Preliminary Evaluation of a Clinical Syndrome Approach to Assessing Cancer-Related Fatigue

406 Journal of Pain and Symptom Management Vol. 23 No. 5 May 2002 Original Article Preliminary Evaluation of a Clinical Syndrome Approach to Assessing Cancer-Related Fatigue Ian J. Sadler, PhD, Paul B. Jacobsen, PhD, Margaret Booth-Jones, PhD, Heather Belanger, PhD, Michael A. Weitzner, MD, and Karen K. Fields, MD Psychosocial and Palliative Care Program (I.J.S., P.B.J., M.B.-J., H.B., M.A.W.) and the Blood and Marrow Transplant Program (K.K.F.), H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA Abstract The objectives of this study were to evaluate the reliability, validity, and utility of a newly developed clinical syndrome approach to assessing cancer-related fatigue. Fifty-one patients who underwent blood or marrow transplantation an average of 6.9 months previously were administered a standardized interview designed to identify the presence of a clinical syndrome of cancer-related fatigue. Patients also completed self-report measures of fatigue, depression, and health-related quality of life. Comparisons among independent raters demonstrated high rates of reliability for the presence or absence of a cancer-related fatigue syndrome and its symptoms. Twenty-one percent of patients (n 11) were found to meet criteria for diagnosis of a cancer-related fatigue syndrome. Compared to patients not meeting the diagnostic criteria, patients meeting the criteria reported fatigue that was greater (P 0.05) in its severity, frequency, pervasiveness, and interference with quality of life. Patients who met criteria also demonstrated poorer role functioning, less vitality, and more depressive symptomatology (P 0.05). These findings provide preliminary evidence of the reliability and validity of the methods used to assess the proposed clinical syndrome and suggest their utility in identifying patients experiencing clinically significant cancer-related fatigue. J Pain Symptom Manage 2002;23:406 416. U.S. Cancer Pain Relief Committee, 2002. Key Words Fatigue, blood or marrow transplantation, quality of life Address reprint requests to: Paul B. Jacobsen, PhD, Psychosocial and Palliative Care Program, MOD3-PSY, 12902 Magnolia Drive, Tampa, FL 33612, USA. Accepted for publication: September 4, 2001. Introduction Fatigue is generally recognized to be one of the most common and distressing side effects of cancer treatment. 1 4 In addition to the fatigue that may be experienced during the course of treatment, there is mounting evidence that many cancer patients suffer from fatigue for months or even years following the completion of chemotherapy, 5 9 radiotherapy, 8 10 and blood or marrow transplantation. 11 15 As cancer treatments becomes more effective and survival rates increase, improved symptom management becomes increasingly important. Accordingly, there is a compelling need to better understand the nature of fatigue in cancer patients. Although much has been learned in the past few years, a lack of consensus about the defini- U.S. Cancer Pain Relief Committee, 2002 0885-3924/02/$ see front matter Published by Elsevier, New York, New York PII S0885-3924(02)00388-3

Vol. 23 No. 5 May 2002 Cancer-Related Fatigue Syndrome Approach 407 tion of cancer-related fatigue has hindered progress. In the absence of a common definition, researchers have used a variety of assessment approaches. Much of the time, fatigue has been assessed using a single item embedded in a symptom checklist such as the Symptom Distress Scale 16 and the Rotterdam Symptom Checklist. 17 Due to their format, these single item measures have limited reliability and provide only the most perfunctory information about the patient s experience of fatigue. Multi-item measures, such as Profile of Mood States Fatigue Scale, 18 have better psychometric properties but are limited in providing information about only the general level of fatigue severity. In a more comprehensive approach to the assessment of fatigue, several investigators have developed multidimensional measures. 19 21 For example, the Fatigue Symptom Inventory includes scales that assess the duration and severity of fatigue as well as its perceived interference with quality of life. 22 All of these approaches to assessing cancerrelated fatigue share a common feature. That is, they yield continuous measures of fatigue along one or more dimensions. In addition to assessing fatigue along a continuum, it may also be possible to identify a set of diagnostic criteria that could be used to identify the presence or absence of a clinical syndrome of cancer-related fatigue. An analogy can be drawn to the assessment of depression. In addition to assessing the severity of depressive symptomatology along a continuum, it is also possible to identify the presence or absence of the clinical syndrome of major depressive disorder using standard criteria adopted by the American Psychiatric Association. 23 Based on this model, a group of researchers recently proposed criteria for the diagnosis of a clinical syndrome of cancer-related fatigue. 24 These diagnostic criteria, which have been submitted for inclusion in the tenth edition of the International Classification of Diseases (ICD-10), are presented in Table 1. In order to facilitate and standardize the diagnostic process, a diagnostic interview guide has been developed based on these criteria (see Appendix). 