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Review
Therapeutic effects of aerobic and resistance exercises for cancer survivors: a systematic review of meta-analyses of clinical trials
  1. Joel T Fuller1,2,
  2. Michael C Hartland2,
  3. Luke T Maloney2,
  4. Kade Davison2
  1. 1 Faculty of Medicine and Health Sciences, Macquarie University, Sydney, New South Wales, Australia
  2. 2 Alliance for Research in Exercise, Nutrition and Activity (ARENA), University of South Australia, Adelaide, South Australia, Australia
  1. Correspondence to Joel T Fuller, Department of Health Professions, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia; joel.fuller{at}mq.edu.au

Abstract

Objective To systematically appraise and summarise meta-analyses investigating the effect of exercise compared with a control condition on health outcomes in cancer survivors.

Design Umbrella review of intervention systematic reviews.

Data sources Web of Science, Scopus, Cochrane Library, CINAHL and MEDLINE databases were searched using a predefined search strategy.

Eligibility criteria Eligible meta-analyses compared health outcomes between cancer survivors participating in an exercise intervention and a control condition. Health outcomes were cardiovascular fitness, muscle strength, health-related quality of life, cancer-related fatigue and depression. Pooled effect estimates from each meta-analysis were quantified using standardised mean differences and considered trivial (<0.20), small (0.20–0.49), moderate (0.50–0.79) and large (≥0.80). Findings were summarised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system.

Results There were 65 eligible articles that reported a total of 140 independent meta-analyses. 139/140 meta-analyses suggested a beneficial effect of exercise. The beneficial effect was statistically significant in 104 (75%) meta-analyses. Most effect sizes were moderate for cardiovascular fitness and muscle strength and small for cancer-related fatigue, health-related quality of life and depression. The quality of evidence was variable according to the GRADE scale, with most studies rated low or moderate quality. Median incidence of exercise-related adverse events was 3.5%.

Conclusion Exercise likely has an important role in helping to manage physical function, mental health, general well-being and quality of life in people undergoing and recovering from cancer and side effects of treatment.

PROSPERO registration number CRD42015020194.

  • cancer
  • fatigue
  • quality of life
  • aerobic fitness
  • physical activity

https://doi.org/10.1136/bjsports-2017-098285

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    Introduction 

    The number of cancer survivors is increasing worldwide due to improved detection and treatment of cancer1 and the ageing population.2 This growing population of cancer survivors experiences ongoing physical and psychological side effects associated with their cancer or treatment and is more likely to suffer from another chronic disease.3 4 Reports of these poor health outcomes among cancer survivors have created a greater emphasis on health interventions that reduce side effects and improve quality of life among cancer survivors.5 6 Exercise is one health strategy that is associated with numerous health benefits in survivors of a variety of cancers,7–9 and cancer survivors are now encouraged to undertake regular exercise during and after cancer treatment.10

    Meta-analyses of controlled trials are the highest level of evidence (ie, level 1 evidence) to support the use of a clinical intervention.11 Where multiple meta-analyses have been published on similar and overlapping questions over a relatively short timeframe, there is a need for a systematic overview of the meta-analytic data (called an umbrella review) to determine the overarching quality and strength of the evidence and the level of consistency or potential contradiction in outcomes.11 The first meta-analysis investigating the effect of exercise interventions in cancer survivors was published in 2005,12 and since then, there has been a rapidly increasing number of meta-analyses published on the topic. Summarising these findings is important for informing health guidelines and policies that need to consider the breadth and quality of evidence.

    The aim of this umbrella review was to systematically appraise and summarise meta-analyses investigating the effect of exercise compared with a control condition on health outcomes in cancer survivors. Health outcomes in this review were limited to cardiovascular fitness, muscle strength, health-related quality of life, cancer-related fatigue and depression. Cardiovascular fitness and muscle strength were investigated because they are health outcomes that are known to respond favourably to exercise in healthy populations. Health-related quality of life, cancer-related fatigue and depression were investigated because they are often adversely affected by cancer or cancer treatment side effects.

