclophosphamide [500 mg/m² IV] repeated every 3 weeks followed by high-dose cyclophosphamide [6 g/m² IV], thiotepa [480 mg/m² IV], and carboplatin [1.6 g/m² IV] with autologous stem-cell support) showed significantly more cognitive impairment than those receiving either standard-dose adjuvant chemotherapy (fluorouracil, epidoxorubicin, and cyclophosphamide) or no chemotherapy. These neurotoxic effects were observed approximately 2 years after the last chemotherapy course, suggesting that long-term cognitive deficits result that may impair the quality of life of breast cancer survivors. The standard-dose chemotherapy group showed a nonsignificant trend to cognitive impairment compared with controls.

Recently, the same group has demonstrated significantly more late cognitive impairment in breast cancer patients receiving adjuvant CMF chemotherapy than in those not treated with chemotherapy.²³ The treated group in this study had axillary node-positive breast cancer, whereas the untreated controls had node-negative disease. The cognitive impairment was not simply because of anxiety or depression.

There are many methodologic challenges in assessing the effects of adjuvant chemotherapy on cognitive function in patients with breast cancer. Confounding causes, such as subclinical CNS metastases, paraneoplastic syndromes, or metabolic abnormalities, are likely to be rare in this population. However, other problems include identifying subtle cognitive impairment and differentiating the cognitive effects of mood alterations secondary to stress from those caused by the diagnosis and treatment of cancer. In addition, identification of appropriate control populations can be challenging.

The aim of the present study was to investigate whether cognitive impairment is present in women receiving standard-dose adjuvant chemotherapy for breast cancer. Objective cognitive function and mood state were assessed in women currently undergoing adjuvant chemotherapy, in a group of women who had previously received adjuvant chemotherapy, and in a control group of women without breast cancer. The primary hypothesis was that there would be a difference in overall cognitive score between women currently receiving adjuvant chemotherapy and the control group of women.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Study Population
Study participants were recruited from the Princess Margaret Hospital and the Toronto General Hospital, Toronto, Canada, over a 3-month period between June and August 1998. There were three groups in the study. Group A consisted of breast cancer patients currently undergoing standard-dose adjuvant chemotherapy (either cyclophosphamide [75 mg/m² orally days 1 to 14], epirubicin [60 mg/m² IV days 1 and 8], and fluorouracil [500 mg/m² IV days 1 and 8], cycles repeated every 4 weeks [CEF] or CMF) who had received this chemotherapy for a minimum of 8 weeks (two complete cycles). Group B consisted of patients who had completed a full course of adjuvant chemotherapy at least 1 year ago and had no clinical evidence of locally recurrent or metastatic breast cancer. Group C consisted of healthy female controls.

Individuals in groups A and B had a diagnosis of early-stage breast cancer (stage I or II), but no previous history of cancer or other major illnesses. Individuals in group C had no history of any major illnesses. Other eligibility criteria for all groups were female sex, age between 25 and 70 years, at least an eighth-grade education, fluency in English, and informed consent. Individuals with gross cognitive dysfunction (such as delirium, moderate to severe dementia, or aphasia), those with a previously diagnosed psychiatric illness, those using psychoactive medication, and those with a history of drug or alcohol addiction were excluded from the study. Individuals in groups A and B were identified and offered participation in the study at their prechemotherapy (group A) or follow-up (group B) hospital appointment. Group C consisted of individuals who were either relatives of individuals in groups A and B (recruited at the same time) or various hospital personnel who volunteered for the study in response to advertisements within the hospitals. The study was approved by the ethics committees of the Princess Margaret Hospital and the University of Toronto.

Measures
The High Sensitivity Cognitive Screen (HSCS) was used to assess all subjects in the study.²⁴ The HSCS is a test that is sensitive for detecting subtle cognitive impairment that has been validated for subjects in the age range of 16 to 65 years (only two of our subjects were outside this range, aged 66 and 70 years). It predicts the overall qualitative results of formal neuropsychologic testing with a high degree of accuracy, predicting a normal versus abnormal result of comprehensive neuropsychologic assessment with 93% accuracy, and predicting global versus restricted deficits with 87% accuracy. It has high inter-rater and test-retest reliability. The HSCS tests six cognitive domains: memory, language, visual-motor, spatial, attention and concentration, and self-regulation and planning. Most of the items are adapted from standard neuropsychologic tests. Test items are either presented orally or with printed forms; responses consist of oral answers, a writing sample, drawings, and, for one item, arm movements to command. The test takes approximately 25 to 30 minutes, and once completed, the items are scored according to a detailed manual.

