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Cognitive Function, Fatigue, and Menopausal Symptoms in Women Receiving Adjuvant Chemotherapy for Breast Cancer

Nadine Tchen, Helen G. Juffs, Fiona P. Downie, Qi-Long Yi, Hanxian Hu, Irene Chemerynsky, Mark Clemons, Michael Crump, Paul E. Goss, David Warr, Mary E. Tweedale, Ian F. Tannock

From the Princess Margaret Hospital and University of Toronto, Toronto; Toronto-Sunnybrook Regional Cancer Centre, and North York General Hospital, North York, Ontario, Canada; and Institut Bergonié, Bordeaux, France.

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

	ABSTRACT

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Purpose: There is evidence that cognitive dysfunction, fatigue, and menopausal symptoms may occur in women receiving adjuvant chemotherapy for breast cancer. Here, we determine their incidence and severity, and interrelationships between them and quality of life.

Patients and Methods: In this study, 110 women receiving adjuvant chemotherapy each nominated a female relative, friend, or neighbor (matched by age) as a control; 100 eligible matched pairs were evaluated. Patients and controls completed the following assessments: the High-Sensitivity Cognitive Screen, and the Functional Assessment of Cancer Therapy–General (FACT-G) quality of life scale with subscales for fatigue (FACT-F) and endocrine symptoms (FACT-ES). They also performed tests of attention and reaction time.

Results: Patients and controls were well matched for age and level of education. There was a higher incidence of moderate or severe cognitive impairment in the patient group (16% v 4%; P = .008). Patients experienced much more fatigue than controls (median FACT-F scores, 31 v 46; P < .0001) and more menopausal symptoms (median FACT-ES scores, 58 v 64; P < .0001). Self-reported quality of life of the patients was poorer than for controls, especially in physical and functional domains (median FACT-G scores, 77 v 93; P < .0001). There was strong correlation between fatigue, menopausal symptoms, and quality of life (P < .0001 for each pair), but none were significantly associated with the presence of cognitive dysfunction.

Conclusion: Adjuvant chemotherapy causes cognitive dysfunction, fatigue, and menopausal symptoms in women with breast cancer. Priority should be given to the study of strategies that might reduce these toxic effects.

	INTRODUCTION

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MULTIPLE RANDOMIZED trials have shown that adjuvant chemotherapy improves long-term survival for most women with breast cancer.¹ According to international recommendations, we offer such treatment to almost all premenopausal women, and to most postmenopausal women with estrogen receptor–negative (ER-) tumors. All women with estrogen receptor–positive (ER+) tumors are offered tamoxifen for 5 years,² but this is not started until completion of adjuvant chemotherapy. Some patients receive chemotherapy before surgery, and clinical trials indicate that outcome is independent of the order of these treatments.

Adverse effects of anticancer drugs include myelosuppression with consequent risks of infection or bleeding, nausea and vomiting, and hair loss. Better antiemetics and antibiotics and the development of growth factors have increased the safety and immediate tolerability of adjuvant chemotherapy. However, more subtle and chronic adverse effects of adjuvant chemotherapy have been recognized—fatigue, cognitive dysfunction, and symptoms associated with an accelerated menopause.

Fatigue is probably the most common symptom experienced by cancer patients, and it is both underrecognized and undertreated.³ High and fluctuating rates of fatigue have been found during and after adjuvant chemotherapy, and the intensity of fatigue seems to be stable throughout the treatment cycles⁴; fatigue is associated with poor quality of life (QL).^5,6 Fatigue is multidimensional, and questionnaires have been developed to assess attributes that contribute to this problem.⁷

The probability that adjuvant chemotherapy will lead to permanent cessation of menses increases with the age of the patient, and is approximately 40% in 40-year-old women.⁸ Symptoms due to an accelerated menopause include night sweats, hot flashes, and sexual problems.^6,9–11 They are probably underreported, in part because until recently, there was a lack of appropriate questionnaires to assess menopausal symptoms. Appropriate interventions can assist in controlling these symptoms.^11,12

