A Randomized Controlled Trial to Evaluate the Effectiveness of a Brief, Behaviorally Oriented Intervention for Cancer-related Fatigue

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1 1385 A Randomized Controlled Trial to Evaluate the Effectiveness of a Brief, Behaviorally Oriented Intervention for Cancer-related Fatigue Jo Armes, PhD, MSc, BSc, RGN 1 Trudie Chalder, PhD, MSc, RMN 2 Julia Addington-Hall, PhD, BSc 3 Alison Richardson, PhD, MSc, BN, RN 1 Matthew Hotopf, PhD, MSc, MRCPsych, MBBS, BSc 2 1 Florence Nightingale School of Nursing and Midwifery, King s College London, Waterloo Bridge Wing, Franklin Wilkins Building, Stamford Street, London, United Kingdom. 2 Department of Psychological Medicine, King s College London, Weston Education Centre, London, United Kingdom. 3 School of Nursing and Midwifery, University of Southampton, Highfield, Southampton, United Kingdom. Supported by the Cancer Research UK Nursing Research Training Fellowship (CP1052/0101 and C1428/A180). We thank all of the individuals who participated, without whom this study would not have been possible. Address for reprints: Jo Armes, PhD, MSc, BSc, RGN, Florence Nightingale School of Nursing and Midwifery, Specialist and Palliative Nursing Section, King s College London, Waterloo Bridge Wing, Franklin Wilkins Building, Stamford Street, London SE1 9NH, United Kingdom; Fax: (011) 44 (0) ; jo.armes@kcl.ac.uk Received March 8, 2007; revision received May 1, 2007; accepted May 14, BACKGROUND. It has been shown that nonpharmacologic interventions are effective management techniques for cancer-related fatigue (CRF) in cancer survivors. However, few studies have investigated their effectiveness in patients who are receiving chemotherapy. In this study, the authors tested the effectiveness of a brief behaviorally oriented intervention in reducing CRF and improving physical function and associated distress in individuals who were receiving chemotherapy. METHODS. For this randomized controlled trial, 60 patients with cancer were recruited and received either usual care or the intervention. The intervention was delivered on an individual basis on 3 occasions over a period from 9 weeks to 12 weeks, and the objective of the intervention was to alter fatigue-related thoughts and behavior. Primary outcomes were assessed as follows: CRF using the Visual Analogue Scale-Global Fatigue; physical functioning using the European Organization for Research and Treatment of Cancer Quality-of-Life Core 30 Questionnaire, and CRF-associated distress using the Fatigue Outcome Measure. Assessments were made on 4 occasions: at baseline (), at the end of chemotherapy (), 1 month after chemotherapy (), and 9 months after recruitment (). Normally distributed data were analyzed using t tests and random-slope/ random-intercept mixed models. RESULTS. The intervention demonstrated a trend toward improved CRF, although this effect was reduced once confounders had been controlled statistically. There was a significant improvement in physical functioning (coefficient, 10.0; 95% confidence interval, ; P 5.009), and this effect remained once the confounding effects of mood disturbance and comorbid disorders were controlled statistically. No decrease in fatigue-related distress was detected. CONCLUSIONS. The behaviorally oriented intervention brought about significant improvements in physical functioning, indicated a trend toward improved CRF, but detected no effect for fatigue-related distress. Cancer 2007;110: Ó 2007 American Cancer Society. KEYWORDS: fatigue, neoplasms, randomized controlled trial, behavior therapy, chemotherapy. Cancer-related fatigue (CRF) has been defined as a persistent, subjective sense of tiredness related to cancer or cancer treatment that interferes with usual functioning. 1 The pathophysiology of CRF is understood poorly and is believed to be complex and multifactorial. 2 Among patients with cancer, it has been identified as one of the most common symptoms experienced during cytotoxic treatment, with reported prevalence rates from 65% to 99%. 3 Although cancer patients report that CRF has a deleterious impact on normal functioning and quality of life, evidence indicates that ª 2007 American Cancer Society DOI /cncr Published online 27 July 2007 in Wiley InterScience (