24 The primary aim of the current study was to examine the prevalence of the proposed clinical syndrome of cancer-related fatigue in a well-defined patient sample. Additional aims were to determine the inter-rater reliability of diagnoses based on the interview guide and identify the demographic, medical, and quality of life correlates of the clinical syndrome. With regard to the latter, it was hypothesized that patients meeting diagnostic criteria for the clinical syndrome would manifest poorer healthrelated quality of life, worse fatigue, and greater depressive symptomatology than patients not meeting diagnostic criteria for the clinical syndrome. Methods Participants Participants were patients who had completed either autologous or allogeneic blood or marrow transplantation (BMT) at the Moffitt Cancer Center between September 1997 and April 1999. To be eligible for the current study, these patients also had to: 1) be between 18 and 65 years of age; 2) be able to speak and read English; 3) have completed at least eight years of formal education; 4) have no clinical evidence of disease progression or recurrence at the most recent follow-up visit; and 5) be no less than five and no more than 12 months post-bmt at the time of follow-up contact. Of the 83 BMT recipients meeting these eligibility criteria, 15 patients could not be reached, 15 refused to participate, and 2 provided incomplete data. Thus, complete data were obtained from 51 BMT recipients (61%). Analyses comparing participants to eligible nonparticipants indicated that there were no significant differences between the groups with regard to demographic variables (i.e., age, gender, education, ethnicity, marital status, and employment status), cancer diagnosis, or length of hospitalization (P values 0.15). Compared to eligible non-participants, participants were found to be more likely to have undergone allogeneic transplantation and less likely to have undergone autologous transplantation (chi 2 4.32, P 0.04). Procedure Approximately five months post-transplant, medical records were reviewed to determine if patients met eligibility criteria. A letter was sent to eligible patients informing them that they would be contacted by telephone to discuss

408 Sadler et al. Vol. 23 No. 5 May 2002 Table 1 Proposed ICD-10 Criteria for Cancer-Related Fatigue A. Six (or more) of the following symptoms have been present every day or nearly every day during the same 2-week period in the past month, and at least one of the symptoms is (1) significant fatigue. 1. Significant fatigue, diminished energy, or increased need to rest, disproportionate to any recent change in activity level. 2. Complaints of generalized weakness or limb heaviness. 3. Diminished concentration or attention. 4. Decreased motivation or interest to engage in usual activities. 5. Insomnia or hypersomnia. 6. Experience of sleep as unrefreshing or nonrestorative. 7. Perceived need to struggle to overcome inactivity. 8. Marked emotional reactivity (e.g., sadness, frustration, or irritability) to feeling fatigued. 9. Difficulty completing daily tasks attributed to feeling fatigued. 10. Perceived problems with short-term memory. 11. Post-exertional malaise lasting several hours. B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. C. There is evidence from the history, physical examination, or laboratory findings that the symptoms are a consequence of cancer or cancer therapy. D. The symptoms are not primarily a consequence of co-morbid psychiatric disorders such as major depression, somatization disorder, somatoform disorder, or delirium. Reprinted with permission. 24 study participation. Approximately one week later, patients were contacted by telephone and details of the study were provided. The larger study, of which the current report is a component, involved the assessment of a number of quality of life outcomes by means of both patient self-report measures and clinicianadministered measures. Measures that are a focus of this report are described below. Those patients who provided verbal informed consent during the telephone contact were given an appointment for an outpatient research visit in order to complete the clinician-administered measures. They were also sent a written informed consent form and a package of self-report questionnaires that included measures of demographic characteristics, depressive symptomotology, fatigue symptoms, and health-related quality of life (see below). Patients were asked to complete the questionnaires at home in the days just before their outpatient appointment. Upon arriving for their appointment, patients returned the signed consent forms and completed questionnaires. They then completed a series of clinician-administered measures that included the diagnostic interview for cancer-related fatigue (see below). Measures Demographic Data Form. Demographic data were obtained through use of a standard self-report questionnaire. Variables assessed included age, gender, ethnicity, marital status, employment status, and education level. Medical Record Review Form. Medical records were reviewed to obtain information on type of cancer, type of transplant, and dates of admission and discharge for BMT. Diagnostic Interview Guide for Cancer-Related Fatigue (1998 Draft-Revised). This structured interview guide was designed to assess whether respondents meet proposed ICD-10 criteria for the diagnosis of cancer-related fatigue. 