Comparison of Pharmaceutical, Psychological, and Exercise Treatments for Cancer-Related Fatigue: A Meta-analysis
Open accessAbstract
IMPORTANCE: Cancer-related fatigue (CRF) remains one of the most prevalent and troublesome adverse events experienced by patients with cancer during and after therapy. OBJECTIVE: To perform a meta-analysis to establish and compare the mean weighted effect sizes (WESs) of the 4 most commonly recommended treatments for CRF-exercise, psychological, combined exercise and psychological, and pharmaceutical-and to identify independent variables associated with treatment effectiveness. DATA SOURCES: PubMed, PsycINFO, CINAHL, EMBASE, and the Cochrane Library were searched from the inception of each database to May 31, 2016. STUDY SELECTION: Randomized clinical trials in adults with cancer were selected. Inclusion criteria consisted of CRF severity as an outcome and testing of exercise, psychological, exercise plus psychological, or pharmaceutical interventions. DATA EXTRACTION AND SYNTHESIS: Studies were independently reviewed by 12 raters in 3 groups using a systematic and blinded process for reconciling disagreement. Effect sizes (Cohen d) were calculated and inversely weighted by SE. MAIN OUTCOMES AND MEASURES: Severity of CRF was the primary outcome. Study quality was assessed using a modified 12-item version of the Physiotherapy Evidence-Based Database scale (range, 0-12, with 12 indicating best quality). RESULTS: From 17 033 references, 113 unique studies articles (11 525 unique participants; 78% female; mean age, 54 [range, 35-72] years) published from January 1, 1999, through May 31, 2016, had sufficient data. Studies were of good quality (mean Physiotherapy Evidence-Based Database scale score, 8.2; range, 5-12) with no evidence of publication bias. Exercise (WES, 0.30; 95% CI, 0.25-0.36; P < .001), psychological (WES, 0.27; 95% CI, 0.21-0.33; P < .001), and exercise plus psychological interventions (WES, 0.26; 95% CI, 0.13-0.38; P < .001) improved CRF during and after primary treatment, whereas pharmaceutical interventions did not (WES, 0.09; 95% CI, 0.00-0.19; P = .05). Results also suggest that CRF treatment effectiveness was associated with cancer stage, baseline treatment status, experimental treatment format, experimental treatment delivery mode, psychological mode, type of control condition, use of intention-to-treat analysis, and fatigue measures (WES range, -0.91 to 0.99). Results suggest that the effectiveness of behavioral interventions, specifically exercise and psychological interventions, is not attributable to time, attention, and education, and specific intervention modes may be more effective for treating CRF at different points in the cancer treatment trajectory (WES range, 0.09-0.22). CONCLUSIONS AND RELEVANCE: Exercise and psychological interventions are effective for reducing CRF during and after cancer treatment, and they are significantly better than the available pharmaceutical options. Clinicians should prescribe exercise or psychological interventions as first-line treatments for CRF.
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Fewer than 10% of prior interventions targeting cancer-related fatigue have included patients with metastatic disease.
“fewer than 10% of prior interventions targeting cancer-related fatigue have included patients with metastatic disease [42].”
From Pilot randomized trial of an acceptance-based telehealth intervention for women with ovarian cancer and PARP inhibitor-related fatigue (2023) · cites this paper as [42]
The Results > Participants section reports that 11 of 113 studies (9.7%) enrolled patients with metastatic cancer only, but another 33 (29.2%) enrolled patients with both metastatic and nonmetastatic cancer. Thus 44 studies (38.9%) included patients with metastatic disease; the fewer-than-10% figure applies only to metastatic-only studies. No page number is supplied in our copy. (LLM, conf=0.90)
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Experimental — accuracy not yet measuredExisting behavioral symptom management interventions for cancer survivors have been primarily developed and tested among older cancer survivors aged over 40.
“Existing behavioral symptom management interventions for cancer survivors have been primarily developed and tested among older cancer survivors (aged > 40) [27–32].”
From Improving symptom management for survivors of young adult cancer: rationale and study protocol for a pilot randomized controlled trial (2024) · cites this paper as [29]
The Results > Participants section reports a mean age of 54 years across 113 cancer-related fatigue intervention studies, and Results > Intervention and Control Conditions identifies exercise and psychological interventions among them. This supports the general point that many studied participants were older than 40, but the paper does not establish the proportion aged over 40 or characterize behavioral symptom-management interventions beyond cancer-related fatigue. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPrior exercise and psychosocial interventions for cancer-related fatigue have been long and demanding, requiring an average of 43 one-hour sessions.
“prior exercise and psychosocial interventions for cancer-related fatigue have beenlong and demanding, requiring an average of 43 one-hour sessions [42]”
From Pilot randomized trial of an acceptance-based telehealth intervention for women with ovarian cancer and PARP inhibitor-related fatigue (2023) · cites this paper as [42]
The Results, “Intervention and Control Conditions” (page not provided), report a mean of 43 sessions lasting a mean of 60 minutes. Those averages describe the interventions reviewed overall, including pharmaceutical treatments; the paper does not give them specifically for exercise and psychological interventions. Calling the interventions “long and demanding” is the citing authors’ characterization. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPhysical activity training has proven effective and is recommended in guidelines for treating CRF.
“Physical activity training has proven effective and is recommended in guidelines for treating CRF.10,42”
From Exploring the dynamic interconnectedness of protective and perpetuating factors of cancer-related fatigue (2023) · cites this paper as [42]
The few studies that have included patients with advanced cancers have demonstrated smaller effect sizes compared with early-stage cancers.