2 1386 CANCER September 15, 2007 / Volume 110 / Number 6 CRF often is overlooked by health professionals. 4,5 When advice is given on managing CRF, the most commonly reported suggestion made is rest and relaxation. 5 Two systematic reviews have confirmed that there are no proven pharmacologic treatments for CRF; however, research testing the effectiveness of psychosocial/psychoeducational interventions in helping patients adapt to having cancer has demonstrated concomitant improvements in fatigue. 3,6 Controlled clinical trials of exercise interventions have reported improvements in CRF. 3,6 However, although the results from a recent meta-analysis of exercise for women who were receiving adjuvant therapy for breast cancer indicated a statistically significant improvement in cardiorespiratory fitness, no improvement was observed for CRF. 7 Only 2 randomized controlled trials (RCTs) have been conducted of psychoeducational interventions specifically for CRF in patients who were receiving cytotoxic treatment. 8,9 Both of those interventions were reported as bringing about improvements in CRF. The intervention developed by Barsevick et al. 8 was based on a model of energy conservation, whereas Ream et al. 9 developed a supportive approach. The results reported by Barsevick et al. reflected their model, in that significant improvements in CRF were observed, but there were no differences between the experimental group and the control group in terms of physical functioning. 8 The improvement reported by Ream et al. 9 was based on a mean score derived from 4 fatigue visual analogue scales (VAS). Although no differences were observed between the control and experimental groups in the severity of fatigue, significant improvements were noted for distress caused by fatigue and disruption to pastimes/hobbies by fatigue. In both studies, patients were eligible to participate whether or not they had fatigue at the time of recruitment; thus, it is unclear whether the objective of the interventions was prevention or treatment of CRF. Although these studies provide some evidence that such interventions are effective, important gaps remain in our current understanding of the best way to manage CRF. Several studies in individuals with chronic fatigue syndrome have reported that cognitive behavioral therapy (CBT) brings about significant improvements not only in fatigue but also in physical functioning The interventions that were used in those studies were based broadly on a fear-avoidance model of understanding responses to fatigue. On the basis of this evidence, we investigated whether a brief, CRF-specific, behaviorally oriented intervention would be of benefit to patients with cancer who were receiving cytotoxic treatment and were experiencing significant CRF. The fear-avoidance model of symptom management guided the development of the intervention, and the objective of the intervention was to alter fatigue-related behavior. We hypothesized that, compared with usual care, 1) the behaviorally oriented intervention would be superior in reducing CRF, and 2) the intervention would bring about greater improvements in physical function and CRF-associated distress. MATERIALS AND METHODS We obtained approval for the study from the following local research ethics committees: Guys and St. Thomas Hospital National Health Service (NHS) Trust and Bromley Hospitals NHS Trust. All participants provided written informed consent. Design A parallel-groups, RCT methodology was used. Patients Consecutive patients who were attending for chemotherapy treatment at 2 cancer centers/units in South London between October 15, 2001 and March 24, 2003 were screened for eligibility. We excluded patients who 1) were not aware of their cancer diagnosis; 2) were aged < 18 years; 3) did not have histologically proven cancer; 4) were receiving the last half of the planned course of cytotoxic treatment; 5) were unable to speak and understand English; 6) did not report significant fatigue, diminished energy, or increased need to rest disproportionate to any recent change in activity level 17 ; 7) had a poor Eastern Cooperative Oncology Group performance status (>3) 18 ; 8) had a previous history of psychotic disorder; 9) had evidence of cognitive impairment (as judged by the health professionals who were caring for them) or central nervous system metastases; 10) were receiving psychotherapy or CBT at the time of recruitment; 11) were receiving cytokine treatment at the time of recruitment; or 12) had an uncontrolled infection at the time of recruitment. Consecutive potential participants were approached in the oncology day unit by the research fellow (J.A.), who explained the study and provided a written information sheet. Randomization Patients were randomized once they had provided written informed consent. Originally, we chose minimization as the method of treatment allocation. Thus, patients were allocated on the basis of age,