24 The criteria specify that: 1) six or more symptoms out of 11 possible symptoms of fatigue have been present every day or nearly every day during the same two week period in the past month; 2) one of the six or more symptoms is significant fatigue; 3) the symptoms cause clinically significant distress or impairment in functioning; 4) there is evidence that the symptoms are a consequence of cancer or cancer therapy; and 5) the symptoms are not primarily a consequence of a co-morbid psychiatric disorder, such as depression. These criteria were evaluated based on responses to interview questions and a review of available medical chart data. Prior to data collection for the current study, the developer of the interview (P.J.) met with study interviewers for training purposes. Training involved a review of the diagnostic criteria, the completion of simulated interviews, and the completion of practice interviews conducted

Vol. 23 No. 5 May 2002 Cancer-Related Fatigue Syndrome Approach 409 with patients who were not study participants. Study interviews were conducted by two graduate students in clinical psychology experienced in working with cancer patients. Eighteen interviews were audio tape-recorded for purposes of determining inter-rater reliability. Ratings provided by study interviewers were compared with those of an independent rater (I.S.) who was trained in the administration of the interview but not involved in data collection for the current study. There was 94% overall agreement between the study interviewers and the independent rater regarding the presence/ absence of cancer-related fatigue. Calculation of kappa, 25 a measure of agreement adjusted for base rates, yielded a coefficient of 0.87. There was 98% overall agreement between the study interviewers and the independent rater regarding the presence/absence of the 14 individual criteria that comprise the interview (kappa 0.96). Center for Epidemiological Studies Depression Scale (CES-D). The CES-D is a 20-item measure of depressive symptomatology. 26 Respondents indicate on a four-point rating scale (0 rarely or none of the time, 3 most or all of the time) the extent to which they experienced each depressive symptom during the past week. The reliability and validity of the CES-D has been demonstrated with a wide range of populations, including cancer patients. 27,28 Fatigue Symptom Inventory (FSI). The FSI assesses the frequency and severity of fatigue as well as its perceived interference with quality of life. 22 Frequency is measured as the number of days in the past week (0 7) respondents felt fatigued as well as the extent of each day on average they felt fatigued (0 none, 10 entire day). Severity is measured on separate 11-point scales (0 not at all fatigued, 10 as fatigued as I could be) that assess most, least, and average fatigue during the past week as well as current fatigue. Perceived interference is measured on separate 11-point scales (0 no interference, 10 extreme interference) that assess the degree to which fatigue in the past week is judged to interfere with general level of activity, ability to bathe and dress, normal work activity, ability to concentrate, relations with others, mood, and enjoyment of life. The interference ratings can be summed to obtain a total perceived interference score. Previous research has demonstrated the reliability and validity of the FSI with cancer patients. 22,29 Medical Outcome SF-36 Health Survey (SF-36). The SF-36 is a 36-item self-report measure designed to assess perceived health and functioning. 30 It contains eight subscales that measure the extent to which health status impacts each of the following areas; 1) physical functioning; 2) role functioning-physical; 3) bodily pain; 4) general health; 5) vitality; 6) social functioning; 7) role functioning-emotional; and 8) mental health. On all SF-36 scales, a higher score indicates a better health state. The SF-36 has been found to have acceptable reliability and validity when administered to healthy and chronically-ill individuals. 30,31 Results Demographic and Medical Characteristics Study participants ranged in age from 23 to 63 years (M 48, SD 9). The majority of participants were female (75%), Caucasian (90%), currently married (65%), and had some schooling beyond high school (63%). Forty-five percent were currently working, 10% were on leave, and the remaining 45% were not currently employed. Seventy-six percent of the sample underwent autologous transplantation and 24% underwent allogeneic transplantation. The majority of patients (61%) were diagnosed with breast cancer, followed by multiple myeloma (14%), leukemia (13%), lymphoma (10%), and aplastic anemia (2%). Participants were hospitalized for BMT an average of 23 days (SD 10; range 16 77). Participants were approximately 6.9 months post-discharge (SD 1.1; range 5 11) at the time of followup assessment. Prevalence of Cancer-Related Fatigue Twenty-two participants (43% of sample) indicated during the structured interview that they had experienced significant fatigue every day or nearly every day during the same twoweek period in the past month. Among these 22 patients, endorsement of the 10 additional symptoms was as follows: complaints of generalized weakness or limb heaviness (77%); perceived need to struggle to overcome inactivity (73%); insomnia or hypersomnia (64%); experience of sleep as unrefreshing or nonrestor-

