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Effects of Cognitive Behavior Therapy in Severely Fatigued Disease-Free Cancer Patients Compared With Patients Waiting for Cognitive Behavior Therapy: A Randomized Controlled Trial

Marieke F.M. Gielissen, Stans Verhagen, Fred Witjes, Gijs Bleijenberg

From the Expert Centre Chronic Fatigue Nijmegen, and the Department of Medical Oncology and Urology, Radboud University, Nijmegen Medical Centre, Nijmegen, the Netherlands

Address reprint requests to Marieke Gielissen, MS, Expert Centre Chronic Fatigue (4628), Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, the Netherlands; e-mail: m.gielissen{at}nkcv.umcn.nl

	ABSTRACT

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PURPOSE: Persistent fatigue is a long-term adverse effect experienced by 30% to 40% of patients cured of cancer. The main objective of this randomized controlled trial was to show the effectiveness of cognitive behavior therapy (CBT) especially designed for fatigue in cancer survivors.

PATIENTS AND METHODS: A total of 112 cancer survivors with somatically unexplained fatigue were allocated randomly to immediate cognitive behavior therapy or to a waiting list condition for therapy. Both conditions were assessed two times, at baseline and 6 months later. The primary outcome variables were fatigue severity (Checklist Individual Strength) and functional impairment (Sickness Impact Profile). Data were analyzed by intention to treat.

RESULTS: Analyses were based on 50 patients in the intervention condition and 48 patients in the waiting list condition. Patients in the intervention condition reported a significantly greater decrease than patients in the waiting list condition in fatigue severity (difference, 13.3; 95% CI, 8.6 to 18.1) and in functional impairment (difference, 383.2; 95% CI, 197.1 to 569.2). Clinically significant improvement for the CBT group compared with the waiting list group was seen in fatigue severity (54% v 4% of the patients, respectively) and in functional impairment (50% v 18% of the patients, respectively).

CONCLUSION: Cognitive behavior therapy has a clinically relevant effect in reducing fatigue and functional impairments in cancer survivors.

	INTRODUCTION

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Current cancer treatments are increasingly effective in improving survival. However, with larger numbers of survivors a variety of long-term adverse effects have emerged. One of these adverse effects is persistent fatigue, which occurs in at least 30% to 40% of the cancer survivors, with profound effects on quality of life.^1-6

The etiology of postcancer fatigue is unknown. Fatigue seems to be elicited during the treatment phase, but later there is no clear relationship between persistent fatigue and initial disease and cancer treatment variables.^1-3,7,8 Hypotheses have been proposed about increased proinflammatory cytokine activity and dysregulation in hypothalamic-pituitary-adrenal axis responsiveness^9-11; however, contradictory findings exist.²At present, there is no somatic strategy in managing fatigue in cancer survivors.

We believe it is useful to make a distinction between precipitating factors and perpetuating factors of fatigue after cancer. The assumption is that cancer itself and/or cancer treatment may have triggered fatigue (precipitating factors), but other factors are responsible for persistence of fatigue complaints (perpetuating factors); for example, physical activity,^1,2,7 sleep quality,^1,2 cognitions related to fatigue,⁴ the use of catastrophizing as a coping strategy,¹² and fear of disease recurrence.^7,13

Exercise is one of the few interventions suggested to decrease fatigue among cancer survivors,^14,15 but randomized controlled trials (RCTs) supporting this are absent.^16,17 The main objective of this RCT was to study the effectiveness of cognitive behavior therapy (CBT), directed at perpetuating factors of postcancer fatigue. Our hypothesis is that fatigue severity and functional impairment will decrease significantly more in a group of patients assigned to CBT than in patients waiting for the therapy.

	PATIENTS AND METHODS

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Sample
Between December 2001 and September 2004, disease-free cancer patients with severe fatigue (score of 35 or higher on the Checklist Individual Strength [CIS], fatigue subscale) were recruited from outpatient clinics of medical oncology, urology, surgery, orthopedics, hematology, and gynecology. Patients were screened by their physician on clinically relevant systematic diseases (eg, malnutrition, hemoglobin level, presence of hypothyroidism, and other physical comorbidities). If a physician was certain that the fatigue had no somatic cause, the patient was invited to participate. Patients completed curative treatment for cancer at least 1 year previously and had no evidence of disease recurrence at the time of participation. The minimum age at disease onset was 18 years, and patients were no older than 65 years and had no current psychological or psychiatric treatment when participating in the study. The ethics committee of the hospital approved the study.