In the clinical setting, the pattern of scores is used to classify performance as normal, borderline, or abnormal and to identify the degree of abnormality (mild, moderate, or severe) and type of cognitive impairment. The authors of the HSCS recommend that when the test is used for research purposes that direct analysis of item scores is generally more appropriate than the use of the categorical interpretive rules used in the clinical setting. In the current study, a measure of the overall cognition of each subject (total HSCS score) was derived for each individual by summing the scores across all six cognitive domains, with higher scores representing worse cognition. For completeness, we have also classified patients and controls by their degree of impairment.

The Profile of Mood States (POMS)²⁵ is a self-administered test that identifies and assesses transient, fluctuating affective states in individuals and is also highly sensitive for determining mood disorders, such as anxiety and depression. The test assesses the following six components: tension-anxiety, anger-hostility, fatigue-inertia, depression-dejection, vigor-activity, and confusion-bewilderment. Each component is scored, and a total score is then calculated by summing each of the individual parameters; higher scores indicate greater disturbances in mood. The POMS takes approximately 3 to 5 minutes to complete.

Administration of Measures
The HSCS and POMS were administered in a private room in the outpatient clinic by the same investigator (C.B.B.) to all study participants. In each case, the HSCS was administered first and immediately followed by the POMS. For individuals in group A, testing was performed on the day of chemotherapy but before administration of antiemetics or chemotherapy.

Statistical Analysis
Descriptive statistics were used to summarize the demographic characteristics and the cognitive domain scores of the subjects. The distributions of the different variables were tested to determine whether there was any substantial deviation from normality or whether the assumptions of equal variance when comparing two groups were violated. There was sufficient evidence to warrant the use of nonparametric methods in the case of comparing two groups and a normalizing transformation of the response in the case of parametric modeling using analysis of covariance.

Comparisons of some demographic characteristics and of scores for cognitive domains between groups A versus C and B versus C were made using the Wilcoxon rank sum test; the total HSCS and total POMS scores were similarly analyzed. The ² test was used for categorical variables.

Parameters such as age, menopausal status, and level of education are known a priori to influence cognitive ability and were included in the analysis of covariance when modeling the logarithmic transformation of total HSCS score. The statistical analysis was performed using the SAS system (SAS/STAT User’s Guide, version 6; SAS Institute Cary, NC)²⁶ and the plots were generated using S-plus (Math Soft, Inc, Seattle, WA).^27,28

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Demographic Data
Table 1 lists the demographics of the women who participated in the study. A total of 107 women participated, of whom 31 (group A) were breast cancer patients currently receiving adjuvant chemotherapy (median number of cycles completed, three cycles; range two to eight cycles). Group B consisted of 40 patients with breast cancer and no evidence of recurrence who had completed adjuvant chemotherapy at least 1 year before the study (median time since chemotherapy, 25 months; 18 patients ranged from 12 to 24 months; 11 patients ranged from 25 to 36 months; and 11 patients’ times since chemotherapy was > 36 months). Group C consisted of 36 healthy female controls. All patients had high performance status. Sixteen patients in group B were currently taking tamoxifen, and two had had previous tamoxifen treatment. No woman in group A had current or previous exposure to tamoxifen. The age of individuals in group C was significantly younger (median, 41.5 years) than that of those in groups A (median, 49 years; P = .0067) or B (median, 46 years; P = .035). Significantly more patients in both treatment groups (A and B) were postmenopausal when compared with the control group (C) (A v C, P = .0075; B v C, P = .027). Two patients in group B and five in group C were on hormone replacement therapy. There were no other significant differences in demographic variables between the three groups.

View larger version (16K): [in this window] [in a new window]   Fig 1. Box and whisker plots of HSCS and POMS scores by group. Higher scores represent greater cognitive impairment or mood disturbance. The boxes on either side of the medians (horizontal lines) indicate lower and upper quartiles. The whiskers indicate the closer of the 1.5x interquartile range or the minimum/maximum data points. Outlying points are plotted individually.