410 Sadler et al. Vol. 23 No. 5 May 2002 ative (62%); marked emotional reactivity to feeling fatigued (59%); diminished concentration or attention (55%); perceived problems with short-term memory (55%); decreased motivation or interest to engage in usual activities (50%); difficulty completing daily tasks attributed to feeling fatigued (36%); and post-exertional malaise lasting several hours (32%). Thirteen patients (25% of sample) met the criterion of experiencing at least six symptoms including significant fatigue every day or nearly every day during the same two-week period in the past month. Twelve patients (n 23%) met the additional criterion that their symptoms had caused significant distress or impairment in functioning. In all of these cases, there was evidence that the symptoms were a consequence of cancer or its treatment. Eleven patients met the additional criterion that their symptoms were not primarily a consequence of a co-morbid psychiatric disorder. Thus, 21% of the sample (n 11) met criteria for the diagnosis of cancer-related fatigue and 79% (n 40) did not meet the criteria. Relation of Demographic and Medical Variables to Cancer-Related Fatigue Chi-square analyses were conducted to examine the relation of gender, ethnicity, education level, employment status, marital status, type of BMT, and type of cancer to the presence/absence of cancer-related fatigue as defined by the proposed ICD-10 criteria. As shown in Table 2, there were no significant (P 0.05) associations between these variables and cancer-related fatigue. T-tests were conducted to examine the relation of age, length of hospitalization, and time since discharge to the presence/absence of cancer-related fatigue. As shown in Table 3, none of these variables was significantly (P 0.05) associated with cancerrelated fatigue. Relation of Depressive Symptoms, Fatigue Symptoms, and Health-Related Quality of Life to Cancer-Related Fatigue A series of t-tests was conducted to examine the relation of depressive symptoms, fatigue symptoms, and health-related quality of life to cancer-related fatigue (see Table 4). Patients who met criteria for cancer-related fatigue reported more depressive symptoms than patients who did not meet criteria for cancerrelated fatigue (P 0.02). Results for the FSI indicated that individuals who met criteria for cancer-related fatigue reported higher levels of current fatigue (P 0.03), most fatigue in the past week (P 0.002), least fatigue in the past week (P 0.02), and average fatigue in the past week (P 0.05) than patients who did not meet criteria for cancer-related fatigue. A diagnosis of cancer-related fatigue was also associated with reports on the FSI of more days of fatigue in the past week (P 0.0006), fatigue for a greater proportion of each day in the past week (P 0.008), and greater interference with quality of life due to fatigue (P 0.01). With regard to SF-36, significant (P 0.05) differences were evident on three of the eight scales. Compared to patients who did not meet the criteria, patients who met the criteria reported less vitality (P 0.004), as well as more problems with role functioning due to physical problems (P 0.04) and emotional problems (P 0.006). Discussion The purpose of the present study was to examine the prevalence of cancer-related fatigue in a sample of BMT survivors using a newly developed clinical syndrome approach. Of additional interest was the examination of the inter-rater reliability of diagnoses based on an interview guide and the identification of the demographic, medical, and quality of life correlates of the clinical syndrome of cancerrelated fatigue. Fatigue has been noted to be a prominent concern among patients previously treated with BMT. 11,12,15,32 Consistent with these findings, we found that 43% of our sample of BMT survivors had experienced significant fatigue every day or nearly every day during the same two-week period in the past month and that 21% of the sample fulfilled the remaining criteria specified in the clinical syndrome definition. Among patients experiencing significant fatigue on a daily basis, eight of the ten additional symptoms considered to be part of the clinical syndrome were found to be present in a majority of patients. The relatively high prevalence of these additional symptoms in patients experiencing daily fatigue provides support for the clinical syndrome as described. The presence of these additional symptoms also

Vol. 23 No. 5 May 2002 Cancer-Related Fatigue Syndrome Approach 411 Table 2 Relation of Categorical Demographic and Medical Variables to Cancer-Related Fatigue Variable Criteria Met n (%) Criteria Not Met n (%) Gender 0.81 Male 2 (4 %) 11 (21%) Female 9 (18%) 29 (57%) Education 0.83 13 years 6 (12%) 18 (35%) 13 years 5 (10%) 22 (43%) Ethnicity 0.51 White 11 (22%) 35 (68%) Non-white 0 (0%) 5 (10%) Employment Status 0.29 Employed 3 (6%) 20 (39%) On leave/not employed 8 (16%) 20 (39%) Marital Status 0.33 Married 9 (18%) 24 (47%) Not married 2 (4%) 16 (31%) BMT Type 0.94 Autologous 9 (18%) 30 (59%) Allogeneic 2 (4%) 10 (19%) Cancer Diagnosis 0.21 Breast 9 (18%) 22 (43%) Other 2 (4%) 18 (35%) Note: P values are based on chi-square tests of association. P provides support for a multidimensional conceptualization of fatigue. Although there is continuing debate on this topic, research suggests that fatigue in cancer patients has physical, cognitive, emotional, and behavioral manifestations. 