3 Fatigue Intervention RCT/Armes et al sex, site of cancer, stage, and Hospital Anxiety and Depression Scale (HADS) scores with the objective of minimizing differences in these factors between the 2 groups. 19 This method of allocation was suspended after 10 patients were allocated, because the research fellow could predict the group to which participants would be allocated according to sex. To ensure allocation concealment, simple random, permuted, block randomization was implemented. The block lengths were 4 and 6 and varied randomly. A statistician who was unconnected to the study generated the randomization, provided a central telephone service for patient allocation, and kept a copy of the randomization codes. Thus, allocation concealment was attained for the remainder of the study, and the allocation sequence was not revealed until completion of the trial. Treatments The research fellow was trained to deliver the intervention as described in a manual that was written for the study by J.A. and T.C. The intervention consisted of 3 individual, face-to-face, 60-minute sessions at 3 to 4 weekly intervals (coinciding with administration of chemotherapy). Because the intervention was designed to be brief and to ensure some standardization, a skeleton plan for each session was devised that could be modified to meet individual needs. An outline of the proposed strategies to be used in each session and associated intended outcomes is provided in Table 1. Those patients who were allocated to the control group received standard care. CRF was not assessed routinely at either center, and the provision of advice regarding its management was delivered in an ad hoc manner. Sessions were audiotaped for supervisory purposes and to check the integrity of the intervention. Individual supervision was conducted throughout the trial, depending on need and to ensure that treatment was conducted according to the manual. In addition, 2 independent raters evaluated the integrity of the intervention on a random selection of the taped sessions using the Primary Care Rating Scale. 20 This measure assesses both the extent of the therapeutic alliance between therapist and patient and evaluates the extent to which CBT and counseling techniques are used. Outcome Measures Three primary outcomes were selected for the study: 1) reduction in fatigue, 2) improvement in physical functioning, and 3) reduction in distress associated with fatigue. Fatigue was assessed using a VAS of global fatigue (VAS-F). Patients rated their overall fatigue on a 100-mm line anchored at each end by the following statements: not at all tired or extremely tired. In a review of patient-based outcome measures for clinical trials, Fitzpatrick et al. 21 reported that such global measures are valid, reliable, and sensitive to change, and they recommend their use when investigators want to assess the overall value of health care interventions. The Physical Functioning subscale on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30, version 3 22 (EORTC-QLQc30) was used as the measure of physical functioning. The EORTC- QLQc30 is a 30-item measure that consists of both multi-item and single-item subscales. These include 5 Functional scales (physical, role, emotional, cognitive, and social), 9 Symptom-Severity scales (fatigue, pain, nausea and vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties), and a Global Quality-of-Life (QOL) scale. Scores are transformed onto a scale from 0 to 100. High scores on the Functioning and QOL scales indicate high-level functioning or QOL. However, high symptom-severity scores represent greater severity. Fatigue-related distress was assessed using a Fatigue Outcome Measure (FOM) that was designed specifically for the study. The FOM consisted of 7 graphic rating scales with scores from 0 to 100. These rated not only the level of fatigue, distress caused by it, and ability to cope with CRF but also the extent to which fatigue was overwhelming, uncontrollable, unpredictable, and abnormal. Secondary outcomes and potential confounding variables were assessed using the Multidimensional Fatigue Inventory 20,21 (MFI), which is a multidimensional measure of CRF; the EORTC-QLQc30 23,24 ; and the HADS. 25 Relevant personal and disease-related data also were collected. One month after completing cytotoxic treatment, all participants were asked to describe the advice and information received on managing CRF and to rate its usefulness and their satisfaction with it. Patient assessments were made on 4 occasions over 36 weeks or less if the patient did not complete the cytotoxic treatment protocol. These assessments were as follows: Cycle 3 of chemotherapy (baseline assessment []), end of cytotoxic treatment (), 4 weeks after the end of cytotoxic treatment (), and 9 months after recruitment to the study (). A priori, was identified as the main outcome for the study. The assessment was added shortly after data collection commenced and after the publication of a systematic review of psychosocial intervention studies in cancer patients reporting that the strongest

