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Fatigue in Women Receiving Adjuvant Chemotherapy for Breast Cancer
Vol. 18 No. 4 October 1999
Journal of Pain and Symptom Management 233
Original Article
Fatigue in Women Receiving Adjuvant Chemotherapy for Breast Cancer: Characteristics, Course, and Correlates Paul B. Jacobsen, PhD, Danette M. Hann, PhD, Lora M. Azzarello, BS, John Horton, MB, ChB, Lodovico Balducci, MD, and Gary H. Lyman, MD, MPH Moffitt Cancer Center and Research Institute and University of South Florida (P.B.J., L.M.A., J.H., L.B., G.H.L.), Tampa, Florida; and American Cancer Society (D.M.H.), Atlanta, Georgia, USA
Abstract This study investigated the characteristics, course, and correlates of fatigue in women receiving adjuvant chemotherapy for breast cancer. Fifty-four patients were assessed before the start of chemotherapy and during the first three treatment cycles. An age-matched sample of women with no cancer history was assessed at similar time intervals for comparison purposes. Results indicated that breast cancer patients experienced worse fatigue than women with no cancer history. These differences were evident before and after patients started chemotherapy. In addition, fatigue worsened among patients after treatment started. More severe fatigue before treatment was associated with poorer performance status and the presence of fatiguerelated symptoms (e.g., sleep problems and muscle weakness). Increases in fatigue after chemotherapy started were associated with continued fatigue-related symptoms and the development of chemotherapy side effects (e.g., nausea and mouth sores). These findings demonstrate the clinical significance of fatigue in breast cancer patients before and during adjuvant chemotherapy treatment. Results also suggest that aggressive management of common side effects, such as nausea and pain, may be useful in relieving chemotherapyrelated fatigue. J Pain Symptom Manage 1999;18:233–242. © U.S. Cancer Pain Relief Committee, 1999. Key Words Fatigue, chemotherapy, breast cancer
Introduction Scientific interest in the fatigue experienced by cancer chemotherapy patients has grown substantially in recent years.1–4 This trend
Address reprint requests to: Paul B. Jacobsen, PhD, Psychosocial Oncology Program, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA. Accepted for publication: December 24, 1998. © U.S. Cancer Pain Relief Committee, 1999 Published by Elsevier, New York, New York
would appear to reflect the increasing importance placed on physical well-being and quality of life as treatment outcomes in oncology.5,6 The rising interest is also consistent with reports indicating that fatigue remains one of the most common and disabling symptoms experienced by cancer patients.7–11 To date, most studies of fatigue related to chemotherapy have focused on the patients’ subjective experience. Although this research has increased our understanding of the nature and impact of fatigue, many of the studies pos0885-3924/99/$–see front matter PII S0885-3924(99)00082-2
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sess methodological features which limit the conclusions that can be drawn. The use of cross-sectional research designs is an important example.9,12–14 Studies in which patients are followed for only a single treatment cycle do not provide information about changes in fatigue that may have already occurred following the start of chemotherapy or that may occur over the course of repeated infusions. Another restrictive design feature is the use of patient samples which are heterogeneous with regard to disease site and/or disease stage.12,14–16 Since the experience of fatigue appears to vary with both disease site and stage,15,17 the results of these studies are of limited usefulness to clinicians and patients seeking information about the nature of fatigue to be expected with specific regimens for specific diseases. The absence of normative or comparison group data in many studies is yet another limiting design feature.8,12,14 In the absence of such data, it is difficult to know the degree to which levels of fatigue reported by chemotherapy patients differ from levels that are commonly experienced by healthy individuals of the same age and gender. The present study was designed to address each of these limitations in prior research. Specifically, we restricted participation to women receiving adjuvant chemotherapy for breast cancer in order to characterize fatigue in a sample of patients with similar disease undergoing similar treatment. Second, we assessed patients before the start of chemotherapy and on multiple occasions after the start of chemotherapy in order to identify changes in fatigue that could occur following the initiation of treatment and over the course of repeated infusions. Third, we assessed fatigue in an agematched sample of women with no history of cancer in order to distinguish levels of fatigue associated with chemotherapy from “normal” levels of fatigue. The data generated by this study were used to test the hypothesis that women undergoing adjuvant chemotherapy would experience significantly worse fatigue than their healthy counterparts. The data were also used to test the hypothesis that the prevalence and severity of fatigue in breast cancer patients would increase following the initiation of adjuvant chemotherapy treatment. Additional analyses explored the contribution of demographic, disease, and treatment characteristics, as well as symptoms other than fatigue, to pa-
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tients’ reports of fatigue before and after initiation of adjuvant chemotherapy treatment.
Methods Participants Data were collected from two samples: women receiving adjuvant chemotherapy for breast cancer (hereafter referred to as the chemotherapy group) and women with no history of breast cancer (hereafter referred to as the noncancer comparison group). To be eligible for the chemotherapy group, participants had to: a) be 18 years or older; b) have no known major psychiatric or neurological conditions that would interfere with study participation; c) be able to speak and read standard English; d) have no history of cancer other than breast cancer; e) have no previous chemotherapy experience; and f) be scheduled to receive a minimum of four cycles of adjuvant chemotherapy without concurrent radiotherapy. Sixty women met all eligibility criteria and provided informed consent. Results are reported here for the 54 women (90%) who provided complete data on the principal outcome measures. Using peer nomination procedures (see below), a noncancer comparison group was also recruited. In addition to having no history of cancer, these women had to: a) be 18 years or older; b) have no known major psychiatric or neurological conditions that would interfere with study participation; and c) be able to speak and read standard English. Results are reported here for 54 women who met these criteria and provided complete data on the principal outcome measures.
Procedures Potential participants for the chemotherapy group were recruited during an outpatient visit that occurred prior to their first chemotherapy treatment. Those patients who met all eligibility criteria and provided informed consent were given a baseline questionnaire at this visit. Patients were instructed to complete this questionnaire at home and return it when they arrived for their first chemotherapy treatment. Similar questionnaires were distributed to patients in the clinic upon completion of their
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second and third chemotherapy cycles. Patients were instructed to complete each of these questionnaires at home in the week before the next treatment and to return it when they arrived to start their next chemotherapy cycle. Thus, patients completed questionnaires at home on three occasions: before the start of chemotherapy (Home 1), between the second and third cycles (Home 2), and between the third and fourth cycles (Home 3). In addition to these questionnaires, patients completed other measures in the clinic immediately before the start of each of the first four cycles of chemotherapy (Clinic 1 to Clinic 4). Noncancer comparison subjects were recruited using a peer nomination procedure. Specifically, breast cancer patients participating in studies of fatigue were asked to nominate a female friend or relative who might be willing to serve as a participant. These nominees had to be within 5 years of the patient’s age and have no known history of cancer. The nominees were initially contacted by telephone in order to explain the study, confirm their eligibility, and obtain verbal informed consent. Those women who agreed to participate were then mailed an informed consent form, a questionnaire (Home 1), and a stamped preaddressed envelope with which to return these materials. Two additional questionnaires (Home 2 and Home 3) were mailed at 3- to 6-week intervals in order to correspond to the time between questionnaire administrations for the chemotherapy group. Telephone reminders were used to ensure the prompt return of study questionnaires.
Measures The Fatigue Scale from the Profile of Mood States (POMS-F)18 is a widely used seven-item measure of fatigue severity. Respondents indicate on a five-point rating scale (0 5 not at all, 4 5 extremely) how well each adjective describes how they have been feeling during the preceding week. The POMS-F was included in the Home 1–3 questionnaires completed by all participants. The Fatigue Symptom Inventory (FSI)19 assesses the frequency and severity of fatigue as well as its perceived interference with quality of life. Frequency is measured as the number of days in the past week (0–7) respondents felt fa-
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tigued as well as the percentage of each day on average they felt fatigued (0 5 not at all, 10 5 entire day). Severity is measured on an 11point scale (0 5 not at all fatigued, 10 5 as fatigued as I could be) that assesses average fatigue during the past week. Perceived interference is measured on seven separate 11-point scales (0 5 no interference, 10 5 extreme interference) that assess the degree to which fatigue was judged to interfere with general activity, ability to bathe and dress, normal work activity, ability to concentrate, relations with others, enjoyment of life, and mood in the past week. Interference ratings are also summed to yield a total interference score. Previous research has demonstrated the reliability and validity of the FSI when administered to both breast cancer patients and women with no history of cancer.19,20 The FSI was included in the Home 1–3 questionnaires completed by all participants. The Memorial Symptom Assessment Scale (MSAS)21 assesses symptoms commonly associated with cancer and its treatment in terms of their prevalence, severity, and distress. The present study used a modified version which consisted of 26 symptoms including fatigue. Respondents rated each symptom in terms of its: a) presence/absence; b) intensity (0 5 absent, 3 5 severe); and c) distress or bothersomeness (0 5 not at all, 3 5 very much). The MSAS was included in the Clinic 1–4 questionnaires completed only by chemotherapy patients. At Clinic 1, patients rated their experience of symptoms during the preceding week. At Clinics 2–4, participants rated their experience of symptoms for the period since the last infusion. A self-report form was used to obtain information regarding the age, marital status, menopausal status, ethnicity, income, and education of both the chemotherapy patients and noncancer comparison subjects. Participants also provided ratings of their performance status using a self-report version of the Eastern Cooperative Oncology Group (ECOG) Performance Status Scale.22 These forms were included in the Home 1 questionnaire. In addition, the medical charts of chemotherapy patients were reviewed to obtain information about stage of disease, type of breast cancer surgery performed, and type of chemotherapy agents administered.