“the few studies that have included patients with advanced cancers have demonstrated smaller effect sizes compared with early-stage cancers [42].”
From Pilot randomized trial of an acceptance-based telehealth intervention for women with ovarian cancer and PARP inhibitor-related fatigue (2023) · cites this paper as [42]
Patients are recommended various forms of psychotherapy such as relaxation, guided imagery, mindfulness meditation, music therapy, occupational therapy, and breathing exercises.
“Patients are also recommended various forms of psychotherapy [10,11,12], such as relaxation and guided imagery [13,14], mindfulness meditation (mindfulness-based stress reduction) [14], music therapy [15,16], occupational therapy [17,18,19], and breathing exercises [20,21,22].”
From The Effect of Vinyasa Yoga Practice on the Well-Being of Breast-Cancer Patients during COVID-19 Pandemic (2023) · cites this paper as [11]
The basis for screening and intervention is the National Comprehensive Cancer Network guideline on fatigue.
“The basis for screening and intervention is the National Comprehensive Cancer Network guideline on fatigue [38–42].”
From The BrEasT cancer afTER-CARE (BETTER-CARE) programme to improve breast cancer follow-up: design and feasibility study results of a cluster-randomised complex intervention trial (2024) · cites this paper as [39]
The References list the NCCN guideline on cancer-related fatigue, but the paper does not say that it is the basis for screening and intervention. Its Conclusions recommend exercise and psychological interventions; a search for NCCN guidance on screening and intervention did not establish the claimed basis. (LLM, conf=0.70)
Experimental — accuracy not yet measuredThe effect of exercise on cancer-related fatigue is strongest for moderate to vigorous intensity exercise.
“The effect of exercise was strongest for moderate to vigorous intensity exercise whereas the effect for low intensity training was weak and this level of exercise is unlikely to reduce fatigue(22, 24, 26, 28).”
From Exercise Guidelines for Cancer Survivors: Consensus Statement from International Multidisciplinary Roundtable (2019) · cites this paper as [26]
Moderate intensity combined aerobic plus resistance training 2-3 times per week may reduce cancer-related fatigue.
“Moderate intensity combined aerobic plus resistance training sessions performed 2–3 times per week or twice weekly moderate intensity resistance training may also be effective(21, 24–26), and the latter particularly in prostate cancer(27).”
From Exercise Guidelines for Cancer Survivors: Consensus Statement from International Multidisciplinary Roundtable (2019) · cites this paper as [26]
Low intensity exercise is unlikely to reduce cancer-related fatigue.
“The effect of exercise was strongest for moderate to vigorous intensity exercise whereas the effect for low intensity training was weak and this level of exercise is unlikely to reduce fatigue(22, 24, 26, 28).”
From Exercise Guidelines for Cancer Survivors: Consensus Statement from International Multidisciplinary Roundtable (2019) · cites this paper as [26]
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Durosini, I., Triberti, S., Sebri, V., Giudice, A. V., Guiddi, P., & Pravettoni, G. (2021) · Frontiers in Psychology · doi:10.3389/fpsyg.2021.751077 · Cited by 49 · see citing works
- Authors
- Mustian, K. M., Alfano, C. M., Heckler, C., Kleckner, A. S., Kleckner, I. R., Leach, C. R., Mohr, D., Palesh, O. G., Peppone, L. J., Piper, B. F., Scarpato, J., Smith, T., Sprod, L. K., & Miller, S. M.
- Affiliations
- University of Rochester Medicine (US)
- American Cancer Society (US)
- Northwestern University (US)
- Stanford Cancer Institute (US)
- National University (US)
- Fox Chase Cancer Center (US)
- University of North Carolina Wilmington (US)
- Corresponding author
- Mustian, Karen M.
- ORCID
- Venue
- JAMA Oncology
- Publisher
- American Medical Association (AMA)
- Published
- 2017-07-01
- Volume
- 3
- Issue
- 7
- Pages
- 961
- ISSN
- 2374-2437 (ISSN-L)
- PMC
- PMC5557289
- OpenAlex
- W2593266874
- Cited by
- 932
- References
- 71
- Citations by year
- 2026: 126 · 2025: 97 · 2024: 96 · 2023: 109 · 2022: 129 · 2021: 116 · 2020: 97 · 2019: 78 · 2018: 57 · 2017: 25
- FWCI
- 30.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Oncology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR001422)
- National Cancer Institute (R01CA181659, K07CA168911, R25CA102618, R01CA181064, UG1CA189961, R21CA185678, T32CA102618)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Oncology › Cancer survivorship and care
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cancer-related cognitive impairment studies
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Childhood Cancer Survivors' Quality of Life
- Keywords
- cancer-related fatigue, exercise therapy, psychological intervention, pharmacotherapy, treatment effectiveness comparison, cancer survivors, cancer patients, fatigue severity, quality of evidence, publication bias, treatment effect heterogeneity, exercise duration, exercise frequency
- MeSH terms
- Modafinil, Central Nervous System Stimulants, Benzhydryl Compounds, Dextroamphetamine, Exercise Therapy, Fatigue, Glucocorticoids, Humans, Methylphenidate, Methylprednisolone, Neoplasms, Psychotherapy, Cognitive Behavioral Therapy, Selective Serotonin Reuptake Inhibitors, Paroxetine, Wakefulness-Promoting Agents, Dexmethylphenidate Hydrochloride
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