The effect of exercise on cancer-related fatigue in cancer survivors: a systematic review and meta-analysis

Figures & data

Table 1 PICOS eligibility criteria

Parameter	Inclusion criteria	Exclusion criteria
Patients	Adults >18 years living with, through, or beyond a cancer diagnosis not receiving palliative care	Patients under 18 years of age Patients receiving palliative care Patients with metastatic cancer
Intervention	Physical activity intervention of sufficient intensity as measured by METs	An information letter/session Education Yoga (of insufficient METs) Stretching
Comparator	Non-exercise control group	Non-exercise control group receiving additional care, such as CBT
Outcomes	Primary outcome: intensity of CRF as measured by self-report questionnaire Secondary outcome: adherence	CRF is not the primary outcome
Study design	Randomized controlled trials published between January 1st 2000 and August 17th 2016 No language restrictions	Non-randomized controlled trials Retrospective, prospective, or concurrent cohort studies Cross-sectional studies Case reports Editorials and opinion pieces

Abbreviations: CBT, cognitive behavioral therapy; CRF, cancer-related fatigue; METs, metabolic equivalents of task; PICOS, patients, intervention, comparator, outcomes, study design.

Table 2 Data extraction table

Study	– n intervention – n control group – Sample mean age – Setting	Type of cancer	– Outcome instrument – p-value	– MET – Adherence – Effect size	– T1 timing – Outcome compared to non-exercise control group	Intervention	Control group
Trials included in the meta-analysis
Aerobic exercise intervention (n =2)
Cantarero-Villanueva et al^Citation42	– n=34 – n=34 – 48 years – Outpatient clinic	Breast (100%)	– Piper fatigue scale – p<0.001	– 12= low METs – 84% = high – Δ=1.40 (95% Cl 0.869 –1.930)	– T1 8 weeks – Improved CRF – Improved strength	Aquatic exercise: warm-up, aerobic and endurance exercises, cool-down.	Usual care: followed the oncologist recommendations for maintaining a healthy lifestyle based on adequate nutrition, energy balance, and maintaining usual activities.
Yeo et al^Citation50	– n=54 – n=48 – 66.5 years – Thomas Jefferson University Hospital Department of Surgery	Pancreas (91%) and periampullary cancer	– FACIT-FS – p=0.05	– 8= low METs – 80% self-report = moderate – Δ=0.60 (95% Cl 0.003 –1.189)	– T1 12–24 weeks – Improved CRF – Less pain – Better overall physical functioning – Better mental functioning	Aerobic: walking program.	Usual care: perform usual activity/exercise.
Combination of aerobic and resistance exercise intervention (n =4)
Adamsen et al^Citation41	– n=118 – n=117 – 47.2 years – Copenhagen University Hospital	Mixed (44% breast, 0% prostate, 18% gynecological, 1% pancreatic)	– EORTC QLQ-C30 fatigue subscale – p=0.02	– 43= high METs – 71% = moderate – Δ=0.27 (95% Cl 0.015–0.529)	– T1 6 weeks – Improved CRF – Improved vitality and functioning – Improved physical capacity – No significant effects on quality of life	Multimodal exercise intervention: high intensity physical training (warm-up exercises, resistance and cardiovascular training) and low intensity physical training (relaxation, body awareness and restorative training, and massages).	Conventional medical care: allowed to freely increase physical activity.
Donnelly et al^Citation44	– n=16 – n=17 – 53 years – Gynecological clinics	Gynecological (100%)	– MFSI-SF – p=0.046	– Cannot be determined – 44%–58% = low – Δ=0.21 (95% Cl −0.477 to 0.892)	– T1 12 weeks – Improved CRF – Improved sleep quality – Improved quality of life	Walking and strengthening exercises.	Standard care and no advice on how to change physical activity levels during the study period.
Mustian et al^Citation46	– n=19 – n=19 – 56.6 years – Standard radiation therapy center	Breast (71% and prostate 29%)	– FACIT-FS – p<0.05	– 38= high METs – 79% = moderate – Δ=0.56 (95% Cl −0.089 to 1.207)	– T1 4 weeks – Improved CRF – Improved aerobic capacity – Improved quality of life	Aerobic (walking) and progressive resistance (therapeutic resistance bands) exercises.	Instructed not to begin any new formal physical exercise program (eg, joining a gym or a walking group).
Rogers et al^Citation47	– n=20 – n=24 – 56.2 years – Academic center	Breast (100%)	– PROMIS fatigue – p<0.01	– 21.6= high METs – 92% = high – Δ=0.64 (95% Cl 0.030 –1.247)	– T1 12 weeks – Improved CRF – Higher baseline CRF predicted a greater decline during intervention – Fewer anxiety symptoms	Aerobic walking and strength training using resistance bands.	Exercise behaviour at time of study enrollment.
Studies excluded in the meta-analysis
Aerobic exercise intervention (n =5)
Dodd et al^Citation43	– n=44 – n=39 – 50.5 years – Outpatient clinics	Mixed (100%): breast, colorectal or ovarian	– Piper fatigue scale – p=0.048	– High METs – 73% = high – Δ=0.39 (95% Cl −0.050 to 0.820)	– T1 16–24 weeks – No effect on CRF or related symptoms	Cardiovascular/aerobic exercise. (Two experimental groups. 1) Exercise prescription throughout the study period [during and after cancer treatment]. 2) Exercise prescription after completed cancer treatment.)	Usual care: no exercise prescription during and after cancer treatment.
Mock et al^Citation45	– n=60 – n=59 – 52 years – University teaching centers and community cancer centers	Breast (100%)	– Piper fatigue scale – p=0.003	– Low METs – 72% = moderate – Δ=0.08 (95% Cl −0.280 to 0.439)	– T1 6 weeks – No group differences due to dilution of treatment effect from exercise adherence – Significant effect of exercise if corrected for adherence – Improvement in walking distance	Aerobic activity.	Usual care: encouraged to maintain current levels of activity, and no exercise prescriptions or formal programs were offered.
Wang et al^Citation48	– n=30 – n=392 – 50.4 years – Chang-Gung Memorial Hospital and National Taiwan University Hospital	Breast (100%)	– FACIT-FS – p=0.003	– Low METs – 93% = high – Δ<0.01 (95% Cl −0.458 to 0.466)	– T1 6 weeks – Improved CRF – Improved quality of life – Less sleep disturbances – Higher self-efficacy for exercise – More exercise behavior – Better exercise capacity	Aerobic: walking program.	Usual care.
Windsor et al^Citation49	– n=33 – n=33 – 68.8 years – Men on the outpatient waiting list	Prostate (100%)	–Brief fatigue inventory –p=0.18	– Low METs – 100% = high – Δ=0.32 (95% Cl −0.165 to 0.807)	–T1 8 weeks –No improvement in CRF –Improvement in walking distance –Improvement in physical functioning	Aerobic: walking intervention. (All participants were selected from a waiting list?)	Control group was not discouraged from performing normal activities but was advised to rest and take things easy if they became fatigued.
Yuen and Sword^Citation51	– n=7 – n=7 – 53.9 years – Medical University of South Carolina	Breast (100%)	–Piper fatigue scale –p=0.06 (one-tailed)	– Low METs – 73% = moderate – Δ=1.78 (95% Cl 0.542 −3.018)	–T1 12 weeks –Improved CRF –Improved subjective CRF	Aerobic or resistance exercises (two experimental groups)	Usual care: continued with normal activities and received no exercise related instruction.

