Study Overview
Objective. To compare the effect of 4 commonly recommended treatments for cancer-related fatigue (CRF): exercise, psychological, combined exercise and psychological, and pharmaceutical.
Design. Meta-analysis.
Study selection . The authors searched electronic databases (PubMed, PsycINFO, CINAHL, EMBASE and Cochrane Library) for randomized controlled trials published on or before 31 May 2016 that tested exercise, psychological treatment, exercise plus psychological, and pharmaceutical intervention and used CRF severity as a study outcome. Other inclusion criteria included randomized controlled study design, age > 18 with cancer, and CRF assessment independent of cancer treatment. Studies that included use of erythropoietin drugs as the pharmacological intervention, alternative physical modalities (eg, yoga, tai chi) as the exercise therapy, and reduced energy, vitality, or vigor as the fatigue outcome were excluded. Article review was performed independently by 3 reviewers. Independent third-party reviewers resolved all discrepancies. The methodologic quality of the selected studies were evaluated using the previously validated Physiotherapy Evidence-Based Database (PEDro) scale. This scale ranks studies numerically from 0–12 with 12 being the highest quality. Exercise interventions were defined as aerobic, anaerobic, or both based on the provided description in the original published article. Similarly, psychological interventions were categorized as cognitive behavioral, psychoeducational, or eclectic based on the original study.
Main outcome measure . Severity of CRF.
Results. The authors identified 17,033 potential studies during the screening period. After applying exclusion criteria, 351 articles were selected for full review. Of the selected articles, 113 studies were included and analyzed in this meta-analysis. Fourteen articles had more than 1 intervention arm, which resulted in a total of 127 effect sizes: 69 evaluated exercise, 34 evaluated psychological intervention, 10 evaluated the combination of exercise and psychological interventions, and 14 evaluated pharmaceutical intervention. The pooled analysis of all 113 studies yielded a sample size of 11,525 participants. Of these, 78% were female and 22% were male. The majority of included studies were conducted on a cohort of women with breast cancer (~47%). 44% of the studies enrolled patients with nonmetastatic cancer while only 10% enrolled patients with metastatic disease.
Pharmaceutical interventions included the use of paroxetine hydrochloride ( n = 2 studies), modafinil or armo-dafinil (4), methylphenidate or dexymethylphenidate (5), dexamphetamine (1) and methylprednisolone (1). Exercise studies used aerobic modes (36), anaerobic modes (13), and a combination of aerobic and anaerobic modes (20). Psychological interventions included cognitive behavioral therapy (19), psychoeducational methods (14), and a combination of psychotherapeutic methods (1). There were 10 studies that assessed the combination of combined exercise plus psychological interventions.
The authors found a significant improvement in CRF across all included studies. The studies that used exercise as their intervention had the greatest improvement in CRF ( P < 0.001). Psychological interventions also yielded significant improvements in CRF ( P < 0.001). When combined, exercise and psychological interventions also showed significant improvement of CRF ( P < 0.001). On the other hand, pharmaceutical interventions yielded a much smaller albeit significantimprovement in CRF ( P = 0.05). Comparison across all interventions types showed that pharmaceutical interventions yielded the least improvement in CRF.
Further analysis of independent variables showed that the greatest effect was seen in patients with early stage, nonmetastatic disease who had completed their primary treatment. Group-based and in-person intervention methods were found to be more effective than individual interventions. Of the psychological interventions used, cognitive behavioral therapy was the most effective. This intervention was particularly effective in those who had early stage disease who had completed their primary treatment. Type of cancer, patient age, and exercise modality were not associated with treatment effectiveness.
Conclusion. The results of this study suggest that exercise with or without psychological interventions are effective at reducing CRF with greater improvement than with pharmaceutical interventions.
Commentary
Fatigue has been recognized as one of the most common symptoms associated with cancer and CRF. Some authors have estimated the prevalence of CRF may vary from 60% to 90% [1]. Moreover, the type of anti-cancer therapy appears to impact the severity of CRF. For example, patients receiving chemotherapy have reported CRF more commonly than those undergoing radiation therapy [1]. It is vital that the treating oncologist as well as the primary care provider be able to recognize CRF early in the treatment course and intervene in order to improve quality of life in this patient population.
According to the authors, this study is one of the first and most comprehensive attempts to examine the influence of various interventions on CRF. The results of this meta-analysis suggest that exercise (both aerobic and anaerobic), psychological therapy, or the combination of exercise and psychological therapy are more effective means to improve CRF compared with pharmacologic interventions. Notably, these results may suggest that specific interventions may be more effective depending on where the patient is in their treatment course. For example, the effect of exercise seemed greatest for patients who were receiving their primary treatment while the addition of psychological interventions may be best reserved for those who have completed their primary therapy. In addition, the greatest effect seemed to be seen in patients who had early stage disease following completion of definitive therapy.
Numerous authors have sought to assess the impact of various interventions on CRF; however, such studies have had small sample sizes and were often limited to a certain group of patients (eg, breast cancer). Despite these limitations, numerous trials have demonstrated improved fatigue, decreased emotional distress, and improved sleep and better quality of life with exercise [2–4]. This study corroborates the effects of exercise noted previously and further supports evidence that pharmacological therapy offers limited clinical benefit in the management of CRF.
There are some noteworthy limitations to the current meta-analysis. Most of the studies included in this analysis were among patients with breast cancer or patients who had completed primary therapy for breast cancer. Furthermore, the severity of fatigue was not quantified in many of the included trials. This analysis excluded pharmaceutical interventions that evaluated the use of an erythropoietin-stimulating agents (ESAs). ESAs have been widely studied in cancer patients and are currently recommended for patients with a hemoglobin less than 10 g/dL due to chemotherapy who being treated for a nonhematologic malignancy and have no other treatable cause of anemia. Numerous randomized trials have shown decreased red blood cell transfusion with the use of ESAs; however, the impact on CRF has been difficult to correlate. A meta-analysis by Cella and colleagues failed to demonstrated an improvement in fatigue-related symptoms with the use of ESAs in cancer patients [5]. In general, the use of ESAs is controversial in patients who are receiving myelosuppressive therapy for curative intent. This is largely related to the associated thromboembolic risks as well as data suggesting higher mortality rates. Finally, this analysis included patients with primarily non-metastatic disease and the effect of such interventions on patients with advance cancer requires further analysis.
Applications for Clinical Practice
CRF remains a common problem encountered in clinical practice. The treating oncologist and primary care provider must be astute at recognizing and promptly intervening in order to improve quality of life in patients with cancer. This study and prior trials continue to demonstrate the clinical benefits of exercise and psychological interventions in improving quality of life measures in this patient population and these interventions should be recommended. Pharmacologic therapies continue to offer little in the management of CRF and should be reserved for those who fail other intervention strategies. Such an approach is reinforced by the NCCN guidelines, which recommend nonpharmacologic interventions such as physical activity, psychosocial interventions, and nutrition counseling as front-line therapy (category 1) while reserving psychostimulants for those who do not derive benefit from these interventions [6].
—Daniel Isaac, DO, MS