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JNCI Monographs 2004 2004(32):112-118; doi:10.1093/jncimonographs/lgh025
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2004 © Oxford University Press

ARTICLE

Evidence-Based Treatment for Cancer-Related Fatigue

Victoria Mock

Correspondence to: Victoria Mock, DNSc, FAAN, Kimmel Cancer Center, Johns Hopkins University, P.O. Box 50250, Baltimore, MD 21211-4250 (e-mail: vmock{at}son.jhmi.edu)


    ABSTRACT
 Top
 Notes
 Abstract
 Evidence-Based Treatment for...
 Pharmacologic Therapy
 Nonpharmacologic Interventions
 Conclusions and Recommendations...
 References
 
Despite the high prevalence of cancer-related fatigue and its documented negative effects on patients’ quality of life, limited evidence is available to support interventions to prevent or treat cancer-related fatigue. Both pharmacologic and nonpharmacologic interventions have been tested, with aerobic exercise programs and anemia correction by erythropoietin demonstrating greatest effectiveness. This article reviews the available evidence and describes gaps in knowledge. Recommendations for future research on interventions for cancer-related fatigue are presented.



    EVIDENCE-BASED TREATMENT FOR CANCER-RELATED FATIGUE
 Top
 Notes
 Abstract
 Evidence-Based Treatment for...
 Pharmacologic Therapy
 Nonpharmacologic Interventions
 Conclusions and Recommendations...
 References
 
Despite the acknowledgment of fatigue as the most prevalent symptom reported by individuals with cancer, interventions to manage cancer-related fatigue are limited in number and in evidence to support their efficacy. The most effective approach to management of any symptom is identifying the cause of the disturbing symptom, if it can be identified, and correcting it, if it can be corrected. In the published National Comprehensive Cancer Network Fatigue Practice Guidelines, seven factors are identified as frequently contributing to cancer-related fatigue: pain, emotional distress, sleep disturbance, anemia, nutritional deficiencies, deconditioning, and comorbidities (1). The National Comprehensive Cancer Network (NCCN) panel recommended that these factors be assessed and treated as a first step in managing the symptom (2). Although the factors may not be the sole or even primary cause of the individual’s fatigue, because these factors are known to increase the level as well as the distress of fatigue, treating these seven factors—if present—as an initial approach may decrease perceived fatigue to a tolerable level.

There has been considerable research to support the close relationships between pain and fatigue (35), distress and fatigue (6,7), and deconditioning and fatigue (8,9). Good evidence also supports the correlation between anemia and fatigue (10) and sleep disturbance and fatigue (11,12). If none of these seven factors can be identified as being present, a comprehensive assessment is indicated, including a careful review of systems, evaluation of disease status, and review of current medications (1,2). Data from a comprehensive assessment may indicate appropriate strategies for overall management (13).

However, in many cancer patients, the cause of fatigue cannot be readily identified, and the approach to management is a more generalized one. Although cancer-related fatigue has been recognized as a significant problem over the last decade, the underlying mechanisms of cancer-related fatigue are uncertain (14), and few evidence-based interventions are available to mitigate this distressing symptom. Interventions can be classified as pharmacologic and nonpharmacologic.


    PHARMACOLOGIC THERAPY
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 Notes
 Abstract
 Evidence-Based Treatment for...
 Pharmacologic Therapy
 Nonpharmacologic Interventions
 Conclusions and Recommendations...
 References
 
Pharmacologic interventions include erythropoietin for chemotherapy-induced anemia, other cause-specific treatments such as antidepressants when depression is a cause of fatigue, and psychostimulants to help patients feel energized and less fatigued. Preliminary evidence from clinical trials of erythropoietin in anemic patients with nonmyeloid malignancies receiving chemotherapy indicates that increases in hemoglobin levels are reflected in improved energy and physical functioning, decreased fatigue, and increased quality of life (10,15,16). However, although many anemic patients report moderate to high levels of fatigue (15), most fatigued cancer patients are not anemic (7).

Aside from the treatment with erythropoietin, there are few controlled studies investigating pharmacologic therapy for cancer-related fatigue or therapy-related fatigue. In one study, megestrol acetate pharmaceutical was described as reducing fatigue to some degree in advanced cancer patients (17). Psychostimulants have been effective in reducing fatigue related to HIV infection (18) and in multiple sclerosis (19), but there are limited data concerning their efficacy in cancer-related fatigue.