4 1388 CANCER September 15, 2007 / Volume 110 / Number 6 TABLE 1 Core Components of the Intervention Approach/Strategy Session 1 Cognitive approach Clarify meaning of CRF Clarify aim and effectiveness of current CRF coping strategies Behavioral approach Self-monitoring of CRF and sleep disturbance using diary General approach Education on CRF and provision of written information Praise and encouragement Session 2 Cognitive approach Goal setting Behavioral approach Activity scheduling Graded task management Distraction General Provision of written information on management CRF Praise and encouragement Session 3 Cognitive approach Clarify aim and effectiveness of current CRF coping strategies Behavioral approach Modification of goal setting, activity scheduling, and graded task management Cognitive restructuring General approach Provision of written information on management CRF Praise and encouragement Intended outcomes Identify core thoughts and feelings about CRF Provide a rationale for adopting new coping methods Identification of patterns to aid the development of goals and so enhance approach coping Normalize CRF; development of alternative illness perceptions on CRF to enhance approach coping Enhance optimism and self-confidence and encourage persistence in trying to attain goals Increased self-efficacy, enhanced feelings of being in control, and positive mood Prioritization and planning of activities to improve performance through approach coping Goals divided into manageable, small steps to encourage task performance and goal persistence and so approach coping; enhancement of self-efficacy and positive mood Engagement in valued activities to increase enjoyment and challenge unhelpful thoughts Reinforcement of behavioral strategies for managing CRF Enhance optimism and self-confidence and encourage persistence in trying to attain goals Encourage self-monitoring of CRF and modification of goals, activity scheduling, and graded task management Gradual increase in activity level in small and manageable increments to achieve stated goals Identification of unhelpful thoughts about CRF and the impact they make on behavioral responses; enhancement of approach coping through the development of alternative thoughts Reinforcement of cognitive strategies for managing CRF Enhance optimism and self-confidence and encourage persistence in trying to attain goals CRF indicates cancer-related fatigue. treatment effect often was several months after the completion of an intervention. 26 Questionnaires either were posted or were given to patients in the chemotherapy clinic by J.A. Power Calculation An a priori power calculation based on a study by Spiegel et al. 27 assumed that, at, there would be a 5-unit decrease (0 100 scale) in mean fatigue scores for the experimental group and no change for the control group. This indicated that 39 patients would be required in each group to give the study 80% power at the 5% significance level. Accounting for drop-outs, we estimated that we required 100 patients. However, we recognized that this difference was unlikely to be clinically significant 28 ; thus, the hypotheses were worded so that a mean difference of 10 units was sought. Nine months after the commencement of data collection, recruitment to the trial was lower than anticipated (n 5 23 patients). Consequently a reassessment of power was undertaken by a statistician who was unconnected to the study. This was achieved by simulating data collected from patients who were recruited to the study and who had completed more than 1 assessment (n 5 13 patients) without breaking the blindness of group allocation. The distribution of group allocation, outcome, and missing data was modeled; thus, any discrepancies in the original data, such as unequal sample size, were replicated in the modeled data. The optimal threshold sample size, at a 5% significance level, yielded a total sample size of 52 patients. Consequently and because of time limitations, we reduced the sample size to be recruited to 60 patients.

