Fatigue and Sleep Disturbance in Patients with Cancer, Patients with Clinical Depression, and Community-Dwelling Adults

Vol. 25 No. 4 April 2003 Journal of Pain and Symptom Management 307 Original Article Fatigue and Sleep Disturbance in Patients with Cancer, Patients with Clinical Depression, and Community-Dwelling Adults Karen O. Anderson, PhD, Carl J. Getto, MD, Tito R. Mendoza, PhD, Stephen N. Palmer, PhD, Xin Shelley Wang, MD, Cielito C. Reyes-Gibby, DrPH, and Charles S. Cleeland, PhD Department of Symptom Research, Division of Anesthesiology and Critical Care (K.O.A., T.R.M., S.N.P., X.S.W., C.C.R.-G., C.S.C.), The University of Texas M. D. Anderson Cancer Center, Houston, Texas, and Department of Psychiatry (C.J.G.), University of Wisconsin-Madison, Madison, Wisconsin, USA Abstract This study compared the severity of fatigue in patients with cancer to the fatigue reported by depressed psychiatric patients and community-dwelling adults. Data were collected for this study during the process of validating a new fatigue assessment tool, the Brief Fatigue Inventory (BFI). The sample included 354 cancer patients, 72 psychiatric patients, and 290 non-patient volunteers. Study subjects reported severity of fatigue and the degree to which fatigue interfered with various aspects of life. Data were also collected on sleep disturbance and demographic variables that might correlate with fatigue. The psychiatric patients reported significantly higher levels of fatigue and fatigue-related interference than the cancer patients, who reported more severe fatigue and interference than the community subjects. The sleep disturbance scores of the cancer patients and the community subjects were significantly correlated with fatigue severity. Although the majority of the psychiatric patients reported sleep disturbance, their sleep disturbance scores were not significantly associated with fatigue severity. J Pain Symptom Manage 2003;25:307 318. 2003 U.S. Cancer Pain Relief Committee. Published by Elsevier. All rights reserved. Key Words Fatigue, cancer, depression, mood disorder, sleep disorder Introduction Fatigue is the most frequently reported symptom of cancer patients. 1 Moreover, it is often reported as the symptom that is the most Address reprint requests to: Karen O. Anderson, PhD, Department of Symptom Research, U.T.M.D. Anderson Cancer Center, 1100 Holcombe Boulevard, Box 221, Houston, TX 77030, USA. Accepted for publication: June 7, 2002. distressing and causes the greatest amount of interference with daily life. 2 The majority of patients undergoing cancer treatments such as chemotherapy, radiotherapy, biological therapy, or surgery report significant fatigue. 3 6 Fatigue is also very common in patients with advanced disease who are receiving palliative treatment. 7 9 In addition, many cancer survivors report continued fatigue that adversely impacts their quality of life. 10 12 2003 U.S. Cancer Pain Relief Committee 0885-3924/03/$ see front matter Published by Elsevier. All rights reserved. doi:10.1016/s0885-3924(02)00682-6

308 Anderson et al. Vol. 25 No. 4 April 2003 Fatigue in cancer patients may be caused by multiple factors that include the disease process itself, cancer treatments, nutritional status, deconditioning, activity level, anemia, medications, sleep disturbance, and psychological factors. The possible role of depression in cancerrelated fatigue has been explored in several studies. Some investigations of patients with cancer have reported a significant association between fatigue and depression, whereas other studies have not found a strong relation. 6,12 18 Many cancer patients experience depression at some point during their illness. 19,20 The prevalence rate of depression in cancer patients is two to three times the rate found in the general population. 21 Fatigue is a common somatic symptom of clinical depression and is included in the diagnostic criteria for major depressive disorder, bipolar disorder, and dysthymic disorder. 22 It has been estimated that more than two-thirds of patients with depression present with signs of fatigue that may include low energy and listlessness. 23 Several investigators have suggested that fatigue and depression are overlapping conditions that may share similar underlying mechanisms. 