Although methylphenidate has been found to be effective in relieving opiate-induced somnolence and in treating acute depression as well as improving cognitive function in the palliative setting (20), only two reports described use of methylphenidate as treatment for fatigue. One was a clinical report on its use in 11 patients with advanced cancer, in which nine responded with a reduction in fatigue (21). The second was a pilot project investigating effects on fatigue levels of an exercise program plus methylphenidate in 12 patients with melanoma who were receiving interferon (22). Although one-third of the sample stopped taking the methylphenidate because of side effects, all subjects reported less fatigue than historic controls receiving interferon.

Pemoline is a central nervous system stimulant with similar indications for use as those for methylphenidate (23), and it has been tested to treat fatigue in multiple sclerosis (46% response) but not in cancer. Serious liver problems have been reported in some patients. Modafinil has been approved by the Food and Drug Administration for use in narcolepsy and has been reported to be helpful in cancer-related fatigue (24), but no studies have been published.


    NONPHARMACOLOGIC INTERVENTIONS
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 Notes
 Abstract
 Evidence-Based Treatment for...
 Pharmacologic Therapy
 Nonpharmacologic Interventions
 Conclusions and Recommendations...
 References
 
Nonpharmacologic interventions for cancer-related fatigue can be categorized as alterations in rest and activity, including exercise and sleep therapy, and psychosocial support programs and coping strategies to reduce stress and conserve energy.

Exercise

Strong evidence from clinical trials supports the use of exercise to manage fatigue in cancer patients (8,2530). The rationale for testing exercise as a treatment for fatigue is based on the proposition that the toxic effects of cancer and treatment as well as deconditioning caused by a decreased level of physical activity during treatment may lead to a reduction in the capacity for physical performance (31). When deconditioned, patients must use greater effort and expend more energy to perform usual activities, resulting in increased fatigue levels. Exercise training can reduce the loss of energy or even increase functional capacity, leading to reduced effort and decreased fatigue (31). An additional hypothesis is that the increased circulation accompanying exercise may facilitate reduction of circulating cytokines or other substances mediating the fatigue response.

To date, there have been numerous reports from studies conducted by a variety of research teams testing the effects of exercise on fatigue during active cancer treatment, and several additional reports of exercise programs after completion of cancer treatment (Table 1). Although the sample sizes for many of the studies were small, all demonstrated lower levels of fatigue in subjects who exercised when compared with control or comparison groups. All of the forms of exercise were designed to be aerobic and included some home-based walking programs (8,9,22,26,28,30,3234) as well as some supervised laboratory treadmill or exercise bicycle formats (25,3537). Resistive strength training was found to decrease fatigue in a recent report of men with prostate cancer receiving androgen deprivation therapy (27).


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Table 1. Effects of exercise interventions on cancer-related fatigue*

 
Aerobic exercise interventions have consistently exhibited a powerful effect on cancer-related fatigue: Significant differences were seen between experimental and control groups even with small sample sizes. Fatigue levels were approximately 40%–50% lower in exercising subjects. The exercise programs varied in length of time, consistent with the cancer treatment, from 6 weeks for patients undergoing radiation therapy to 6 months for chemotherapy and extensive peripheral blood stem cell transplantation. In posttreatment exercise studies, the exercise programs have ranged from 10 to 20 weeks. Adherence to the exercise programs, defined in diverse ways, ranged from 60% to 80% in the home-based programs to 100% in laboratory studies—a significant contrast to the 50% dropout rate for healthy individuals who begin an exercise program (38).

Most of the samples were composed of women with breast cancer receiving adjuvant chemotherapy or radiation therapy or following cancer treatment. However, single studies of individuals with melanoma (22), Hodgkin’s disease (39), and multiple myeloma (40) have demonstrated beneficial outcomes for exercising. Several studies of laboratory-based exercise training in individuals receiving or following peripheral blood stem cell transplants have revealed decreased fatigue and emotional distress as well as improved hematologic parameters in exercisers (29,36). Fatigue was measured by a variety of self-report instruments that included visual analog scales, the Piper Fatigue Scale, the Profile of Mood States Fatigue Subscale, and the Schwartz Cancer Fatigue Scale—all of which are considered reliable and valid and were previously tested in cancer populations. Changes in exercise tolerance and functional capacity were measured by symptom-limited treadmill tests or a 12-minute walk test and were correlated with fatigue levels. The studies included randomized clinical trials, single-group pretest/posttest, and quasi-experimental designs. The level of evidence supporting exercise as an intervention for fatigue in cancer populations is considered to be strong as a result of the large number of studies conducted, the overall good quality of the designs, the large effect size of exercise on fatigue, and the consistency of beneficial outcomes across all studies reviewed.

