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Effects and moderators of exercise on quality of life and physical function in patients with cancer: An individual patient data meta-analysis of 34 RCTs

Open AccessPublished:December 03, 2016DOI:https://doi.org/10.1016/j.ctrv.2016.11.010

      Highlights

      • This meta-analysis of individual patient data from 34 randomised controlled trials (n = 4519 patients) found significant benefits of exercise effects on quality of life and physical function.
      • Exercise effects on quality of life and physical function were comparable across patients with different demographic and clinical characteristics.
      • Exercise effects on quality of life and physical function were significantly larger for supervised than unsupervised interventions.

      Abstract

      This individual patient data meta-analysis aimed to evaluate the effects of exercise on quality of life (QoL) and physical function (PF) in patients with cancer, and to identify moderator effects of demographic (age, sex, marital status, education), clinical (body mass index, cancer type, presence of metastasis), intervention-related (intervention timing, delivery mode and duration, and type of control group), and exercise-related (exercise frequency, intensity, type, time) characteristics.
      Relevant published and unpublished studies were identified in September 2012 via PubMed, EMBASE, PsycINFO, and CINAHL, reference checking and personal communications. Principle investigators of all 69 eligible trials were requested to share IPD from their study. IPD from 34 randomised controlled trials (n = 4519 patients) that evaluated the effects of exercise compared to a usual care, wait-list or attention control group on QoL and PF in adult patients with cancer were retrieved and pooled. Linear mixed-effect models were used to evaluate the effects of the exercise on post-intervention outcome values (z-score) adjusting for baseline values. Moderator effects were studies by testing interactions.
      Exercise significantly improved QoL (β = 0.15, 95%CI = 0.10;0.20) and PF (β = 0.18, 95%CI = 0.13;0.23). The effects were not moderated by demographic, clinical or exercise characteristics. Effects on QoL (βdifference_in_effect = 0.13, 95%CI = 0.03;0.22) and PF (βdifference_in_effect = 0.10, 95%CI = 0.01;0.20) were significantly larger for supervised than unsupervised interventions.
      In conclusion, exercise, and particularly supervised exercise, effectively improves QoL and PF in patients with cancer with different demographic and clinical characteristics during and following treatment. Although effect sizes are small, there is consistent empirical evidence to support implementation of exercise as part of cancer care.

      Keywords

      Introduction

      As a consequence of the increased number of cancer diagnoses, and concomitant mortality reductions for most types of cancer [
      • Torre L.A.
      • Siegel R.L.
      • Ward E.M.
      • Jemal A.
      Global cancer incidence and mortality rates and trends–an update.
      ,
      • Ferlay J.
      • Soerjomataram I.
      • Dikshit R.
      • Eser S.
      • Mathers C.
      • Rebelo M.
      • et al.
      Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.
      ,
      • Hashim D.
      • Boffetta P.
      • La Vecchia C.
      • Rota M.
      • Bertuccio P.
      • Malvezzi M.
      • et al.
      The global decrease in cancer mortality: trends and disparities.
      ], many patients live with physical and psychosocial problems associated with the disease and its treatment that may compromise their quality of life (QoL). Exercise has been recommended as part of standard care for patients with cancer to help prevent and manage physical and psychosocial problems, and improve QoL [
      • Schmitz K.H.
      • Courneya K.S.
      • Matthews C.
      • Demark-Wahnefried W.
      • Galvao D.A.
      • Pinto B.M.
      • et al.
      American College of Sports Medicine roundtable on exercise guidelines for cancer survivors.
      ,
      • Rock C.L.
      • Doyle C.
      • Demark-Wahnefried W.
      • Meyerhardt J.
      • Courneya K.S.
      • Schwartz A.L.
      • et al.
      Nutrition and physical activity guidelines for cancer survivors.
      ].
      Previous meta-analyses of randomised controlled trials (RCT) reported benefits of exercise during and following cancer treatment [
      • Speck R.M.
      • Courneya K.S.
      • Masse L.C.
      • Duval S.
      • Schmitz K.H.
      An update of controlled physical activity trials in cancer survivors: a systematic review and meta-analysis.
      ]. Benefits include improved physical fitness, function, and quality of life (QoL), and reduced fatigue, and depression [
      • Speck R.M.
      • Courneya K.S.
      • Masse L.C.
      • Duval S.
      • Schmitz K.H.
      An update of controlled physical activity trials in cancer survivors: a systematic review and meta-analysis.
      ,
      • Buffart L.M.
      • Galvao D.A.
      • Brug J.
      • Chinapaw M.J.
      • Newton R.U.
      Evidence-based physical activity guidelines for cancer survivors: current guidelines, knowledge gaps and future research directions.
      ,
      • Mishra S.I.
      • Scherer R.W.
      • Geigle P.M.
      • Berlanstein D.R.
      • Topaloglu O.
      • Gotay C.C.
      • et al.
      Exercise interventions on health-related quality of life for cancer survivors.
      ,
      • Mishra S.I.
      • Scherer R.W.
      • Snyder C.
      • Geigle P.M.
      • Berlanstein D.R.
      • Topaloglu O.
      Exercise interventions on health-related quality of life for people with cancer during active treatment.
      ]. However, average reported effect sizes on these outcomes were small to moderate.
      To maximize benefits of exercise, it is important to target subgroups of patients that respond best to a particular intervention [
      • Kraemer H.C.
      • Wilson G.T.
      • Fairburn C.G.
      • Agras W.S.
      Mediators and moderators of treatment effects in randomized clinical trials.
      ]. A number of RCTs showed that demographic, clinical, and personal factors, such as age, marital status, disease stage and type of treatment, moderate the effects of exercise in patients with cancer [
      • Buffart L.M.
      • Newton R.U.
      • Chinapaw M.J.
      • Taaffe D.R.
      • Spry N.A.
      • Denham J.W.
      • et al.
      The effect, moderators, and mediators of resistance and aerobic exercise on health-related quality of life in older long-term survivors of prostate cancer.
      ,
      • Kalter J.
      • Buffart L.M.
      • Korstjens I.
      • van Weert E.
      • Brug J.
      • Verdonck-de Leeuw I.M.
      • et al.
      Moderators of the effects of group-based physical exercise on cancer survivors’ quality of life.
      ,
      • Courneya K.S.
      • McKenzie D.C.
      • Mackey J.R.
      • Gelmon K.
      • Reid R.D.
      • Friedenreich C.M.
      • et al.
      Moderators of the effects of exercise training in breast cancer patients receiving chemotherapy: a randomized controlled trial.
      ,
      • Courneya K.S.
      • Sellar C.M.
      • Stevinson C.
      • McNeely M.L.
      • Friedenreich C.M.
      • Peddle C.J.
      • et al.
      Moderator effects in a randomized controlled trial of exercise training in lymphoma patients.
      ,
      • Carmack Taylor C.L.
      • de Moor C.
      • Basen-Engquist K.
      • Smith M.A.
      • Dunn A.L.
      • Badr H.
      • et al.
      Moderator analyses of participants in the Active for Life after cancer trial: implications for physical activity group intervention studies.
      ]. However, these single studies are generally underpowered to analyse moderators of intervention effects and conduct subsequent stratified analysis. Meta-analyses based on aggregate data are limited to using summary data, such as the mean age of the patients or the proportion of men in a study, and they are unable to investigate intervention-covariate interactions at the level of the patient [
      • Tierney J.F.
      • Vale C.
      • Riley R.
      • Smith C.T.
      • Stewart L.
      • Clarke M.
      • et al.
      Individual participant data (IPD) meta-analyses of randomised controlled trials: guidance on their use.
      ,
      • Riley R.D.
      • Lambert P.C.
      • Abo-Zaid G.
      Meta-analysis of individual participant data: rationale, conduct, and reporting.
      ].
      Optimizing benefits of exercise also requires a better understanding of important intervention-related characteristics, including the timing and mode of intervention delivery, intervention duration, and exercise dimensions, in terms of frequency, intensity, type and time (FITT factors).
      Meta-analyses of raw individual patient data (IPD) are suggested as the preferred method to evaluate moderators of intervention effects, since the large number of raw data points facilitates testing of interactions at the patient level, conducting subsequent stratified analyses, and standardizing analytic techniques across the included studies [
      • Teramukai S.
      • Matsuyama Y.
      • Mizuno S.
      • Sakamoto J.
      Individual patient-level and study-level meta-analysis for investigating modifiers of treatment effect.
      ,
      • Fisher D.J.
      • Copas A.J.
      • Tierney J.F.
      • Parmar M.K.
      A critical review of methods for the assessment of patient-level interactions in individual participant data meta-analysis of randomized trials, and guidance for practitioners.
      ]. In the current IPD meta-analysis we used data collected in the Predicting OptimaL Cancer RehabIlitation and Supportive care (POLARIS) study [
      • Buffart L.M.
      • Kalter J.
      • Chinapaw M.J.
      • Heymans M.W.
      • Aaronson N.K.
      • Courneya K.S.
      • et al.
      Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS): rationale and design for meta-analyses of individual patient data of randomized controlled trials that evaluate the effect of physical activity and psychosocial interventions on health-related quality of life in cancer survivors.
      ]. The aims were to evaluate the effects of exercise on QoL and physical function (PF) in patients with cancer, and to identify demographic, clinical, intervention-, and exercise-related moderators of intervention effects.

      Methods

      The conduct and reporting of this IPD meta-analysis is based on the Preferred Reporting Items for Systematic Review and Meta-Analyses of Individual Participant Data (PRISMA-IPD) statement [
      • Stewart L.A.
      • Clarke M.
      • Rovers M.
      • Riley R.D.
      • Simmonds M.
      • Stewart G.
      • et al.
      Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data: the PRISMA-IPD Statement.
      ].