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Results Demographic and Medical Characteristics Information about the demographic characteristics of the chemotherapy group and the noncancer comparison group is listed in Table 1. The chemotherapy group ranged in age from 28 to 77 years. A majority of these women were white (91%), postmenopausal (56%), married (63%), and college graduates (69%); 50% reported a household income of $40,000 or more per annum. The noncancer comparison group ranged in age from 32 to 77 years. A majority of these women were also white (100%), postmenopausal (61%), married (70%), and college graduates (65%); 48% reported a household income of $40,000 or more per annum. There were no significant (P # 0.05) differences between the chemotherapy group and the noncancer comparison group on any demographic variables. Disease stage for the chemotherapy patients was as follows: stage I, 9 patients (16.7%); stage II, 36 patients (66.7%); and stage III, 9 patients (16.7%). With regard to surgical treatment, 25 women (46.3%) underwent mastectomy, 24 women (44.4%) underwent lumpectomy, 1 woman (1.9%) underwent both mastectomy and lumpectomy, and 4 women (7.4%) did not undergo surgery other than breast biopsy prior to chemotherapy. With regard to chemotherapy regimens, 14 women (25.9%) received Table 1 Demographic Characteristics of the Chemotherapy and Noncancer Comparison Groupsa Group Variable Age, yearsb Income $ $40,000 , $40,000 Marital status Married Unmarried Education College graduates Other Ethnic group White Nonwhite Menopausal status Post Pre/peri a All
Chemotherapy (n = 54)
Noncancer (n = 54)
51 6 10
54 6 11
27 27
26 28
34 20
38 16
37 17
35 19
49 5
54 0
30 24
33 21
comparisons were nonsignificant (P . 0.05). expressed as mean 6 SD.
b Value
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doxorubicin, 25 women (46.3%) received doxorubicin and cyclophosphamide, 11 women (20.4%) received doxorubicin, cyclophosphamide, and fluorouracil, and 4 women (7.4%) received doxorubicin, cyclophosphamide, and methotrexate.
Group Differences in Fatigue The first set of analyses tested the hypothesis that fatigue would be greater in chemotherapy patients than in noncancer comparison subjects. To test this hypothesis, scores on each fatigue measure administered to both groups were entered into separate 2 (Group: chemotherapy, noncancer comparison) 3 3 (Time: Home 1–3) repeated measures analyses of variance (ANOVA) designs. The study hypothesis was evaluated by examining the significance of the Group effect. If the overall Group effect was significant (P # 0.05), additional simple effect analyses were conducted to determine the specific time or times of assessment that the groups differed significantly in fatigue. Mean scores and standard deviations for each group at each time of assessment are listed in Table 2. Analysis of POMS-F scores yielded the expected Group effect (F 5 12.24, P 5 0.0007). Simple effects analyses indicated that the chemotherapy group reported significantly (P # 0.05) greater fatigue at Home 1 and Home 3. Analysis of FSI scores yielded the expected Group effects for average fatigue (F 5 12.82, P 5 0.0005), number of days fatigued (F 5 22.40, P , 0.0001), and amount of each day fatigued (F 5 29.44, P , 0.0001) in the past week. The expected Group effect was also observed for the total fatigue interference score (F 5 21.28, P , 0.0001). Simple effects analyses indicated that differences between groups on these measures were in the predicted direction and were significant (P # 0.05) at all three times of assessment. In order to further examine the impact of fatigue on quality of life, repeated measures ANOVAs were performed on each of the seven FSI ratings which were summed to obtain the total interference score. The expected Group effects were observed for ratings of the degree to which fatigue interfered with general activity (F 5 26.76, P , 0.0001), ability to bathe and dress (F 5 10.48, P 5 0.002), normal work activity (F 5 27.39, P , 0.0001), ability to concentrate (F 5 7.96, P 5 0.006), relations with oth-
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Table 2 POMS-F and FSI Scores of the Chemotherapy and Noncancer Comparison Groups Assessment Scale Group POMS-F Chemotherapy Noncancer FSI-Average Chemotherapy Noncancer FSI–No. of days Chemotherapy Noncancer FSI–Amt. of each day Chemotherapy Noncancer FSI–Summary interference Chemotherapy Noncancer a Mean b Mean
Home 1
Home 2
Home 3
M
(SD)
M
(SD)
M
(SD)
9.90a 6.59
(7.03) (5.74)
9.18 6.83
(7.29) (5.19)
11.06a 5.11
(8.13) (4.96)
4.03a 2.91
(2.09) (1.98)
4.11a 3.30
(1.93) (1.82)
4.13a 2.76
(2.15) (2.07)
5.09a 3.09
(2.36) (2.20)
4.74a 3.63
(2.25) (2.22)
4.89a 3.06
(2.41) (2.18)
3.76a 2.50
(2.52) (1.84)
4.44a 2.50
(2.76) (1.62)
4.67a b 2.35
(2.82) (1.59)
2.72a 1.42
(2.15) (1.49)
2.71a 1.51
(2.29) (1.49)
2.92a 1.16
(2.32) (1.21)
scores at this assessment for chemotherapy and noncancer groups differ significantly (P # 0.05). scores for chemotherapy at Home 1 and this assessment differ significantly (P # 0.05).
ers (F 5 12.98, P 5 0.0005), enjoyment of life (F 5 15.77, P , 0.0001), and mood (F 5 14.06, P 5 0.0003). With two exceptions (ability to bathe/dress and ability to concentrate at Home 2), simple effects analyses indicated that chemotherapy patients reported significantly (P # 0.05) greater interference due to fatigue than noncancer comparison subjects on each rating at each time of assessment (results not shown).
Changes in Fatigue During Adjuvant Chemotherapy The next set of analyses tested the hypothesis that fatigue would increase following the initiation of adjuvant chemotherapy. To test this hypothesis, scores on each fatigue measure administered to the chemotherapy patients during the Home 1–3 assessments were entered into separate repeated measures ANOVA designs with one within-groups factor (Time: Home 1–3). The study hypothesis was evaluated by examining the significance of the Time effect. If the overall Time effect was significant (P # 0.05), simple effects analyses were conducted. Specifically, scores for the assessment conducted before the start of chemotherapy (Home 1) were compared to those for the assessments conducted between the second and third cycles (Home 2) and the third and fourth cycles (Home 3) to identify changes in fatigue following initiation of chemotherapy. Simple
effects analyses were also conducted to identify changes in fatigue over the course of treatment (i.e., between Home 2 and Home 3). Analysis of POMS-F scores did not yield the expected Time effect (F 5 2.31, P 5 0.10). Analysis of FSI scores yielded a significant Time effect only for the amount of time each day patients experienced fatigue (F 5 3.13, P 5 0.047). Simple effects analyses indicated that the amount of time each day patients experienced fatigue increased significantly (P # 0.03) between Home 1 and Home 3. Patients’ MSAS ratings of fatigue were also available to evaluate the study hypothesis (Table 3). MSAS fatigue severity and distress ratings obtained at each clinic assessment were entered into separate repeated measures ANOVA designs with one within-groups factor (Time: Clinics 1–4). If the overall Time effect was significant (P # 0.05), simple effects analyses were conducted in order to identify changes in fatigue following initiation of chemotherapy. In these analyses, scores obtained before the start of chemotherapy (Clinic 1) were compared with those obtained before the second cycle (Clinic 2), third cycle (Clinic 3), and fourth cycle (Clinic 4). Simple effects analyses were also conducted to identify changes in fatigue over the course of treatment (i.e., between Clinic 2, Clinic 3, and Clinic 4). The expected Time effect was observed for MSAS ratings of both severity (F 5 6.36, P 5
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Table 3 MSAS Fatigue Scores of the Chemotherapy Group Prevalence Assessment Clinic 1 Clinic 2 Clinic 3 Clinic 4
Severity
Distress
N
%
M
(SD)
M
(SD)
38 49a 50a 48a
(72%) (92%) (94%) (91%)
1.35 1.87a 1.75a 1.96a
(0.93) (0.83) (0.79) (0.90)
1.17 1.56a 1.40 1.66a
(1.08) (0.98) (0.88) (0.94)
a Value differs significantly (P # 0.05) from corresponding value at Clinic 1.