Several comprehensive reviews of exercise studies in cancer patients have also concluded that exercise reduces fatigue and improves quality of life (13,41,42). Although little research has been conducted on fatigue interventions in the palliative care setting, a pilot study of increased activity in nine advanced cancer patients demonstrated reductions in fatigue (43).

An important limitation of the studies on exercise to manage cancer-related fatigue is that they were offered to groups of patients at a set point in their therapy before or after cancer treatment regardless of their current level of fatigue. There is limited information on the effectiveness and acceptability of an exercise program with patients who already suffer from high levels of fatigue. Only two small pilot studies of the investigations of effects of exercise on fatigue involved exercise training for individuals identified as having high levels of fatigue (37,39). However, prevention of fatigue by initiation of exercise programs early in cancer treatment may be more effective, cost saving, and humane than treatment after fatigue levels reach moderate to severe levels.

Rest and Sleep

Health care professionals commonly recommend additional rest and sleep to patients who report cancer-related fatigue (44,45), and these may be the most frequent self-care activities of fatigued patients. The relationship between sleep disturbance and fatigue in cancer patients has received limited investigation (11). Cancer patients report significant disruptions in sleep patterns, and the essential issue may be quality of sleep rather than quantity (4648). Several studies using actigraphy to measure sleep demonstrated that cancer patients spend increased time resting and sleeping, but that their pattern of sleep is often severely disrupted (49,50). Patients who use rest and sleep to manage cancer-related fatigue report that this method is not particularly effective (51). Research testing rest or sleep interventions to manage fatigue is in preliminary stages, and only one pilot project has been published (52).

Psychosocial Interventions

Studies testing interventions to reduce stress and increase psychosocial support in cancer populations have demonstrated reductions in level of perceived fatigue, usually as a component of mood state (5356). Most of these studies did not have fatigue as a primary endpoint, and fatigue measures were limited to a subscale on an instrument to measure emotional distress. It has been proposed that cancer-related fatigue is essentially a response to the stress of cancer diagnosis and treatment (57) or that emotional state influences perception and reporting of cancer-related fatigue. Although a strong correlation exists between emotional distress and cancer-related fatigue (9,28,32), the precise relationship is not clearly understood. Anxiety and depression may be characterized by fatigue, but it is also evident that high levels of fatigue may cause emotional distress when fatigue affects functional status and the ability to engage in valued activities (30,58).

The psychosocial interventions tested have included support groups, individual counseling, a comprehensive coping strategy, stress management training, and energy conservation (Table 2). In the studies testing effects of support groups, the experimental groups have shown less overall mood disturbance, less depression, less fatigue, and greater vigor than control groups, as measured by the Profile of Mood States Scale (54,56). A comprehensive coping strategy program, which included education and relaxation with guided imagery, was found to significantly reduce fatigue combined with nausea 7 days post-BMT, but there were no significant differences in the two groups in fatigue alone (59).


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Table 2. Effects of psychosocial interventions on cancer-related fatigue*

 
A professionally administered stress management training program was compared with a patient self-administered form of stress management training and with usual psychosocial care in a three-group experimental design with 411 patients beginning chemotherapy (60). Patients receiving the self-administered intervention reported significantly better mental health, greater vitality, and better physical functioning than either the usual care group or the group receiving the professionally administered stress management training. Both types of training programs included techniques of abdominal breathing, progressive muscle relaxation, and self statements about coping. The study investigators interpreted low levels on the vitality outcome as representing cancer-related fatigue.

Recently, a behavioral supportive care nursing intervention to manage pain and fatigue was tested in a randomized clinical trial, with 113 cancer patients with mixed cancer diagnoses and stages receiving chemotherapy treatments (61). The intervention was tailored to address individual patients’ problems and included teaching, counseling and support, coordination, and communication as appropriate for each situation, but standardized by computer-based guidelines. Both pain and fatigue were reduced in the experimental group, whereas physical and social role function were significantly increased over the control group levels.