      Identification and inclusion of studies

      Detailed descriptions of the design and procedures of the POLARIS study were published previously [
      • Buffart L.M.
      • Kalter J.
      • Chinapaw M.J.
      • Heymans M.W.
      • Aaronson N.K.
      • Courneya K.S.
      • et al.
      Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS): rationale and design for meta-analyses of individual patient data of randomized controlled trials that evaluate the effect of physical activity and psychosocial interventions on health-related quality of life in cancer survivors.
      ]. In short, relevant published and unpublished studies (e.g. study protocol papers) were identified in September 2012 via systematic searches in four electronic databases (PubMed, EMBASE, PsycINFO, and CINAHL), reference checking of systematic reviews, meta-analyses, and personal communication with collaborators, colleagues, and other experts in the field [
      • Buffart L.M.
      • Kalter J.
      • Chinapaw M.J.
      • Heymans M.W.
      • Aaronson N.K.
      • Courneya K.S.
      • et al.
      Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS): rationale and design for meta-analyses of individual patient data of randomized controlled trials that evaluate the effect of physical activity and psychosocial interventions on health-related quality of life in cancer survivors.
      ]. POLARIS included RCTs that evaluated the effects of exercise interventions and/or psychosocial interventions on QoL compared to a wait-list, usual care or attention control group in adult patients with cancer. We excluded studies focusing on spiritual or existential therapy, yoga, and diet or multimodal lifestyle interventions. The study protocol was registered in PROSPERO in February 2013 (CRD42013003805) [
      • Buffart L.M.
      • Kalter J.
      • Chinapaw M.J.
      • Heymans M.W.
      • Aaronson N.K.
      • Courneya K.S.
      • et al.
      Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS): rationale and design for meta-analyses of individual patient data of randomized controlled trials that evaluate the effect of physical activity and psychosocial interventions on health-related quality of life in cancer survivors.
      ].
      A letter of invitation to join the POLARIS consortium and share data was sent to the principal investigator (PI) of eligible RCTs. In case of no response, we sent reminders or contacted another PI. In case the study was not yet published, we maintained contact about the study completion date, to allow inclusion at a later stage during the data collection process of approximately 3 years. After PI’s expressed interest in data sharing, they were requested to sign a data sharing agreement stating that they agreed with the POLARIS policy document, and were willing to share and transform anonymised data of study participants who were randomised. Data could be sent in various formats, were re-coded according to standardised protocols, and were checked for completeness, improbable values, consistency with published articles, and missing items. Subsequently, datasets were imported into the POLARIS database where they were harmonized [
      • Buffart L.M.
      • Kalter J.
      • Chinapaw M.J.
      • Heymans M.W.
      • Aaronson N.K.
      • Courneya K.S.
      • et al.
      Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS): rationale and design for meta-analyses of individual patient data of randomized controlled trials that evaluate the effect of physical activity and psychosocial interventions on health-related quality of life in cancer survivors.
      ].

      Data extraction and quality assessment

      Two independent researchers (LB and MS) extracted study characteristics and rated the quality of included studies from published papers, using the ‘risk-of-bias’ assessment tool of the Cochrane Collaboration. The quality of following aspects was graded as high (‘+’), low (‘−’) or unclear (‘?’) quality: random sequence generation (high quality if random component was used), allocation concealment (high quality if central, computerized allocation or sequentially numbered sealed envelopes were used), incomplete outcome (high quality if intention-to-treat analyses were performed and missing outcome data were <10% or adequate imputation techniques were used), and incomplete reporting (high quality if QoL or PF was reported such that data could be entered in an aggregate data meta-analysis). We also included ratings of adherence (high quality if ⩾80% of patients had high attendance, defined as ⩾80% of sessions attended [
      • Courneya K.S.
      • Segal R.J.
      • Gelmon K.
      • Reid R.D.
      • Mackey J.R.
      • Friedenreich C.M.
      • et al.
      Predictors of supervised exercise adherence during breast cancer chemotherapy.
      ,
      • Kampshoff C.S.
      • van Mechelen W.
      • Schep G.
      • Nijziel M.R.
      • Witlox L.
      • Bosman L.
      • et al.
      Participation in and adherence to physical exercise after completion of primary cancer treatment.
      ]) and contamination (high quality if no or limited exercise was present in the control group, i.e. moderate to vigorous exercise was present in <25% of patients or increased less than 60 min [
      • Steins Bisschop C.N.
      • Courneya K.S.
      • Velthuis M.J.
      • Monninkhof E.M.
      • Jones L.W.
      • Friedenreich C.
      • et al.
      Control group design, contamination and drop-out in exercise oncology trials: a systematic review.
      ]). Items related to blinding were omitted because blinding of patients and personnel is difficult in the case of exercise interventions, and QoL and PF were assessed using patient-reported outcomes. Quality assessments of both reviewers were compared and disagreements in the scores were resolved by discussion.

      Representativeness of included studies

      To examine whether the included RCTs were a representative sample of all eligible RCTs, we compared pooled effect sizes of RCTs included versus those not included. Effect sizes per RCT were calculated by subtracting the published average post-intervention value of QoL or PF of the control group from that of the intervention group, and dividing the result by the pooled standard deviation. We corrected effect sizes for small samples as suggested by Hedges and Olkin. Effect sizes (Hedges’ g) were pooled with a random effects model and differences in effects between studies providing data and those that did not were examined using Comprehensive Meta-analysis software (version 2.2.064).
      We evaluated publication bias for all eligible studies and for studies providing data by inspecting the funnel plot and by the Duval and Tweedie’s trim and fill procedure [
      • Ahmed I.
      • Sutton A.J.
      • Riley R.D.
      Assessment of publication bias, selection bias, and unavailable data in meta-analyses using individual participant data: a database survey.
      ,
      • Duval S.
      • Tweedie R.
      Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis.
      ]. The procedure provides estimates of the number of missing studies and the effect size after the publication bias has been taken into account. The Egger’s test was used to test whether the bias captured by the funnel plot was significant.

      Outcome variables

      QoL and PF were assessed with patient reported outcomes (PRO, Table 1). In the present paper, we used baseline (pre-intervention) and post-intervention values. To allow pooling of the different PROs, we recoded the individual scores into z-scores by subtracting the individual score from the mean score at baseline, and dividing the result by the mean standard deviation at baseline. Subsequently, the pooled z-scores were used for further analyses. If studies used both a cancer-specific and a generic QoL PRO, data from the cancer-specific PRO were used.
      Table 1Descriptives of studies evaluating the effects of exercise on quality of life and physical function included in the database (n = 34), in alphabetical order of first author.
      Author (year)

      Acronym
      CountryNAge, mean (SD)Gender (% female)Cancer typeInterventionExerciseControlQuality
      TimingDelivery modeDuration (weeks)FITTPRORSGACIOIRAdhCon
      Arbane (2011)
      • Arbane G.
      • Tropman D.
      • Jackson D.
      • Garrod R.
      Evaluation of an early exercise intervention after thoracotomy for non-small cell lung cancer (NSCLC), effects on quality of life, muscle strength and exercise tolerance: randomised controlled trial.
      UK5164.0 (11.0)48.1LungPostUnsupervised12F: ?

      I: moderate

      T: RE + AE

      T: ?
      Usual careC30++-+??
      Cadmus, (2009)
      • Cadmus L.A.
      • Salovey P.
      • Yu H.
      • Chung G.
      • Kasl S.
      • Irwin M.L.
      Exercise and quality of life during and after treatment for breast cancer: results of two randomized controlled trials.


      IMPACT
      USA5054.2 (9.6)100BreastDuringUnsupervised26F: aim 5x/week

      I: moderate

      T: AE

      T: 30 min
      Usual careFACT++++-?
      Cormie (2015)
      • Cormie P.
      • Galvao D.A.
      • Spry N.
      • Joseph D.
      • Chee R.
      • Taaffe D.R.
      • et al.
      Can supervised exercise prevent treatment toxicity in patients with prostate cancer initiating androgen-deprivation therapy: a randomised controlled trial.
      AUS6467.9 (7.1)0ProstateDuring ADTSupervised12F: 2x/week

      I: moderate-vigorous

      T: RE + AE

      T: 60 min
      Usual careC30++++??
      Couneya (2003)
      • Courneya K.S.
      • Friedenreich C.M.
      • Quinney H.A.
      • Fields A.L.
      • Jones L.W.
      • Fairey A.S.
      A randomized trial of exercise and quality of life in colorectal cancer survivors.


      CANHOPE
      CAN9360.3 (10.4)41.9ColorectalDuring or postUnsupervised16F: 3-5x/week

      I: moderate

      T: AE

      T: 20–30 min
      Wait-listFACT+?++--
      Courneya (2003)
      • Courneya K.S.
      • Mackey J.R.
      • Bell G.J.
      • Jones L.W.
      • Field C.J.
      • Fairey A.S.
      Randomized controlled trial of exercise training in postmenopausal breast cancer survivors: cardiopulmonary and quality of life outcomes.
      REHAB
      CAN5258.6 (5.7)100BreastPostSupervised15F: 3x/week

      I: moderate-vigorous

      T: AE

      T: 15–35 min
      Wait-listFACT++++++
      Courneya (2007)
      • Courneya K.S.
      • Segal R.J.
      • Mackey J.R.
      • Gelmon K.
      • Reid R.D.
      • Friedenreich C.M.
      • et al.
      Effects of aerobic and resistance exercise in breast cancer patients receiving adjuvant chemotherapy: a multicenter randomized controlled trial.
      START
      CAN24249.2 (9.3)100BreastDuring CTSupervisedMedian: 17F: 3x/week

      I: moderate-vigorous

      T: AE vs RE

      T: AE: 15–45 min
      Usual careFACT++++-+
      Courneya (2009)
      • Courneya K.S.
      • Sellar C.M.
      • Stevinson C.
      • McNeely M.L.
      • Peddle C.J.
      • Friedenreich C.M.
      • et al.
      Randomized controlled trial of the effects of aerobic exercise on physical functioning and quality of life in lymphoma patients.