0.0004) and distress (F 5 4.68, P 5 0.004). Simple effects analyses indicated that patients reported significantly (P # 0.05) more severe fatigue at Clinic 2, Clinic 3, and Clinic 4 than at Clinic 1. Similarly, patients reported significantly (P # 0.05) greater fatigue-related distress at Clinic 2 and Clinic 4 than at Clinic 1. To further characterize the changes in fatigue severity during chemotherapy, the percentages of patients reporting each level of severity (0–3) at Clinic 1 and Clinic 4 were calculated. Inspection of the data indicated that the greatest changes were in the percentages of patients reporting no fatigue (0) and severe fatigue (3). Between Clinic 1 and Clinic 4, the percentage of patients reporting no fatigue declined from 28% to 9%, whereas the percentage of patients reporting severe fatigue increased from 4% to 28%. MSAS ratings of fatigue prevalence (presence/absence) obtained at each clinic assessment were analyzed by conducting the nonparametric McNemar change test.23 Consistent with predictions, fatigue was significantly (P # 0.05) more prevalent at Clinic 2, Clinic 3, and Clinic 4 than at Clinic 1. For example, the prevalence of fatigue was found to increase from 72% at Clinic 1 to 91% at Clinic 4.
Factors Associated with Fatigue Severity Before the Start of Chemotherapy The next set of analyses focused on identifying factors associated with individual differences in patients’ reports of fatigue severity before the start of chemotherapy. The MSAS rating of fatigue severity obtained at Clinic 1 served as the outcome measure for these analyses and for those that follow. The MSAS severity rating was chosen based on results demonstrating the presence of significant increases on this measure following the initiation of che-
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motherapy. This feature means that MSAS severity ratings can also be used to identify factors that are associated with increases in fatigue after the start of chemotherapy (see below). Results of correlational analyses and ANOVAs yielded nonsignificant (P $ 0.10) relationships between the following demographic and medical variables and fatigue severity before the start of chemotherapy: age, menopausal status, type of surgery, and stage of disease. In contrast, performance status was found to be significantly related to fatigue severity (F 5 7.14, P 5 0.01). As would be expected, patients who reported no restrictions were less fatigued than patients who reported restrictions (M 5 0.75 vs. M 5 1.52). Correlational analyses were also conducted to examine the relationship between fatigue severity and reports of other symptoms on the MSAS before the start of chemotherapy. Results indicated a significant positive relationship between the number of other symptoms reported and fatigue severity (r 5 0.53, P , 0.0001). Examination of individual MSAS items indicated that the presence of the following symptoms was significantly (P # 0.05) positively correlated with more severe fatigue before the start of chemotherapy: emotional upset (r 5 0.44), muscle weakness (r 5 0.43), pain (r 5 0.37), numbness (r 5 0.35), sleep problems (r 5 0.34), problems with concentration (r 5 0.34), and heartburn (r 5 0.28). Based on the results obtained, a hierarchical multiple regression analysis was conducted to determine the amount of variability in fatigue severity accounted for by performance status and the number of other symptoms reported. As shown in Table 4, performance status accounted for 12% of the variability in fatigue severity; after accounting for performance status, the number of symptoms other than fatigue accounted for an additional 18% of the variability in fatigue severity.
Table 4 Multiple Regression Analysis of Fatigue Severity Before the Start of Chemotherapya b
Variable Performance status No. of other symptoms a Multiple bP
# 0.01.
0.15 0.47
R = 0.55; F (2, 53) = 11.20, P , 0.0001.
r2 change 0.12b 0.18b
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Factors Associated with Changes in Fatigue Severity After the Start of Chemotherapy The last set of analyses focused on identifying factors associated with changes in patients’ reports of fatigue severity after the start of chemotherapy. In order to conduct these analyses, residualized fatigue severity change scores were created by partialling MSAS fatigue severity at Clinic 1 from MSAS fatigue severity at Clinic 4.24 The resulting variable represents the change in fatigue severity between Clinic 1 and Clinic 4 that is not related to baseline (Clinic 1) levels of fatigue. Results of regression analyses yielded nonsignificant (P $ 0.10) relationships between the following demographic and medical variables and changes in fatigue severity between Clinic 1 and Clinic 4: age, menopausal status, performance status, stage of disease, type of surgery, and chemotherapy regimen. In contrast, there was a significant positive relationship between the number of symptoms other than fatigue experienced after the first, second, and third cycles as measured by the MSAS and changes in fatigue severity between Clinic 1 and Clinic 4 (t 5 3.42, P 5 0.001). Number of symptoms was found to account for 18% of the variability in changes in fatigue severity. Additional regression analyses were conducted to examine the relationship between the frequency of occurrence of individual symptoms and changes in fatigue severity. Results indicated that the more frequent occurrence of the following symptoms was associated with significant (P # 0.05) increases in fatigue severity between Clinic 1 and Clinic 4: pain (t 5 3.45), emotional upset (t 5 2.83), nausea (2.70), mouth sores (t 5 2.62), muscle weakness (t 5 2.60), change in taste (t 5 2.10), sleep problems (t 5 2.08), chills (t 5 2.00), and vomiting (t 5 2.00).
Discussion Women receiving adjuvant chemotherapy for breast cancer were found to experience significantly worse fatigue than an age-matched comparison group of women with no cancer history. Differences between patients and comparison subjects were evident on measures of the severity and frequency of fatigue as well as its perceived interference with quality of life.
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These differences were observed both before and after chemotherapy was initiated for the breast cancer patients. Changes in fatigue following the start of treatment were evident mostly on ratings that encompassed the interval between infusions. Analysis of these ratings indicated that fatigue increased in prevalence, severity, and disruptiveness after the start of treatment. More severe fatigue before the start of treatment was associated with poorer performance status and with the presence of several fatigue-related symptoms (e.g., sleep problems and muscle weakness). Increases in fatigue severity following the start of chemotherapy were associated with the continued presence of fatigue-related symptoms and the development of treatment side effects (e.g., nausea and mouth sores). The following discussion integrates these findings with previous research, considers the clinical implications, and identifies directions for future research. The present study provides strong evidence that fatigue is a significant clinical problem during adjuvant chemotherapy for breast cancer. As predicted, the fatigue experienced by women undergoing adjuvant chemotherapy was considerably more severe than the fatigue experienced by women of similar age with no cancer history. For example, the average level of fatigue reported on the POMS-F by breast cancer patients before their third treatment cycle was more than twice that reported by the age-matched comparison group. These findings are consistent with results from one of the few other studies of chemotherapy-related fatigue to include a noncancer comparison group. Irvine and colleagues16 assessed fatigue in chemotherapy patients (predominantly women with breast cancer) and a comparison group of women described as auxiliary staff members. The authors found that fatigue was significantly more severe in the chemotherapy group when assessed 10 to 14 days after their last treatment. Additional findings from the present study support the view that the observed differences in fatigue severity were clinically as well as statistically significant. Compared to women with no history of cancer, women receiving chemotherapy reported that fatigue interfered to a greater extent with their general activity, ability to bathe and dress, normal work activity, ability to concentrate, relations with others, enjoyment of life, and mood.