19 21 Consistent with this view, we observed that the presence of a general symptom of fatigue (i.e., significant fatigue on a daily basis) was accompanied in a majority of patients by perceived impairments in the physical domain (e.g., generalized weakness or limb heaviness), cognitive domain (e.g., diminished attention and concentration), behavioral domain (e.g., decreased motivation to engage in usual activities), and emotional domain (e.g., marked emotional reactivity to feeling fatigued). We are aware of only one other published study that has used this clinical syndrome approach to diagnosing cancer-related fatigue. 33 Participants in this study were 379 individuals with a variety of cancer diagnoses who were previously treated with chemotherapy (with or without radiotherapy). Elements of Criteria A and B of the proposed clinical syndrome were evaluated as part of a larger telephone survey. The prevalence rates reported in this study are similar to those observed in the present study. Among 108 participants who completed treatment within the past year, 50% reported significant fatigue every day or nearly every day during the same two-week period in the past month, and 20% reported the presence of six symptoms including significant fatigue (Criterion A) plus clinically significant distress or impairment in functioning (Criterion B). Results from the present study suggest that the presence or absence of cancer-related fatigue and its symptoms can be evaluated in a Table 3 Relation of Continuous Demographic and Medical Variables to Cancer-Related Fatigue Criteria Met Criteria Not Met Variable M SD M SD t P Age (years) 47.2 5.1 48.5 9.5 0.6 0.54 Length of Hospital Stay (days) 21.7 5.5 23.9 10.6 0.9 0.37 Time Since Discharge (months) 6.8 0.9 6.9 1.1 0.4 0.69 Note: Criteria Met n 11; Criteria Not Met n 40.

412 Sadler et al. Vol. 23 No. 5 May 2002 Table 4 Relation of Quality of Life Variables to Cancer-Related Fatigue Criteria Met Criteria Not Met Variable M SD M SD t P FSI Current fatigue 4.8 3.2 2.6 2.7 2.3 0.03 Most fatigue 7.5 1.9 4.5 2.9 3.3 0.002 Least fatigue 3.3 2.2 1.7 1.8 2.5 0.02 Average fatigue 4.8 2.4 3.1 2.4 2.0 0.05 No. of days fatigued 5.8 1.4 3.5 2.8 3.8 0.0006 Percent of day fatigued 4.9 2.4 2.7 2.3 2.8 0.008 Fatigue interference 28.8 18.7 11.5 12.0 2.9 0.01 CES-D 17.5 11.2 9.6 9.3 2.4 0.02 SF-36 Subscale Scores Physical Functioning 58.6 27.8 73.1 22.4 1.8 0.08 Role Physical 25.0 35.4 54.4 43.1 2.1 0.04 Bodily Pain 62.0 30.9 73.3 25.7 1.2 0.22 General Health 53.3 24.1 67.4 22.1 1.8 0.07 Vitality 35.0 18.8 57.9 23.2 3.0 0.004 Social Functioning 64.7 26.7 78.1 25.1 1.5 0.13 Role Emotional 45.5 37.3 80.8 36.1 2.9 0.006 Mental health 72.0 18.5 79.5 19.8 1.1 0.26 Note: Criteria Met n 11; Criteria Not Met n 40. reliable manner using a brief semi-structured interview. Among two independent raters, there was 94% agreement about the presence/absence of cancer-related fatigue and 98% agreement about the presence/absence of the individual diagnostic criteria. It should be noted that these rates were achieved by clinicians who had undergone brief training in the use of a structured interview guide. Those seeking to use this clinician syndrome approach for either clinical or research purposes are encouraged to use similar training and interviewing procedures to insure the reliability of their diagnoses. None of the demographic or medical variables assessed in the current study was found to be significantly related to the presence or absence of cancer-related fatigue. The lack of positive findings with regard to demographic characteristics is partially consistent with previous research. Although some studies have found significant relationships between measures of fatigue severity and variables such as age, gender, and education, 6,34,35 several other studies have not. 7,13,36 38 With regard to medical characteristics, the lack of positive findings in the present study is consistent with previous research. Along these lines, at least two prior studies reported no differences in fatigue based on whether patients had previously undergone autologous versus allogeneic transplantation. 11,39 There was considerable evidence in the present study of the utility of the clinical syndrome approach in identifying cancer patients experiencing heightened fatigue. Comparisons indicated that, relative to patients who did not meet the diagnostic criteria, patients who met the criteria were experiencing fatigue that was significantly greater in terms of its current, most, least, and average severity as well as its frequency, pervasiveness, and interference with quality of life. The magnitude of these differences appears to be clinically as well as statistically significant. For example, the group that met the diagnostic criteria reported being fatigued an average of 2.3 more days per week. Similarly, current fatigue was 85% greater and interference from fatigue was 143% greater in patients who met diagnostic criteria for cancerrelated fatigue. Taken together, these findings suggest that the clinical syndrome approach captures important distinctions in the experience of fatigue among cancer patients. Results from the SF-36 regarding quality of life suggest that the impact of the cancerrelated fatigue syndrome is most evident in the domain of role functioning. Along these lines, we observed that patients who met the diagnostic criteria reported significantly more problems with work or other daily activities due to both physical and emotional problems than patients who did not meet the diagnostic criteria.