      HELP
      CAN12253.2 (14.8)41.0HaematologicalDuring or postSupervised12F: 3x/week

      I: moderate-vigorous

      T: AE

      T: 15–45 min
      Usual careFACT+++++-
      Daley (2007)
      • Daley A.J.
      • Crank H.
      • Saxton J.M.
      • Mutrie N.
      • Coleman R.
      • Roalfe A.
      Randomized trial of exercise therapy in women treated for breast cancer.
      UK10851.1 (8.6)100BreastPostSupervised8F: 3x/week

      I: moderate-vigorous

      T: AE

      T: 50 min
      Attention control vs usual careFACT++++--
      Duijts (2012)
      • Duijts S.F.
      • van Beurden M.
      • Oldenburg H.S.
      • Hunter M.S.
      • Kieffer J.M.
      • Stuiver M.M.
      • et al.
      Efficacy of cognitive behavioral therapy and physical exercise in alleviating treatment-induced menopausal symptoms in patients with breast cancer: results of a randomized, controlled, multicenter trial.


      EVA
      NL20747.8 (5.8)100BreastPostUnsupervised12F: 5x per 2 weeks

      I: vigorous

      T: AE

      T: 45–60 min
      Personal communication with authors.
      Wait-listSF-36++-+-?
      Galvão (2010)
      • Galvao D.A.
      • Taaffe D.R.
      • Spry N.
      • Joseph D.
      • Newton R.U.
      Combined resistance and aerobic exercise program reverses muscle loss in men undergoing androgen suppression therapy for prostate cancer without bone metastases: a randomized controlled trial.
      AUS5769.8 (7.3)0ProstateDuring ADTSupervised12F: 2x/week

      I: moderate

      T: RE + AE

      T: 60 min
      Usual CareC30++++??
      Galvão (2014)
      • Galvao D.A.
      • Spry N.
      • Denham J.
      • Taaffe D.R.
      • Cormie P.
      • Joseph D.
      • et al.
      A multicentre year-long randomised controlled trial of exercise training targeting physical functioning in men with prostate cancer previously treated with androgen suppression and radiation from TROG 03.04 RADAR.
      RADAR-exercise
      AUS10071.7 (6.4)0ProstatePost ADTSupervised26F: 2x/week

      I: moderate-vigorous

      T: RE + AE

      T: 60 min
      Usual care with PA brochureC30++++-?
      Goedendorp (2010)
      • Goedendorp M.M.
      • Peters M.E.
      • Gielissen M.F.
      • Witjes J.A.
      • Leer J.W.
      • Verhagen C.A.
      • et al.
      Is increasing physical activity necessary to diminish fatigue during cancer treatment? Comparing cognitive behavior therapy and a brief nursing intervention with usual care in a multicenter randomized controlled trial.
      NL14457.2 (10.5)63.2MixedDuringHome-basedMean: 31.7F: towards 5d/week

      I: ?

      T: AE

      T: towards 60 min
      Usual careC30+++-??
      Griffith (2009)
      • Griffith K.
      • Wenzel J.
      • Shang J.
      • Thompson C.
      • Stewart K.
      • Mock V.
      Impact of a walking intervention on cardiorespiratory fitness, self-reported physical function, and pain in patients undergoing treatment for solid tumors.
      USA12660.2 (10.6)38.9MixedDuring CT, RT or bothHome-basedMean: 12.8F: 5x/week

      I: low-moderate

      T: AE

      T: 25-35 min
      Usual careSF-36??+---
      Hayes (2013)
      • Hayes S.C.
      • Rye S.
      • Disipio T.
      • Yates P.
      • Bashford J.
      • Pyke C.
      • et al.
      Exercise for health: a randomized, controlled trial evaluating the impact of a pragmatic, translational exercise intervention on the quality of life, function and treatment-related side effects following breast cancer.


      Exercise for Health
      AUS19452.4 (8.5)100BreastDuring and/or postUnsupervised35F: aim: ⩾ 4x/week

      I: moderate

      T: RE + AE

      T: 20–45 min
      Usual careFACT+++++-
      Herrero (2006)
      • Herrero F.
      • San Juan A.F.
      • Fleck S.J.
      • Balmer J.
      • Perez M.
      • Canete S.
      • et al.
      Combined aerobic and resistance training in breast cancer survivors: a randomized, controlled pilot trial.
      Spain16?100BreastPostSupervised8F: 3x/week

      I: moderate-vigorous

      T: RE + AE

      T: 90 min
      Usual careC30?+--+?
      Irwin (2009)
      • Irwin M.L.
      • Varma K.
      • Alvarez-Reeves M.
      • Cadmus L.
      • Wiley A.
      • Chung G.G.
      • et al.
      Randomized controlled trial of aerobic exercise on insulin and insulin-like growth factors in breast cancer survivors: the Yale Exercise and Survivorship study.


      YES
      USA7555.8 (8.7)100BreastPostSupervised26F: 3 supervised (+ 2 unsupervised)

      I: moderate

      T: AE (walking)

      T: 15–30 min
      Usual careFACT+?-+-+
      Kampshoff (2015)
      • Kampshoff C.S.
      • Chinapaw M.J.
      • Brug J.
      • Twisk J.W.
      • Schep G.
      • Nijziel M.R.
      • et al.
      Randomized controlled trial of the effects of high intensity and low-to-moderate intensity exercise on physical fitness and fatigue in cancer survivors: results of the Resistance and Endurance exercise After ChemoTherapy (REACT) study.


      REACT
      NL27753.5 (11.0)80.1MixedPostSupervised12F: 2x/week

      I: moderate vs vigorous

      T: RE + AE

      T: 60 min
      Wait-listC30++++-+
      Korstjens (2008)
      • Korstjens I.
      • May A.M.
      • van Weert E.
      • Mesters I.
      • Tan F.
      • Ros W.J.
      • et al.
      Quality of life after self-management cancer rehabilitation: a randomized controlled trial comparing physical and cognitive-behavioral training versus physical training.


      OncoRev
      NL13350.6 (10.2)85MixedPostSupervised12F: 2x/week

      I: AE: moderate-vigorous, RE: low-moderate

      T: RE + AE

      T: 120 min
      Wait-listC30+?+++?
      Mehnert (2011)
      • Mehnert A.
      • Veers S.
      • Howaldt D.
      • Braumann K.M.
      • Koch U.
      • Schulz K.H.
      Effects of a physical exercise rehabilitation group program on anxiety, depression, body image, and health-related quality of life among breast cancer patients.
      GER5851.9 (8.5)100BreastPostSupervised10F: 2x/week

      I: moderate

      T: AE + gymnastics + movement games + relaxation

      T: 90 min
      Wait-listSF-36?++-+?
      Mutrie (2007)
      • Mutrie N.
      • Campbell A.M.
      • Whyte F.
      • McConnachie A.
      • Emslie C.
      • Lee L.
      • et al.
      Benefits of supervised group exercise programme for women being treated for early stage breast cancer: pragmatic randomised controlled trial.
      UK20151.6 (9.5)100BreastDuring CT and/or RTSupervised12F: 2 supervised (+1 unsupervised)

      I: low-moderate

      T: RE + AE

      T: 45 min
      Usual careFACT++++??
      Newton (2009)
      • Newton R.U.
      • Taaffe D.R.
      • Spry N.
      • Gardiner R.A.
      • Levin G.
      • Wall B.
      • et al.
      A phase III clinical trial of exercise modalities on treatment side-effects in men receiving therapy for prostate cancer.
      AUS15469.0 (9.0)0ProstateDuring ADTSupervised24F: 2x/week

      I: moderate-vigorous

      T: RE + AE vs RE + impact

      T: 60 min
      Wait-listC30
      quality rating could not be performed because papers are not yet published. ADT=androgen deprivation therapy; AE=Aerobic exercise training; CARES-SF=cancer rehabilitation evaluation system short form; C30=European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; CT=chemotherapy; FACT=Functional Assessment of Cancer Therapy; PRO=patient reported outcome; RE=Resistance exercise training; RT=radiotherapy; SF36=Short Form-36 Item Health Survey. Quality assessment: +=high quality; −=low quality; ?=unclear quality; RSG=random sequence generation; AC=allocation concealment; IO=incomplete outcome; IR=incomplete reporting; Adh=adherence; Con=contamination.
      Ohira (2006)
      • Ohira T.
      • Schmitz K.H.
      • Ahmed R.L.
      • Yee D.
      Effects of weight training on quality of life in recent breast cancer survivors: the Weight Training for Breast Cancer Survivors (WTBS) study.


      WTBS
      USA8652.7 (8.3)100BreastPostSupervised26 (13 super-vised)F: 2x/week

      I: ?

      T: RE

      T: ?
      Wait-listCares-SF+?++??
      Persoon, (2010)
      • Persoon S.
      • Kersten M.J.
      • Chinapaw M.J.
      • Buffart L.M.
      • Burghout H.
      • Schep G.
      • et al.
      Design of the EXercise Intervention after Stem cell Transplantation (EXIST) study: a randomized controlled trial to evaluate the effectiveness and cost-effectiveness of an individualized high intensity physical exercise program on fitness and fatigue in patients with multiple myeloma or (non-) Hodgkin’s lymphoma treated with high dose chemotherapy and autologous stem cell transplantation.