5 Fatigue Intervention RCT/Armes et al Statistical Analysis We analyzed the data using SPSS software (version 11) and Stata software (version 9) on an intention-totreat basis. Measures of central tendency were generated for the primary (VAS-F, FOM Distress, EORTC Physical Functioning) and secondary outcome variables related to fatigue (MFI General Fatigue, MFI Physical Fatigue, MFI Mental Fatigue, MFI Reduced Motivation, and EORTC QLQc30 Fatigue), distress (HADS Anxiety and Depression), and physical functioning (MFI Reduced Activity). Comparisons of group means at,, and were performed for normally distributed primary and secondary outcomes using unpaired t tests. When data were not distributed normally, group differences were assessed using the Mann-Whitney test. Although this gave an indication of the treatment effect, as judged by between-group differences, it did not take into account the probable correlation between repeated measurements on the same individuals, and it did not accommodate missing data. Thus, we analyzed normally distributed data using either random-intercept or random-slope/random-intercept mixed models using a generalized linear latent and mixed model. 29 The baseline score on the dependent variable was included in all models, and we tested for interactions between treatment group and time. If they were present, then these were retained; if not, then we present results of the main effect of treatment group on the dependent variable. In these models, we included potential confounders, which were defined as variables that were related to outcome (P <.25) in univariate regression analysis. 30 RESULTS Recruitment took place over 18 months. Figure 1 shows the flow of the patients through the study. We screened 531 consecutive patients for eligibility, and 283 patients were excluded. The remaining 249 patients were invited to participate. One hundred forty-seven did not consider themselves tired enough to participate, and 42 patients refused. Thus, 60 patients were recruited and consented to the study. We excluded 5 patients who did not return the baseline questionnaires from the analysis, because only clinical data were available for them. The final sample size was 55 patients. The number of questionnaires that were returned varied across the assessments, with the greatest nonresponse rate being at, when patients were completing chemotherapy treatment. At the main outcome (), 1 patient withdrew, 7 questionnaires were not returned, and 4 patients had died. By, the number of patients who died increased to 14. The majority of patients (n 5 22) attended all 3 intervention sessions. Baseline Patient Characteristics The baseline characteristics of participants are shown in Table 2. The mean age of the 55 patients who agreed to participate was 59.1 years (standard deviation, 11.5 years), the majority of whom (n 5 33 patients) were women and white British (n 5 46 patients). Of these, 27 patients had a diagnosis of colorectal cancer, 44 patients had late-stage disease (stage III or IV), and 42 patients had at least 1 metastasis. Most patients had at least 1 comorbid disorder (n 5 42 patients), and the most common comorbidities were cardiac disease (n 5 21 patients) and musculoskeletal disease (n 5 10 patients). All patients were receiving chemotherapy and were recruited at either the second or third cycle of their course of treatment. There were few obvious differences between the 2 groups. However, the control group was slightly older and included more men and individuals who lived alone. Furthermore, there were more patients in the control group with nonsmall cell lung cancer, stage IV disease, liver metastases, and comorbid cardiac disorders. This suggests that the physical condition of the control group was poorer at the baseline assessment. Main Outcomes The mean difference between the experimental and control groups for the normally distributed primary outcomes (global fatigue and physical functioning) at,, and was assessed using 2-tailed t tests for independent groups, and the results are shown in Table 3. Statistically significant differences in favor of the experimental group were observed for VAS Global Fatigue at and EORTC Physical Functioning at and. Scores on the FOM Distress scale were not distributed normally; thus, group differences in ranked scores were assessed using nonparametric tests (Mann-Whitney), and the results are shown in Table 4. No significant difference was observed between the 2 groups at any time point. Data were then analyzed using a random-slope/ random-intercept mixed model. For fatigue, we detected no interaction between group allocation and time. There was a trend toward a significant difference for treatment group favoring the experimental arm (coefficient, 10.1; 95% confidence interval [95% CI], ; P 5.07), as shown in Figure 2. This became smaller after controlling for comorbid medical conditions and HADS score at baseline (coefficient, 8.9: 95% CI, ; P 5.095). For

6 1390 CANCER September 15, 2007 / Volume 110 / Number 6 FIGURE 1. Flow of the participants through the study. CNS indicates central nervous system; ECOG, Eastern Cooperative Oncology Group (performance status);, baseline assessment;, assessment at the end of chemotherapy;, assessment 1 month after chemotherapy;, assessment 9 months after recruitment.