17,23 25 In order to better understand the nature of fatigue in cancer, it is important to determine how cancer-related fatigue differs from the fatigue associated with clinical depression. As part of a larger project developed to describe cancer-related fatigue, this study was designed to look at the severity of fatigue in cancer patients and compare it to the fatigue reported by depressed psychiatric patients and a control group of community-dwelling subjects. We were also interested in the relationship of sleep disturbance to fatigue in each population. Sleep disturbance, a frequent correlate of fatigue, is commonly reported by the general population, patients with cancer, and patients with clinical depression. 26 29 Sleep disturbance, defined as insomnia or hypersomnia occurring nearly every day, is a symptom of clinical depression. Studies on sleep disturbance among the general population have found that lack of sleep is significantly associated with reported fatigue. 27,29 Sleep disturbance among cancer patients has received limited research attention. Estimates of the prevalence of sleep disturbance in samples of cancer patients range from 23% to over 50%. 26 Some evidence suggests that sleep disturbance is associated with patients fatigue levels. 17 For example, a recent study of cancer patients undergoing radiotherapy found that improvements in sleep patterns were associated with decreases in patients fatigue. 30 Additional research is needed to explore the relationship of fatigue and sleep disturbance among cancer patients. It is also important to understand how this relationship may differ from that found in the general population and in patients experiencing clinical depression. The purpose of the present study was to compare fatigue severity, fatigue-related interference in daily activities, and sleep disturbance in samples of cancer patients, depressed psychiatric patients, and non-patient, communitydwelling adults. Methods Study Design and Overview The Brief Fatigue Inventory (BFI) was developed by the Department of Symptom Research to measure and describe fatigue in cancer populations. 31 In the process of validating this new assessment tool, the BFI was administered to samples of depressed psychiatric patients, community-dwelling adults, and patients with cancer. The present study was approved by the Institutional Review Boards of the University of Wisconsin-Madison and the University of Texas M.D. Anderson Cancer Center. Data were collected on various measures indicating severity of fatigue, interference of fatigue with several activities, sleep patterns, and demographic variables. In this paper, we compare the fatigue experience of the cancer patients, psychiatric patients, and community subjects. Study Subjects The data from cancer patients (n 354) were collected at the University of Texas M.D. Anderson Cancer Center in the departments of Blood and Marrow Transplantation, Leukemia, Lymphoma, Gastrointestinal Oncology, and Radiation Oncology. We recruited both inpatients and outpatients in order to explore the full spectrum of cancer-related fatigue. Patients were at least 18 years of age, able to read and understand English, had a pathological diagnosis of cancer, and had given verbal consent to participate. Patients were excluded if their

Vol. 25 No. 4 April 2003 Fatigue and Sleep Disturbance 309 clinical status was judged to be too poor to allow them to complete the survey. The eligible patients who agreed to participate in the study were administered the questionnaire packet. The depressed patients (n 72) were recruited from the outpatient affective disorders clinic in the Department of Psychiatry at the University of Wisconsin-Madison. The second author (CG) identified patients who met the eligibility criteria for the study. The patients were at least 18 years of age, able to read and understand English, and were receiving treatment for clinical depression. Forty-three percent of the patients were diagnosed with Major Depressive Disorder, 28% with Bipolar Disorder (most recent episode depressed), 8% with Dysthymic Disorder, 7% with Adjustment Disorder with depressed mood, 5% with a Mood Disorder not otherwise specified, 3% with Posttraumatic Stress Disorder, and 6% with other diagnoses (Cocaine-Induced Mood Disorder, Somatization Disorder, undifferentiated Schizophrenia) from the Diagnostic and Statistical Manual of Mental Disorders. 