      EXIST
      NL10952.4 (11.2)36.7HaematologicalPost SCTSupervised18F: 2x/week

      I: moderate-vigorous

      T: RE + AE

      T: 60 min
      Usual careC30
      quality rating could not be performed because papers are not yet published. ADT=androgen deprivation therapy; AE=Aerobic exercise training; CARES-SF=cancer rehabilitation evaluation system short form; C30=European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; CT=chemotherapy; FACT=Functional Assessment of Cancer Therapy; PRO=patient reported outcome; RE=Resistance exercise training; RT=radiotherapy; SF36=Short Form-36 Item Health Survey. Quality assessment: +=high quality; −=low quality; ?=unclear quality; RSG=random sequence generation; AC=allocation concealment; IO=incomplete outcome; IR=incomplete reporting; Adh=adherence; Con=contamination.
      Schmidt (2015)
      • Schmidt M.E.
      • Wiskemann J.
      • Armbrust P.
      • Schneeweiss A.
      • Ulrich C.M.
      • Steindorf K.
      Effects of resistance exercise on fatigue and quality of life in breast cancer patients undergoing adjuvant chemotherapy: a randomized controlled trial.


      BEATE
      GER8852.5 (10.0)100BreastDuring CTSupervised12F: 2x/week

      I: moderate-vigorous

      T: RE

      T: 60 min
      Attention controlC30++++-?
      Short (2015)
      • Short C.E.
      • James E.L.
      • Girgis A.
      • D’Souza M.I.
      • Plotnikoff R.C.
      Main outcomes of the Move More for Life Trial: a randomised controlled trial examining the effects of tailored-print and targeted-print materials for promoting physical activity among post-treatment breast cancer survivors.


      MM4L
      AUS33055.9 (8.3)100BreastPostUnsupervised16F: AE: 5x/week; RE: 1-3x/week

      I: moderate

      T: RE + AE

      T: AE: 30 min
      Usual careFACT+++++?
      Speck (2010)
      • Speck R.M.
      • Gross C.R.
      • Hormes J.M.
      • Ahmed R.L.
      • Lytle L.A.
      • Hwang W.T.
      • et al.
      Changes in the Body Image and Relationship Scale following a one-year strength training trial for breast cancer survivors with or at risk for lymphedema.


      PAL
      USA29556.0 (8.8)100BreastPostSupervised52 (13 super-visedF: 2x/week

      I: ?

      T: RE

      T: 90 min
      Wait-listSF-36++-++?
      Steindorf (2014)
      • Steindorf K.
      • Schmidt M.E.
      • Klassen O.
      • Ulrich C.M.
      • Oelmann J.
      • Habermann N.
      • et al.
      Randomized, controlled trial of resistance training in breast cancer patients receiving adjuvant radiotherapy: results on cancer-related fatigue and quality of life.


      BEST
      GER14156.3 (8.9)100BreastDuring RTSupervised12F: 2x/week

      I: moderate-vigorous

      T: RE

      T: 60 min
      Attention controlC30++++-?
      Thorsen (2005)
      • Thorsen L.
      • Skovlund E.
      • Stromme S.B.
      • Hornslien K.
      • Dahl A.A.
      • Fossa S.D.
      Effectiveness of physical activity on cardiorespiratory fitness and health-related quality of life in young and middle-aged cancer patients shortly after chemotherapy.
      NOR13939.4 (8.3)67.1MixedPostUnsupervised14F: 2x/week or more

      I: moderate-vigorous

      T: RE + AE

      T: 30 min or more
      Usual careC30+++-+-
      Travier (2015)
      • Travier N.
      • Velthuis M.J.
      • Steins Bisschop C.N.
      • van den Buijs B.
      • Monninkhof E.M.
      • Backx F.
      • et al.
      Effects of an 18-week exercise programme started early during breast cancer treatment: a randomised controlled trial.
      ; van Vulpen (2015)
      • van Vulpen J.K.
      • Velthuis M.J.
      • Steins Bisschop C.N.
      • Travier N.
      • VDB B.J.
      • Backx F.J.
      • et al.
      Effects of an exercise program in colon cancer patients undergoing chemotherapy.
      PACT
      NL23750.7 (8.8)100Breast and ColonDuring CTSupervised18F: 2x/week

      I: moderate-vigorous

      T: RE + AE

      T: 60 min
      Usual careC30+++++?
      Van Waart (2015)
      • van Waart H.
      • Stuiver M.M.
      • van Harten W.H.
      • Geleijn E.
      • Kieffer J.M.
      • Buffart L.M.
      • et al.
      Effect of low-intensity physical activity and moderate- to high-intensity physical exercise during adjuvant chemotherapy on physical fitness, fatigue, and chemotherapy completion rates: results of the PACES randomized clinical trial.


      PACES
      NL25351.4 (9.5)95.7Breast and ColonDuring CTUnsupervised vs supervisedMean: 15.9F: supervised: 2x/week; unsupervised towards 5x/week

      I: supervised: moderate-vigorous

      Unsupervised: moderate

      T: supervised: RE + AE; unsupervised: AE

      T: supervised: 60 min; unsupervised: aim 30 min
      Usual careC30++++-?
      Winters-Stone (2012)
      • Winters-Stone K.M.
      • Dobek J.
      • Bennett J.A.
      • Nail L.M.
      • Leo M.C.
      • Schwartz A.
      The effect of resistance training on muscle strength and physical function in older, postmenopausal breast cancer survivors: a randomized controlled trial.
      USA10662.2 (6.7)100BreastPostSupervised52F: 2x/week supervised (+ 1x/week unsupervised)

      I: moderate-vigorous

      T: RE + impact

      T: 60 min
      Attention controlSF-36++++++
      Winters-Stone (2013)
      • Winters-Stone K.M.
      • Dobek J.
      • Nail L.M.
      • Bennett J.A.
      • Leo M.C.
      • Torgrimson-Ojerio B.
      • et al.
      Impact + resistance training improves bone health and body composition in prematurely menopausal breast cancer survivors: a randomized controlled trial.
      USA7146.4 (4.9)100BreastPostSupervised52F: 2x/week supervised + 1x/week unsupervised

      I: moderate

      T: RE + impact

      T: 60 min
      Attention controlSF-36+++--+
      Winters-Stone (2015)
      • Winters-Stone K.M.
      • Dobek J.C.
      • Bennett J.A.
      • Dieckmann N.F.
      • Maddalozzo G.F.
      • Ryan C.W.
      • et al.
      Resistance training reduces disability in prostate cancer survivors on androgen deprivation therapy: evidence from a randomized controlled trial.
      USA5170.1 (8.6)0ProstateDuring ADTSupervised52F: 2x/wk supervised (+1x/week unsupervised)

      I: moderate

      T: RE + impact

      T: 60 min
      Attention controlC30??++++
      Wiskemann (2011)
      • Wiskemann J.
      • Dreger P.
      • Schwerdtfeger R.
      • Bondong A.
      • Huber G.
      • Kleindienst N.
      • et al.
      Effects of a partly self-administered exercise program before, during, and after allogeneic stem cell transplantation.
      GER8048.4 (14.4)31.3HaematologicalPre-during-postSupervisedMedian exercise: 16.4

      Control: 15.7
      F: 5x/week

      I: moderate-vigorous

      T: RE + AE

      T: AE: 20–40 min
      Attention controlC30++-++?
      low asterisk Personal communication with authors.
      quality rating could not be performed because papers are not yet published. ADT = androgen deprivation therapy; AE = Aerobic exercise training; CARES-SF = cancer rehabilitation evaluation system short form; C30 = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; CT = chemotherapy; FACT = Functional Assessment of Cancer Therapy; PRO = patient reported outcome; RE = Resistance exercise training; RT = radiotherapy; SF36 = Short Form-36 Item Health Survey. Quality assessment: + = high quality; − = low quality; ? = unclear quality; RSG = random sequence generation; AC = allocation concealment; IO = incomplete outcome; IR = incomplete reporting; Adh = adherence; Con = contamination.