Vol. 23 No. 5 May 2002 Cancer-Related Fatigue Syndrome Approach 413 These results underscore the clinical significance of a diagnosis of cancer-related fatigue and provide further support for the view that fatigue has both physical and mental components. Other findings from the SF-36 indicated that patients who met the diagnostic criteria scored lower on a measure of vitality (i.e., energy level) than patients who did not meet the diagnostic criteria. This pattern of results provides additional support for the view that the clinical syndrome approach can be used to distinguish levels of fatigue among cancer patients. In previous research with cancer patients, relatively large positive relationships have been noted between levels of fatigue and levels of depressive symptomatology. 20,21,33,40,41 These findings are not surprising. Fatigue is among the more common symptoms of depression, and negative mood states are a common reaction to heightened fatigue. Consistent with this view and previous research, we found that patients meeting the diagnostic criteria for the cancerrelated fatigue syndrome reported significantly greater depressive symptomatology than patients who did not meet the diagnostic criteria. It should be noted, however, that the diagnostic criteria specifically exclude patients whose fatigue is considered to be a primary consequence of psychiatric disorder from receiving a diagnosis of cancer-related fatigue. Based on this criterion, one patient in the current study who otherwise met diagnostic criteria for cancer-related fatigue was excluded from receiving this diagnosis. Several limitations of the current study should be noted. First, the present study involved the assessment of cancer-related fatigue only in patients treated with BMT. Accordingly, findings cannot be generalized to patients receiving other forms of cancer treatment. Second, the present study focused on the experience of off-treatment fatigue. The reliability and validity of the clinical syndrome approach with patients undergoing active treatment is still to be determined. Third, the design of the current study was cross-sectional in nature. That is, the presence of cancer-related fatigue was assessed on only a single occasion. Consequently, the course of cancer-related fatigue following treatment completion remains unknown. These limitations can be addressed in future research by studying other treatment populations, by assessing patients during the active phase of treatment, and by conducting longitudinal research in which the same patients are assessed on multiple occasions during and following completion of cancer treatment. Additional limitations include the relatively low statistical power for the primary analyses due the relatively small sample size and the increased potential for Type I error due to the performance of multiple statistical tests. In conclusion, the present study provides preliminary information about the utility, validity, and reliability of a clinical syndrome approach to assessing fatigue in cancer patients. Results demonstrate that this clinical syndrome can be diagnosed in a reliable manner by appropriately trained clinicians using a structured interview guide. The validity and utility of the approach were supported by results indicating that patients meeting the diagnostic criteria for cancer-related fatigue differed from patients not meeting the criteria in ways that would be expected. Specifically, the presence of a cancer-related fatigue syndrome was found to be associated with clinically and statistically significant differences in the severity, frequency, and pervasiveness of fatigue as well as its interference with quality of life. Thus, the diagnostic criteria and the interview guide appear to show considerable promise as a method for assessing cancer-related fatigue. In turn, the ability to reliably diagnose a well-defined clinical syndrome of cancer-related fatigue has the potential to advance research into the prevalence, etiology, and treatment of fatigue in cancer patients. Acknowledgments This study was supported in part by an American Cancer Society Institutional Research Grant awarded to Moffitt Cancer Center. The authors thank Elizabeth Soety, James Partyka, and Susan Arab for their assistance. References 1. Richardson A. Fatigue in cancer patients: A review of the literature. Eur J Cancer Care 1995;4:20 32. 2. Winningham ML, Nail LM, Burke MB, et al. Fatigue and the cancer experience: The state of the knowledge. Oncol Nursing Forum 1994;21:23 36. 3. Stone P, Richards M, Hardy J. Fatigue in patients with cancer. Eur J Cancer 1998;34:1670 1676.