22 None of the psychiatric patients had a current or prior diagnosis of cancer. The patients who agreed to participate and provided signed informed consent were administered a questionnaire packet. The community sample (n 290) was recruited from various service organizations in the Houston metropolitan area. Each organization was contacted in advance and permission was granted to introduce the study and recruit participants at a future organization meeting. Any person attending the organization meeting on the scheduled date was eligible to participate. In order to obtain a representative sample of the general community, no attempt was made to exclude people with cancer, depression, or any other medical condition. Study team members attended the organization meeting, explained the study to attendees, and distributed the questionnaire packets to attendees who gave verbal consent. A cover letter to the packet further explained the study and indicated that completing the questionnaires implied informed consent. Measures Data collected for this study included: The Brief Fatigue Inventory (BFI). The BFI was developed to assess the severity of fatigue and the amount of interference with function caused by fatigue. 31 In the initial validation study, the BFI demonstrated good internal stability, with a Cronbach s coefficient alpha of 0.94. It was also significantly correlated with two previously validated measures, the Fatigue Subscales of the Profile of Mood States 32 (POMS; r 0.64, P 0.001) and the Functional Assessment of Cancer Therapy 33 (FACT; r 0.74, P 0.001). Factor analysis of the BFI revealed a single dimension of fatigue report. 31 Three items in the BFI ask subjects to rate their fatigue during the past 24 hours at its worst, usual or average, and now, with 0 being no fatigue, and 10 being fatigue as bad as you can imagine. Additional items assess how much fatigue has interfered with different aspects of the subject s life during the past 24 hours. The interference items included in the present study were mood, normal work, relations with other people, and enjoyment of life. Each interference item is scored on an elevenpoint rating scale from 0 ( does not interfere ) to 10 ( completely interferes ). A mean BFI score is calculated as the mean of the intensity and interference items. Sleep Disturbance Scale. A three-item sleep disturbance scale was constructed to assess sleep patterns and severity of sleep disturbance during the past 24 hours. The items were chosen after a review of the literature and discussion with experts on sleep disorders. Items included waking up during the night, waking up too early in the morning, and difficulty falling asleep. A fourth item, feeling rested and refreshed on awakening, was included in the original scale but was subsequently eliminated due to poor reliability. The subjects were also asked to report how many hours per night they usually slept. Each item (except hours of sleep) was scored on a Likert scale with anchors of not at all true of me to extremely or completely true of me. The sleep items administered to the depressed patients were scored on a 5-point Likert scale. The sleep items administered to the cancer patients and community subjects were scored on an 11-point Likert scale. In order to control for the differences in the scales, standardized z scores were used for the statistical analyses. An overall sleep disturbance score for each subject was calculated as the mean of the sum

310 Anderson et al. Vol. 25 No. 4 April 2003 of scores on the three sleep items: waking up too early in the morning, waking up during the night, and having difficulty falling asleep. The sleep disturbance scale demonstrated adequate internal reliability, with a coefficient alpha of 0.71. Construct validity was supported using factor analysis of the scale. This procedure identified a single underlying construct. The factor loadings were high, and ranged from 0.75 to 0.83. The Profile of Mood States (POMS). The Vigor and Fatigue subscales of the POMS were administered to all subjects. 32 These subscales include eight items describing feelings of vigor (e.g., energetic, full of pep ) and seven items describing feelings of fatigue (e.g., listless, bushed ). Each question is scored on a fivepoint rating scale from 0 ( not at all ) to 4 ( extremely ). Zung Self-Rating Depression Scale. The Zung Self-Rating Depression Scale was administered to the psychiatric patients. The Zung is a commonly used self-report measure of depression and has well-established psychometric properties. 34 Beck Depression Inventory (BDI). The BDI was administered to the psychiatric patients. The BDI contains 21 items that assess cognitive, affective, and somatic symptoms of depression rated on 4-point scales. Numerous studies have found the BDI to be a valid (predictive validity of 0.91) and reliable (internal consistency of 0.91) measure of depression. 