      Possible moderators

      Potential demographic and clinical moderators were identified from single studies that reported on the moderating effects with some inconsistent findings [
      • Buffart L.M.
      • Newton R.U.
      • Chinapaw M.J.
      • Taaffe D.R.
      • Spry N.A.
      • Denham J.W.
      • et al.
      The effect, moderators, and mediators of resistance and aerobic exercise on health-related quality of life in older long-term survivors of prostate cancer.
      ,
      • Kalter J.
      • Buffart L.M.
      • Korstjens I.
      • van Weert E.
      • Brug J.
      • Verdonck-de Leeuw I.M.
      • et al.
      Moderators of the effects of group-based physical exercise on cancer survivors’ quality of life.
      ,
      • Courneya K.S.
      • McKenzie D.C.
      • Mackey J.R.
      • Gelmon K.
      • Reid R.D.
      • Friedenreich C.M.
      • et al.
      Moderators of the effects of exercise training in breast cancer patients receiving chemotherapy: a randomized controlled trial.
      ,
      • Courneya K.S.
      • Sellar C.M.
      • Stevinson C.
      • McNeely M.L.
      • Friedenreich C.M.
      • Peddle C.J.
      • et al.
      Moderator effects in a randomized controlled trial of exercise training in lymphoma patients.
      ,
      • Kampshoff C.S.
      • Chinapaw M.J.
      • Brug J.
      • Twisk J.W.
      • Schep G.
      • Nijziel M.R.
      • et al.
      Randomized controlled trial of the effects of high intensity and low-to-moderate intensity exercise on physical fitness and fatigue in cancer survivors: results of the Resistance and Endurance exercise After ChemoTherapy (REACT) study.
      ].
      Potential demographic moderators included baseline age, sex, marital status, and education level. Marital status was dichotomised into single versus married or living with partner. As a consequence of different coding schemes of the original RCTs, education level was dichotomised into low-medium (elementary, primary, or secondary school, lower or secondary vocational education) or high (higher vocational, college, or university education). Potential clinical moderators included body mass index (BMI), type of cancer, the presence of distant metastases, and type of treatment. BMI was categorised into underweight (<18.5 kg/m2), normal weight (18.5–<25 kg/m2), overweight (25–<30 kg/m2) and obese (⩾30 kg/m2) according to the World Health Organization. The type of cancer was categorised into breast, male genitourinary, gastrointestinal, haematological, gynaecological, respiratory tract, and other types. Treatment with surgery, chemotherapy, radiotherapy, hormone therapy or stem cell transplantation were each dichotomised into previous or current treatment versus no such treatment. As the majority of men diagnosed with prostate cancer received androgen deprivation therapy, we were unable to study the moderating effects of hormone therapy in prostate cancer.
      Timing of intervention delivery in relation to primary cancer treatment was categorised into pre-treatment, during treatment, post-treatment and end-of-life, according to the Physical Activity and Cancer Control (PACC) framework [
      • Courneya K.S.
      • Friedenreich C.M.
      Physical activity and cancer control.
      ]. Because interventions pre-treatment and during end-of-life were not available, we tested differences in intervention effects between those delivered during treatment versus post-treatment. As hormone therapy for breast cancer may continue for five years post-treatment, we considered women on hormone therapy who completed other primary cancer treatments as being post-treatment. Men receiving androgen deprivation therapy for prostate cancer were considered as being during treatment. Delivery mode of intervention was dichotomized into supervised (in case (part of) the weekly exercise sessions were conducted under supervision) versus unsupervised (in case exercise sessions were performed unsupervised from or at home). Intervention duration was categorised based on tertiles (⩽12 weeks; >12–24 weeks; >24 weeks). Exercise frequency was dichotomised based on the median, into ⩽2 versus >2 supervised sessions per week for supervised exercise and into <5 versus ⩾5 sessions per week for unsupervised exercise. Exercise intensity was categorised from low to high intensity using the definitions of the American College of Sports Medicine [
      • American Collega of Sports Medicine
      ACSM’s guidelines for exercise testing and prescription.
      ]. Exercise type was categorised into aerobic, resistance, combined aerobic and resistance and combined resistance and impact loading (e.g. skipping, jumping) exercise. Exercise time per session was categorised into ⩽30 min, >30–60 min and >60 min.

      Statistical analysis

      We conducted one-step IPD meta-analyses to study the effects and moderators of exercise on QoL and PF. The effects were evaluated by regressing the intervention on the post-intervention value (z-score) of the outcome adjusted for the baseline value (z-score) using linear mixed model analyses with a two-level structure (1: patient; 2: study) to take into account the clustering of patients within studies by using a random intercept on study level. Moderators of exercise effects were examined by adding the moderator and its interaction term with the intervention into the regression model, for each moderator separately. To reduce ecological bias for patient-level interactions, we separated within-trial interaction from between-trial interaction by centring the individual value of the covariate around the mean study value of that covariate [
      • Fisher D.J.
      • Copas A.J.
      • Tierney J.F.
      • Parmar M.K.
      A critical review of methods for the assessment of patient-level interactions in individual participant data meta-analysis of randomized trials, and guidance for practitioners.
      ]. If interaction terms were significant (p < 0.05), stratified analyses were performed. In case a RCT had three study arms with different study-level moderators across study arms, interaction testing for a study-level moderator was not possible. Therefore, in those situations, we tested differences between subgroups using dummy variables. Regression coefficients and 95% confidence intervals (CI) were reported, which represent the between group difference in z-scores of QoL and PF, and correspond to a Cohen’s d effect size. Effects of 0.2 were considered small, 0.50 as moderate and at or above 0.8 as large.
      Since the majority of patients were women with breast cancer, we performed a sensitivity analysis to check robustness of findings in the subgroup of patients that were not women with breast cancer, despite non-significant overall interaction effects for women with breast cancer vs other (β = 0.09, 95%CI = −0.12; 0.29 for QoL; β = −0.06, 95%CI = −0.27;0.14 for PF). Statistical analyses were performed using SPSS 22.0 and R Studio.

      Results

      Characteristics of studies and patients

      Of the 136 RCTs that met the inclusion criteria (Fig. 1), 66 evaluated the effects of exercise and three [
      • Korstjens I.
      • May A.M.
      • van Weert E.
      • Mesters I.
      • Tan F.
      • Ros W.J.
      • et al.
      Quality of life after self-management cancer rehabilitation: a randomized controlled trial comparing physical and cognitive-behavioral training versus physical training.
      ,
      • Duijts S.F.
      • van Beurden M.
      • Oldenburg H.S.
      • Hunter M.S.
      • Kieffer J.M.
      • Stuiver M.M.
      • et al.
      Efficacy of cognitive behavioral therapy and physical exercise in alleviating treatment-induced menopausal symptoms in patients with breast cancer: results of a randomized, controlled, multicenter trial.
      ,
      • Goedendorp M.M.
      • Peters M.E.
      • Gielissen M.F.
      • Witjes J.A.
      • Leer J.W.
      • Verhagen C.A.
      • et al.
      Is increasing physical activity necessary to diminish fatigue during cancer treatment? Comparing cognitive behavior therapy and a brief nursing intervention with usual care in a multicenter randomized controlled trial.
      ] evaluated the effects of a combined exercise and psychosocial intervention and also included a third arm with exercise only. Principal investigators of 34 of these 69 RCTs (response 49%) shared IPD. In total, 27 RCTs reported adequate random sequence generation, 26 studies reported adequate allocation concealment, 26 RCTs had adequate completeness of outcome data, and 26 RCTs had complete outcome reporting (Table 1). Intervention adherence was reported in 26 RCTs, and was of high quality in 13 RCTs, and 7 of the 13 RCTs that provided information on contamination met the criteria for high quality.
      Figure thumbnail gr1
      Fig. 1Flow chart of study inclusion IPD = individual patient data; PSI = psychosocial interventions; RCT = randomised controlled trial.
      The sample included 4519 patients with cancer, of whom 2514 were randomized to the intervention group and 2005 to the control group. The mean age was 54.6 (SD 11.3) years, 78% were women, 70% were diagnosed with breast cancer, 2% had metastatic disease, 51% exercised following cancer treatment, and 65% received supervised exercise (Table 2).
      Table 2Demographic, clinical, intervention-, and exercise-related characteristics, quality of life and physical function of patients in the exercise and control group.
      Exercise (n = 2514)Control (n = 2005)
      Demographic
      Age, mean (SD) years54.6 (11.5)54.5 (11.2)
      Age categories, n (%)
       <50 years850 (33.8)663 (33.1)
       50–70 years1405 (55.9)1143 (57.0)
       ⩾70 years249 (9.9)185 (9.2)
       Unknown10 (0.4)14 (0.7)
      Sex, n (%)
       Men553 (22.0)438 (21.8)
       Women1961 (78.0)1567 (78.2)
      Married/living with partner, n (%)
       Yes1587 (63.1)1209 (60.3)
       No442 (17.6)389 (19.4)
       Unknown485 (19.3)407 (20.3)
      Education level, n (%)
       Low/middle1095 (43.6)857 (42.7)
       High1018 (40.5)728 (36.3)
       Unknown401 (16.0)420 (20.9)
      Clinical
      BMI, mean (SD) kg/m227.1 (5.1)27.2 (5.3)
      BMI categories, n (%)
       Underweight (BMI <18.5 kg/m2)18 (0.7)23 (1.1)
       Normal weight (BMI 18.5 to <25 kg/m2)859 (34.2)651 (32.5)
       Overweight (BMI 25 to <30 kg/m2)827 (32.9)639 (31.9)
       Obese (BMI ⩾ 30 kg/m2)551 (21.9)450 (22.4)
       Unknown259 (10.3)242 (12.1)
      Cancer type, n (%)
       Breast1757 (69.9)1406 (70.1)
       Male genitourinary326 (13.0)248 (12.4)
       Haematological199 (7.9)195 (9.7)
       Gastrointestinal146 (5.8)87 (4.3)
       Gynaecological44 (1.8)33 (1.6)
       Respiratory track28 (1.1)29 (1.4)
       Other14 (0.6)7 (0.3)
      Distant metastasis at baseline, n (%)
      Proportion of survivors of solid tumors (n=4124).
       No2241 (96.8)1762 (97.3)
       Yes47 (2.0)33 (1.8)
       Unknown27 (1.2)15 (0.8)
      Surgery, n (%) yes
      Proportion of survivors without SCT (n=4326).
       No299 (12.4)242 (12.7)
       Yes1989 (82.3)1552 (81.3)
       Unknown130 (5.4)114 (6.0)
      Chemotherapy, n (%)
       No692 (27.5)562 (28.0)
       Prior to intervention988 (39.3)866 (43.2)
       During intervention761 (30.3)513 (25.6)
       Unknown73 (2.9)64 (3.2)
      Radiotherapy, n (%)
       No1030 (41.0)760 (37.9)
       Prior to intervention1037 (41.2)877 (43.7)
       During intervention364 (14.5)314 (15.7)
       Unknown83 (3.3)54 (2.7)
      Hormone therapy
       Breast cancer (n = 3163), n (%)
      No860 (48.9)671 (47.7)
      Yes631 (35.9)481 (34.2)
      Unknown266 (15.1)254 (18.1)
       Prostate cancer (n = 536), n (%)
      No16 (5.2)11 (4.8)
      Prior to intervention50 (16.2)50 (21.9)
      During intervention204 (66.2)135 (59.2)
       Unknown38 (12.3)32 (14.0)
      SCT, n (%)
      Proportion of survivors with SCT (n=193).
       Allogeneic42 (43.7)42 (43.3)
       Autologous54 (56.3)55 (56.7)
      Intervention-related
      Proportion of survivors from intervention groups (n=2514).
       Timing of intervention, n (%)
       Pre-during-post treatment80 (1.8)
       During treatment2122 (47.0)
       Post treatment2314 (51.2)
      Mode of intervention delivery, n (%)
       (partly) Supervised1643 (65.4)
       Unsupervised871 (34.6)
      Duration of intervention, n (%)
       ⩽12 weeks822 (32.7)
       12–24 weeks683 (27.2)
       >24 weeks741 (29.5)
       Unknown
      Intervention duration of individual patients unknown for three studies, but mean or median was reported.
      268 (10.7)
      Exercise frequency, n (%)
       2 times per week1349 (53.7)
       3 times per week323 (12.8)
       4 times per week203 (8.1)
       ⩾5 times per week509 (20.2)
       Unknown130 (5.2)
      Exercise Intensity, n (%)
       Low0 (0)
       Low-moderate167 (6.6)
       Moderate884 (35.2)
       Moderate-vigorous1005 (40.0)
       High195 (7.8)
       Unknown263 (10.5)
      Exercise type, n (%)
       AE686 (27.3)
       RE385 (15.3)
       AE + RE1270 (50.5)
       RE + Impact training173 (6.9)
      Exercise session duration, n (%)
       ⩽30 min928 (36.9)
       >30–60 min1260 (50.1)
       >60 min257 (10.2)
       Unknown69 (2.7)
      Type of control group, n (%)
      Proportion of survivors from the control groups (n=2005).
       Usual care control1265 (63.1)
       Wait list control435 (21.7)
       Attention control305 (15.2)
      Intervention (n = 2514)Control (n = 2005)
      Baseline values
      Scores are from 0 to 100 with higher scores representing higher QoL and PF for FACT-G, EORTC QLQ-C30 and SF-36, and lower QoL and PF for CARES-SF.
      pre

