This review represents the largest and most comprehensive exploration to date of RCTs of nonpharmacological interventions for cancer-related fatigue. In contrast to a previous review that identified only 10 RCTs (Lawrence et al., 2004
), we identified 24 studies of psychological interventions and 17 studies of activity-based interventions. Nevertheless, the current review is not without its limitations. The possibility remains that some potentially relevant studies were not identified despite the use of multiple search strategies. Even with this limitation, the review yielded important information about the characteristics, quality, and efficacy of studies investigating psychological and activity-based interventions for cancer-related fatigue.
Information abstracted about patient characteristics demonstrates both the strengths and weaknesses of existing research. Close to a majority of studies were conducted on women with breast cancer, indicating the depth of research on the most common cancer among U.S. women. On the other hand, very few studies were conducted on men with prostate cancer, the most common cancer among U.S. men, or individuals with lung or colorectal cancer, the second and third most common cancers among U.S. men and women. We also found that less than 10% of studies focused on patients whose disease had metastasized. Evidence indicating that more severe disease is associated with worse fatigue (Hwang, Chang, Rue, & Kasimis, 2003
; Stone, Richards, A’hern, & Hardy, 2000
) suggests that many current interventions have not been evaluated in patients for whom disease burden is a likely cause of their fatigue. In addition, fewer than 15% of studies were conducted only on patients experiencing fatigue in the post-treatment period (i.e., following completion of chemotherapy or radiotherapy) and just one of these studies evaluated a psychological intervention. In contrast to predictable relationships between receipt of chemotherapy or radiotherapy and changes in fatigue (Donovan et al., 2004
), the factors contributing to fatigue during the posttreatment period are not as well defined, suggesting the need to carefully evaluate intervention efficacy in each treatment period separately.
Information abstracted about intervention characteristics indicated that the psychological interventions were very heterogeneous. With the exception of three studies that evaluated weekly supportive-expressive group psychotherapy, there were numerous differences in the number and content of sessions and the mode of intervention delivery (i.e., telephone or in-person), even among just those studies evaluating cognitive– behavioral interventions. Consequently, the replicability of results for most of these interventions remains unknown. Activity-based interventions all involved exercise recommendations; however, 39% were conducted in supervised settings while 61% were home-based. Although details were not included in this review, there were also numerous differences across these studies in the type (e.g., aerobic or resistance), mode (e.g., walking or cycle ergometer) and intensity of exercise evaluated. Thus, replicability of results for specific exercise regimens is also an issue for many activity-based interventions. Other methodological information abstracted indicated that fatigue, vigor, or vitality were more likely to have been identified as a primary outcome in activity-based studies (53%) than in psychological studies (21%). This feature suggests that the activity-based interventions were better designed to evaluate fatigue, assuming other aspects of study design (e.g., statistical power and Type I error) were consistent with the identification of fatigue as a primary outcome.
A notable methodological feature that characterized all the studies reviewed was the absence of eligibility criteria related to current level of fatigue. As a result, the possibility exists that many participants were experiencing little or no fatigue at the time of recruitment, thus limiting the ability of the study designs to detect intervention effects. In addition to improving the power to detect effects, limiting eligibility to patients experiencing heightened fatigue would provide a test of intervention strategies more consistent with how they are being used or would be used in clinical practice.
The system used to evaluate methodological quality indicated that few psychological or activity-based intervention studies met the criterion for either “good” or “poor” with most studies earning a “fair” rating. Among the more common methodological limitations were nonrandom or nonconsecutive recruitment of participants, absence of intent-to-treat analyses, and administration of outcome measures by personnel not blinded to intervention assignment. Activity-based studies were more likely to report acceptable intervention adherence and provide detailed loss to follow-up information, while psychological studies were more likely to report monitoring interventionists’ protocol adherence. With increasing numbers of journals adopting reporting standards such as the Consolidated Standards of Reporting Trials (CONSORT) (Moher, Schulz, & Altman, 2001
), it seems likely that methodological quality and its documentation will improve over time.
Meta-analysis showed a small but significant intervention effect that, upon further analysis, reflected a significant effect size for psychological but not activity-based interventions. Among the psychological studies, there was evidence that intervention was more likely to decrease fatigue than increase vigor. This pattern suggests a difference in efficacy based on whether patients were rating negative or positive perceptions of energy and is consistent with other evidence indicating that fatigue and vigor are distinct constructs (Christensen & Piper-Terry, 2004
). The lack of sufficient numbers of activity-based intervention trials assessing vigor precluded a similar comparison among these studies.