Several small studies have suggested that cognitive dysfunction may occur in a proportion of patients who receive chemotherapy.^13–18 One study reported poorer scores on cognitive tests for patients who had received adjuvant chemotherapy for breast cancer, but compared patients with population norms rather than with controls.¹⁴ Two studies by Dutch investigators reported cognitive impairment in women who completed adjuvant chemotherapy a median of 2 years previously. In one study, patients received high-dose chemotherapy,¹⁵ but in the other, there were greater cognitive deficits in node-positive women who had received adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy than in node-negative women who did not.¹⁶ Our group undertook a pilot study in which the High Sensitivity Cognitive Screen (HSCS) ^19,20 was administered to 31 patients receiving adjuvant chemotherapy, to 40 patients who had completed chemotherapy at least 1 year earlier, and to 36 healthy women; there were substantial differences in cognitive function between the 3 groups.¹⁷ Finally, in a study of patients treated for lymphoma or breast cancer at least 5 years earlier, cognitive function was poorer in patients who had received chemotherapy.¹⁸ Despite methodological problems in the aforementioned studies, the consistency of the data provides evidence that cognitive dysfunction is an important and hitherto largely unrecognized effect of treatment.

Prior studies of cognitive dysfunction have been small, and the underlying mechanisms remain unknown. Fatigue has been associated with cognitive dysfunction in patients with chronic fatigue syndrome,²¹ and might be a factor leading to cognitive impairment in women with breast cancer. There is also some evidence that estrogen is necessary for maintenance of cognitive function in women,²² so that hormonal changes associated with an accelerated menopause might influence cognitive function in women undergoing chemotherapy. The hypotheses evaluated in this study are that cognitive dysfunction results from the fatigue and menopausal symptoms that are associated with chemotherapy. The study was therefore designed to evaluate cognitive function, fatigue, and menopausal symptoms, and to explore the relationships between them, in a substantial series of patients receiving adjuvant chemotherapy for breast cancer.

	PATIENTS AND METHODS

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Study Population
Participants with breast cancer were recruited from outpatient clinics of the Princess Margaret Hospital, and collaborating hospitals in Toronto, Canada. Patients had complete resection of all evident breast cancer (by lumpectomy or mastectomy) and were receiving adjuvant chemotherapy or neoadjuvant chemotherapy before scheduled surgery. Eligible women had to be 60 years or younger and be fluent in English.

A control group of healthy women was recruited by a peer nomination procedure. Patients were asked to nominate a control who was a relative or acquaintance, aged 60 years, and with a difference in age to the patient of no more than 5 years. If a patient gave informed consent and was able to nominate a control, an appointment for assessment of the patient was scheduled. Women nominated as controls were contacted, and the study was described to them; if they gave informed consent, an appointment for assessment was scheduled.

Patients or controls with history of other major illness, those with a major pre-existing psychiatric history, and those taking neuroleptic drugs (with the exception of short-acting benzodiazepines or serotonin reuptake inhibitors) were excluded. Participants were classified as premenopausal (menses in the last 3 months), perimenopausal (menses in the last 3 to 12 months), or postmenopausal (> 12 months since last menses).¹⁰

The protocol was approved by the institutional review boards of the University of Toronto and/or of the participating hospitals, and all subjects gave written informed consent.

Chemotherapy
Patients received usual doses of any of several regimens of chemotherapy. Standard antiemetic treatments with dexamethasone + ondansetron or granisetron, with prochlorperazine, domperidone, or metaclopramide were used as needed. Chemotherapy regimens included: six monthly cycles of oral cyclophosphamide, with intravenous (IV) methotrexate and fluorouracil (CMF), or eight to nine 3-week cycles of IV CMF; six cycles of cyclophosphamide, epirubicin, and fluorouracil (CEF)²³; and four cycles of doxorubicin (Adriamycin; Pharmacia and Upjohn Co, Kalamazoo, MI) and cyclophosphamide (AC), sometimes followed by 4 cycles of paclitaxel. Since toxic effects are likely to depend on the amount of chemotherapy received, women had to have completed at least three courses at the time of assessment. The preferred time for assessment was between 2 and 6 weeks after the previous injection of IV chemotherapy. The study has been designed such that all participants (excluding patients with relapse of their cancer) will be reassessed at 1 and 2 years after their initial assessments to determine the time course of any effects that are observed.