7 Fatigue Intervention RCT/Armes et al TABLE 2 Personal and Clinical Characteristics at Baseline Characteristic Experimental group (n 5 28) No. of patients (%) Control group (n 5 27) Total (n 5 55) TABLE 3 Difference (T Tests) in Primary Outcomes at Baseline (),,, and Time* No. of patients score (SD) difference 95% CI P age SD, y Sex Men 10 (36) 12 (44) 22 (40) Women 18 (64) 15 (56) 33 (60) Ethnicity White UK 23 (82) 23 (85) 46 (84) Black UK 2 (7) 2 (4) Black Caribbean 2 (7) 2 (4) Black African 2 (7) 2 (7) 4 (7) Asian 1 (4) 1 (2) Home occupancy Lives alone 3 (11) 5 (18.5) 8 (14.5) Lives with someone 25 (89) 22 (81.5) 47 (85.5) Diagnosis Colon 10 (36) 8 (30) 18 (33) Rectum 4 (14) 5 (18.5) 9 (16) Esophagus 1 (4) 1 (4) 2 (4) Ovary 4 (14) 4 (15) 8 (14.5) Breast 4 (14) 2 (7) 6 (11) Nonsmall cell lung cancer 1 (4) 4 (15) 5 (9) Bladder 1 (4) 1 (4) 2 (4) Pancreas 1 (4) 2 (7) 3 (5.5) Testicular 2 (7) 2 (4) Stage* I 2 (7) 2 (4) II 5 (18) 4 (15) 9 (16) III 15 (54) 13 (48) 28 (51) IV 6 (21) 10 (37) 16 (29) Sites of metastasis Local* 16 (52) 15 (46) 31 (49) Liver 7 (22.5) 11 (33) 18 (28) Lung 7 (22.5) 6 (18) 13 (20) Bone 1 (3) 1 (3) 2 (3) No. of sites of metastasis 0 7 (25) 6 (22) 13 (23) 1 14 (50) 14 (52) 28 (51) 2 4 (14) 3 (11) 7 (13) 3 3 (11) 3 (9) 6 (11) 4 1(4) 1(2) Comorbid disease Cardiac 9 (32) 12 (44) 21 (38) Endocrine 2 (7) 2 (7) 4 (7) Musculoskeletal 6 (21) 4 (15) 10 (18) Respiratory 1 (4) 3 (11) 4 (7) Renal 2 (7) 2 (4) Genitourinary 3 (11) 1 (4) 4 (7) Blood and lymphatic 3 (11) 2 (7) 5 (9) Other 9 (32) 8 (30) 17 (31) No. of comorbid disorders 0 5 (18) 8 (30) 13 (24) 1 12 (43) 9 (33) 21 (38) 2 8 (29) 8 (30) 16 ( (7) 1 (4) 3 (5.5) 4 1 (4) 1 (4) 2 (4) SD indicates standard deviation. * Defined according to the International Union Against Cancer TNM classification. VAS global fatigue Control group (20.3) NA NA NA Experimental group (20.9) NA NA NA Control group (17.7) to Experimental group (23) Control group (21.6) Experimental group (24) Control group (25.1) Experimental group (29.2) EORTC QLQc30 Physical Functioning Control group (16.2) NA NA NA Experimental group (19.5) NA NA NA Control group (14.6) to Experimental group (16.8) Control group (19.8) to Experimental group (14.4) Control group (24.8) to Experimental group (17.3) SD indicates standard deviation; 95% CI, 95% confidence interval; MFI, Multidimensional Fatigue Inventory; NA, not applicable; EORTC QLQc30, European Organization for Research and Treatment of Cancer Core 30 Quality-of-Life Questionnaire. *, baseline assessment;, assessment at the end of chemotherapy;, assessment 1 month after chemotherapy;, assessment 9 months after recruitment. TABLE 4 Ranked Differences (Mann-Whitney) in Fatigue Outcome Measure Distress Associated With Cancer-related Fatigue Time* No. of patients Median score U test score Control group NA NA Experimental group NA NA Control group Experimental group Control group Experimental group Control group Experimental group Exact P NA indicates not applicable. *, baseline assessment;, assessment at the end of chemotherapy;, assessment 1 month after chemotherapy;, assessment 9 months after recruitment.