414 Sadler et al. Vol. 23 No. 5 May 2002 4. 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(suppl 2):4 12. 5. Beisecker AE, Cook MR, Ashworth J, et al. Side effects of adjuvant chemotherapy: Perceptions of node-negative breast cancer patients. Psycho-Oncol 1997;6:85 93. 6. Bower JE, Ganz PA, Desmond KA, et al. Fatigue in breast cancer survivors: Occurrence, correlates, and impact on quality of life. J Clin Oncol 2000;18: 743 753. 7. Broeckel JA, Jacobsen PB, Horton J, et al. Characteristics and correlates of fatigue following adjuvant chemotherapy for breast cancer. J Clin Oncol 1998;16:1689 1696. 8. Berglund G, Bolund C, Fornander T, et al. Late effects of adjuvant chemotherapy and post-operative radiotherapy on quality of life among breast cancer patients. Eur J Cancer 1991; 27:1075 1081. 9. Lindley C, Vasa S, Sawyer WT, et al. Quality of life and preferences for treatment following systemic adjuvant therapy for early-stage breast cancer. J Clin Oncol 1998;16:1380 1387. 10. Smets EM, Visser MR, Willems-Groot AF, et al. Fatigue and radiotherapy: (B) experience in patients 9 months following treatment. Br J Cancer 1998;78:907 912. 11. Andrykowski MA, Carpenter JS, Greiner CB, et al. Energy level and sleep quality following bone marrow transplantation. Bone Marrow Transpl 20: 669 679, 1997. 12. Bush NE, Haberman M, Donaldson G, et al. Quality of life of 125 adults surviving 6 18 years after bone marrow transplantation. Soc Sci Med 1995;40: 479 490. 13. Hann DM, Jacobsen PB, Martin S, et al. Fatigue in women treated with bone marrow transplantation for breast cancer: A comparison in women with no history of breast cancer. Support Care Cancer 1997;5:44 52. 14. van Dam FS, Schagen SB, Muller MJ, et al. Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: High- dose versus standard-dose chemotherapy. J Natl Cancer Inst 1998;90:210 218. 15. Winer EP, Lindley C, Hardee M, et al. Quality of life in patients surviving at least 12 months following high dose chemotherapy with autologous bone marrow support. Psycho-Oncol 1999;8:167 176. 16. McCorkle R, Quint-Benoliel J. Symptom distress, current concerns and mood disturbance after diagnosis of life-threatening disease. Soc Sci Med 1983;17:431 438. 17. de Haes JC, van Knippenberg FC, Neijt JP. Measuring psychological and physical distress in cancer patients: Structure and application of the Rotterdam Symptom Checklist. Br J Cancer 1990; 62:1034 1038. 18. McNair DM, Lorr M, Droppleman L. Profile of Mood States, 2nd ed. San Diego CA: Educational and Industrial Testing Service, 1992. 19. Piper BF, Dibble SL, Dodd, MJ, et al. The revised Piper Fatigue Scale: Psychometric evaluation in women with breast cancer. Oncol Nursing Forum 1998;25:677 684. 20. Smets, EMA, Garssen, B, Cull, A, et al. Application of the multidimensional fatigue inventory (MFI- 20) in cancer patients receiving radiotherapy. Br J Cancer 1996;73:241 245. 21. Stein K, Martin SC, Hann DM, et al. A multidimensional measure of fatigue for use with cancer patients. Cancer Practice 1998;6:143 152. 22. 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. 23. American Psychiatric Association. Diagnostic and statistical manual of mental disorders (4th ed.). Washington, DC: American Psychiatric Association, 1994. 24. Cella DF, Peterman A, Breitbart W, et al. Progress toward guidelines for the management of fatigue. Oncology 1998;12:369 377. 25. Cohen J. A coefficient of agreement for nominal scales. Educ Psychol Measurement 1960; 20:37 46. 26. Radloff LS. The CES-D Scale: A self-report depression scale for research in the general population. Applied Psychological Measures 1977;1:385 401. 27. Hann D, Winter K, Jacobsen P. Measurement of depressive symptoms in cancer patients: Evaluation of the Center for Epidemiological Studies Depression Scale (CES-D). J Psychosom Res 1999;46:437 443. 28. Beeber LS, Shea J, McCorkle R: The Center for Epidemiologic Studies Depression Scale as a measure of depressive symptoms in newly diagnosed patients. J Psychosocial Oncol 1998;16:1 20. 29. Hann DM, Denniston MM, Baker F. Measurement of fatigue in cancer patients: Further validation of the Fatigue Symptom Inventory. Qual Life Res 2000;9:847 854. 30. Ware JE. SF-36 Health Survey. Manual and interpretation guide. Boston, MA: The Health Institute, New England Medical Center, 1993. 31. Ware JE. SF-36 physical and mental health summary scales: A user s manual. Boston, MA: The Health Institute, New England Medical Center, 1994. 32. Andrykowski MA, Cordova MJ, Hann DM, et al. Patients psychosocial concerns following stem cell transplantation. Bone Marrow Transpl 1999;24: 1121 1129. 33. Cella D, Davis K, Breitbart W, et al. Cancer-