Assessment of Patients and Controls
A member of the research team interviewed patients and controls, either at home or in a quiet room of the hospital. After collection of demographic information, the following tests were administered:

Neuropsychologic tests. The HSCS^19,20 is a test for detecting subtle cognitive impairment. The HSCS has been used to detect cognitive changes in elderly patients,²⁴ and was able to discriminate between breast cancer patients and healthy women in our preliminary study.¹⁷ The brevity (~25 minutes) of the HSCS is an advantage for subjects who are receiving stressful treatment. It has been validated for subjects in the age range of 14 to 70 years, and has good test-retest and interrater reliability. The HSCS assesses six domains: verbal memory (sentence and word-pair repetition, recall), language (fluency, response naming, reading, and writing from dictation), visual-motor, spatial (shape rotation and completion), attention and concentration (immediate and divided), and self-regulation and planning (conflicting stimuli and sentence construction). The test is sensitive, and some subjects without overt cognitive dysfunction are classified as borderline or mildly impaired; however, when compared with more comprehensive neuropsychological evaluations, the HSCS correctly classified 93% of subjects across the normal versus abnormal dichotomy.¹⁹ Subjects are classified as normal, or as having borderline, mild, moderate, or severe dysfunction, and a major advantage of the HSCS is this overall classification of cognitive function that can be used as a primary end point in clinical trials. However, the HSCS is not designed to yield an overall summary score for cognitive function.

The Mini-Mental Status Exam (MMSE) is a brief test of mental status.²⁵ A perfect test score is 30, and subjects are required to score at least 20 for the HSCS to be valid. It was included to ensure validity of the HSCS.

The Conner’s Continuous Performance Test (CPT) is a computer-interactive test that assesses reaction time and sustained attention. Letters are presented on the screen of a laptop computer in random order, and at different speeds.²⁶ The subject responds by pressing the space bar in response to all letters other than "X." This test has been validated for adults with attention problems that affect daily life.²⁷

The trail-making test is a brief two-part test that evaluates psychomotor speed, attention, and visual-motor scanning.²⁸ Subjects are asked to rapidly draw lines to connect consecutive numbers (part A) and to alternate between connecting consecutive numbers and letters (part B). Scoring is based on time required to complete the tasks, and number of errors.

QL questionnaires. Fatigue, menopausal symptoms, and health-related QL were assessed by the series of subject-completed Functional Assessment of Cancer Therapy (FACT) questionnaires developed for use in clinical trials.^29–31 Included questionnaires are presented in the following paragraphs.

The FACT-General (FACT-G) Version 4²⁹ is a 27-item core questionnaire evaluating various domains of QL including, physical, functional, family-social, and emotional domains. Items are summed to give scores for each domain, and an overall QL score.

The FACT for fatigue (FACT-F),^7,30 a 13-item subscale that evaluates dimensions that contribute to fatigue, was initially validated in a cohort of 50 cancer patients. The summed FACT-F score was found to be stable on test-retest with good internal consistency, and convergent and discriminant validity revealed a positive correlation with other questionnaires that evaluate fatigue, and a negative relationship with vigor. It separated patients on the basis of performance status.⁷

The FACT for endocrine symptoms (FACT-ES)³¹ is an 18-item endocrine subscale evaluating menopausal and sexual symptoms, including hot flashes. Items can be summed to give a summary score. The FACT-ES was validated in 268 women with breast cancer who were receiving endocrine treatments.

Patients and subjects were asked to donate a sample of blood for determination of estradiol, follicle-stimulating hormone (FSH), and luteinizing hormone (LH), and to allow storage of frozen serum for possible future studies of mechanisms that might underlie the clinical effects examined. Refusal to donate blood did not preclude participation in the study.

Statistical Analysis
The primary end points of the study were overall classification of cognitive functioning as evaluated by the HSCS, fatigue score as evaluated by the FACT-F, menopausal symptoms score as evaluated by the FACT-ES scale, and global evaluation of QL using the FACT-G score. In view of the four primary end points, differences between groups have been regarded as significant for two-sided P values less than .01.

The sample size of 100 pairs of patients and controls was selected on the basis of prior studies^16,17 and issues of feasibility. In prior studies, comparisons between groups of 30 to 40 subjects demonstrated differences in cognitive function at significance levels in the range of .01 to .05. Our study sought to extend these results to two additional measures—fatigue and menopausal symptoms—and to address the hypothesis that cognitive dysfunction was associated with them.

To evaluate differences between paired cases and controls, results for the primary end points of HSCS category, FACT-F, FACT-ES, and FACT-G scores, were tabulated according to their relative severity, and scored as "patient worse," "no difference," or "control worse." For the FACT scales, patients and controls were regarded as having the same score if they differed by less than ± 5%; this threshold of discrimination is supported by a study that has correlated changes in QL scales with subjective changes in clinical status.³² The four primary end points and the results from the CPT and trail-making tests (A and B) have been compared between paired cases and controls using the paired Wilcoxon test. The Wilcoxon test was selected over other tests that allow for ordinal parameters because it takes into account both the magnitude and direction of differences, and uses an adjusted formula that allows for equality between patients and controls.