8 1392 CANCER September 15, 2007 / Volume 110 / Number 6 FIGURE 2. Fatigue scores on the Visual Analogue Scale. 95% CI indicates 95% confidence interval. physical functioning, we detected no interaction between group and time. There was a statistically significant difference between treatment groups (coefficient, 10; 95% CI, ; P 5.009), as demonstrated in Figure 3. This reduced after controlling for baseline HADS score and comorbid illness (coefficient, 8.3; 95% CI, ; P 5.04). Secondary Outcomes Two-tailed t tests for independent groups were used to assess mean differences at,, and between the 2 groups for normally distributed secondary outcomes (MFI General Fatigue, MFI Physical Fatigue, MFI Mental Fatigue, MFI Reduced Motivation, and EORTC QLQc30 Fatigue), and the results are shown in Table 5. Statistically significant differences in favor of the experimental group were observed for MFI Physical Fatigue at and and for EORTC Fatigue at. Scores on the MFI Reduced Activity scale were not distributed normally; thus, group differences in ranked scores were assessed using nonparametric tests (Mann-Whitney), and the results are shown in Table 6. There was a statistically significant difference at, and this reduced to borderline significance at. No statistically significant differences were observed for the remaining MFI scales. The mean difference in HADS Anxiety and Depression scores at,, and were assessed using 2-tailed t tests for independent groups. No statistically significant differences were observed between the 2 groups at any time point. Data were then analyzed using a random-intercept mixed model. There was an interaction between group and time for MFI Physical Fatigue, indicating that patients in the treatment group experienced greater improvement on this dimension (coefficient, 1.6; 95% CI, ; P 5.02), as shown in Figure 4. FIGURE 3. Physical Functioning scores on the European Organization for Research and Treatment of Cancer Quality-of-Life Core 30 Questionnaire. 95% CI indicates 95% confidence interval. This effect remained after controlling for potential confounders (coefficient, 1.6; 95% CI, ; P 5.03), as shown in Figure 4. The intervention was not associated with any improvement in other dimensions or measures of fatigue, including EORTC-QLQc30 Fatigue, MFI General Fatigue, MFI Mental Fatigue, and MFI Reduced Motivation. Results from the assessment of the intervention integrity suggest not only that there was a good therapeutic alliance with patients but also that the approach adopted in the intervention contained more elements categorized as CBT than counseling, thus confirming that the intervention was congruent with what had been planned. DISCUSSION The results from this study indicated a trend toward the intervention resulting in improved CRF, although this was reduced once the most obvious confounders had been controlled statistically. This finding is supported by a statistically significant improvement in the secondary outcome: MFI Physical Fatigue. There was improvement in physical functioning at and, and this effect remained once the confounding effect of HADS score and comorbid disorders was controlled statistically. A statistically significant improvement in MFI Reduced Activity further supports this finding, contrary to the findings of Barsevick et al., 8 who reported a statistically significant difference in fatigue for patients who received the psychoeducational intervention compared with the control group. However, those authors were unable to detect an improvement in physical functioning. This may have been because the basis of the inter-

9 Fatigue Intervention RCT/Armes et al TABLE 5 Difference (t Tests) in Secondary Outcomes at Baseline (),,, and Time* No. of patients score (SD) difference 95% CI P Time* No. of patients score (SD) difference 95% CI P MFI General Fatigue Control group (3.1) NA NA NA Experimental group (3.2) NA NA NA Control group (3.6) Experimental group (3.6) Control group (3) , Experimental group (4.8) Control group (4) Experimental group (5.1) MFI Physical Fatigue Control group (3.7) NA NA NA Experimental group (3.9) NA NA NA Control group (3.6) Experimental group (4.6) Control group (3.3) Experimental group (4.5) Control group (4.2) Experimental group (4.6) MFI Mental Fatigue Control group (4.6) NA NA NA Experimental group (5.4) NA NA NA Control group (4.1) Experimental group (5.5) Control group (4.1) Experimental group (5.1) Control group 19 9 (3.9) Experimental group (4.7) MFI Reduced Motivation Control group (4.2) NA NA NA Experimental group (4) NA NA NA Control group (5.5) Experimental group (4.6) Control group (3) Experimental group (2.9) Control group (36.3) Experimental group (2.9) EORTC QLQc30 Fatigue Control group (22.3) NA NA NA Experimental group (26.9) NA NA NA Control group (21.8) Experimental group (24.9) Control group (26) Experimental group (25.4) Control group (21.4) Experimental group (24.5) SD indicates standard deviation; 95% CI, 95% confidence interval; MFI, Multidimensional Fatigue Inventory; NA, not applicable; EORTC QLQc30, European Organization for Research and Treatment of Cancer Core 30 Quality-of-Life Questionnaire. *, baseline assessment;, assessment at the end of chemotherapy;, assessment 1 month after chemotherapy;, assessment 9 months after recruitment. vention used by Barsevick et al. was energy conservation. The objectives of our intervention were to regulate and increase physical