35,36 Other Data. Data were collected on other potential risk factors for fatigue including gender, ethnic background, age, education level, marital status, and employment status. Statistical Analyses Patients were classified as having severe (ratings of 7 to 10), or non-severe (ratings of 6 or less) fatigue ased on their BFI fatigue worst responses. This classification system was developed in the initial validation study of the BFI and is based on the relationship of fatigue worst to fatigue-related interference. 31 A cut point of 7 is associated with a large increase in fatigue-related interference. Patients with severe fatigue report significantly greater interference in their lives due to fatigue than patients with non-severe fatigue. Data on fatigue severity, fatigue interference, and other variables were categorized and summarized by subject group. Given that the length of the Likert scales for the sleep disturbance items differed among the three subject groups, the sleep disturbance scores were transformed into standardized z scores prior to analysis. The relationships among fatigue, sleep disturbance, and demographic variables were explored using descriptive statistics and bivariate correlations. Analyses of variance and covariance were used to compare the BFI and sleep disturbance scores of the three subject groups: cancer patients, depressed psychiatric patients, and community subjects. Fisher s LSD test was used for post-hoc comparisons among groups. We were interested in identifying predictors of subjects fatigue levels. Using the mean BFI fatigue score as the dependent variable, we developed multiple linear regression models for each subject group. The possible predictors in the models included gender, age, race, education, employment status, marital status, and sleep disturbance. Results Demographic Characteristics Table 1 presents the descriptive characteristics of the cancer patients, depressed patients, and community subjects who participated in the study. The cancer patients and community subjects were approximately the same age; the depressed patients had a significantly younger mean age (P 0.01). Most of the community subjects were male, and most of the depressed patients were female. The cancer patient sample was evenly represented by gender. The patients in all three samples tended to be white, married, and well educated, with at least a college degree. The majority of the community subjects and depressed patients were employed full-time, but 21% of the cancer patients were disabled due to illness. The three most common primary cancer diagnoses for the cancer patients were lymphoma, leukemia, and gastrointestinal malignancies. Fatigue Severity and Interference Scores Table 2 presents a descriptive summary of the fatigue measures completed by the three sub-

Vol. 25 No. 4 April 2003 Fatigue and Sleep Disturbance 311 Table 1 Demographic Characteristics of Cancer Patients, Depressed Psychiatric Patients, and Community Subjects Cancer Patients (n 354) Depressed Patients (n 72) Community Adults (n 290) Gender n % n % n % Female 173 49 50 69 88 30 Male 181 51 22 31 201 70 Race a White 279 79 240 85 Others 75 21 44 15 Marital status Married 263 74 38 53 229 79 Single 29 8 22 31 25 9 Divorced 29 8 8 11 22 8 Other 33 9 4 6 14 5 Educational level Elementary 5 1 0 0 4 1 High school 138 39 12 17 31 11 College 127 36 29 40 128 46 Post-graduate 73 21 18 25 118 42 Not reported 11 3 13 18 0 0 Employment Full or part-time 58 16 41 57 178 61 Homemaker 25 7 9 13 20 7 Retired 57 16 1 1 61 21 Disabled 76 21 0 0 2 1 Other 13 4 16 22 29 10 Not reported 125 35 5 7 0 0 Disease type Leukemia (acute) 56 16 Leukemia (chronic) 50 14 Lymphoma 134 38 Myeloma 13 4 Breast 29 8 Gastrointestinal 57 16 Gynecologic 5 1 Genitourinary 2 1 Other 8 2 Median age in years (range) 56 (18 88) 36 (17 72) 57 (17 100) a The race of the depressed psychiatric patients was not assessed. ject groups. On the three BFI fatigue severity items, the depressed patients reported a significantly higher level of fatigue than the cancer patients, who reported more severe fatigue than the community subjects (Ps 0.001). Seventyeight percent of the depressed patients rated their fatigue at its worst in the severe range ( 7 on the 0 10 scale), as compared to 42% of the cancer patients and 17% of the community subjects (P 0.001). The majority of the community subjects reported fairly low levels of fatigue. The analyses of variance on the fatigue severity items revealed main effects for gender, as well as the main effects for group (Ps 0.05). Across all three groups, female subjects tended to report greater fatigue intensity than male subjects (P 0.09). Among the depressed patients, the mean intensity of usual fatigue for the female patients (mean 5.7, SD 2.3) was significantly higher than the mean for the male patients (mean 4.2, SD 2.0, P 0.02). The mean intensity of worst fatigue of the female patients with depression (mean 8.1, SD 2.2) tended to be higher than the mean of the male patients (mean 6.8, SD 2.4, P 0.06). The fatigue now ratings of the female (mean 5.6, SD 3.2) and male (mean 5.1, SD 3.3) patients with depression did not differ (P 0.57). Gender differences were also evident among the community subjects. The female subjects (mean 2.7, SD 2.8) in the community reported higher levels of fatigue now than the male subjects (mean 1.7, SD 1.8, P 0.001). The mean intensity of usual fatigue of