Design and Procedure
We gave patients verbal and written information about the study and obtained informed consent before randomly assigning them to either the intervention condition (CBT) or the waiting list condition. Random assignment was done by means of a sequence of labeled cards contained in sealed, numbered envelopes prepared by a statistical adviser. The envelopes were opened by the researcher (M.G.) in the presence of the patient. Both conditions were assessed two times, at baseline and 6 months later. Patients in the waiting list condition were informed beforehand that, if desired, they could start therapy after the second assessment.

Intervention
The rationale of the intervention was based on the model of precipitating and perpetuating factors. CBT was focused on six perpetuating factors (six modules) of postcancer fatigue, which were based on existing literature and experience in clinical practice. They involve insufficient coping with the experience of cancer, fear of disease recurrence,^7,13 dysfunctional cognitions concerning fatigue,^4,12 dysregulation of sleep,^1,2 dysregulation of activity,^1,2,7 and low social support and negative social interactions.⁴

Because of the existence of large differences within the group of fatigued cancer survivors,¹⁸ therapy was adapted to each individual. To determine which modules were necessary, each perpetuating factor was measured with specific questionnaires. If a patient had a score on one of these questionnaires indicating problems, the accessory module became part of the treatment, resulting in an individualized treatment protocol per patient. Notably, the therapy only varied in the number of modules, but within each module the therapy is standardized. The number of sessions was determined by the number of modules used and whether the goal of the therapy was reached. Therapy sessions varied between five and 26 sessions (mean, 12.5 sessions; standard deviation [SD], 4.7 sessions) with a duration of 1 hour during a 6-month period. Patients were offered a maximum of two sessions during a 6-month follow-up period.

Three therapists with previous CBT experience with patients with chronic fatigue (eg, patients with chronic fatigue syndrome [CFS], neuromuscular diseases, and other chronic diseases) treated the patients. The therapists were trained in the use of instruments to determine which module should be included in the therapy. Therapists were also trained in instrument application. Role-playing was an important part of this training. The therapists were supervised throughout the study by one author (G.B.). During supervision, it was discussed how the relevant module should be applied to a particular patient.

To give some insight into cognitive and behavioral techniques used in the therapy, we illustrate briefly how the six perpetuating factors were challenged during CBT.¹⁹

Insufficient coping with the experience of cancer. A patient can continue to be occupied with the period of being diagnosed or treated for cancer (similar to a patient with a post-traumatic stress disorder). By means of talking, or writing about this experience (which we would refer to as exposure), the patient will acquire better coping skills.

Fear of disease recurrence. The therapist helps the patient to formulate explicit words to describe the thoughts of fear of disease recurrence. These thoughts are challenged against reality (reality testing). In this way, daily unhelpful thoughts about the possibility of a recurrence are reduced and put into perspective.

Dysfunctional cognitions regarding fatigue. Dysfunctional cognitions relate to a variety of ideas, including a patient's idea of lack of control over symptoms ("I cannot do anything about it, I am helpless"), unhelpful attributions ("the chemotherapy caused the fatigue"), and dysfunctional cognitions about fatigue, such as catastrophizing ("this fatigue is awful—I can't stand it"). These cognitions are disputed and more helpful ways of thinking are taught. Explaining the distinction between precipitating and perpetuating factors can also help reduce dysfunctional cognitions.

Dysregulation of sleep. An irregular sleep-wake rhythm can perpetuate fatigue. To restore the biologic rhythm, patients are encouraged to adhere to fixed bedtimes and wake-up times and are discouraged from sleeping during the day.

Dysregulation of activity. Some patients experience fluctuating periods of activity with subsequent periods of rest during a longer period. Others avoid activity because they are concerned that activity increases fatigue; consequently, they are physically inactive. For patients with fluctuating activity levels, a base level should be established by alternating rest and activities to prevent bursts of activity. Once the patient has set a base level, the physical activity program is started, usually twice a day, starting with 5 to 10 minutes of an activity such as walking or cycling. The activity is increased by 1 minute a day each time the activity is performed (ending at a maximum of 120 minutes per day). The inactive patient will start the activity program immediately. Gradually, physical activities are replaced by other activities.