Some patients (n = 10) and controls (n = 7) did not have a matched partner (because of subsequent refusal or ineligibility, which was not disclosed to the partner to maintain confidentiality). A second analysis compared distributions of the primary end points among patients and controls (irrespective of pairing) to allow inclusion of all subjects who were evaluated (110 patients and 107 controls). The ² and nonpaired Wilcoxon tests were used for this comparison.

To evaluate the relationships in breast cancer patients between cognitive dysfunction, menopausal symptoms, fatigue, and QL, Spearman correlation coefficients were calculated for each pair of primary end points. All patients were included in this analysis since it did not depend on the availability of a matched control. Exploratory multivariate analyses were also undertaken to determine the influence of factors in patients that might reasonably be expected to influence cognitive function, fatigue, menopausal symptoms, and QL.

The statistical analysis was performed using Version 6 of the SAS system and User’s Guide (SAS Institute, Cary, NC).

	RESULTS

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Patients and Controls
Between March 2000 and June 2002, 291 patients receiving adjuvant or neoadjuvant chemotherapy were identified. The results of the screening are presented in Figure 1. The most common reasons for ineligibility were inadequate knowledge of the English language and inability to nominate an aged-matched control. Agreement to participate among eligible patients in the primary center was 70%. The final sample consisted of 110 patients and 107 controls, with 100 patient-control pairs. Nonmatching occurred because ineligibility was discovered after the initial screen because of a prior history of cancer (two patients), problems with fluency in English (two patients), and assessment after only two cycles of chemotherapy (two patients). Four controls withdrew. To maintain confidentiality, the matched partners of excluded patients or controls were evaluated as per protocol.

View larger version (23K): [in this window] [in a new window]   Fig 1. Results of the screening between March 2000 and June 2002. pts, patients; CT, chemotherapy.

The interviews were scheduled after cycle 3 (n = 36), cycle 4 (n = 28), cycle 5 (n = 14), cycle 6 (n = 20), and after cycle 7 for two of the patients receiving IV CMF chemotherapy. Testing was undertaken at home for 114 subjects, and at the hospital for 86 subjects. The impact of test site on each of the primary end points was evaluated separately for patients and controls; there was no effect of test site except for fatigue, for which there was a trend for patients tested at home to have worse FACT-F scores than those tested in the hospital (P = .03, uncorrected for multiple comparisons).

Table 1 lists the demographics of the women who participated in the study. The patients and controls were well matched for age, educational level, marital status (as well as number of children), and menopausal status (at time of diagnosis for the patients).

Cognitive Testing
The HSCS. All subjects satisfied the criterion (score, 20 on the MMSE) for validity of the HSCS, with median MMSE scores equal to the perfect score of 30. The distributions of patients and controls among the categories of cognitive impairment defined by the HSCS are shown in Figure 2. The global distribution of cognitive function was poorer for the patients than the controls (P = .0008, paired Wilcoxon test). Forty-five patients performed more poorly on cognitive testing than did their matched controls, 21 controls had poorer global classification than their matched patients, and 34 pairs had similar cognitive function. Sixteen patients and four controls had moderate or severe cognitive dysfunction. When the covariates of age, education, and menopausal status at time of diagnosis were included in the analysis of the HSCS, the differences between the two groups retained statistical significance (P = .008).

View larger version (44K): [in this window] [in a new window]   Fig 2. Distribution of classification of cognitive function for the 100 patients and their matched controls.

Fatigue
Patients experienced much more fatigue than the controls (P < .0001). The median FACT-F scores (possible range, 0 to 52) and their interquartile ranges were 31 (range, 22 to 39) for patients, and 46 (range, 41 to 49) for controls (Fig 3A). All of the 13 items that were evaluated by the FACT-F showed poorer scores for the patients as compared with the controls. This included difficulty starting and finishing tasks, being too tired to act, needing help with activity, and frustration. In the matched-pair analysis, 83% of patients had poorer scores on the FACT-F than their matched controls (v 10% of controls worse than patients).

View larger version (13K): [in this window] [in a new window]   Fig 3. Box-and-whisker plots of the Functional Assessment of Cancer Therapy for (A) fatigue (FACT-F; score range, 0 to 52) and (B) endocrine symptoms (FACT-ES; score range, 0 to 72) subscale scores for eligible matched pairs. Higher scores represent better function. The box shows median and upper and lower quartiles, the brackets indicate the extent of the data beyond the quartiles, and longitudinal lines indicate outliers.