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An unexpected finding in the current study was that breast cancer patients reported more severe fatigue than a comparison group even before chemotherapy was initiated. There are at least two possible explanations for this finding. First, the heightened fatigue in the patient group before the start of chemotherapy may reflect lingering physical and psychological stresses associated with having recently undergone breast cancer surgery. Previous research25 has demonstrated that cognitive manifestations of fatigue may persist for as long as 90 days following mastectomy or lumpectomy. A second and not mutually exclusive explanation is that heightened fatigue before the start of chemotherapy may be a reflection of the heightened emotional distress. We26 have previously shown that adjuvant chemotherapy patients experience significantly greater anxiety before their first infusion than before subsequent infusions. In light of research suggesting that emotional distress is a source of fatigue for cancer patients,16,20,27 it is reasonable to speculate that anticipatory anxiety contributed to the heightened fatigue experienced by patients before the start of chemotherapy. The present study confirmed the prediction that breast cancer patients would experience a worsening of their fatigue following the initiation of chemotherapy. To the best of our knowledge, no previous study of chemotherapy-related fatigue has tested this prediction. As noted above, changes in fatigue were evident mostly for ratings that encompassed the entire interval between infusions. In general, there were no changes from pretreatment levels for ratings of fatigue for the week before the start of each cycle. This pattern of results is consistent with prior research which generally indicates that fatigue reaches its peak intensity at or before the midpoint between treatment cycles and then declines during the remainder of the treatment cycle.13,16,28 Taken together, findings from the present study and past research suggest that the ability to detect changes in fatigue from pretreatment levels may be a function of the time period covered by the ratings. There was no evidence in the present study that, following the initiation of adjuvant chemotherapy, fatigue worsened over the course of subsequent infusions. Although this finding may seem to contradict conventional wisdom,
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it is supported by previous research. In a study that is similar to the present study, Berger28 assessed fatigue over the course of the first three treatment cycles in breast cancer patients receiving adjuvant chemotherapy. Levels of fatigue were found to be similar in the 48 hours after each treatment. It should be noted that the results of these studies do not rule out the possibility that fatigue may worsen over time after additional treatment cycles or with other forms of chemotherapy. In general, the severity of fatigue experienced by patients before and after initiation of chemotherapy was unrelated to demographic, disease, or treatment variables. These results may reflect the fact that, by design, there was limited variability in patients’ medical characteristics and, to a lesser extent, in their demographic characteristics. The one exception was the significant relationship between poorer ECOG performance status and greater fatigue before the start of chemotherapy. This relationship has been reported in at least one previous study.15 In a sample of chemotherapy patients heterogeneous in terms of both disease site and stage, ECOG performance status was found to be a better predictor of fatigue severity than age, gender, or extent of disease. The present study identified an interesting pattern of relationships between fatigue and the experience of other symptoms before and after the start of chemotherapy. Before the start of chemotherapy, more severe fatigue was related to the presence of emotional upset, pain, muscle weakness, sleep problems, numbness, heartburn, and problems with concentration. Moreover, the continued presence of emotional upset, pain, muscle weakness, and sleep problems was associated with increases in fatigue severity following the start of treatment. The co-occurrence of these symptoms with fatigue does not appear to be unique to the situation of cancer patients receiving chemotherapy. Emotional upset, pain, muscle weakness, sleep problems, and problems with concentration have been shown to be associated with fatigue in cancer patients who have successfully completed treatment20,29,30 and with chronic fatigue in individuals with no history of cancer or other major illnesses.31,32 Indeed, these symptoms are among those included in many descriptions of chronic fatigue syndromes.33 Of particular interest in the present study was
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evidence that several symptoms which are not typically associated with fatigue, but are common side effects of chemotherapy, were also related to increases in fatigue severity following the start of treatment. Specifically, patients who reported the more frequent occurrence of nausea, mouth sores, changes in taste, chills, and vomiting were also more likely to experience a worsening of their fatigue after the start of chemotherapy. This pattern of results suggests that the development of aversive treatment side effects is an important mechanism by which the initiation of chemotherapy results in a worsening of fatigue in women with breast cancer. Several recommendations for clinical practice can be drawn from the present study. Treatment providers and patients need to know that many women receiving chemotherapy for breast cancer will experience severe fatigue that can seriously compromise their physical and mental well-being and ability to function. This information should be communicated routinely as part of pretreatment education so that patients can form accurate expectations and plan for the possibility that they may have to restrict their daily activities. Patients can be reassured, however, that fatigue is unlikely to continue to worsen as they return for additional cycles of adjuvant chemotherapy. Finally, the results of the present study underscore the importance of providing chemotherapy patients with effective analgesic and antiemetic regimens. In addition to relieving pain and gastrointestinal distress, appropriate use of these therapies may serve to reduce the fatigue that most patients also experience. The current study suggests two directions for future research. First, there is a need for research into the biological correlates of changes in fatigue severity among adjuvant chemotherapy patients. A recent study of cancer patients not receiving chemotherapy or radiotherapy demonstrated that lower hemoglobin levels were associated with greater subjective reports of fatigue.34 It would be of interest to determine if a similar relationship exists between changes in fatigue severity and changes in hemoglobin levels following the start of chemotherapy. Evidence of such a relationship would support the use of agents that increase hemoglobin production (e.g., erythropoietin) as treatments for chemotherapy-related fatigue. A second direction for future research is to ex-
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amine psychosocial correlates of individual differences in fatigue severity during chemotherapy. Along these lines, we recently demonstrated that reliance on catastrophizing as a coping strategy was associated with significantly worse fatigue among women with breast cancer previously treated with adjuvant chemotherapy.20 Demonstration of a similar relationship among women currently undergoing treatment would suggest that psychological interventions may also play a role in the treatment of chemotherapyrelated fatigue. By reducing reliance on catastrophizing and promoting more adaptive coping strategies, it may be possible to relieve patients’ fatigue and improve their quality of life. In conclusion, the results of this study provide new information about the characteristics, course, and correlates of fatigue in women receiving adjuvant chemotherapy for breast cancer. With regard to characteristics, findings clearly demonstrate that the degree of fatigue experienced by women with breast cancer is significantly worse than that reported by women with no cancer history even before the start of chemotherapy. With regard to course, there is evidence that the prevalence, severity, and disruptiveness of fatigue increased following the start of chemotherapy but did not increase further over the first three treatment cycles. With regard to correlates, results suggest that the development of aversive treatment side effects such as nausea and mouth sores contributes to increases in fatigue following the start of chemotherapy. Although this study answered several questions about chemotherapy-related fatigue, there is much that still remains to be learned. Identifying biological and psychosocial mechanisms that underlie the development of chemotherapy-related fatigue should be a high priority for future research. Beyond this, there is a need to identify pharmacologic and/or psychosocial interventions that are effective in relieving the fatigue so commonly experienced by cancer chemotherapy patients.
Acknowledgment This work was supported by an Institutional Research Grant from the American Cancer Society (ACS IRG202) to the Moffitt Cancer Center and Research Institute.
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References 1. Groopman JE. Fatigue in cancer and HIV/ AIDS. Oncology 1998;12:335–351. 2. Richardson A. Fatigue in cancer patients: a review of the literature. Eur J Cancer Care 1995;4:20–32. 3. Smets EMA, Garssen B, Schuster-Uitterhoeve ALJ, et al. Fatigue in cancer patients. Br J Cancer 1993;68:220–224. 4. Winningham ML, Nail LM, Burke MB, et al. Fatigue and the cancer experience: the state of the knowledge. Oncol Nurs Forum 1994;21:23–36. 5. Cella DF. Quality of life as an outcome of cancer treatment. In: Groenwald SL, Goodman M, Frogge MH, et al., eds. Cancer nursing: principles and practice, 3rd ed. Boston: Jones and Bartlett Publishers, 1993: 197–207. 6. Ganz PA. Quality of life and the patient with cancer. Cancer 1994;74:1445–1452. 7. Beisecker AE, Cook MR, Ashworth J, et al. Side effects of adjuvant chemotherapy: perceptions of node-negative breast cancer patients. Psycho-Oncology 1997;6:85–93. 8. Greene D, Nail LM, Fieler VK, et al. A comparison of patient-reported side effects among three chemotherapy regimens for breast cancer. Cancer Pract 1994;2:57–62. 9. Knobf T. Physical and psychologic distress associated with adjuvant chemotherapy in women with breast cancer. J Clin Oncol 1986;4:678–684. 10. Longman AJ, Braden CJ, Mishel MH. Side effects burden in women with breast cancer. Cancer Pract 1996;4:274–280. 11. Vogelzang NJ, Breitbart W, Cella D, et al. Patient, caregiver, and oncologist perceptions of cancer-related fatigue: results of a tripart assessment survey. Semin Hematol 1997;34:4–12. 12. Blesch KS, Paice JA, Wickham R, et al. Correlates of fatigue in people with breast or lung cancer. Oncol Nurs Forum 1991;18:81–87. 13. Pickard-Holley S. Fatigue in cancer patients. Cancer Nurs 1991;14:13–19. 14. Richardson A, Ream E. The experience of fatigue and other symptoms in patients receiving chemotherapy. Eur J Cancer Care 1996;5:24–30. 15. Pater JL, Zee B, Palmer M, Johnston D, Osoba D. Fatigue in patients with cancer: results with National Cancer Institute of Canada Clinical Trials Group studies employing the EORTC QLQ-C30. Supportive Care Cancer 1997;5:410–413. 16. Irvine D, Vincent L, Graydon JE, et al. The prevalence and correlates of fatigue in patients receiving treatment with chemotherapy and radiotherapy. Cancer Nurs 1994;17:367–378. 17. Glaus A. Fatigue in patients with cancer. New York: Springer-Verlag, 1998. 18. McNair DM, Lorr M, Droppleman L. Profile of Mood States manual. San Diego: Educational and Industrial Testing Service, 1971.