312 Anderson et al. Vol. 25 No. 4 April 2003 Table 2 Means and Standard Deviations on Brief Fatigue Inventory Items and POMS Fatigue and Vigor Scores for Cancer Patients, Depressed Psychiatric Patients, and Community Subjects Measures Range of Possible Scores Cancer Patients Depressed Psychiatric Patients Community Subjects BFI items 0 10 Mean (SD) Mean (SD) Mean (SD) Fatigue worst a 5.5 (2.9) 7.6 (2.4) 3.8 (2.4) Fatigue usual a 3.9 (2.7) 5.2 (2.2) 2.4 (2.0) Fatigue now a 4.1 (2.9) 5.4 (3.2) 2.0 (2.2) Normal work b 5.1 (3.6) 5.3 (3.5) 2.1 (2.3) Mood a 4.3 (3.3) 6.7 (2.4) 2.4 (2.4) Relations with others a 3.7 (3.2) 5.6 (2.9) 2.1 (2.3) Enjoyment of life a 4.7 (3.5) 7.0 (2.9) 2.1 (2.3) POMS fatigue b 0 28 15.1 (8.8) 11.7 (5.6) 6.3 (5.7) POMS vigor b 0 32 11.5 (7.6) 9.7 (7.7) 20.8 (6.7) BFI: Brief Fatigue Inventory; POMS: Profile of Mood States; SD: standard deviation. a Statistically significant differences among the three subject groups (cancer patients versus depressed patients, cancer patients versus community subjects, depressed patients versus community subjects), P 0.001. b Statistically significant differences between the depressed patients and community subjects and between the cancer patients and community subjects, P 0.001. the female subjects (mean 2.7, SD 2.3), tended to be higher than the mean of the male subjects (mean 2.2, SD 1.8, P 0.06). Similarly, the female subjects tended to report slightly higher levels of worst fatigue (mean 4.1, SD 2.7) than the male subjects (mean 3.6, SD 2.3, P 0.09). In contrast to the depressed patients and the community subjects, the patients with cancer did not demonstrate any gender differences with regard to their fatigue intensity ratings (P values ranging from 0.2 to 0.5). Table 2 demonstrates that the depressed patients reported greater fatigue-related interference than cancer patients or community subjects (Ps 0.001). Fatigue severity was used as a covariate in these analyses in order to control for varying levels of fatigue in the three subject samples. The depressed patients reported significantly greater interference in mood, relations with others, and enjoyment of life than the cancer patients or the community subjects. The cancer patients reported greater interference due to fatigue in these areas and in normal work than the community subjects. The cancer patients and the depressed patients reported similar levels of interference in work due to fatigue. The analyses of covariance on the fatigue interference items revealed main effects for gender, as well as the main effect for group (Ps 0.05). Among the depressed patients, the females tended to report greater mood interference due to fatigue (mean 7.0, SD 2.5) than the male patients (mean 5.8, SD 2.0, P 0.07). No other gender differences in fatigue-related interference items were evident among the depressed patients. Among the community subjects, the female subjects reported greater interference with relations with others (mean 2.7, SD 2.8) than the male subjects (mean 1.8, SD 2.0, P 0.003). The female subjects (mean 2.6, SD 2.7) also reported greater interference in enjoyment of life than the male subjects in the community (mean 1.8, SD 2.0, P 0.007). Similarly, the females reported more fatiguerelated work interference (mean 2.5, SD 2.7) than the males in the community (mean 1.9, SD 2.0, P 0.03). In contrast to the depressed patients and the community subjects, the patients with cancer did not demonstrate any gender differences with regard to their fatigue-related interference (P values ranging from 0.2 to 0.9). On the POMS Fatigue subscale, both the depressed patients and the cancer patients reported significantly more fatigue than the community individuals. Similarly, both patient groups reported less vigor than the community subjects on the Vigor subscale of the POMS. Table 2 shows that the depressed patients and cancer patients did not differ significantly with regard to their scores on the two POMS subscales.