Low social support and negative social interactions. If a patient still has unrealistic expectations of others (eg, expecting that others still recognize him or her as a patient who has experienced something terrible) or perceives a discrepancy between actual support and desired support, the therapist helps to instill more realistic expectations toward the patient's social support group.

Assessment
Primary outcome variables. Fatigue severity was measured by the fatigue severity subscale of the CIS.^20-22 The subscale consists of eight items, each scored on a 7-point Likert scale (range, 8 to 56 points), in which the patient is asked about fatigue in the 2 weeks preceding the assessment. Based on research with CFS patients, a score of 35 or higher indicates severe fatigue.²⁰ The questionnaire has been used in cancer survivors,^4,13,18 and showed good reliability, discriminative validity, and sensitivity to change.^21,23,24

Functional impairment was measured by the Sickness Impact Profile-8 (SIP-8). The SIP-8 consists of eight subscales: home management, mobility, alertness behavior, sleep/rest, ambulation, social interactions, work and recreation, and pastimes. A total score was calculated by addition of the weights of items (range, 0 to 5,799). This widely used measure has good reliability and content validity.²⁵

Secondary outcome variable. Psychological distress was measured by the Symptom Check List 90. The scale consists of 90 items scored on a 5-point Likert scale. The total score ranges from 90 to 450. The Symptom Check List 90 has good reliability and discriminating validity.²⁶

Clinically Significant Improvement
There has been growing recognition that the clinical importance of a treatment effect is not equivalent to the statistical effect. The following questions can be addressed regarding this issue. First, is the amount of change in fatigue that has occurred after CBT large enough to be considered meaningful? Second, are patients comparable with a normative group with respect to their fatigue after CBT? A patient was classified as showing clinically significant improvement if both criteria were met. A meaningful change was calculated with the reliable change index.²⁷ The method of normative comparison was used in answering the second question.²⁸

A patient's own opinion about improvement is another possible approach in investigating the clinical importance of a treatment effect. Self-rated improvement was measured on the second assessment by one specific question: patients indicated whether they had completely recovered, felt much better, had the same complaints, or had become worse compared with the baseline assessment.^23,24,29

Statistical Analysis
Power calculations showed that 49 patients were needed in each condition assuming a significance of 5% (two tailed), power of 85%, and a dropout rate of 20%, in detecting a clinically relevant change of 8 points on the primary outcome variable (CIS-fatigue).^4,18,20 Data analyses were performed using SPSS, version 12.1 (SPSS Inc, Chicago, IL). Analyses were conducted on an intention-to-treat basis and the last observation was carried forward if data were missing. Independent samples t tests and ² tests were performed testing baseline differences between the two conditions. If a significant difference was present, the baseline assessment was used as a covariate in additional analyses.

Differences between the two conditions on the amount of change in the outcome variables were calculated with analyses of variance on change from baseline to 6 months, with 95% CIs. A patient was defined as having a clinically significant improvement if he or she had a reliable change index more than 1.96 and decreased to a normal range (defined as any score < 1 SD above the mean of a normative group).^23,24,27,28 The normative group consisted of 93 nonfatigued breast cancer survivors (mean age, 46.4 years; SD, 6.3⁴). Normal range was defined as less than 30.4 on CIS-fatigue and less than 643 on SIP-8-total. Patients who reported "I have completely recovered" or "I feel much better" on self-rated improvement were also seen as clinically significant improved. ² tests were used to analyze the differences between the proportions of patients meeting these criteria for clinically significant improvement.

	RESULTS

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Trial Profile
Figure 1 shows the trial profile. Of the 145 patients who met the eligibility criteria, 33 refused to take part (23%). There were no differences in baseline characteristics (demographic characteristics, disease and cancer treatment characteristics, or fatigue severity) between participants and nonparticipants (data not shown).

View larger version (22K): [in this window] [in a new window]   Fig 1. Trial profile. CBT, cognitive behavior therapy.