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19. Hann DM, Jacobsen PB, Azzarello LM, et al. Measurement of fatigue in cancer patients: development and validation of the Fatigue Symptom Inventory. Qual Life Res 1998;7:301–310. 20. Broeckel JA, Jacobsen PB, Horton J, et al. Characteristics and correlates of fatigue after adjuvant chemotherapy for breast cancer. J Clin Oncol 1998; 16:1689–1696. 21. Portenoy RK, Thaler HT, Kornblith AB, et al. The Memorial Symptom Assessment Scale: an instrument for the evaluation of symptom prevalence, characteristics and distress. Eur J Cancer 1994;30A:1326–1336. 22. Zubrod CG, Schneiderman M, Frei E, et al. Appraisal of methods for the study of chemotherapy of cancer in man: comparative therapeutic trial of nitrogen mustard and triethylene thiophosphoramide. J Chronic Dis 1960;11:7–33. 23. Siegel S, Castellan Jr NJ. Nonparametric statistics for the behavioral sciences, 2nd ed. New York: McGraw-Hill, 1988. 24. Cohen J, Cohen P. Applied multiple regression/ correlation analysis for the behavioral sciences, 2nd ed. Hillsdale, NJ: Lawrence Erlbaum Associates, 1983. 25. Cimprich B. Development of an intervention to restore attention in cancer patients. Cancer Nurs 1993;16:83–92. 26. Jacobsen PB, Bovbjerg DH, Redd WH. Anticipatory anxiety in women receiving chemotherapy for breast cancer. Health Psychol 1993;12:469–475. 27. Dimeo F, Stieglitz RD, Novelli-Fischer U, et al. Correlation between physical performance and fatigue in cancer patients. Ann Oncol 1997;8:1251–1255. 28. Berger AM. Patterns of fatigue and activity and rest during adjuvant breast cancer chemotherapy. Oncol Nurs Forum 1998;25:51–62. 29. Hann DM, Jacobsen PB, Martin SC, et al. Fatigue in women treated with bone marrow transplantation for breast cancer: a comparison with women with no history of cancer. Supportive Care Cancer 1997;5:44–52. 30. Smets EMA, Visser MRM, Willems-Groot AFMN, et al. Fatigue and radiotherapy: (B) experience in patients 9 months following treatment. Br J Cancer (in press). 31. Sharpe M, Chalder T, Palmer I, et al. Chronic fatigue syndrome. Gen Hosp Psychiatry 1997;19:185–199. 32. Wessely S, Powell R. Fatigue syndromes: a comparison of chronic “postviral” fatigue with neuromuscular and affective disorders. J Neurol Neurosurg Psychiatry 1989;52:940–948. 33. Wessely S, Hotopf M, Sharpe M. Chronic fatigue and its syndromes. Oxford: Oxford University Press, 1998. 34. Yellen SB, Cella DF, Webster K, et al. Measuring fatigue and other anemia-related symptoms with the Function Assessment of Cancer Therapy (FACT) Measurement System. J Pain Symptom Manage 1997;13:63–74.
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Original Article
Fatigue in Women Receiving Adjuvant Chemotherapy for Breast Cancer: Characteristics, Course, and Correlates Paul B. Jacobsen, PhD, Danette M. Hann, PhD, Lora M. Azzarello, BS, John Horton, MB, ChB, Lodovico Balducci, MD, and Gary H. Lyman, MD, MPH Moffitt Cancer Center and Research Institute and University of South Florida (P.B.J., L.M.A., J.H., L.B., G.H.L.), Tampa, Florida; and American Cancer Society (D.M.H.), Atlanta, Georgia, USA
Abstract This study investigated the characteristics, course, and correlates of fatigue in women receiving adjuvant chemotherapy for breast cancer. Fifty-four patients were assessed before the start of chemotherapy and during the first three treatment cycles. An age-matched sample of women with no cancer history was assessed at similar time intervals for comparison purposes. Results indicated that breast cancer patients experienced worse fatigue than women with no cancer history. These differences were evident before and after patients started chemotherapy. In addition, fatigue worsened among patients after treatment started. More severe fatigue before treatment was associated with poorer performance status and the presence of fatiguerelated symptoms (e.g., sleep problems and muscle weakness). Increases in fatigue after chemotherapy started were associated with continued fatigue-related symptoms and the development of chemotherapy side effects (e.g., nausea and mouth sores). These findings demonstrate the clinical significance of fatigue in breast cancer patients before and during adjuvant chemotherapy treatment. Results also suggest that aggressive management of common side effects, such as nausea and pain, may be useful in relieving chemotherapyrelated fatigue. J Pain Symptom Manage 1999;18:233–242. © U.S. Cancer Pain Relief Committee, 1999. Key Words Fatigue, chemotherapy, breast cancer
Introduction Scientific interest in the fatigue experienced by cancer chemotherapy patients has grown substantially in recent years.1–4 This trend
Address reprint requests to: Paul B. Jacobsen, PhD, Psychosocial Oncology Program, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA. Accepted for publication: December 24, 1998. © U.S. Cancer Pain Relief Committee, 1999 Published by Elsevier, New York, New York
would appear to reflect the increasing importance placed on physical well-being and quality of life as treatment outcomes in oncology.5,6 The rising interest is also consistent with reports indicating that fatigue remains one of the most common and disabling symptoms experienced by cancer patients.7–11 To date, most studies of fatigue related to chemotherapy have focused on the patients’ subjective experience. Although this research has increased our understanding of the nature and impact of fatigue, many of the studies pos0885-3924/99/$–see front matter PII S0885-3924(99)00082-2
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sess methodological features which limit the conclusions that can be drawn. The use of cross-sectional research designs is an important example.9,12–14 Studies in which patients are followed for only a single treatment cycle do not provide information about changes in fatigue that may have already occurred following the start of chemotherapy or that may occur over the course of repeated infusions. Another restrictive design feature is the use of patient samples which are heterogeneous with regard to disease site and/or disease stage.12,14–16 Since the experience of fatigue appears to vary with both disease site and stage,15,17 the results of these studies are of limited usefulness to clinicians and patients seeking information about the nature of fatigue to be expected with specific regimens for specific diseases. The absence of normative or comparison group data in many studies is yet another limiting design feature.8,12,14 In the absence of such data, it is difficult to know the degree to which levels of fatigue reported by chemotherapy patients differ from levels that are commonly experienced by healthy individuals of the same age and gender. The present study was designed to address each of these limitations in prior research. Specifically, we restricted participation to women receiving adjuvant chemotherapy for breast cancer in order to characterize fatigue in a sample of patients with similar disease undergoing similar treatment. Second, we assessed patients before the start of chemotherapy and on multiple occasions after the start of chemotherapy in order to identify changes in fatigue that could occur following the initiation of treatment and over the course of repeated infusions. Third, we assessed fatigue in an agematched sample of women with no history of cancer in order to distinguish levels of fatigue associated with chemotherapy from “normal” levels of fatigue. The data generated by this study were used to test the hypothesis that women undergoing adjuvant chemotherapy would experience significantly worse fatigue than their healthy counterparts. The data were also used to test the hypothesis that the prevalence and severity of fatigue in breast cancer patients would increase following the initiation of adjuvant chemotherapy treatment. Additional analyses explored the contribution of demographic, disease, and treatment characteristics, as well as symptoms other than fatigue, to pa-
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tients’ reports of fatigue before and after initiation of adjuvant chemotherapy treatment.
Methods Participants Data were collected from two samples: women receiving adjuvant chemotherapy for breast cancer (hereafter referred to as the chemotherapy group) and women with no history of breast cancer (hereafter referred to as the noncancer comparison group). To be eligible for the chemotherapy group, participants had to: a) be 18 years or older; b) have no known major psychiatric or neurological conditions that would interfere with study participation; c) be able to speak and read standard English; d) have no history of cancer other than breast cancer; e) have no previous chemotherapy experience; and f) be scheduled to receive a minimum of four cycles of adjuvant chemotherapy without concurrent radiotherapy. Sixty women met all eligibility criteria and provided informed consent. Results are reported here for the 54 women (90%) who provided complete data on the principal outcome measures. Using peer nomination procedures (see below), a noncancer comparison group was also recruited. In addition to having no history of cancer, these women had to: a) be 18 years or older; b) have no known major psychiatric or neurological conditions that would interfere with study participation; and c) be able to speak and read standard English. Results are reported here for 54 women who met these criteria and provided complete data on the principal outcome measures.