Vol. 25 No. 4 April 2003 Fatigue and Sleep Disturbance 313 Fatigue and Depression The mean BDI score of the psychiatric patients was 20.5 (SD 13.6) and the mean Zung score was 59.1 (SD 15.4). Among the psychiatric patients, current levels of depression were significantly correlated with fatigue. The mean BFI score was significantly associated with the mean BDI (r 0.32, P 0.03) and Zung scores (r 0.48, P 0.001). Both the BDI (r 0.42, P 0.002) and Zung (r 0.47, P 0.001) scores also were significantly associated with fatigue now ratings on the BFI. However, BFI ratings of usual fatigue and worst fatigue were not significantly correlated with the depression scores. Analysis of the BFI scores of the DSM-IV diagnostic groups revealed that the patients with bipolar disorder reported lower levels of fatigue now (mean 3.9, SD 3.4) than the patients with a major depressive disorder (mean 6.5, SD 2.7, P 0.05). No significant differences on the other BFI items were evident among the diagnostic groups. Sleep Disturbance One possible explanation for differences in fatigue is varying sleep patterns or occurrence of sleep disturbance. To investigate this possibility further, we looked at the three sleep disturbance items, the total number of hours slept in the past 24 hours, and an overall sleep disturbance score for the three subject groups. This overall score was the mean of the sum of the scores on the three sleep items: waking up too early in the morning, waking up during the night, and having difficulty falling asleep. The results for the sleep items and sleep disturbance scores are shown in Table 3. The cancer patients reported sleeping significantly more hours per night than the depressed patients or the community subjects. However, the cancer patients reported significantly more difficulty than the community subjects on all three sleep items. Table 3 shows that the cancer patients also had a significantly higher mean total sleep disturbance score than the community subjects. Sixty-two percent of the cancer patients reported moderate to severe sleep disturbance (defined as a score of 5 or above on the 0 10 scale). In contrast, 30% of the community subjects and 52% of the depressed patients reported moderate or severe sleep disturbance (P 0.001). Although the majority of the depressed patients reported sleep disturbance, the ratings on the individual sleep items and the total sleep disturbance score of the depressed patients did not differ significantly from that of the cancer patients or the community subjects. It should be noted that only 63 of the 73 depressed patients completed all of the sleep disturbance items. The relationship between sleep disturbance and fatigue was investigated by looking at correlations between BFI items and the total sleep disturbance score. Table 4 shows that the fatigue and interference ratings of the cancer patients and the community subjects were significantly associated with the total sleep disturbance score. In contrast, the total sleep disturbance scores of the depressed patients were not significantly correlated with fatigue intensity. The depressed Sleep Item a Table 3 Comparison of Mean Scores on Sleep Disturbance Items Among Cancer Patients, Depressed Psychiatric Patients, and Community Adults Cancer Patients Mean (SD) Depressed Psychiatric Patients Mean (SD) Community Subjects Mean (SD) Difficulty falling asleep b 4.7 (3.5) 4.1 (3.5) 2.1 (2.7) Wake up during the night b 7.0 (3.0) 5.5 (3.8) 5.6 (3.4) Wake up too early in the morning b 5.1 (3.5) 4.6 (4.0) 3.3 (3.3) Total sleep disturbance score b 5.6 (2.6) 4.8 (2.8) 3.7 (2.3) Hours slept per night b,c 8.2 (3.4) 7.2 (2.3) 7.0 (1.5) a The scores obtained on the 5-point Likert scales administered to the depressed patients were transformed to 11-point scales to facilitate comparison with the scores obtained on the 11-point scales administered to the cancer patients and community subjects. The original scores of all subjects were converted to standardized z scores for the analyses. b Statistically significant difference between the cancer patients and the community subjects, P 0.001. c Statistically significant difference between the cancer patients and the depressed subjects, P 0.02.

314 Anderson et al. Vol. 25 No. 4 April 2003 BFI Item Table 4 Correlations Between Sleep Disturbance and Brief Fatigue Inventory Items Among Cancer Patients, Depressed Psychiatric Patients, and Community Adults Sleep Disturbance Score Cancer Patients Depressed Psychiatric Patients Community Subjects Fatigue worst 0.44 a 0.08 0.21 a Fatigue usual 0.46 a 0.11 0.21 a Fatigue now 0.44 a 0.12 0.23 a Normal work 0.48 a 0.33 b 0.17 b Mood 0.46 a 0.26 b 0.15 b Relations with others 0.45 a 0.14 0.21 a Enjoyment of life 0.52 a 0.16 0.17 b a P 0.001. b P 0.05. patients ratings of fatigue-related interference in work and mood were significantly associated with sleep disturbance. Predictors of Severe Fatigue Multiple regression analyses were performed to identify significant predictors of fatigue in each subject group. The candidate predictors included gender, age, race, education, employment status, marital status, and the total sleep disturbance score. Table 5 presents the multiple regression models for the three groups. For the cancer patients, sleep disturbance (P 0.001) and employment status (P 0.001) were significant predictors of fatigue. Patients who reported sleep disturbance were significantly more likely to report high levels of fatigue than patients with