Note: T1= timing of post-intervention measurement.

Abbreviations: CBT, cognitive behavioral therapy; CRF, cancer-related fatigue; MET, metabolic equivalent of task; FACIT-FS, Functional Assessment of Chronic Illness Therapy - Fatigue Scale; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; MFSI-SF, Multidimensional Fatigue Symptom Inventory-Short Form; PROMIS, Patient-Reported Outcomes Measurement Information System.

Table 3 Risk-of-bias table

Study	Sequence generation	Allocation concealment	Blind outcome assessor	Blind other	Loss to follow-up reported/ITT analysis	Free of selective outcome reporting	Free of other bias	Appraisal of quality	Comment
Trials included in meta-analysis (n =6)
Adamsen et al^Citation41	Yes	Yes	Yes	No	No	Yes	Yes	B	Missing data not addressed explicitly, good quality study.
Cantarero-Villanueva et al^Citation42	Yes	Yes	Yes	No	In part	Yes	Yes	B	Missing data not addressed explicitly, good quality study.
Donnelly et al^Citation44	Yes	Yes	Yes	No	Yes	Yes	Yes	A	Good quality study.
Mustian et al^Citation46	Yes	Yes	Yes	No	Yes	Yes	Yes	A	Good quality study.
Rogers et al^Citation47	Yes	Yes	No	No	Yes	Yes	Yes	B	Blinding not addressed explicitly, good quality study.
Yeo et al^Citation50	Yes	Yes	No	No	Yes	Yes	Yes	B	Blinding not addressed explicitly, good quality study. Missing data reported.
Trials excluded from meta-analysis (n =6)
Dodd et al^Citation43	In part randomization not described	No	No	No	In part	Yes	Yes	C	Randomization not described, most risk of bias not addressed, dropout shown.
Mock et al^Citation45	No	Yes	No	No	Yes	No	No	C	Blinding not addressed. Selective reporting.
Wang et al^Citation48	In part randomization not described	No	No	No	Yes	Yes	In part	C	Randomization not described, most risk of bias not addressed. Missing data addressed.
Windsor et al^Citation49	In part randomization method unclear	No	No	No	Yes	Yes	Yes	C	Unclear what randomization entails, blinding and allocation concealment not addressed.
Yuen and Sword^Citation51	Yes	No	No	No	Yes	Yes	No	C	Blinding and allocation concealment not addressed, analysis one-sided.

Note: A = excellent, B = very good, C = insufficient as in Cochrane handbook of systematic reviews.

Abbreviation: ITT, intention-to-treat.

Figure 1 PRISMA 2009 flow diagram.

Abbreviation: CRF, cancer-related fatigue.

Figure 2 Forest plot of effect on CRF.

Abbreviation: CRF, cancer-related fatigue; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; PFS, Piper Fatigue Scale; MFSI-SF, Multidimensional Fatigue Symptom Inventory-Short Form; PROMIS, Patient-Reported Outcomes Measurement Information System; Std diff, standard difference.

Figure 3 Meta-regression plot of adherence.

Abbreviation: Std diff in means, standard difference in means.

Figure S1 PRISMA checklist.

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