Subsequent comparisons guided by the qualitative review indicated that psychological interventions yield significant effect sizes for group-based interventions and for studies in which the sample was not limited to breast cancer patients. Although marked heterogeneity in content among psychological interventions limits the conclusions that can be drawn, findings suggest that characteristics differentiating group-based interventions from individual interventions may facilitate management of fatigue. One possibility is the greater opportunity for downward social comparison that exists in a group format. Similar to the impact on emotional distress (VanderZee et al., 1996
), individuals may benefit from group-based interventions, in part, by perceiving that their problems with fatigue are not as severe as those of others. Heterogeneity in content also obscures the relationship of disease type to intervention efficacy. This finding may primarily reflect gender differences in that samples limited and not limited to breast cancer patients also differ in their representation of male and female participants. The absence of any studies limited to male participants among the psychological studies reviewed precludes any comparison of efficacy based on gender.
We are aware of only three previous meta-analytic findings about the effects of psychological or activity-based interventions on cancer-related fatigue. Analysis of two RCTs of relaxation training interventions yielded an effect size (dw
) of .24 (Luebbert, Dahme, & Hasenbring, 2001
). Given the limited scope and number of publications reviewed, comparison with our findings must be considered with caution. With regard to activity-based interventions, one publication (Conn, Hafdahl, Porock, McDaniel, & Nielsen, 2006
) reported an effect size (d
) of .11 based on six studies that included nonrandomized trials. A second publication (Schmitz et al., 2005
), which also included nonrandomized trials, reported effect sizes (dw
) separately for fatigue/tiredness based on whether the intervention was conducted during the active treatment or posttreatment period. Effect sizes were .13 for six on-treatment studies and .16 for five posttreatment studies. Comparison with the present study suggests that effect sizes are reduced when more recent studies are added and meta-analysis is limited to RCTs.
The results of this review provide limited support for the clinical use of nonpharmacological interventions to prevent or relieve cancer-related fatigue. As noted previously, evidence of efficacy is stronger for psychological interventions than for activity-based interventions. The current recommendation is based on evidence compiled primarily from women with breast cancer, patients with nonmetastatic disease, and patients undergoing active treatment. Future research should expand the evidence base to include more patients with other forms of cancer, more patients with metastatic disease, and more patients who have completed active treatment. Evidence is also lacking for patients experiencing heightened fatigue. This situation reflects the fact that none of the studies reviewed used level of fatigue as an eligibility criterion, an issue that also needs to be addressed in future research. As a result, it is unclear whether interventions found to be effective are preventing fatigue (e.g., among patients about to undergo chemotherapy) or are relieving fatigue once it has developed. The studies reviewed also do not provide evidence that would assist clinicians in treatment selection. That is, there have been no direct comparisons of activity-based and psychological interventions that might indicate the superiority of one approach over the other or identify moderators of intervention efficacy that might be used to match patients to a particular treatment.
In addition to addressing these issues, future research should examine mechanisms suggested by previous research and theory that may underlie intervention efficacy. Understanding why interventions work could lead to refinement and enhancement of current intervention strategies and greater knowledge about factors that cause and contribute to cancer-related fatigue. Biological, cognitive, and behavioral mechanisms all merit investigation. With regard to biological mechanisms, there is preliminary evidence that improvements in cardiopulmonary function mediate the beneficial effects of exercise training on fatigue in cancer survivors (Courneya, Mackey et al., 2003
). Evidence that persistent fatigue is associated with increased cytokine production in some cancer survivors (Bower, Ganz, Aziz, & Fahey, 2002
; Collado-Hidalgo, Bower, Ganz, Cole, & Irwin, 2006
) should also encourage study of the immune effects of current intervention strategies. With regard to cognitive and behavioral mechanisms, we have already described evidence indicating that catastrophic coping and physical inactivity are contributing factors to cancer-related fatigue. In addition to studying whether these variables mediate intervention efficacy, it may be useful to examine whether an intervention strategy that targets both cognitive and behavioral mechanisms (e.g., a combined stress management and exercise training intervention) is more effective than a strategy that targets only one mechanism (e.g., exercise training alone).