no or minimal sleep disturbance. Patients who were disabled, unemployed, or retired reported more severe fatigue than patients who were employed full or part-time (including homemakers). Table 5 shows that sleep disturbance (P 0.001) and gender (P 0.002) were significant predictors of fatigue level among the community subjects. The subjects who reported sleep disturbance were significantly more likely to report fatigue than subjects with no or minimal sleep disturbance. In addition, the women in the community sample were more likely to report fatigue than the men. Table 5 shows that gender was the only significant predictor of fatigue for the depressed subjects. The female patients were significantly more likely to report high fatigue levels than the male patients (P 0.02). Discussion The present study provided evidence that cancer-related fatigue does differ in significant ways from fatigue associated with clinical depression and from fatigue found in community subjects. The patients with cancer reported significantly more severe fatigue and fatigue- Table 5 Predictors of Fatigue for Cancer Patients, Depressed Psychiatric Patients, and Community Adults Subject Group Predictor R 2 beta Unstandardized Standardized beta P value Cancer patients Sleep disturbance 0.32 0.48 0.47 0.001 Employment status 1.38 0.26 0.001 Gender 0.34 0.06 0.31 Community subjects Sleep disturbance 0.08 0.18 0.22 0.001 Employment status 0.39 0.09 0.14 Gender 0.77 0.19 0.002 Depressed patients Sleep disturbance 0.13 0.25 0.15 0.24 Employment status 0.45 0.11 0.40 Gender 1.21 0.30 0.02

Vol. 25 No. 4 April 2003 Fatigue and Sleep Disturbance 315 related interference in their daily lives than the community-dwelling subjects. Furthermore, patients with a depressive disorder reported more severe fatigue and more interference in their daily lives due to fatigue than either cancer patients or community individuals. More than 75% of the depressed patients described severe fatigue, as compared to 42% of the cancer patients and 17% of the community subjects. The differences in fatigue-related interference among the three subject groups were significant even when controlling for fatigue severity. In addition to the differences in fatigue intensity and interference due to fatigue across the three groups, gender differences in reported fatigue and interference in daily activities due to fatigue were evident in the depressed patients and the community subjects, but not in the sample of cancer patients. Previous studies of community subjects have found higher levels of fatigue among women. 37 40 Investigators have speculated that gender differences in fatigue may be related to sociocultural, physiological, and/or psychological variables. In addition, women are more likely to visit a health care provider and receive a diagnosis related to fatigue. 38,40 In contrast to the depressed patients and community subjects, the cancer patients in our study did not demonstrate any gender differences in fatigue levels. The reasons for the lack of gender differences among the cancer patients are not clear. However, these results suggest that the etiology of cancer-related fatigue may differ from that of depression-related fatigue and the fatigue found in community subjects. The Brief Fatigue Inventory successfully differentiated the reported fatigue levels of the three subject groups. In contrast, the Fatigue and Vigor subscales of the POMS only differentiated between the community subjects and the depressed patients. The POMS subscale scores of the patients with cancer did not differ from those of the patients with a depressive disorder. Thus, the BFI appears to be more useful than the POMS for distinguishing levels of fatigue among the three groups. The reasons for the high prevalence of severe fatigue among the depressed patients are not clear. The sample of depressed patients represented multiple psychiatric diagnoses, including major depression, bipolar disorder, dysthymic disorder, and adjustment disorder with depressed mood. Different results might have been obtained with a more homogenous group of depressed patients. Analyses of the fatigue ratings of diagnostic subgroups, however, did not reveal many differences. Across all subgroups, the psychiatric patients reported levels of depression were significantly associated with their ratings of fatigue now on the BFI but not with ratings of usual or worst fatigue. Several investigators have suggested that depression and fatigue may have overlapping but nonequivalent pathophysiological mechanisms. 15,23,25 This hypothesis is supported by the finding that patients with clinical depression who respond to antidepressant medication may continue to experience residual fatigue. 41 Additional research is needed to identify the pathophysiological mechanisms underlying the fatigue associated with depression and to differentiate it from the fatigue associated with cancer. Sleep disturbance was frequently reported by the patients with cancer and the patients suffering from depression. In spite of reportedly sleeping more hours per night than the community subjects, the patients with cancer reported more initial insomnia, nighttime awakenings, and waking up too early in the morning than the community subjects. Although the depressed patients reported more initial insomnia and waking up too early in the morning than the community subjects, these differences were not statistically significant. The relatively small sample size of the patients with depression limited the power of these analyses. Sixty-two percent of the cancer patients in the present study reported moderate to severe sleep disturbance. This prevalence rate is higher than those reported in previous studies of cancer patients. 