Procedures Potential participants for the chemotherapy group were recruited during an outpatient visit that occurred prior to their first chemotherapy treatment. Those patients who met all eligibility criteria and provided informed consent were given a baseline questionnaire at this visit. Patients were instructed to complete this questionnaire at home and return it when they arrived for their first chemotherapy treatment. Similar questionnaires were distributed to patients in the clinic upon completion of their
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second and third chemotherapy cycles. Patients were instructed to complete each of these questionnaires at home in the week before the next treatment and to return it when they arrived to start their next chemotherapy cycle. Thus, patients completed questionnaires at home on three occasions: before the start of chemotherapy (Home 1), between the second and third cycles (Home 2), and between the third and fourth cycles (Home 3). In addition to these questionnaires, patients completed other measures in the clinic immediately before the start of each of the first four cycles of chemotherapy (Clinic 1 to Clinic 4). Noncancer comparison subjects were recruited using a peer nomination procedure. Specifically, breast cancer patients participating in studies of fatigue were asked to nominate a female friend or relative who might be willing to serve as a participant. These nominees had to be within 5 years of the patient’s age and have no known history of cancer. The nominees were initially contacted by telephone in order to explain the study, confirm their eligibility, and obtain verbal informed consent. Those women who agreed to participate were then mailed an informed consent form, a questionnaire (Home 1), and a stamped preaddressed envelope with which to return these materials. Two additional questionnaires (Home 2 and Home 3) were mailed at 3- to 6-week intervals in order to correspond to the time between questionnaire administrations for the chemotherapy group. Telephone reminders were used to ensure the prompt return of study questionnaires.
Measures The Fatigue Scale from the Profile of Mood States (POMS-F)18 is a widely used seven-item measure of fatigue severity. Respondents indicate on a five-point rating scale (0 5 not at all, 4 5 extremely) how well each adjective describes how they have been feeling during the preceding week. The POMS-F was included in the Home 1–3 questionnaires completed by all participants. The Fatigue Symptom Inventory (FSI)19 assesses the frequency and severity of fatigue as well as its perceived interference with quality of life. Frequency is measured as the number of days in the past week (0–7) respondents felt fa-
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tigued as well as the percentage of each day on average they felt fatigued (0 5 not at all, 10 5 entire day). Severity is measured on an 11point scale (0 5 not at all fatigued, 10 5 as fatigued as I could be) that assesses average fatigue during the past week. Perceived interference is measured on seven separate 11-point scales (0 5 no interference, 10 5 extreme interference) that assess the degree to which fatigue was judged to interfere with general activity, ability to bathe and dress, normal work activity, ability to concentrate, relations with others, enjoyment of life, and mood in the past week. Interference ratings are also summed to yield a total interference score. Previous research has demonstrated the reliability and validity of the FSI when administered to both breast cancer patients and women with no history of cancer.19,20 The FSI was included in the Home 1–3 questionnaires completed by all participants. The Memorial Symptom Assessment Scale (MSAS)21 assesses symptoms commonly associated with cancer and its treatment in terms of their prevalence, severity, and distress. The present study used a modified version which consisted of 26 symptoms including fatigue. Respondents rated each symptom in terms of its: a) presence/absence; b) intensity (0 5 absent, 3 5 severe); and c) distress or bothersomeness (0 5 not at all, 3 5 very much). The MSAS was included in the Clinic 1–4 questionnaires completed only by chemotherapy patients. At Clinic 1, patients rated their experience of symptoms during the preceding week. At Clinics 2–4, participants rated their experience of symptoms for the period since the last infusion. A self-report form was used to obtain information regarding the age, marital status, menopausal status, ethnicity, income, and education of both the chemotherapy patients and noncancer comparison subjects. Participants also provided ratings of their performance status using a self-report version of the Eastern Cooperative Oncology Group (ECOG) Performance Status Scale.22 These forms were included in the Home 1 questionnaire. In addition, the medical charts of chemotherapy patients were reviewed to obtain information about stage of disease, type of breast cancer surgery performed, and type of chemotherapy agents administered.
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Results Demographic and Medical Characteristics Information about the demographic characteristics of the chemotherapy group and the noncancer comparison group is listed in Table 1. The chemotherapy group ranged in age from 28 to 77 years. A majority of these women were white (91%), postmenopausal (56%), married (63%), and college graduates (69%); 50% reported a household income of $40,000 or more per annum. The noncancer comparison group ranged in age from 32 to 77 years. A majority of these women were also white (100%), postmenopausal (61%), married (70%), and college graduates (65%); 48% reported a household income of $40,000 or more per annum. There were no significant (P # 0.05) differences between the chemotherapy group and the noncancer comparison group on any demographic variables. Disease stage for the chemotherapy patients was as follows: stage I, 9 patients (16.7%); stage II, 36 patients (66.7%); and stage III, 9 patients (16.7%). With regard to surgical treatment, 25 women (46.3%) underwent mastectomy, 24 women (44.4%) underwent lumpectomy, 1 woman (1.9%) underwent both mastectomy and lumpectomy, and 4 women (7.4%) did not undergo surgery other than breast biopsy prior to chemotherapy. With regard to chemotherapy regimens, 14 women (25.9%) received Table 1 Demographic Characteristics of the Chemotherapy and Noncancer Comparison Groupsa Group Variable Age, yearsb Income $ $40,000 , $40,000 Marital status Married Unmarried Education College graduates Other Ethnic group White Nonwhite Menopausal status Post Pre/peri a All
Chemotherapy (n = 54)
Noncancer (n = 54)
51 6 10
54 6 11
27 27
26 28
34 20
38 16
37 17
35 19
49 5
54 0
30 24
33 21
comparisons were nonsignificant (P . 0.05). expressed as mean 6 SD.
b Value
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doxorubicin, 25 women (46.3%) received doxorubicin and cyclophosphamide, 11 women (20.4%) received doxorubicin, cyclophosphamide, and fluorouracil, and 4 women (7.4%) received doxorubicin, cyclophosphamide, and methotrexate.
Group Differences in Fatigue The first set of analyses tested the hypothesis that fatigue would be greater in chemotherapy patients than in noncancer comparison subjects. To test this hypothesis, scores on each fatigue measure administered to both groups were entered into separate 2 (Group: chemotherapy, noncancer comparison) 3 3 (Time: Home 1–3) repeated measures analyses of variance (ANOVA) designs. The study hypothesis was evaluated by examining the significance of the Group effect. If the overall Group effect was significant (P # 0.05), additional simple effect analyses were conducted to determine the specific time or times of assessment that the groups differed significantly in fatigue. Mean scores and standard deviations for each group at each time of assessment are listed in Table 2. Analysis of POMS-F scores yielded the expected Group effect (F 5 12.24, P 5 0.0007). Simple effects analyses indicated that the chemotherapy group reported significantly (P # 0.05) greater fatigue at Home 1 and Home 3. Analysis of FSI scores yielded the expected Group effects for average fatigue (F 5 12.82, P 5 0.0005), number of days fatigued (F 5 22.40, P , 0.0001), and amount of each day fatigued (F 5 29.44, P , 0.0001) in the past week. The expected Group effect was also observed for the total fatigue interference score (F 5 21.28, P , 0.0001). Simple effects analyses indicated that differences between groups on these measures were in the predicted direction and were significant (P # 0.05) at all three times of assessment. In order to further examine the impact of fatigue on quality of life, repeated measures ANOVAs were performed on each of the seven FSI ratings which were summed to obtain the total interference score. The expected Group effects were observed for ratings of the degree to which fatigue interfered with general activity (F 5 26.76, P , 0.0001), ability to bathe and dress (F 5 10.48, P 5 0.002), normal work activity (F 5 27.39, P , 0.0001), ability to concentrate (F 5 7.96, P 5 0.006), relations with oth-
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Table 2 POMS-F and FSI Scores of the Chemotherapy and Noncancer Comparison Groups Assessment Scale Group POMS-F Chemotherapy Noncancer FSI-Average Chemotherapy Noncancer FSI–No. of days Chemotherapy Noncancer FSI–Amt. of each day Chemotherapy Noncancer FSI–Summary interference Chemotherapy Noncancer a Mean b Mean
Home 1
Home 2
Home 3
M
(SD)
M
(SD)
M
(SD)
9.90a 6.59
(7.03) (5.74)
9.18 6.83
(7.29) (5.19)
11.06a 5.11
(8.13) (4.96)
4.03a 2.91
(2.09) (1.98)
4.11a 3.30
(1.93) (1.82)
4.13a 2.76
(2.15) (2.07)
5.09a 3.09
(2.36) (2.20)
4.74a 3.63
(2.25) (2.22)
4.89a 3.06
(2.41) (2.18)
3.76a 2.50
(2.52) (1.84)
4.44a 2.50
(2.76) (1.62)
4.67a b 2.35
(2.82) (1.59)
2.72a 1.42
(2.15) (1.49)
2.71a 1.51
(2.29) (1.49)
2.92a 1.16
(2.32) (1.21)
scores at this assessment for chemotherapy and noncancer groups differ significantly (P # 0.05). scores for chemotherapy at Home 1 and this assessment differ significantly (P # 0.05).
ers (F 5 12.98, P 5 0.0005), enjoyment of life (F 5 15.77, P , 0.0001), and mood (F 5 14.06, P 5 0.0003). With two exceptions (ability to bathe/dress and ability to concentrate at Home 2), simple effects analyses indicated that chemotherapy patients reported significantly (P # 0.05) greater interference due to fatigue than noncancer comparison subjects on each rating at each time of assessment (results not shown).