    Method

    This umbrella review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for improved reporting of systematic reviews.13 The review protocol was prospectively registered (PROSPERO ID: CRD42015020194).

    Information sources

    The final literature search was conducted on 2 October 2017. The following databases were searched: MEDLINE, CINAHL, Cochrane Library, Web of Science and Scopus. Searches were supplemented by hand searching of reference lists for additional relevant records.

    Search strategy

    Title, abstract and keyword search fields were searched in each database using the following search strategy: exercise OR aerobic OR resistance AND cancer OR malignan* OR oncology OR neoplasm OR tumor OR tumour OR carcinoma OR chemotherapy OR radiotherapy OR androgen deprivation OR mastectomy OR lumpectomy OR pneumonectomy OR lobectomy OR colectomy OR bowel resection OR prostatectomy OR laryngectomy OR esophagectomy OR gastrectomy AND meta-analysis NOT children NOT adolescent.

    No limitations were placed on publication date. Searches were limited to English language articles. Two reviewers independently assessed the eligibility of each article. The title and abstract of each article were screened, and obviously, irrelevant articles were excluded. The full text of each remaining article was then assessed, and any disagreements between reviewers were settled with a discussion among all authors.

    Inclusion and exclusion criteria

    Eligibility criteria followed the participant, intervention, comparison, outcomes and study design system. Eligible participants were adults (aged ≥18 years) diagnosed with cancer. Eligible intervention types were exercise interventions involving aerobic, resistance or combined aerobic and resistance exercises. Interventions that involved only yoga, tai chi or pelvic floor training were excluded because while they may include activity that would be considered as exercise, they also may not. In the case of yoga and tai  chi, they include a deliberate aspect of mental training that may independently affect some outcomes. The eligible comparison type was standard care. Eligible outcomes were cardiovascular fitness, muscle strength, health-related quality of life, depression and cancer-related fatigue. The eligible study design was systematic review with meta-analysis of controlled parallel intervention trials (ie, systematic reviews with meta-analysis of randomised controlled trials and quasiexperimental design studies were eligible, but systematic reviews with meta-analysis of observational prospective studies were not). Only peer-reviewed publications were included.

    Risk of bias assessment and data extraction

    Four reviewers independently assessed risk of bias and extracted relevant data for each eligible meta-analysis. Risk of bias assessment and data extraction was performed twice (by two independent reviewers) for each meta-analysis. Results were compared for accuracy, and any inconsistencies were resolved with a discussion among all reviewers.

    The data extracted from each meta-analysis included: publication details, cancer types, treatment types, stage of treatment, description of interventions, description of outcome measures, number of studies and participants, results of risk of bias assessment, number of exercise-related adverse events, pooled effect estimate and 95% CI and measures of statistical heterogeneity.

    Risk of bias was assessed using the tool for assessing quality of meta-analyses described by Higgins and colleagues.14 The 43-item tool is divided into four categories (data sources, analysis of individual studies, meta-analysis methods and reporting and interpretation), and each category ends with a summary question.14 The four summary questions were: (1) were the review methods adequate such that biases in location and assessment of studies were minimised or able to be identified?, (2) were the individual studies analysed appropriately and without avoidable bias?, (3) were the basic meta-analysis methods appropriate? and (4) are the conclusions justified and the interpretation sound?. Each question was answered ‘yes’, ‘probably yes’, ‘unclear’, ‘probably no’ or ‘no’.