Baseline Comparison
Table 1 demonstrates baseline demographic, disease and cancer treatment characteristics, and the outcome variables in both conditions. Compared with the intervention condition, patients in the waiting list condition underwent chemotherapy more often and had less psychological distress.

	DISCUSSION

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The model of precipitating and perpetuating factors is also used in patients with CFS.^23,24,31 However, it is important to note that there are differences between patients with CFS and cancer survivors with fatigue.¹⁸ Therefore, CBT for fatigue also is different for both patient groups. For cancer survivors, there is a distinct starting point of fatigue complaints, namely the period in which they were diagnosed and treated for cancer. For patients with CFS, the onset differs per patient and often is unknown. This suggests automatically that the attributions relating to the cause of the fatigue are different for both groups. In addition, there is a difference in perpetuating factors. Dealing with fear of disease recurrence and coping with the experience of cancer are important factors in CBT of fatigued cancer survivors and are not present in CBT for CFS. Intraindividual differences are larger in fatigued cancer survivors than in CFS patients, especially for physical activity.¹⁸ Therefore, CBT for cancer survivors is tailored more to the individual, unlike CBT for CFS.

The dropout rate in this study was slightly higher than assumed in the power calculation. In the CBT condition, the dropout rate was 24%; in the waiting list condition, the dropout rate was only 8%. However, many patients who dropped out were willing to attend for the assessment. At the second assessment only 7% of the total group had missing data. Because analyses were conducted on an intention-to-treat basis and the last observation was carried forward if data were missing, the dropout rate will not weaken our findings.

Although the normative group used in analyzing clinically significant improvement were all female cancer survivors and were slightly older than the patients in the present study, it is a more adequate control group than healthy controls. Servaes et al⁴ demonstrated that in general, these breast cancer survivors with nonsevere fatigue were comparable to a healthy control group, with the exception of functional impairment. The cancer and/or the cancer treatment seem to be responsible for permanent impairments and therefore comparison with nonfatigued cancer survivors is more appropriate.

Our study was limited to patients no older than age 65 years, whereas almost 50% of the cancer will be diagnosed after this age. Furthermore, the study was performed with frequently diagnosed tumors. Replication of this study is necessary for older cancer survivors and survivors with other diagnoses.

Controlled follow-up was not possible in this RCT because patients in the waiting list were offered CBT immediately after the second assessment. Therefore, future research should give more insight into the long-term effects of CBT.

Another limitation of this study is the omission of an attention placebo control group. Previous studies showed no effect of an attention placebo group on fatigue in CFS patients.^24,32 However, as described herein, there are differences between CFS patients and fatigued cancer survivors. Therefore, we can not rule out that mere attention for the patient has contributed to the outcome.

For a medical specialist, it is difficult to treat postcancer fatigue when a somatic explanation is excluded. However, with a growing number of cancer survivors and given the substantial adverse physical, psychosocial, and economic consequences of postcancer fatigue, rehabilitation is critical. Even more desirable would be to prevent postcancer fatigue by intervening during cancer treatment. Additional investigation is needed to demonstrate the usefulness of CBT just after or during cancer treatment in preventing persistent fatigue.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Stans Verhagen, Gijs Bleijenberg Administrative support: Marieke F.M. Gielissen Provision of study materials or patients: Stans Verhagen, Fred Witjes Collection and assembly of data: Marieke F.M. Gielissen Data analysis and interpretation: Marieke F.M. Gielissen, Stans Verhagen, Gijs Bleijenberg Manuscript writing: Marieke F.M. Gielissen, Stans Verhagen, Gijs Bleijenberg Final approval of manuscript: Marieke F.M. Gielissen, Stans Verhagen, Fred Witjes, Gijs Bleijenberg Other: Gijs Bleijenberg [training and supervision of therapists and development of the treatment protocol]

 

	ACKNOWLEDGMENTS

 
We thank all of patients who gave their time to participate; Tiny Fasotti for assisting in data collection; Ellen Bazelmans, Thea Berends, and Hein Voskamp for carrying out the therapy; and all participating physicians for referring patients.

	NOTES

 
Supported by the Dutch Cancer Society Grant No. KUN 2001-2378.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted March 29, 2006; accepted August 16, 2006.

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