Changes in Fatigue During Adjuvant Chemotherapy The next set of analyses tested the hypothesis that fatigue would increase following the initiation of adjuvant chemotherapy. To test this hypothesis, scores on each fatigue measure administered to the chemotherapy patients during the Home 1–3 assessments were entered into separate repeated measures ANOVA designs with one within-groups factor (Time: Home 1–3). The study hypothesis was evaluated by examining the significance of the Time effect. If the overall Time effect was significant (P # 0.05), simple effects analyses were conducted. Specifically, scores for the assessment conducted before the start of chemotherapy (Home 1) were compared to those for the assessments conducted between the second and third cycles (Home 2) and the third and fourth cycles (Home 3) to identify changes in fatigue following initiation of chemotherapy. Simple
effects analyses were also conducted to identify changes in fatigue over the course of treatment (i.e., between Home 2 and Home 3). Analysis of POMS-F scores did not yield the expected Time effect (F 5 2.31, P 5 0.10). Analysis of FSI scores yielded a significant Time effect only for the amount of time each day patients experienced fatigue (F 5 3.13, P 5 0.047). Simple effects analyses indicated that the amount of time each day patients experienced fatigue increased significantly (P # 0.03) between Home 1 and Home 3. Patients’ MSAS ratings of fatigue were also available to evaluate the study hypothesis (Table 3). MSAS fatigue severity and distress ratings obtained at each clinic assessment were entered into separate repeated measures ANOVA designs with one within-groups factor (Time: Clinics 1–4). If the overall Time effect was significant (P # 0.05), simple effects analyses were conducted in order to identify changes in fatigue following initiation of chemotherapy. In these analyses, scores obtained before the start of chemotherapy (Clinic 1) were compared with those obtained before the second cycle (Clinic 2), third cycle (Clinic 3), and fourth cycle (Clinic 4). Simple effects analyses were also conducted to identify changes in fatigue over the course of treatment (i.e., between Clinic 2, Clinic 3, and Clinic 4). The expected Time effect was observed for MSAS ratings of both severity (F 5 6.36, P 5
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Table 3 MSAS Fatigue Scores of the Chemotherapy Group Prevalence Assessment Clinic 1 Clinic 2 Clinic 3 Clinic 4
Severity
Distress
N
%
M
(SD)
M
(SD)
38 49a 50a 48a
(72%) (92%) (94%) (91%)
1.35 1.87a 1.75a 1.96a
(0.93) (0.83) (0.79) (0.90)
1.17 1.56a 1.40 1.66a
(1.08) (0.98) (0.88) (0.94)
a Value differs significantly (P # 0.05) from corresponding value at Clinic 1.
0.0004) and distress (F 5 4.68, P 5 0.004). Simple effects analyses indicated that patients reported significantly (P # 0.05) more severe fatigue at Clinic 2, Clinic 3, and Clinic 4 than at Clinic 1. Similarly, patients reported significantly (P # 0.05) greater fatigue-related distress at Clinic 2 and Clinic 4 than at Clinic 1. To further characterize the changes in fatigue severity during chemotherapy, the percentages of patients reporting each level of severity (0–3) at Clinic 1 and Clinic 4 were calculated. Inspection of the data indicated that the greatest changes were in the percentages of patients reporting no fatigue (0) and severe fatigue (3). Between Clinic 1 and Clinic 4, the percentage of patients reporting no fatigue declined from 28% to 9%, whereas the percentage of patients reporting severe fatigue increased from 4% to 28%. MSAS ratings of fatigue prevalence (presence/absence) obtained at each clinic assessment were analyzed by conducting the nonparametric McNemar change test.23 Consistent with predictions, fatigue was significantly (P # 0.05) more prevalent at Clinic 2, Clinic 3, and Clinic 4 than at Clinic 1. For example, the prevalence of fatigue was found to increase from 72% at Clinic 1 to 91% at Clinic 4.
Factors Associated with Fatigue Severity Before the Start of Chemotherapy The next set of analyses focused on identifying factors associated with individual differences in patients’ reports of fatigue severity before the start of chemotherapy. The MSAS rating of fatigue severity obtained at Clinic 1 served as the outcome measure for these analyses and for those that follow. The MSAS severity rating was chosen based on results demonstrating the presence of significant increases on this measure following the initiation of che-
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motherapy. This feature means that MSAS severity ratings can also be used to identify factors that are associated with increases in fatigue after the start of chemotherapy (see below). Results of correlational analyses and ANOVAs yielded nonsignificant (P $ 0.10) relationships between the following demographic and medical variables and fatigue severity before the start of chemotherapy: age, menopausal status, type of surgery, and stage of disease. In contrast, performance status was found to be significantly related to fatigue severity (F 5 7.14, P 5 0.01). As would be expected, patients who reported no restrictions were less fatigued than patients who reported restrictions (M 5 0.75 vs. M 5 1.52). Correlational analyses were also conducted to examine the relationship between fatigue severity and reports of other symptoms on the MSAS before the start of chemotherapy. Results indicated a significant positive relationship between the number of other symptoms reported and fatigue severity (r 5 0.53, P , 0.0001). Examination of individual MSAS items indicated that the presence of the following symptoms was significantly (P # 0.05) positively correlated with more severe fatigue before the start of chemotherapy: emotional upset (r 5 0.44), muscle weakness (r 5 0.43), pain (r 5 0.37), numbness (r 5 0.35), sleep problems (r 5 0.34), problems with concentration (r 5 0.34), and heartburn (r 5 0.28). Based on the results obtained, a hierarchical multiple regression analysis was conducted to determine the amount of variability in fatigue severity accounted for by performance status and the number of other symptoms reported. As shown in Table 4, performance status accounted for 12% of the variability in fatigue severity; after accounting for performance status, the number of symptoms other than fatigue accounted for an additional 18% of the variability in fatigue severity.
Table 4 Multiple Regression Analysis of Fatigue Severity Before the Start of Chemotherapya b
Variable Performance status No. of other symptoms a Multiple bP
# 0.01.
0.15 0.47
R = 0.55; F (2, 53) = 11.20, P , 0.0001.
r2 change 0.12b 0.18b
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Factors Associated with Changes in Fatigue Severity After the Start of Chemotherapy The last set of analyses focused on identifying factors associated with changes in patients’ reports of fatigue severity after the start of chemotherapy. In order to conduct these analyses, residualized fatigue severity change scores were created by partialling MSAS fatigue severity at Clinic 1 from MSAS fatigue severity at Clinic 4.24 The resulting variable represents the change in fatigue severity between Clinic 1 and Clinic 4 that is not related to baseline (Clinic 1) levels of fatigue. Results of regression analyses yielded nonsignificant (P $ 0.10) relationships between the following demographic and medical variables and changes in fatigue severity between Clinic 1 and Clinic 4: age, menopausal status, performance status, stage of disease, type of surgery, and chemotherapy regimen. In contrast, there was a significant positive relationship between the number of symptoms other than fatigue experienced after the first, second, and third cycles as measured by the MSAS and changes in fatigue severity between Clinic 1 and Clinic 4 (t 5 3.42, P 5 0.001). Number of symptoms was found to account for 18% of the variability in changes in fatigue severity. Additional regression analyses were conducted to examine the relationship between the frequency of occurrence of individual symptoms and changes in fatigue severity. Results indicated that the more frequent occurrence of the following symptoms was associated with significant (P # 0.05) increases in fatigue severity between Clinic 1 and Clinic 4: pain (t 5 3.45), emotional upset (t 5 2.83), nausea (2.70), mouth sores (t 5 2.62), muscle weakness (t 5 2.60), change in taste (t 5 2.10), sleep problems (t 5 2.08), chills (t 5 2.00), and vomiting (t 5 2.00).
Discussion Women receiving adjuvant chemotherapy for breast cancer were found to experience significantly worse fatigue than an age-matched comparison group of women with no cancer history. Differences between patients and comparison subjects were evident on measures of the severity and frequency of fatigue as well as its perceived interference with quality of life.