    Statistical considerations

    The magnitude of pooled effect estimates from each meta-analysis was quantified using standardised mean differences (SMDs). If authors reported mean differences rather than SMD, the mean difference was standardised using the pooled SD of all studies included in the respective meta-analysis. Effects were considered trivial (<0.20), small (0.20–0.49), moderate (0.50–0.79) and large (≥0.80).15

    The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to evaluate the quality of evidence provided by each individual meta-analysis.16 Quality of evidence was considered ‘high’ (further research is very unlikely to change our confidence in the effect estimated by this meta-analysis), ‘moderate’ (further research is likely to have an important impact on our confidence in the effect estimated by this meta-analysis and may change the estimate), ‘low’ (further research is very likely to have an important impact on our confidence in the effect estimated by this meta-analysis and is likely to change the estimate) and ‘very low’ (any effect estimated by this meta-analysis is very uncertain). Meta-analyses with consistent effects and no serious limitations were considered high quality. Meta-analyses were downgraded from a ‘high’ GRADE by one category for each of the following criteria that were present: (1) total sample size was <500 participants or total sample size was not reported, (2) statistical heterogeneity (measured using I2) was ≥50% or statistical heterogeneity was not assessed or reported in sufficient detail or (3) low risk of bias was reported in ≤50% of studies included in the meta-analysis, non-randomised controlled trials were included in the meta-analysis or risk of bias was not assessed or reported in sufficient detail.

    Results

    The literature search identified 4258 relevant articles. A total of 4040 articles were excluded after screening of title and abstract, and a further 153 articles were excluded after full-text review. A PRISMA flow chart summary of the literature search is provided in online supplementary file 1. The remaining 65 articles were included in this review.12 17–80 These articles reported a total of 140 independent meta-analyses that are summarised in tables 1–5.

    Supplementary file 1

    View this table:
    Table 1

    Summary of level 1 evidence for the effect of exercise on cardiovascular fitness in cancer populations

    View this table:
    Table 2

    Summary of level 1 evidence for the effect of exercise on muscle strength in cancer populations

    View this table:
    Table 3

    Summary of level 1 evidence for the effect of exercise on cancer-related fatigue

    View this table:
    Table 4

    Summary of level 1 evidence for the effect of exercise on health-related quality of life in cancer populations

    View this table:
    Table 5

    Summary of level 1 evidence for the effect of exercise on depression in cancer populations

    Risk of bias

    Fifty-seven of the 65 articles included in this review were assessed to have low or probably low risk of bias for data sources, analysis of individual studies, meta-analysis methods and reporting and interpretation. Six articles provided insufficient information about how statistical heterogeneity was assessed and addressed.12 29 34 40 45 76 Thus, it is unclear if the basic meta-analysis methods were appropriate. Three articles did not assess risk of bias for the individual studies included in the analysis and were analysed with avoidable bias.28 34 44 Conclusions from these articles are likely to be affected by this bias. A description of the risk of bias assessment for each individual article is provided in online supplementary file 2.

    Supplementary file 2

    Cardiovascular fitness

    A total of 23 meta-analyses investigated the effect of exercise on cardiovascular fitness in cancer survivors using timed walk tests or measurements of peak power output or oxygen uptake (table 1). Each meta-analysis included a mean of 6 studies (range: 2–17 studies) and 396 participants (range: 55–1310 participants). Breast cancer was the most common cancer type included in 13 meta-analyses.18 20 33 36 39 41–45 57 64 69 The most common cancer types included in the other meta-analyses were lung,26 68 73 prostate,21 70 haematological,53 colorectal30 and leukaemia.80 Two meta-analyses did not provide sufficient information about cancer type.12 56

    Pooled effect estimates from all 23 meta-analyses suggested a beneficial effect of exercise on cardiovascular fitness in cancer survivors (table 1). This beneficial effect was statistically significant in 20/23 (87%) meta-analyses. Most meta-analyses (13/23) reported a moderate or greater effect size and provided moderate (eight meta-analyses) or low (nine meta-analyses) quality of evidence (table 1).

    Five meta-analyses included only studies that involved cancer survivors exercising during cancer treatment,42 43 69 70 80 three meta-analyses included only studies that involved cancer survivors exercising after completing treatment26 36 73 and one meta-analysis included only studies involving cancer survivors who were scheduled to undergo lung resection.68 The pooled effect estimates for cardiovascular fitness were similar between the meta-analyses that considered only the during (SMD: 0.42, 0.43, 0.45, 0.66 and 2.28) or after (SMD: 0.24, 0.41 and 0.49) stages of cancer care. Five meta-analyses included only studies that involved cancer survivors who had lung resection26 68 73 or stem cell transplantation53 or were receiving androgen deprivation therapy.70 The remaining meta-analyses did not use treatment stage or type as eligibility criteria and included a variety of treatment stages and types.