      Mean (SD)
      post

      Mean (SD)
      pre

      Mean (SD)
      post

      Mean (SD)
      QoL, mean (SD)
       FACT-G, total score81.3 (13.6)85.6 (13.4)82.2 (14.9)84.3 (14.9)
       EORTC QLQ-C30, subscale global QoL70.4 (18.4)73.2 (18.5)68.8 (19.6)69.0 (19.9)
       CARES-SF, subscale global QoL47.2 (9.3)43.6 (9.0)48.5 (9.1)46.8 (9.5)
       SF-36, subscale general health66.4 (19.0)69.5 (18.2)66.6 (19.2)68.3 (19.4)
      PF, mean (SD)
       FACT-G, subscale PWB21.9 (5.3)23.7 (4.2)22.2 (5.4)23.2 (4.6)
       EORTC QLQ-C30, subscale PF84.1 (15.4)85.0 (15.6)82.7 (16.8)80.8 (18.1)
       CARES-SF, subscale PF46.0 (7.4)43.8 (5.7)46.8 (6.8)48.0 (7.7)
       SF-36, subscale PF82.7 (15.9)85.0 (16.9)82.9 (16.7)82.4 (19.0)
      AE = aerobic exercise; CARES-SF = cancer rehabilitation evaluation system short form; EORTC QLQ-C30 = European Organisation Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; FACT = Functional Assessment of Cancer Therapy; FACT-G = FACT-General; PF = physical function; PWB = physical well-being; RE = resistance exercise; SCT = stem cell transplantation; SF-36 = Short Form-36 Health survey.
      a Proportion of survivors of solid tumors (n = 4124).
      b Proportion of survivors without SCT (n = 4326).
      c Proportion of survivors with SCT (n = 193).
      d Proportion of survivors from intervention groups (n = 2514).
      e Intervention duration of individual patients unknown for three studies, but mean or median was reported.
      f Proportion of survivors from the control groups (n = 2005).
      g Scores are from 0 to 100 with higher scores representing higher QoL and PF for FACT-G, EORTC QLQ-C30 and SF-36, and lower QoL and PF for CARES-SF.

      Representativeness and publication bias

      Published summary data for QoL were available for 36 out of 69 RCTs, of which five [
      • Kampshoff C.S.
      • Chinapaw M.J.
      • Brug J.
      • Twisk J.W.
      • Schep G.
      • Nijziel M.R.
      • et al.
      Randomized controlled trial of the effects of high intensity and low-to-moderate intensity exercise on physical fitness and fatigue in cancer survivors: results of the Resistance and Endurance exercise After ChemoTherapy (REACT) study.
      ,
      • Courneya K.S.
      • Segal R.J.
      • Mackey J.R.
      • Gelmon K.
      • Reid R.D.
      • Friedenreich C.M.
      • et al.
      Effects of aerobic and resistance exercise in breast cancer patients receiving adjuvant chemotherapy: a multicenter randomized controlled trial.
      ,
      • Hayes S.C.
      • Rye S.
      • Disipio T.
      • Yates P.
      • Bashford J.
      • Pyke C.
      • et al.
      Exercise for health: a randomized, controlled trial evaluating the impact of a pragmatic, translational exercise intervention on the quality of life, function and treatment-related side effects following breast cancer.
      ,
      • Short C.E.
      • James E.L.
      • Girgis A.
      • D’Souza M.I.
      • Plotnikoff R.C.
      Main outcomes of the Move More for Life Trial: a randomised controlled trial examining the effects of tailored-print and targeted-print materials for promoting physical activity among post-treatment breast cancer survivors.
      ,
      • Segal R.J.
      • Reid R.D.
      • Courneya K.S.
      • Sigal R.J.
      • Kenny G.P.
      • Prud’Homme D.G.
      • et al.
      Randomized controlled trial of resistance or aerobic exercise in men receiving radiation therapy for prostate cancer.
      ] included two exercise arms. Consequently, 41 exercise arms were included in the analyses of representativeness. For PF, summary data were published for 30 RCTs, with two [
      • Kampshoff C.S.
      • Chinapaw M.J.
      • Brug J.
      • Twisk J.W.
      • Schep G.
      • Nijziel M.R.
      • et al.
      Randomized controlled trial of the effects of high intensity and low-to-moderate intensity exercise on physical fitness and fatigue in cancer survivors: results of the Resistance and Endurance exercise After ChemoTherapy (REACT) study.
      ,
      • van Waart H.
      • Stuiver M.M.
      • van Harten W.H.
      • Geleijn E.
      • Kieffer J.M.
      • Buffart L.M.
      • et al.
      Effect of low-intensity physical activity and moderate- to high-intensity physical exercise during adjuvant chemotherapy on physical fitness, fatigue, and chemotherapy completion rates: results of the PACES randomized clinical trial.
      ] evaluating two exercise arms, resulting in 32 exercise arms. We found no significant differences in effects on QoL (p = 0.25) and PF (p = 0.25) between RCTs of which IPD were shared and those of which were not (Table 3). The trim and fill procedures showed significant publication bias for all eligible RCTs reporting on QoL, but not between RCTs included and those not included (Table 3).
      Table 3Representativeness and publication bias of the pooled effects of studies providing data for the POLARIS study and those not providing data.
      RepresentativenessNPooled effectTest of heterogeneityBetween group differences

      P-value
      g (95%CI)QI2P-value
      Quality of life
      All eligible studies410.22 (0.14; 0.31)71.9644.420.001
      All eligible studies, excluding one outlier400.18 (0.12; 0.24)32.9000.74
      Studies providing data270.16 (0.09; 0.23)22.2200.68
      Studies not providing data140.42 (0.17; 0.67)45.0671.15<0.0010.05
      Studies not providing data, excluding one outlier130.25 (0.12; 0.37)9.3500.670.25
      Physical function
      All eligible studies320.32 (0.20; 0.44)86.0663.98<0.001
      All eligible studies, excluding two outliers300.27 (0.18; 0.35)36.1219.720.17
      Studies providing data240.28 (0.19; 0.37)30.8725.500.13
      Studies not providing data80.54 (0.05; 1.03)53.4486.70<0.0010.31
      Studies not providing data, excluding two outliers60.17 (-0.01; 0.34)3.840.000.590.25
      Publication bias using trim and fill procedureNmissingAdjusted effectPEgger
      Quality of life
      All eligible studies, excluding one outlier100.13 (0.07; 0.20)0.02
      Studies providing data60.12 (0.05; 0.19)0.20
      Physical function
      All eligible studies, excluding two outliers30.29 (0.20; 0.37)0.26
      Studies providing data20.31 (0.21; 0.40)0.33
      CI = confidence interval; g = Hedges’ g effect size; I2 = I2 statistic, which is the percentage of total variance that can be explained by heterogeneity, and 25% is considered low, 50% moderate, and 75% high heterogeneity; n = number of exercise intervention arms; Q = Q-test for heterogeneity, which is significant if there is evidence for heterogeneity.