activity, which explains the sustained improvement in physical functioning. In the study by Ream et al., 9 no effect was observed on the single item extent of fatigue, which may have been because participants without significant fatigue were recruited. In our study, 77% of the sample had metastatic disease, which may have overwhelmed the effect of the intervention on CRF. We were unable to detect decreases in fatiguerelated distress, anxiety, or depression. However, the objective of the intervention was not to ameliorate mood disturbance, as evidenced when the integrity of the intervention was rated independently. Nevertheless, anxiety and depression were statistically significant, independent predictors of fatigue and physical functioning at both time points. Similar associations were observed in cross-sectional studies of CRF prevalence in patients both on and off cytotoxic treatment Jacobsen and Weitzner 34 suggest that part of the reason for this is overlap in the way fatigue and depression are measured. Clearly, the relation between fatigue and mood disturbance requires further investigation. Potential limitations of the current study include inadequate allocation concealment at the start of the study, lack of a control for the behaviorally oriented intervention, and possible observer bias. It is notoriously difficult to develop a placebo intervention to control for nonpharmacologic interventions; thus, we believed that it was more important to test whether

10 1394 CANCER September 15, 2007 / Volume 110 / Number 6 TABLE 6 Ranked Differences (Mann Whitney) in Multidimensional Fatigue Inventory Reduced Activity Assessment* No. of patients Median MFI score U test score Exact P Control group NA NA Experimental group NA NA Control group Experimental group Control group Experimental group Control group Experimental group 17 9 MFI indicates Multidimensional Fatigue Inventory; NA, not applicable. *, baseline assessment;, assessment at the end of chemotherapy;, assessment 1 month after chemotherapy;, assessment 9 months after recruitment. the intervention was beneficial to patients who had significant fatigue. It was not possible to minimize the effect of observer bias by blinding the researcher (J.A.) who conducted the assessments regarding the group to which patients were allocated, because the researcher also was responsible for delivering the intervention. Thus, it is possible that the treatment effect may be attributable to outcome expectations of both the researcher and the patients. The small sample size poses several limitations to the study. First, the power of the study is low, and we are unable to provide precise estimates of treatment effect. Second, despite the use of randomization, there is an increased risk of imbalances occurring between experimental and control groups, leading to confounding of results. The assessment of baseline characteristics suggests that the control group was in poorer physical health. Although data analysis controlled for the effects of such imbalances to an extent, the number of confounding variables that could be included was limited by the small sample size. The results of this study are promising. The patients who were randomized to receive the behaviorally oriented intervention experienced improved physical functioning and a trend toward less fatigue, although these effects were reduced once potential confounding variables were controlled for statistically. However, because the sample was small and heterogeneous and because the power of the study low, we are unable to produce precise estimates of treatment. Next, a larger RCT will be required to detect the precise effect of the intervention and to FIGURE 4. Physical Fatigue scores on the Multidimensional Fatigue Inventory. 95% CI indicates 95% confidence interval. demonstrate that it is applicable under clinical conditions. REFERENCES 1. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Cancer-related Fatigue. Version Available at URL: Accessed February 1, Andrews P, Morrow G, Hickok J, Roscoe J, Stone P. Mechanisms and models of fatigue associated with cancer: evidence of preclinical and clinical studies. In: Armes J, Krishnasamy M, Higginson IJ, eds. Fatigue in Cancer. Oxford, United Kingdom: Oxford University Press; 2004: Servaes P, Verhagen C, Bleijenberg G. Fatigue in cancer patients during and after treatment: prevalence, correlates and interventions. Eur J Cancer. 2002;38: Stone P, Richardson A, Ream E, Smith AG, Kerr DJ, Kearney N. Cancer-related fatigue: inevitable, unimportant and untreatable? Results of a multi-centre patient survey. Ann Oncol. 2000;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: Carr D, Goudas L, Lawrence D, et al. Management of Cancer Symptoms: Pain, Depression and Fatigue. Evidence Report/Technology Assessment no. 61. AHRQ Publication no. 02-E032. Rockville, Md: Agency for Healthcare Research and Quality; Markes M, Brockow T, Resch KL. Exercise for women receiving adjuvant therapy for breast cancer. Cochrane Database Syst Rev. 2006;CD Barsevick AM, Dudley W, Beck S, Sweeney C, Whitmer K, Nail L. A randomized clinical trial of energy conservation for patients with cancer-related fatigue. Cancer. 2004;100: Ream E, Richardson A, Alexander-Dann C. Supportive intervention for fatigue in patients undergoing chemotherapy: a randomized controlled trial. J Pain Symp Manage. 2006;31:

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