    One meta-analysis57 included only studies investigating resistance exercise and reported a pooled effect estimate (SMD: 0.16, 95% CI −0.09 to 0.40) that tended to be smaller than the remaining meta-analyses (median SMD: 0.51; 25th percentile: 0.42; 75th percentile: 0.72), which included a mix of resistance and aerobic exercise studies. One meta-analysis42 included only studies investigating aerobic exercise and reported a pooled effect estimate (SMD: 2.28, 95% CI 2.08 to 2.47) that was larger than the remaining meta-analyses; however, this estimate was based on 55 participants. A list of the exercise intervention eligibility criteria used by all meta-analyses is provided in online supplementary file 3.

    Supplementary file 3

    Muscle strength

    Twenty-one meta-analyses investigated the effect of exercise on upper limb (eight meta-analyses), lower limb (nine meta-analyses) and non-specific muscle strength (four meta-analyses) in cancer survivors using measurements of peak torque or the maximum mass lifted for a given number of repetitions (table 2). Each meta-analysis included a mean of 6 studies (range: 3–13 studies) and 546 participants (range: 230–1254 participants). Breast cancer was the most common cancer type included in 11 meta-analyses (reported in seven articles27 36 44 52 57 64 69). The most common cancer types included in the other meta-analyses were prostate,21 70 77 haematological53 and leukaemia.80 Two meta-analyses did not provide sufficient information about cancer type (reported in one article56).

    Pooled effect estimates from all 21 meta-analyses suggested a beneficial effect of exercise on muscle strength in cancer survivors (table 2). This beneficial effect was statistically significant in 20/21 (95%) meta-analyses (table 2). Most meta-analyses (14/21) reported a moderate or greater effect size and provided moderate (eight meta-analyses) or low (nine meta-analyses) quality of evidence (table 2).

    Five meta-analyses (reported in four articles69 70 77 80) included only studies that involved cancer survivors exercising during cancer treatment, and two meta-analyses (reported in one article36) included only studies that involved cancer survivors exercising after completing treatment. The pooled effect estimates for muscle strength were similar between the meta-analyses that considered only the during (SMD: upper limb 0.71; lower limb 0.58 and 0.78; non-specific 0.27 and 0.67) or after (SMD: upper limb 1.04; lower limb 0.79) stages of cancer care. Six meta-analyses (reported in three articles) included only studies that involved cancer survivors who had androgen deprivation therapy,70 stem cell transplantation53 and breast cancer surgery.52 The remaining meta-analyses did not use treatment stage or type as eligibility criteria and included a variety of treatment stages and types.

    Six meta-analyses (reported across three articles27 52 57) included only studies investigating resistance exercise and reported a pooled effect estimate for upper (SMD: 0.93, 0.57 and 0.70) and lower (SMD: 0.75, 0.48 and 0.50) limbs that were similar to the remaining meta-analyses, which included a mix of resistance and aerobic exercise studies (upper limb SMD: 0.71; 25th percentile: 0.32, 75th percentile: 0.99; lower limb SMD: 0.57, 25th percentile: 0.40, 75th percentile: 0.73).