Energy conservation is a frequent treatment recommendation for cancer-related fatigue from care providers. However, at present, there is limited evidence available testing this intervention in cancer patients (62), although one multicenter study of 296 patients has reported effectiveness in decreasing fatigue during treatment (63). Using limited energy to perform highly valued activities may increase personal satisfaction as well as manage fatigue levels when patients are debilitated.

Cognitive or attentional fatigue in cancer patients had been described by Cimprich (6466). This impairment in the capacity for directed attention may occur during stressful situations, such as during the increased demands of life-threatening illness and treatment, resulting in a loss of ability to concentrate and to problem solve. Using a controlled experimental design, Cimprich developed and tested an attention-restoring intervention involving the natural environment in postsurgical breast cancer patients (65). Subjects in the experimental group demonstrated enhanced attentional capacity on a variety of neurocognitive tests and returned to work earlier than the control group. In a second clinical trial (67), Cimprich tested the intervention in 157 women with newly diagnosed breast cancer who were awaiting surgery. The intervention group showed greater pre- to postoperative recovery of capacity to direct attention, compared with the control group. The research in this field is preliminary and needs further development. For example, the relationship between cognitive or attentional fatigue and the overall bodily fatigue commonly reported by cancer patients is not clear, and the outcomes in the Cimprich studies did not include fatigue as measured by standard fatigue instruments.


    CONCLUSIONS AND RECOMMENDATIONS FOR FUTURE RESEARCH
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 Notes
 Abstract
 Evidence-Based Treatment for...
 Pharmacologic Therapy
 Nonpharmacologic Interventions
 Conclusions and Recommendations...
 References
 
Cancer-related fatigue is the most prevalent symptom reported by cancer patients and may have profound effects on functional status of patients. However, evaluation and management of this distressing side effect of cancer and cancer treatment has been limited in clinical practice (68). This limitation is related to several factors, including a scarcity of evidence-based interventions to manage cancer-related fatigue.

Only two interventions, anemia correction and exercise, have sufficient research evidence at this time to support their effectiveness. Correction of anemia has consistently demonstrated improvement in energy levels and quality of life (2,15,69). Interventions to manage cancer-related fatigue in non-anemic patients have been predominantly behavioral, with exercise being the most widely tested intervention (70). Studies investigating psychosocial support and other biobehavioral interventions such as energy conservation and sleep therapy are beginning to appear in the literature and to show preliminary potential to manage fatigue.

Important gaps exist in our current knowledge of cancer-related fatigue management. Studies of fatigue interventions have been conducted primarily with breast cancer populations, and generalizability to patients with other cancer diagnoses is uncertain. There has been little attention to the investigation of underlying physiologic mechanisms of cancer-related fatigue. Some study designs have been limited by lack of control groups, small sample sizes, and a lack of uniformity of instruments to measure fatigue. Little research has been conducted with children, the elderly, ethnically diverse populations, those of low socioeconomic status, or patients in a palliative care setting.

Future research on cancer-related fatigue should target more diverse populations in regard to cancer diagnosis, stage of cancer, and cancer treatment, as well as age and ethnicity of subjects. Additional investigation might include pharmacologic therapies for fatigue in randomized clinical trials and compare pharmacologic with nonpharmacologic treatments. Intervention-testing research is needed to further evaluate sleep quality therapies and conservation of energy approaches. The rigor of research designs could be improved with larger sample sizes, standardization of instruments to measure fatigue, and use of randomized control groups. Much could be learned about the causes and effects of cancer-related fatigue if investigations included data on potential mediating mechanisms, as the study by Courneya and colleagues (25) documented changes in peak oxygen consumption (functional capacity) as mediator of effects of exercise on fatigue. Finally, the practice guidelines now available for management of cancer-related fatigue need to be tested in clinical settings using appropriate outcomes research designs. Although there is much work yet to be done, the evidence to support interventions for management of cancer-related fatigue is developing rapidly.


    NOTES
 
The National Comprehensive Cancer Network Guidelines (NCCN) is a statement of consensus of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN guideline is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way. These Guidelines are copyrighted by National Comprehensive Cancer Network. All rights reserved. These Guidelines and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the Guidelines, visit http://www.nccn.org. These Guidelines are a work in progress and will be refined as often as new significant data become available.


    REFERENCES
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 Notes
 Abstract
 Evidence-Based Treatment for...
 Pharmacologic Therapy
 Nonpharmacologic Interventions
 Conclusions and Recommendations...
 References
 

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