      Effects and moderators of exercise on QoL and PF

      Exercise effects on QoL (β = 0.15, 95%CI = 0.10;0.20) and PF (β = 0.18, 95%CI = 0.13;0.23, Table 4, Fig. 2) were significant. Patients’ demographic and clinical characteristics, intervention timing and duration, and exercise FITT factors did not significantly moderate the effects on QoL or PF (Table 4). Supervised exercise had significantly larger effects on QoL (βdifference_in_effect = 0.13, 95%CI = 0.04;0.23) and PF (βdifference_in_effect = 0.11, 95%CI = 0.01;0.20) than unsupervised exercise. Compared to the control group, supervised exercise significantly improved both QoL (β = 0.20, 95%CI = 0.14;0.25) and PF (β = 0.22, 95%CI = 0.16;0.27), while unsupervised exercise significantly improved PF (β = 0.11, 95%CI = 0.03;0.19). Effects on PF were significantly larger in RCTs with a usual care control group than those with an attention control group (βdifference_in_effect = 0.12, 95%CI = 0.002;0.23).
      Table 4Effects and moderators of the effects of exercise on quality of life and physical function.
      Quality of lifePhysical function
      β (95%CI)β (95%CI)
      Effect of exercise0.15 (0.10; 0.20)
      p<0.05.
      0.18 (0.13; 0.23)
      p<0.05.
      Demographic moderators
      Interaction age categories
       <50 yearsReferenceReference
       50–70 years0.06 (−0.06; 0.17)−0.01 (−0.12; 0.10)
       ⩾70 years−0.06 (−0.28; 0.16)−0.04 (−0.26; 0.17)
      Interaction women vs. men0.14 (−0.05; 0.32)0.08 (−0.11; 0.26)
      Interaction partner vs. single−0.11 (−0.24; 0.02)−0.07 (−0.22; 0.08)
      Interaction high vs. low-middle education−0.06 (−0.17; 0.05)−0.01 (−0.12; 0.10)
      Clinical moderators
      Interaction BMI categories
       Underweight (BMI <18.5 kg/m2)0.28 (−0.24; 0.81)0.28 (−0.15; 0.88)
       Normal weight (BMI 18.5–<25 kg/m2)ReferenceReference
       Overweight (BMI 25 to <30 kg/m2)−0.03 (−0.15; 0.09)−0.03 (−0.06; 0.17)
       Obese (BMI ⩾30 kg/m2)−0.02 (−0.16; 0.11)−0.02 (−0.08; 0.19)
      Interaction cancer type
       BreastReferenceReference
       Male genitourinary−0.25 (−0.58; 0.07)0.02 (−0.31; 0.35)
       Haematological0.03 (−0.41; 0.47)0.14 (−0.30; 0.59)
       Gastrointestinal0.23 (−0.09; 0.55)0.08 (−0.24; 0.40)
       Gynaecological0.10 (−1.00; 1.18)0.45 (−0.66; 1.55)
       Respiratory tract0.06 (−0.40; 0.52)0.03 (−0.43; 0.49)
       Other−0.43 (−1.65; 0.80)−0.52 (−1.75; 0.72)
      Interaction distant metastasis−0.21 (−0.64; 0.22)−0.06 (−0. 49; 0.37)
      Interaction surgery0.008 (−0.26; 0.28)−0.05 (−0.32; 0.21)
      Interaction chemotherapy0.07 (−0.07; 0.22)0.02 (−0.13; 0.16)
      Interaction radiotherapy−0.02 (−0.14; 0.10)0.04 (−0.08; 0.16)
      Interaction hormone therapy for breast cancer−0.01 (−0.17; 0.14)−0.07 (−0.23; 0.08)
      Intervention-related moderators
      Interaction post vs. during treatment0.02 (−0.08; 0.12)0.04 (−0.39; 0.46)
      Intervention delivery mode
       Effect supervised vs. unsupervised0.13 (0.04; 0.23)
      p<0.05.
      0.11 (0.01; 0.20)
      p<0.05.
       Effect supervised vs. control0.20 (0.14; 0.25)
      p<0.05.
      0.22 (0.16; 0.27)
      p<0.05.
       Effect unsupervised vs. control0.06 (−0.02; 0.14)0.11 (0.03; 0.19)
      p<0.05.
      Interaction intervention duration
       ⩽12 weeksReferenceReference
       12–24 weeks−0.19 (−0.32; −0.07)
      p<0.05.
      Interaction term not significant after adjusting for delivery mode.
      −0.12 (−0.24; 0.00)
      0.05⩽p<0.10.
      Interaction term not significant after adjusting for delivery mode.
       >24 weeks−0.09 (−0.21; 0.03)−0.05 (−0.16; 0.07)
      FITT factors for supervised exercise
      Frequency
       Interaction 3 times/week vs. 2 times/week0.04 (−0.10; 0.18)0.01 (−0.12; 0.15)
      Intensity
       Effect low-moderate and moderate vs. control0.23 (0.12; 0.34)
      p<0.05.
      0.22 (0.12; 0.33)
      p<0.05.
       Effect moderate-vigorous and vigorous vs. control0.21 (0.13; 0.28)
      p<0.05.
      0.22 (0.15; 0.29)
      p<0.05.
       Effect moderate-vigorous and vigorous vs. low-moderate and moderate−0.03 (−0.15; 0.10)−0.007 (−0.13; 0.11)
      Type
      Significantly larger effects of AE, AE+RE and RE than the control group, no significant differences in effects between different exercise types. AE=aerobic exercise; BMI=body mass index; CI=confidence interval; RE=resistance exercise.
       ControlReferenceReference
       AE0.25 (0.13; 0.38)
      p<0.05.
      0.21 (0.10; 0.34)
       AE + RE0.21 (0.13; 0.30)
      p<0.05.
      0.22 (0.14; 0.30)
       RE0.15 (0.04; 0.26)
      p<0.05.
      0.26 (0.16; 0.37)
      p<0.05.
       RE + impact training0.16 (−0.02; 0.34)0.16 (−0.02; 0.34)
      Time of session
       Interaction >30–60 min vs. 0–30 min0.03 (−0.12; 0.19)−0.05 (−0.20; 0.10)
       Interaction >60 vs. 0–30 min0.10 (−0.10; 0.29)0.02 (−0.17; 0.20)
       Interaction >60 min vs. >30–60 min0.06 (−0.10; 0.23)0.07 (−0.09; 0.23)
      FITT factors for unsupervised exercise
      Frequency
       Interaction ⩾5 times/week vs. <5 times/week−0.06 (−0.24; 0.12)−0.01 (−0.20; 0.18)
      Intensity
       Interaction moderate-vigorous and vigorous vs. low-moderate and moderate0.003 (−0.20; 0.21)0.09 (−0.14; 0.31)
      Type
       Interaction RE + AE vs. AE−0.01 (−0.18; 0.16)−0.17 (−0.36; 0.01)
      0.05⩽p<0.10.
      Time
       Interaction >30 min vs.⩽30 min0.18 (−0.02; 0.37)
      0.05⩽p<0.10.
      0.14 (−0.08; 0.37)
      low asterisk p < 0.05.
      # 0.05 ⩽ p < 0.10.
      a Interaction term not significant after adjusting for delivery mode.
      b Significantly larger effects of AE, AE + RE and RE than the control group, no significant differences in effects between different exercise types. AE = aerobic exercise; BMI = body mass index; CI = confidence interval; RE = resistance exercise.
      Figure thumbnail gr2
      Fig. 2Forest plots of the effects of exercise on quality of life (a) and physical function (b). Data represent the regression coefficients [95% confidence intervals] of the effects of exercise on quality of life and physical function (in z-scores). Unsupervised interventions are presented above the dashed line, and supervised interventions below.
      Sensitivity analyses among patients other than women with breast cancer (n = 1360, originating from 17 RCTs) showed slight differences in regression coefficients with larger confidence intervals, but the conclusions on moderator effects were similar.