Vol. 23 No. 5 May 2002 Cancer-Related Fatigue Syndrome Approach 415 related fatigue: Prevalence of proposed diagnostic criteria in a United States sample of cancer survivors. J Clin Oncol 2001;19:3385 3391. 34. Andrykowski MA, Curran SL, Lightner R: Offtreatment fatigue in breast cancer survivors: A controlled comparison. J Beh Med 1998;21:1 18. 35. Pater JL, Zee B, Palmer M, et al. Fatigue in patients with cancer: Results with National Cancer Institute of Canada Clinical Trials Group studies employing the EORTC QLQ-C30. Support Care Cancer 1997;5:410 413. 36. Hickok JT, Morrow GR, McDonald S, et al. Frequency and correlates of fatigue in lung cancer patients receiving radiation therapy: Implications for management. J Pain Symptom Manage 1996;11:370 377. 37. Jacobsen PB, Hann DM, Azzarello LM, et al. Fatigue in women receiving adjuvant chemotherapy for breast cancer: Characteristics, course, and correlates. J Pain Symptom Manage 1999;18:233 242. 38. Mast ME. Correlates of fatigue in survivors of breast cancer. Cancer Nursing 1998;21:136 142. 39. Zittoun R, Achard S, Ruszniewski M. Assessment of quality of life during intensive chemotherapy or bone marrow transplantation. Psycho-Oncol 1999;8: 64 73. 40. Dimeo F, Stieglitz RD, Novelli-Fischer U, et al. Correlation between physical performance and fatigue in cancer patients. Ann Oncol 1997;8:1251 1255. 41. Schneider RA. Concurrent validity of the Beck Depression Inventory and the Multidimensional Fatigue Inventory-20 in assessing fatigue among cancer patients. Psychol Reports 1998;82:883 886. Appendix Diagnostic Interview Guide for Cancer-Related Fatigue NOTE: Capitalized text represents instructions to the interviewer. Text in quotations represents statements to be read verbatim to the respondent. 1. Over the past month, has there been at least a 2-week period when you had significant fatigue, a lack of energy, or an increased need to rest every day or nearly every day? IF NO, STOP HERE. IF YES, CONTINUE. For each of the following questions, focus on the worst 2 weeks in the past month (or else the past 2 weeks if you felt equally fatigued for the entire month). 2. Did you feel weak all over or heavy all over? (every day or nearly every day?) 3. Did you have trouble concentrating or paying attention? (every day or nearly every day?) 4. What about losing your interest or desire to do the things you usually do? (every day or nearly every day?) 5. How were you sleeping? Did you have trouble falling asleep, staying asleep, or waking too early? Or did you find yourself sleeping too much compared to what you usually sleep? (every night or nearly every night?) 6. Have you found that you usually don t feel rested or refreshed after you have slept? (every day or nearly every day?) 7. Did you have to struggle or push yourself to do anything? (every day or nearly every day?) 8. Did you find yourself feeling sad, frustrated, or irritable because you felt fatigued? (every day or nearly every day?) 9. Did you have difficulty finishing something you had started to do because of feeling fatigued? (every day or nearly every day?) 10. Did you have trouble remembering things? For example, did you have trouble remembering where your keys were or what someone had told you a little while ago? (every day or nearly every day?) 11. Did you find yourself feeling sick or unwell for several hours after you had done something that took some effort (every time or nearly every time?)

416 Sadler et al. Vol. 23 No. 5 May 2002 IF LESS THAN SIX ITEMS INCLUDING #1 ARE MARKED YES, STOP HERE. 12. Has fatigue made it hard for you to do your work, take care of things at home, or get along with other people? IF #12 IS NO, STOP HERE. 13. Is there evidence from the history, physical examination or laboratory findings that the symptoms are a consequence of cancer or cancer therapy? IF #13 IS NO, STOP HERE. 14. Are the symptoms primarily a consequence of co-morbid psychiatric disorders such as major depression, somatization disorder, somatoform disorder, or delirium? IF #14 IS YES, PATIENT DOES NOT MEET CRITERIA FOR CANCER-RELATED FATIGUE. IF #14 IS NO, PATIENT MEETS CRITERIA FOR CANCER-RELATED FATIGUE Reprinted with permission. 24