    Cancer-related fatigue

    Forty-two meta-analyses investigated the effect of exercise on fatigue in cancer survivors (table 3). Each meta-analysis included a mean of 15 studies (range: 2–70 studies) and 1365 participants (range: 78–5603 participants). Breast cancer was the most common cancer type (30 meta-analyses17 22 24 25 31 33 34 36 38 40 43–50 57–59 61 62 64 65 69 71 72 75 76). The most common cancer types included in the other meta-analyses were haematological,19 53 60 prostate,66 79 colorectal,30 gynaecological74 and leukaemia.80 Four meta-analyses did not provide sufficient information about cancer type.12 28 54 56

    Cancer-related fatigue was measured using a variety of instruments, including the Functional Assessment of Cancer Therapy (fatigue dimension), Brief Fatigue Inventory, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, Piper Fatigue Scale, Multidimensional Fatigue Inventory, Schwartz Cancer Fatigue Scale and Profile of Mood States. Pooled effect estimates from all 42 meta-analyses suggested a beneficial effect of exercise on fatigue in cancer survivors (ie, reduced fatigue; table 3). This beneficial effect was statistically significant in 32/42 (76%) meta-analyses (table 3). Most meta-analyses (22/42) reported a small effect size (table 3) and provided moderate (19 meta-analyses) or low (13 meta-analyses) quality of evidence (table 3).

    Two meta-analyses36 49 including only studies that involved cancer survivors exercising after completing cancer treatment (SMD: −0.57 and −0.82) reported pooled effect estimates for cancer-related fatigue that tended to be greater than the 11 meta-analyses24 25 43 50 61 62 65 66 69 75 80 that included only studies that involved cancer survivors exercising during cancer treatment (median SMD: −0.29; 25th percentile: −0.37; 75th percentile: −0.23). Ten meta-analyses included only studies that involved cancer survivors receiving chemotherapy or radiation therapy,24 25 61 69 only chemotherapy,65 only radiation therapy,75 only androgen deprivation therapy,66 stem cell transplantation53 60 or induction therapy or postremission therapy.80 The remaining meta-analyses did not use treatment stage or type as eligibility criteria and included a variety of treatment stages and types.

    One low GRADE meta-analysis65 including only studies investigating aerobic exercise reported a pooled effect estimate for cancer-related fatigue (SMD: −0.82, 95% CI −1.04 to –0.60) that tended to be larger than the remaining meta-analyses (median SMD: −0.31; 25th percentile: −0.46; 75th percentile: −0.21), which included a mix of resistance and aerobic exercise studies. However, the other moderate GRADE meta-analysis58 that included only studies investigating aerobic exercise reported a pooled effect estimate (SMD: −0.22, 95% CI −0.39 to –0.04) that was similar to the remaining studies. One moderate GRADE meta-analysis57 included only studies investigating resistance exercise and reported a pooled effect estimate (SMD: −0.19, 95% CI −0.38 to 0.00) that tended to be smaller than the remaining studies.

    Health-related quality of life

    Thirty-four meta-analyses investigated the effect of exercise on health-related quality of life in cancer survivors (table 4). Each meta-analysis included a mean of 10 studies (range: 2–53 studies) and 830 participants (range: 78–4519 participants). Breast cancer was the most common cancer type included in 18 meta-analyses.18 24 25 27 32 34 35 45 49 50 52 63 64 67 69 72 75 78 The most common cancer types included in the other meta-analyses were haematological,19 53 60 prostate,21 66 79 lung,26 73 gynaecological,55 74 colorectal,30 leukaemia80 and mixed cancer types.37 Three meta-analyses did not provide sufficient information about cancer type.12 28 56

    Health-related quality of life was measured using a variety of instruments, including the Functional Assessment of Cancer Therapy, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, Medical Outcomes Trust Short Form-36 and Cancer Rehabilitation and Evaluation System Short Form. Pooled effect estimates from all 34 meta-analyses suggested a beneficial effect of exercise on health-related quality of life in cancer survivors (table 4). This beneficial effect was statistically significant in 20/34 (59%) meta-analyses (table 4). Most meta-analyses (19/34) reported a small effect size and provided moderate (11 meta-analyses) or low (13 meta-analyses) quality of evidence (table 4). Four of five high-quality meta-analyses reported trivial effect sizes (table 4).