Individual Cognitive Domains
An exploratory analysis was undertaken of scores for the six cognitive domains that are evaluated by the HSCS (memory, language, visual-motor, spatial, attention and concentration, and self-regulation and planning). Mean values for each domain were calculated for each group, and the values were compared for statistical differences (Table 3). Memory and language domains were observed to be different between groups A and C (P = .024 and P = .033, respectively), suggesting impairment in these domains for patients receiving chemotherapy. Language and visual-motor skills were also found to differ between groups B and C (P = .047 and P = .024, respectively), suggesting impairment in these domains in patients who had received chemotherapy. Because we did not address these domains in our primary hypothesis and did not correct for confounding factors or multiple significance tests, these data should be regarded as hypothesis-generating.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The present study assessed cognitive ability in breast cancer patients receiving adjuvant chemotherapy as compared with healthy controls or breast cancer patients who had completed therapy. We also investigated whether mood disturbances might contribute to differences in cognition. A significant difference was seen between the scores of the cognitive screen for breast cancer patients currently receiving adjuvant chemotherapy (median score, 37.0) versus healthy controls (median score, 26.0; P = .009). This difference remained significant (P = .046) when the possible confounding factors of age, education level, and menopausal status were included in an analysis of covariance. Patients who had completed adjuvant chemotherapy at least 1 year earlier had total cognitive scores that were intermediate between the other two groups, although differences in total scores were not significant. When the patients were classified by degree of cognitive impairment (Table 2), there was a significant difference between the distributions across different levels of impairment for both the current and previous chemotherapy groups as compared with the controls.

Our results are consistent with the hypothesis that standard-dose adjuvant chemotherapy for breast cancer impairs cognition and that residual effects are seen after completion of chemotherapy. Both the skewed distribution of HSCS scores in Fig 1 for the group of patients receiving chemotherapy and the distribution of levels of impairment in Table 2 indicate substantial impairment in cognitive function in some patients, with minimal effects in others. Our findings are consistent with those of the study by Schagen et al,²³ where a proportion of individuals who had received standard-dose adjuvant chemotherapy a median of 1.9 years earlier showed poorer cognitive functioning than untreated controls. The authors of that study suggested that the methotrexate component of CMF might be a cause of the neurotoxicity, but in our study (with small numbers), we did not see any trend to poorer cognitive function in patients who received CMF as compared with CEF chemotherapy.

When the individual domains of the cognitive screen were compared, significant differences between patients currently undergoing chemotherapy and controls were seen only in the memory and language domains. This is an interesting hypothesis-generating observation, which should be evaluated in future studies.

Mood disturbances in cancer patients, such as depression and anxiety, have been shown to affect cognition.¹⁴ Therefore, the POMS questionnaire was used to assess overall mood in the three groups. The distribution of POMS scores is somewhat broader for the two patient groups compared with controls (Fig 1), but there were no significant differences in the overall POMS scores between the three groups, suggesting that the observed differences in cognition are not explained by mood disturbances. Furthermore, analysis of the individual components of mood disturbance that comprise the overall POMS questionnaire (tension-anxiety, depression-dejection, anger-hostility, vigor-activity, fatigue-inertia, and confusion-bewilderment) revealed no differences between the three study groups (data not shown).

We recognize limitations in the design of the current study. It is relatively small (n = 107), and the use of healthy women without cancer as a control group is not ideal. An attempt was made to minimize potential confounding features such as age, education level, and menopausal status by including them in an analysis of covariance. Use of the POMS questionnaire also suggested no significant influence of the potential confounding factor of mood. It is possible that there are other factors associated with cognitive functioning that relate to having a diagnosis of cancer. An alternative control group might consist of patients with early-stage breast cancer not receiving chemotherapy, but this would result in substitution of one potential confounding factor for others, because such women are likely to be older, postmenopausal, and to have a better prognosis than those who are treated with adjuvant chemotherapy. A longitudinal study in which cognitive assessment is undertaken in breast cancer patients before treatment, during chemotherapy, and 1 to 2 years after therapy, would allow patients to serve as their own controls. Even with this design, however, the results might be confounded because the first (control) assessment would be undertaken at a time when patients have recently learned their diagnosis and are under stress.

The primary finding of this study is that breast cancer patients currently receiving standard-dose adjuvant chemotherapy have decreased cognitive function when compared with healthy controls. There is no perfect design for a study addressing the issue of cognitive impairment in women receiving adjuvant chemotherapy for breast cancer because randomization to receive or not receive chemotherapy is unethical. However, the consistency of the present findings with those of the three studies that have evaluated cognitive function in patients after completion of their chemotherapy supports strongly the existence of an effect. The documentation of cognitive impairment has substantial implications for informed consent and for counseling and psychosocial support of women receiving adjuvant chemotherapy for breast cancer.

	ACKNOWLEDGMENTS

 
Supported in part by a Medical Research Council of Canada Summer Research Scholarship (C.B.B.).

	NOTES

 
C.B.B. and K.A.P. contributed equally to this work.

	REFERENCES

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Submitted April 8, 1999; accepted March 16, 2000.

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