A comparison of scores using the FACT-ES questionnaire is presented in Figure 3B. The patients had significantly worse menopausal symptoms than the controls (P < .0001). In particular, patients had more hot flashes, cold sweats and night sweats, and lost or decreased interest in sex. Vaginal symptoms were less affected. In the matched-pair analysis, 61% of patients had poorer scores on the FACT-ES than their matched controls (v 14% of controls worse than patients).

Only 74 patients and 53 controls agreed to give blood for hormone testing. Patients had much lower serum levels of estradiol, and corresponding higher serum levels of LH and FSH (Table 3).

The overall classification of cognitive dysfunction by the HSCS was not correlated with fatigue, menopausal symptoms, or QL.

Exploratory Analyses
The results of the four multivariate analyses were concordant with the correlations obtained from the Spearman correlation test (Table 5).

We also sought evidence of possible confounding factors (other than breast cancer and its treatment) that might explain cognitive impairment, including a remote history of head injury (two patients and two controls), history of minor depression with or without use of medication (five patients and six controls), use of short-acting benzodiazepines (nine patients and zero controls; four patients took them for nausea associated with chemotherapy, two took them for sleep, and three took them for occasional anxiety), and admission to hospital to manage adverse effects of chemotherapy (nine patients). Six of 16 patients and none of four controls with moderate or severe cognitive impairment were identified as having at least one of these possible confounding factors (one of these patients had previous head injury, three gave a history of minor depression [one of them taking lorazepam], and two patients had required admission to hospital [one also taking lorazepam]). If subjects with any of the above potential confounders are excluded post hoc of the analysis, the difference in distribution of cognitive dysfunction between patients and controls would remain significant (P = .016, paired Wilcoxon test).

Fatigue. Menopausal symptoms, the emotional domain score of the FACT-F, and hemoglobin level each influenced fatigue, but type and number of courses of chemotherapy were not significant factors (Table 5). Further analysis using the variance decomposition method suggested that menopausal status accounts for approximately 30% of the fatigue, and the fall in hemoglobin accounts for approximately 5%.

Menopausal symptoms. None of the factors included in the multivariate analysis for menopausal symptoms had a significant effect (at the predetermined significance level of P < .01), though there was a trend for those with chemotherapy-induced cessation of menses to have worse symptoms (Table 5).

Global QL. For effects on global QL, fatigue was the strongest factor, with menopausal symptoms also being significant. Consistent with the univariate correlation, cognitive dysfunction had no apparent influence on FACT-G score (Table 5).

	DISCUSSION

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In this study, we found that chemotherapy was associated with profound fatigue and menopausal symptoms, and with substantial cognitive dysfunction in some patients. The patients had impaired QL as compared with the control group. Fatigue, menopausal symptoms, and QL were strongly correlated, but none of them were correlated with cognitive dysfunction. Thus, the results of our study do not support our primary hypotheses.

The design of our study succeeded in providing a control group that was similar in age, marital status, and education level (Table 1). Our choice of control group could, however, be criticized because in patients it is difficult to separate cognitive deficits and other symptoms caused by the psychological burden of having cancer from those caused by its treatment. Three alternative designs were considered and rejected. First, we considered a case-control design comparing breast cancer patients receiving chemotherapy or not. A small study that compared node-positive patients receiving chemotherapy with node-negative patients who were not, found more cognitive dysfunction in patients receiving chemotherapy (28% v 12%¹⁶). It could not be repeated since almost all younger node-negative patients now receive adjuvant chemotherapy. Second, we also considered a longitudinal study in which patients act as their own controls, with a baseline assessment before starting chemotherapy. A pilot study indicated that such a baseline assessment is often abnormal and is influenced by the recent anesthesia, surgery, and stress from receiving the diagnosis (Chvetzoff and Tannock, unpublished data); such a study is unlikely to reflect control conditions. Finally, we considered a longitudinal study in which patients are assessed at the time of breast biopsy, before diagnosis is established. This design is impractical since only 20% to 25% of needle biopsies performed for mammographic abnormalities are positive³³ and one would need to evaluate approximately five times the number of patients who will receive adjuvant chemotherapy.

There were marked differences in levels of fatigue between patients and controls, and fatigue had a profound effect on the QL of our patients. Both the severity of menopausal symptoms and the level of hemoglobin were associated with fatigue, as is consistent with the results of some other studies.^34–36 Patients with menopausal symptoms may have disturbed sleep due to night sweats, while reduced hemoglobin may lower energy levels, which might be corrected in part by blood transfusion or administration of erythropoietin.³⁷ However, these factors accounted only partly for fatigue, and it is likely that chemotherapy has direct effects to cause fatigue.