    Seven meta-analyses24 25 49 66 69 75 80 including only studies that involved cancer survivors exercising during cancer treatment reported pooled effect estimates for health-related quality of life (median SMD: 0.34; 25th percentile: 0.19; 75th percentile: 0.40) that tended to be greater than five meta-analyses26 49 55 63 73 that included only studies that involved cancer survivors exercising after treatment (median SMD: 0.17; 25th percentile: 0.15; 75th percentile: 0.38). Twelve meta-analyses included only studies that involved cancer survivors who had lung resection,26 73 chemotherapy or radiation therapy,24 25 69 only chemotherapy,65 only radiation therapy,75 only androgen deprivation therapy,66 stem cell transplantation,53 60 induction therapy or postremission therapy80 and breast cancer surgery.52 The remaining meta-analyses did not use treatment stage or type as eligibility criteria and included a variety of treatment stages and types.

    Three meta-analyses27 32 52 including only studies investigating resistance exercise reported pooled effect estimates for health-related quality of life (SMD: 0.13, 0.17 and 0.17) that tended to be smaller than the remaining meta-analyses (median SMD: 0.29; 25th percentile: 0.17; 75th percentile: 0.36), which included a mix of resistance and aerobic exercise studies.

    Depression

    Twenty meta-analyses investigated the effect of exercise on depression in cancer survivors (table 5). Each meta-analysis included a mean of 9 studies (range: 2–37 studies) and 796 participants (range: 78–2929 participants). Breast cancer was the most common cancer type included in 12 meta-analyses.23–25 29 34 36 48–50 59 64 69 The most common cancer types included in the other meta-analyses were haematological,19 60 prostate,51 79 gynaecological74 and leukaemia.80 Two meta-analyses did not provide sufficient information about cancer type.12 56

    Depression was measured using a variety of instruments, including the Beck Depression Inventory, Center for Epidemiologic Studies Depression Scale, Hospital Anxiety and Depression Scale, Geriatric Depression Scale and Symptom Assessment Scale. Pooled effect estimates from 19/20 meta-analyses suggested a beneficial effect of exercise on depression in cancer survivors (ie, reduced depression; table 5). This beneficial effect was statistically significant in 12/19 (63%) meta-analyses (table 5). Most meta-analyses (12/19) reported a small effect size and provided moderate (six meta-analyses) or low (eight meta-analyses) quality of evidence (table 5).

    Two meta-analyses36 49 including only studies that involved cancer survivors exercising after completing primary treatment for cancer (SMD: −0.41, –0.88) reported pooled effect estimates for depression that tended to be greater than the five meta-analyses24 25 50 69 80 that included only studies that involved cancer survivors exercising during cancer treatment (median SMD: −0.20; 25th percentile: −0.28; 75th percentile: −0.15). Five meta-analyses included only studies that involved cancer survivors receiving chemotherapy or radiation therapy,24 25 69 stem cell transplantation60 or induction therapy or postremission therapy.80 The remaining meta-analyses did not use treatment stage or type as eligibility criteria and included a variety of treatment stages and types.

    Adverse events

    Twenty-one meta-analyses reported the incidence of exercise-related adverse events.17–20 27 32 33 37 39 43 45–50 53 58 62 69 75 The most commonly reported exercise-related adverse event was musculoskeletal pain or injury. The incidence of exercise-related adverse events ranged from 0% to 25.8% (median: 3.5%; 25th percentile: 1.0%; 75th percentile: 6.7%). The remaining meta-analyses did not report information about adverse events or did not provide sufficient detail to calculate a percentage incidence of adverse events for participants allocated to exercise intervention.

    Discussion

    This umbrella review identified 65 articles reporting a total of 140 independent meta-analyses investigating the effect of exercise on cardiovascular fitness, muscle strength, health-related quality of life, cancer-related fatigue and depression. The meta-analyses tended to provide moderate-quality or low-quality evidence for moderate beneficial effects of exercise on cardiovascular fitness and muscle strength and moderate-quality or low-quality evidence for small beneficial effects of exercise on cancer-related fatigue, health-related quality of life and depression. The incidence of exercise-related adverse events was typically very low.