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These differences were observed both before and after chemotherapy was initiated for the breast cancer patients. Changes in fatigue following the start of treatment were evident mostly on ratings that encompassed the interval between infusions. Analysis of these ratings indicated that fatigue increased in prevalence, severity, and disruptiveness after the start of treatment. More severe fatigue before the start of treatment was associated with poorer performance status and with the presence of several fatigue-related symptoms (e.g., sleep problems and muscle weakness). Increases in fatigue severity following the start of chemotherapy were associated with the continued presence of fatigue-related symptoms and the development of treatment side effects (e.g., nausea and mouth sores). The following discussion integrates these findings with previous research, considers the clinical implications, and identifies directions for future research. The present study provides strong evidence that fatigue is a significant clinical problem during adjuvant chemotherapy for breast cancer. As predicted, the fatigue experienced by women undergoing adjuvant chemotherapy was considerably more severe than the fatigue experienced by women of similar age with no cancer history. For example, the average level of fatigue reported on the POMS-F by breast cancer patients before their third treatment cycle was more than twice that reported by the age-matched comparison group. These findings are consistent with results from one of the few other studies of chemotherapy-related fatigue to include a noncancer comparison group. Irvine and colleagues16 assessed fatigue in chemotherapy patients (predominantly women with breast cancer) and a comparison group of women described as auxiliary staff members. The authors found that fatigue was significantly more severe in the chemotherapy group when assessed 10 to 14 days after their last treatment. Additional findings from the present study support the view that the observed differences in fatigue severity were clinically as well as statistically significant. Compared to women with no history of cancer, women receiving chemotherapy reported that fatigue interfered to a greater extent with their general activity, ability to bathe and dress, normal work activity, ability to concentrate, relations with others, enjoyment of life, and mood.
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An unexpected finding in the current study was that breast cancer patients reported more severe fatigue than a comparison group even before chemotherapy was initiated. There are at least two possible explanations for this finding. First, the heightened fatigue in the patient group before the start of chemotherapy may reflect lingering physical and psychological stresses associated with having recently undergone breast cancer surgery. Previous research25 has demonstrated that cognitive manifestations of fatigue may persist for as long as 90 days following mastectomy or lumpectomy. A second and not mutually exclusive explanation is that heightened fatigue before the start of chemotherapy may be a reflection of the heightened emotional distress. We26 have previously shown that adjuvant chemotherapy patients experience significantly greater anxiety before their first infusion than before subsequent infusions. In light of research suggesting that emotional distress is a source of fatigue for cancer patients,16,20,27 it is reasonable to speculate that anticipatory anxiety contributed to the heightened fatigue experienced by patients before the start of chemotherapy. The present study confirmed the prediction that breast cancer patients would experience a worsening of their fatigue following the initiation of chemotherapy. To the best of our knowledge, no previous study of chemotherapy-related fatigue has tested this prediction. As noted above, changes in fatigue were evident mostly for ratings that encompassed the entire interval between infusions. In general, there were no changes from pretreatment levels for ratings of fatigue for the week before the start of each cycle. This pattern of results is consistent with prior research which generally indicates that fatigue reaches its peak intensity at or before the midpoint between treatment cycles and then declines during the remainder of the treatment cycle.13,16,28 Taken together, findings from the present study and past research suggest that the ability to detect changes in fatigue from pretreatment levels may be a function of the time period covered by the ratings. There was no evidence in the present study that, following the initiation of adjuvant chemotherapy, fatigue worsened over the course of subsequent infusions. Although this finding may seem to contradict conventional wisdom,
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it is supported by previous research. In a study that is similar to the present study, Berger28 assessed fatigue over the course of the first three treatment cycles in breast cancer patients receiving adjuvant chemotherapy. Levels of fatigue were found to be similar in the 48 hours after each treatment. It should be noted that the results of these studies do not rule out the possibility that fatigue may worsen over time after additional treatment cycles or with other forms of chemotherapy. In general, the severity of fatigue experienced by patients before and after initiation of chemotherapy was unrelated to demographic, disease, or treatment variables. These results may reflect the fact that, by design, there was limited variability in patients’ medical characteristics and, to a lesser extent, in their demographic characteristics. The one exception was the significant relationship between poorer ECOG performance status and greater fatigue before the start of chemotherapy. This relationship has been reported in at least one previous study.15 In a sample of chemotherapy patients heterogeneous in terms of both disease site and stage, ECOG performance status was found to be a better predictor of fatigue severity than age, gender, or extent of disease. The present study identified an interesting pattern of relationships between fatigue and the experience of other symptoms before and after the start of chemotherapy. Before the start of chemotherapy, more severe fatigue was related to the presence of emotional upset, pain, muscle weakness, sleep problems, numbness, heartburn, and problems with concentration. Moreover, the continued presence of emotional upset, pain, muscle weakness, and sleep problems was associated with increases in fatigue severity following the start of treatment. The co-occurrence of these symptoms with fatigue does not appear to be unique to the situation of cancer patients receiving chemotherapy. Emotional upset, pain, muscle weakness, sleep problems, and problems with concentration have been shown to be associated with fatigue in cancer patients who have successfully completed treatment20,29,30 and with chronic fatigue in individuals with no history of cancer or other major illnesses.31,32 Indeed, these symptoms are among those included in many descriptions of chronic fatigue syndromes.33 Of particular interest in the present study was
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Fatigue During Chemotherapy for Breast Cancer
evidence that several symptoms which are not typically associated with fatigue, but are common side effects of chemotherapy, were also related to increases in fatigue severity following the start of treatment. Specifically, patients who reported the more frequent occurrence of nausea, mouth sores, changes in taste, chills, and vomiting were also more likely to experience a worsening of their fatigue after the start of chemotherapy. This pattern of results suggests that the development of aversive treatment side effects is an important mechanism by which the initiation of chemotherapy results in a worsening of fatigue in women with breast cancer. Several recommendations for clinical practice can be drawn from the present study. Treatment providers and patients need to know that many women receiving chemotherapy for breast cancer will experience severe fatigue that can seriously compromise their physical and mental well-being and ability to function. This information should be communicated routinely as part of pretreatment education so that patients can form accurate expectations and plan for the possibility that they may have to restrict their daily activities. Patients can be reassured, however, that fatigue is unlikely to continue to worsen as they return for additional cycles of adjuvant chemotherapy. Finally, the results of the present study underscore the importance of providing chemotherapy patients with effective analgesic and antiemetic regimens. In addition to relieving pain and gastrointestinal distress, appropriate use of these therapies may serve to reduce the fatigue that most patients also experience. The current study suggests two directions for future research. First, there is a need for research into the biological correlates of changes in fatigue severity among adjuvant chemotherapy patients. A recent study of cancer patients not receiving chemotherapy or radiotherapy demonstrated that lower hemoglobin levels were associated with greater subjective reports of fatigue.34 It would be of interest to determine if a similar relationship exists between changes in fatigue severity and changes in hemoglobin levels following the start of chemotherapy. Evidence of such a relationship would support the use of agents that increase hemoglobin production (e.g., erythropoietin) as treatments for chemotherapy-related fatigue. A second direction for future research is to ex-
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amine psychosocial correlates of individual differences in fatigue severity during chemotherapy. Along these lines, we recently demonstrated that reliance on catastrophizing as a coping strategy was associated with significantly worse fatigue among women with breast cancer previously treated with adjuvant chemotherapy.20 Demonstration of a similar relationship among women currently undergoing treatment would suggest that psychological interventions may also play a role in the treatment of chemotherapyrelated fatigue. By reducing reliance on catastrophizing and promoting more adaptive coping strategies, it may be possible to relieve patients’ fatigue and improve their quality of life. In conclusion, the results of this study provide new information about the characteristics, course, and correlates of fatigue in women receiving adjuvant chemotherapy for breast cancer. With regard to characteristics, findings clearly demonstrate that the degree of fatigue experienced by women with breast cancer is significantly worse than that reported by women with no cancer history even before the start of chemotherapy. With regard to course, there is evidence that the prevalence, severity, and disruptiveness of fatigue increased following the start of chemotherapy but did not increase further over the first three treatment cycles. With regard to correlates, results suggest that the development of aversive treatment side effects such as nausea and mouth sores contributes to increases in fatigue following the start of chemotherapy. Although this study answered several questions about chemotherapy-related fatigue, there is much that still remains to be learned. Identifying biological and psychosocial mechanisms that underlie the development of chemotherapy-related fatigue should be a high priority for future research. Beyond this, there is a need to identify pharmacologic and/or psychosocial interventions that are effective in relieving the fatigue so commonly experienced by cancer chemotherapy patients.
Acknowledgment This work was supported by an Institutional Research Grant from the American Cancer Society (ACS IRG202) to the Moffitt Cancer Center and Research Institute.
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