Most of our patients who were premenopausal at diagnosis had cessation of menses induced by chemotherapy, and changing levels of sex hormones also occurred in patients who continued to have menses. Thus, it is not surprising that patients had more menopausal symptoms than controls; menopausal symptoms contributed to poorer QL of patients even when included with fatigue in a multivariate analysis.

The HSCS was selected as our primary end point to evaluate cognitive function because it has good sensitivity, reliability, and accuracy when compared with more comprehensive tests.^19,20,24 We used Conners’ CPT and the trail-making tests to evaluate attention, reaction time, and psychomotor speed. This small group of tests allowed evaluation of subjects in about 1 to 1.5 hours, thus minimizing the effect of increasing fatigue on compromising the quality of the results. We found a significant difference between the global scores of the HSCS for breast cancer patients and their controls, adding to the evidence that chemotherapy leads to cognitive dysfunction in a subset of patients. The incidence of moderate or severe cognitive dysfunction (16%), fortunately, is lower than that reported in previous studies (range, 17% to 50%), including our own pilot study, in which we also evaluated cognitive function with the HSCS.^15–17 In exploratory analyses, there were trends for patients to have poorer function in most domains of cognitive function, except for visual-motor (Table 2), but we found no differences in sustained attention or reaction time assessed by the CPT or in domains assessed by the trail-making tests. These tests assess slightly different types of functioning than those included in the HSCS, and more detailed tests in selected patients will be required for further characterization of cognitive deficits. Deficits in a fairly broad range of functioning were found in previous small studies.^15–17 The reason for a possible change in incidence of cognitive dysfunction is unknown, but might relate to changes in the type of chemotherapy used. In recent years, anthracyclines have become more widely used, and administration of CMF has declined. Methotrexate is known to have neurotoxic effects, but in the present study, there were not enough patients receiving CMF chemotherapy (n = 11), to examine the relationship between the drugs used and the level of cognitive impairment. It is at least reassuring that the more intensive CEF regimen, received by most of our patients, has not led to an increase in cognitive dysfunction.

Because the incidence of cognitive dysfunction in our study was lower than expected, the multivariate analysis, which evaluated the effects of various factors on cognitive dysfunction, was underpowered. However, there are no trends to suggest that emotional status, fatigue, or menopausal symptoms influence cognitive dysfunction. A recent review of hormone replacement therapy concluded that estrogen does not consistently enhance the cognitive performance of patients without menopausal symptoms, but that it can improve cognitive performance in symptomatic women.^38,39 Although our results are not definitive, they do not support a hormonally mediated mechanism for causing cognitive dysfunction.

Future studies should explore the mechanisms underlying cognitive impairment, using both animal models and detailed neuropsychological testing in selected patients. Possible mechanisms include direct effects of chemotherapy on the CNS, coagulation in small vessels of the brain, since chemotherapy is associated with increased blood clotting⁴⁰ and changes in circulating cytokines, which are known to influence emotional function and memory.⁴¹ To facilitate future studies of mechanisms, frozen serum is available for the majority of our subjects.

The present report compares the assessment of patients toward the end of their period of chemotherapy with that of the untreated matched controls. The study is continuing with reassessment 1 year and 2 years later to determine the time course of fatigue, menopausal symptoms, and cognitive dysfunction. The follow-up will also allow evaluation of the effects of tamoxifen, since all ER+ patients (but not ER- patients) will receive tamoxifen at the end of their chemotherapy. The results of our study can be used to advise patients about adverse effects of treatment. Symptoms such as fatigue, those due to induced menopause, and cognitive dysfunction may be as or more important to patients as the more classical adverse effects of nausea, vomiting, and myelosuppression.⁴² We now have more effective medications to treat these classical adverse effects of chemotherapy. Interventional studies are now being undertaken to investigate strategies for mitigating the effects of fatigue, menopausal symptoms, and cognitive dysfunction.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicated no potential conflicts of interest.

	NOTES

 
This work was supported in part by the 2001 Professor of Survivorship awarded to Dr Tannock by the Susan G. Komen Breast Cancer Foundation. Dr Tchen was supported by a research fellowship from the Association pour la Recherche contre le Cancer.

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Submitted January 21, 2003; accepted August 25, 2003.

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