    With so many meta-analyses published on the topic of exercise in cancer survivors over the last 10 years, there is a growing need for researchers to contrast the findings of each separate meta-analysis and determine whether evidence is consistent or contradictory. The results of this umbrella review suggest that review authors, addressing similar review questions related to exercise in cancer survivors, are observing similar results and independently arriving at similar conclusions.11

    Improved cardiovascular fitness and muscle strength were the largest effects of exercise in cancer survivors. Moderate or greater effect sizes were reported in over half of the meta-analyses investigating cardiovascular fitness and muscle strength, respectively. Meta-analyses investigating the effect of exercise on cardiovascular fitness tended to report moderate or greater effect sizes regardless of the quality of evidence. The estimated effects were similar between the meta-analyses that investigated effects of exercise during cancer treatment compared with after treatment. Meta-analyses that included only studies investigating resistance exercises reported smaller effects on cardiovascular fitness. Moderate or greater effects on muscle strength were more commonly reported in higher-quality meta-analyses. These findings support previous suggestions that cancer survivors can improve physical fitness through regular exercise in a similar manner to adults who have not been diagnosed with cancer.10

    The greatest number of high-quality meta-analyses investigated the effects of exercise on cancer-related fatigue and suggested a small beneficial effect. The high quality of these meta-analyses suggests that the benefit of exercise on cancer-related fatigue is likely to be a true effect.16 Additionally, similar beneficial effects were reported by moderate-quality and low-quality meta-analyses, further increasing confidence in this finding. The estimated effects of exercise on cancer-related fatigue were greater in the meta-analyses that included only studies of cancer survivors who had completed primary treatment. Fatigue is one of the most common symptoms reported by cancer survivors due to both the disease process and the treatment side effects.81 82 The tiredness, weakness and lack of energy associated with cancer-related fatigue reduce the ability to perform activities of daily living, cause considerable psychological distress and impose significant financial burden through missed days at work.83 The National Comprehensive Cancer Network advocates exercise as an important non-pharmacological strategy for treating cancer-related fatigue,84 and the findings of this umbrella review suggest that level 1 evidence consistently supports this recommendation.

    Meta-analyses also consistently demonstrate small beneficial effects of exercise on health-related quality of life and depression in cancer survivors, regardless of the quality of evidence. Meta-analyses that included only cancer survivors who had completed primary treatment reported larger beneficial effects on depressive symptoms but smaller beneficial effects on health-related quality of life when compared with meta-analyses including only cancer survivors undergoing treatment. Smaller beneficial effects on health-related quality of life were also reported by meta-analyses that included only studies of resistance exercise. Reducing depression and improving quality of life in cancer survivors are important because most cancer survivors report ongoing poor health and well-being following cancer treatment.3–5 Exercise is a cost-effective health promotion activity in other health contexts.85 86 The consistent health benefits of exercise in this review suggest that exercise could also be a cost-effective method of addressing the poor long-term outcomes reported by cancer survivors.

    About one-third of meta-analyses provided sufficient information about exercise-related adverse events. Data from these meta-analyses suggest that only 35 out of every 1000 cancer survivors experience an adverse event related to exercise participation. The low rate of adverse events suggests that the consistent benefits of exercise in cancer survivors far outweigh the potential for harm. However, it is important to note that exercise sessions undertaken during clinical trials will usually be prescribed and monitored by suitably qualified professionals. To ensure the same level of safety for this population, the aim should be to replicate this practice, particularly where the cancer survivors are more acutely affected by disease or treatment side effects or have complex symptom or comorbidity profiles.