26,42,43 The reason for the discrepancy may be related to the variable assessment methods employed. Many of the previous studies used only one sleep disturbance item or one item from a symptom or quality of life questionnaire. The sleep disturbance score in the present study was based on multiple items. Sleep disturbance was a significant predictor of severe fatigue for the cancer patients and the community subjects. The cancer patients with sleep disturbance were more likely to report high levels of fatigue than cancer patients with no or minimal sleep problems. Similarly, the community subjects who reported sleep dis-

316 Anderson et al. Vol. 25 No. 4 April 2003 turbance were more likely to report fatigue than subjects with no or minimal sleep problems. In contrast, sleep disturbance was not a significant predictor of fatigue among patients with depression. The sleep disturbance items administered to the psychiatric patients were scaled on a 5-point scale, as compared to the 11-point scale used for the sleep items administered to cancer patients and community subjects. The restricted range of the 5-point scale may have limited the sensitivity of the scale and obscured possible associations of sleep disturbance with fatigue among the depressed psychiatric patients. The relationship between sleep disturbance and fatigue in cancer patients may be related to disease and treatment-induced abnormalities in cytokine levels. Many of the cytokines involved in cancer and cancer treatment have also been associated with fatigue and sleep disturbance. For example, fatigue is a dose-limiting factor in tumor necrosis factor (TNF) and interferon biotherapy. 44,45 Similarly, serum interleukin-1 (IL-1) is associated with fatigue in prostate cancer patients receiving radiation therapy, 46 and injection of IL-1 induces fatigue in colorectal cancer patients. 47 Injection of TNF-alpha or IL-1 induces non-rem sleep, 48 and interferon-alpha (IFN- ) reduces the amount of both slow-wave and REM sleep. 45 Links between these cytokines and depression have been suggested, though the evidence is not consistent. 49 52 Among cancer patients, the evidence for a relationship between the interferons and depression is strong. Patients with chronic myelogenous leukemia who are treated with IFN- are more than twice as likely to report depression than similar patients who are not treated with IFN-. 53 Future research should explore further the role of cytokines in fatigue, sleep disturbance, and depression among patients with cancer. Some limitations are evident in our study. The three subject groups demonstrated significant differences on several demographic characteristics: age, gender, employment status, and geographical location. The depressed patients were younger, predominantly female, and lived in Wisconsin as opposed to Texas. Many of the cancer patients were unable to work due to their disease. However, the three groups did not differ significantly with regard to marital status and educational level. Future research on fatigue and sleep disturbance should attempt to match subject groups with regard to demographic characteristics in order to remove possible confounds. In the present study we did not assess the prevalence of patients meeting specific diagnostic criteria for a sleep disorder, as defined in the DSM-IV or the International Classification of Sleep Disorders. We also did not determine how many patients had a sleep disorder that pre-dated the diagnosis of their cancer. Epidemiologic studies have found prevalence rates of insomnia in the community that range from 9% to 12%. 54,55 An additional shortcoming of the present study is the lack of a measure of depression for the cancer patients and the community subjects. Previous research results have suggested that depression may be a factor associated with sleep disturbance and fatigue for some cancer patients. 12,13 In conclusion, the results of the present study indicate that cancer-related fatigue differs in intensity and interference from the fatigue experienced by depressed psychiatric patients or by community subjects. Our results also demonstrate that symptoms of sleep disturbance are highly prevalent among patients with cancer. Moreover, sleep disturbance is a significant predictor of severe fatigue for cancer patients. Additional research is needed to understand the relationship of fatigue and sleep disturbance. Understanding this relationship should lead to the development of more effective treatment strategies for both of these distressing symptoms. Acknowledgments This study was supported by Public Health Service grants no. CA26582 and No. CA85228 from the National Cancer Institute, Department of Health and Human Services, Bethesda, MD. References 1. Glaus A, Crow R, Hammond S. A qualitative study to explore the concept of fatigue/tiredness in cancer patients and in healthy individuals. Support Care Cancer 1996;4:82 96. 2. Richardson A. Fatigue in cancer patients: a review of the literature. Eur J Cancer Care 1995;4:20 32. 3. Greenberg DB, Sawicka J, Eisenthal S, Ross D. Fatigue syndrome due to localized radiation. J Pain Symptom Manage 1992;7:38 45.

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