    Overall, there is a strong rationale for recommending exercise for improving health outcomes in cancer survivors. The evidence included in this umbrella review is based on controlled parallel intervention trials that were predominantly randomised controlled trials, which increases confidence in the overall findings. However, it is difficult to make strong recommendations about the effects of different exercise types and the effects of exercise at different stages of the cancer care continuum because the majority of meta-analyses did not specify exercise type or cancer treatment stage as eligibility criteria. Most effect sizes suggested only small beneficial effects of exercise on health outcomes. However, when placed in the context of the substantial burden faced by healthcare systems trying to help the growing number of cancer survivors, these small beneficial effects are likely to be clinically relevant. Additionally, the consistent benefits of exercise far outweigh the very low incidence of exercise-related harms. A substantial portion of the meta-analyses informing this recommendation provided only low-quality evidence. However, similar beneficial effects of exercise were reported by meta-analyses of high, moderate, low and very low quality. Thus, it appears unlikely that future research will change the strength of this recommendation.

    The majority of meta-analyses included in this umbrella review were based entirely or mostly on studies undertaken in breast cancer survivors. Therefore, this limits the generalisability of the results of our umbrella review to survivors of other types of cancer. Future research investigating exercise in cancer survivors should seek to address this bias in the literature. Additionally, there needs to be increased emphasis on primary research studies investigating exercise in cancer survivors rather than additional meta-analyses. Our umbrella review identified over 90 meta-analyses across over 40 systematic reviews published in the last 5 years. It is questionable how much new knowledge can be generated from further meta-analyses on this topic until more primary studies have been completed.

    A limitation of this umbrella review is the potential for language bias because searches were limited to English language articles. It is unclear whether including systematic reviews published in other languages would have influenced our findings. Additionally, when interpreting the results of this umbrella review, it is important to acknowledge that the results of each meta-analysis included in this overarching summary are not discreet in that they will have overlapping primary studies included across potentially multiple meta-analyses. Despite this, even where two reviews were asking very similar or even identical questions, each included meta-analysis has a discreet methodological approach including differing search strategy, selection criteria and analytical approach. Thus, the multiplicity in arriving at the same or similar outcomes still serves to increase the confidence in a finding (or contrastingly reduce confidence if conflicting outcomes) and demonstrates the value of the umbrella review process.

    Conclusion

    Exercise has beneficial effects on markers of cardiovascular fitness, muscle strength, health-related quality of life, cancer-related fatigue and depression among cancer survivors. Exercise likely has an important role in helping to manage physical function, mental health, general well-being and quality of life in people undergoing and recovering from cancer and side effects of treatment.

    What is already known?

    • Exercise is associated with numerous health benefits, and cancer survivors are now encouraged to undertake regular exercise during and after cancer treatment.

    • The first meta-analysis investigating the effect of exercise interventions in cancer survivors was published in 2005, and since then, there has been a rapidly increasing number of meta-analyses published on the topic.

    • Where multiple meta-analyses have been published on similar and overlapping questions over a relatively short timeframe, there needs to be a systematic overview of the meta-analytic data (called an umbrella review) to determine the overarching quality and strength of the evidence and the level of consistency or potential contradiction in outcomes.

    What are the new findings?

    • This umbrella review identified 65 articles reporting a total of 140 independent meta-analyses investigating the effect of exercise on cardiovascular fitness, muscle strength, health-related quality of life, cancer-related fatigue and depression.

    • Improved cardiovascular fitness and muscle strength were the largest effects of exercise in cancer survivors. The greatest number of high-quality meta-analyses investigated the effects of exercise on cancer-related fatigue and suggested a small beneficial effect.

    • The incidence of exercise-related adverse events was typically very low.

    • The majority of meta-analyses included in this umbrella review were based entirely or mostly on studies undertaken in breast cancer survivors. Thus, although there is a wealth of level 1 evidence supporting exercise in cancer survivors, the ability to extrapolate this evidence to survivors of cancers other than breast cancer is limited.

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    Footnotes

    • Contributors All authors contributed to the conception and design of the review and completion of the search strategy. JTF drafted the manuscript. All authors edited and revised the manuscript and approved the final version of the manuscript.

    • Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests KD is an elected director for Exercise and Sports Science Australia.

    • Provenance and peer review Not commissioned; externally peer reviewed.