      Discussion

      Based on IPD meta-analyses of 34 RCTs including data from 4519 individual patients with cancer, we found that exercise significantly improved their QoL and PF. The IPD meta-analytical approach of the present paper enabled the testing of potential moderators in a large sample. The exercise effects did not differ significantly across subgroups of age, sex, education level, marital status, BMI, cancer type, metastatic stage or treatment. Further, exercise was equally effective during and following cancer treatment. These findings support and strengthen the evidence base for current exercise recommendations that all patients with cancer should be physically active during and following cancer treatment [
      • Schmitz K.H.
      • Courneya K.S.
      • Matthews C.
      • Demark-Wahnefried W.
      • Galvao D.A.
      • Pinto B.M.
      • et al.
      American College of Sports Medicine roundtable on exercise guidelines for cancer survivors.
      ]. However, the effects were stronger for supervised exercise. We found no significant moderating effects of intervention timing, duration, and exercise FITT factors.
      The exercise effects were significant, but small in general, and comparable across the different subgroups. The lack of demographic and clinical moderators suggests that targeting exercise, based on demographic and clinical characteristics may not be useful for improving QoL and PF.
      The moderating effects of sex, age, education, marital status, BMI and cancer type have been explored in previous single studies reporting inconsistent findings [
      • Buffart L.M.
      • Newton R.U.
      • Chinapaw M.J.
      • Taaffe D.R.
      • Spry N.A.
      • Denham J.W.
      • et al.
      The effect, moderators, and mediators of resistance and aerobic exercise on health-related quality of life in older long-term survivors of prostate cancer.
      ,
      • Kalter J.
      • Buffart L.M.
      • Korstjens I.
      • van Weert E.
      • Brug J.
      • Verdonck-de Leeuw I.M.
      • et al.
      Moderators of the effects of group-based physical exercise on cancer survivors’ quality of life.
      ,
      • Courneya K.S.
      • McKenzie D.C.
      • Mackey J.R.
      • Gelmon K.
      • Reid R.D.
      • Friedenreich C.M.
      • et al.
      Moderators of the effects of exercise training in breast cancer patients receiving chemotherapy: a randomized controlled trial.
      ,
      • Courneya K.S.
      • Sellar C.M.
      • Stevinson C.
      • McNeely M.L.
      • Friedenreich C.M.
      • Peddle C.J.
      • et al.
      Moderator effects in a randomized controlled trial of exercise training in lymphoma patients.
      ,
      • Kampshoff C.S.
      • Chinapaw M.J.
      • Brug J.
      • Twisk J.W.
      • Schep G.
      • Nijziel M.R.
      • et al.
      Randomized controlled trial of the effects of high intensity and low-to-moderate intensity exercise on physical fitness and fatigue in cancer survivors: results of the Resistance and Endurance exercise After ChemoTherapy (REACT) study.
      ]. It has been hypothesized that patients without a partner have less social support at home [
      • Zhang J.
      • Gan L.
      • Wu Z.
      • Yan S.
      • Liu X.
      • Guo W.
      The influence of marital status on the stage at diagnosis, treatment, and survival of adult patients with gastric cancer: a population-based study.
      ,
      • Aizer A.A.
      • Chen M.H.
      • McCarthy E.P.
      • Mendu M.L.
      • Koo S.
      • Wilhite T.J.
      • et al.
      Marital status and survival in patients with cancer.
      ] and may therefore either benefit more from the support associated with supervised or guided exercise [
      • Courneya K.S.
      • McKenzie D.C.
      • Mackey J.R.
      • Gelmon K.
      • Reid R.D.
      • Friedenreich C.M.
      • et al.
      Moderators of the effects of exercise training in breast cancer patients receiving chemotherapy: a randomized controlled trial.
      ,
      • Courneya K.S.
      • Sellar C.M.
      • Stevinson C.
      • McNeely M.L.
      • Friedenreich C.M.
      • Peddle C.J.
      • et al.
      Moderator effects in a randomized controlled trial of exercise training in lymphoma patients.
      ], or may be less likely to adhere to the exercise intervention [
      • Kampshoff C.S.
      • van Mechelen W.
      • Schep G.
      • Nijziel M.R.
      • Witlox L.
      • Bosman L.
      • et al.
      Participation in and adherence to physical exercise after completion of primary cancer treatment.
      ]. We analysed the potential moderating effect of being married/having a partner, although this does not necessarily reflect partner support, and found no moderator effect on QoL and PF.
      Additionally, we found no moderator effect of BMI. However, due to the higher likelihood of sarcopenic obesity (i.e. increased fat mass in combination with reduced muscle mass) caused by cancer and its treatment [
      • Jones L.W.
      • Demark-Wahnefried W.
      Diet, exercise, and complementary therapies after primary treatment for cancer.
      ], BMI may not adequately reflect adiposity in patients with cancer. Additional studies are needed to investigate the moderator effects of muscle and fat mass.
      We found no significant differences in effects on QoL and PF across cancer types or between patients with metastatic and non-metastatic disease. However, sample sizes of some subgroups were small, and due to different coding schemes or lack of information on disease stage we were limited to studying differences in intervention effects between patients with metastatic and non-metastatic disease, and were unable to further disentangle differences in effects between patients with disease stages I, II and III. Furthermore, the majority of studies evaluating the effects of exercise have been conducted in patients with breast cancer, and prostate cancer who were treated with curative intent [
      • Schmitz K.H.
      • Courneya K.S.
      • Matthews C.
      • Demark-Wahnefried W.
      • Galvao D.A.
      • Pinto B.M.
      • et al.
      American College of Sports Medicine roundtable on exercise guidelines for cancer survivors.
      ,
      • Buffart L.M.
      • Galvao D.A.
      • Brug J.
      • Chinapaw M.J.
      • Newton R.U.
      Evidence-based physical activity guidelines for cancer survivors: current guidelines, knowledge gaps and future research directions.
      ]. Therefore exercise effects on QoL and PF remain unclear in understudied cancer populations, such as head and neck, lung, and gynaecological cancers, and in patients with metastatic disease, and they may differ from those with breast and prostate cancer due to differences in treatment trajectories. We were unable to confirm previous findings that radiotherapy [
      • Kalter J.
      • Buffart L.M.
      • Korstjens I.
      • van Weert E.
      • Brug J.
      • Verdonck-de Leeuw I.M.
      • et al.
      Moderators of the effects of group-based physical exercise on cancer survivors’ quality of life.
      ] or chemotherapy [
      • Courneya K.S.
      • McKenzie D.C.
      • Mackey J.R.
      • Gelmon K.
      • Reid R.D.
      • Friedenreich C.M.
      • et al.
      Moderators of the effects of exercise training in breast cancer patients receiving chemotherapy: a randomized controlled trial.
      ] moderate exercise effects, which may be related to the heterogeneous study population. As treatment types are related to cancer types, the moderator effects of treatment should perhaps be investigated separately within each cancer type.
      Intervention goals are likely to differ across phases of the cancer continuum. Exercise during cancer treatment typically seeks to influence treatment effectiveness and coping by managing side effects, maintaining physical fitness, and preventing muscle loss, fat gain, fatigue, and deterioration in QoL [
      • Courneya K.S.
      • Friedenreich C.M.
      Physical activity and cancer control.
      ]. Exercise post-treatment typically aims to speed recovery, improve physical fitness and QoL, reduce fatigue, distress and the risk of developing chronic diseases or secondary cancers [
      • Courneya K.S.
      • Friedenreich C.M.
      Physical activity and cancer control.
      ]. Nevertheless, the exercise effects on QoL and PF were similar, and clearly demonstrate significant benefits both during and post cancer treatment, which is consistent with previous meta-analyses based on aggregate data [
      • Speck R.M.
      • Courneya K.S.
      • Masse L.C.
      • Duval S.
      • Schmitz K.H.
      An update of controlled physical activity trials in cancer survivors: a systematic review and meta-analysis.
      ,
      • Mishra S.I.
      • Scherer R.W.
      • Geigle P.M.
      • Berlanstein D.R.
      • Topaloglu O.
      • Gotay C.C.
      • et al.
      Exercise interventions on health-related quality of life for cancer survivors.
      ,
      • Mishra S.I.
      • Scherer R.W.
      • Snyder C.
      • Geigle P.M.
      • Berlanstein D.R.
      • Topaloglu O.
      Exercise interventions on health-related quality of life for people with cancer during active treatment.
      ].
      Effects of supervised exercise were twice as large as those of unsupervised exercise, which is consistent with a previous systematic review [
      • Baumann F.T.
      • Zopf E.M.
      • Bloch W.
      Clinical exercise interventions in prostate cancer patients–a systematic review of randomized controlled trials.
      ]. The larger effects of supervised exercise may be explained by the attention of the physiotherapist or exercise physiologist delivering the intervention, access to better equipment, more challenging exercise prescriptions, or by better adherence to the prescribed exercise protocol. Reporting adherence and identifying determinants of adherence to unsupervised interventions is important to identify patients who do not need supervision.
      The lack of significant differences in exercise effects across different FITT factors might have resulted from little variation in these factors across studies, or the limited power since FITT factors are moderators at the intervention level instead of the patient level. Previous head-to-head comparisons of exercise FITT factors indicated a dose response effect of aerobic exercise on PF during cancer treatment in patients with breast cancer [
      • Courneya K.S.
      • McKenzie D.C.
      • Mackey J.R.
      • Gelmon K.
      • Friedenreich C.M.
      • Yasui Y.
      • et al.
      Effects of exercise dose and type during breast cancer chemotherapy: multicenter randomized trial.
      ] and larger effects of high intensity compared to moderate intensity exercise post treatment in a population with mixed cancer types [
      • Kampshoff C.S.
      • Chinapaw M.J.
      • Brug J.
      • Twisk J.W.
      • Schep G.
      • Nijziel M.R.
      • et al.
      Randomized controlled trial of the effects of high intensity and low-to-moderate intensity exercise on physical fitness and fatigue in cancer survivors: results of the Resistance and Endurance exercise After ChemoTherapy (REACT) study.
      ]. More RCTs that directly compare exercise FITT factors are warranted to define optimal exercise prescriptions. Also, specific intervention components, including goal-setting, social support and exercise instructions and monitoring, may differ across interventions, and explain differences in effects.
      The effects on QoL and PF were significant, but smaller than expected. There may be several explanations for the smaller effects. First, exercise interventions generally aim to improve exercise behaviour or health-related physical fitness, and probably not all dimensions of QoL (i.e. physical, emotional and social well-being) [
      • The World Health Organization Quality of Life Assessment
      (WHOQOL): development and general psychometric properties.
      ] were affected to the same extent. Second, QoL is susceptible to response shift [
      • Gerlich C.
      • Schuler M.
      • Jelitte M.
      • Neuderth S.
      • Flentje M.
      • Graefen M.
      • et al.
      Prostate cancer patients’ quality of life assessments across the primary treatment trajectory: ‘True’ change or response shift?.
      ,
      • Anota A.
      • Bascoul-Mollevi C.
      • Conroy T.
      • Guillemin F.
      • Velten M.
      • Jolly D.
      • et al.
      Item response theory and factor analysis as a mean to characterize occurrence of response shift in a longitudinal quality of life study in breast cancer patients.
      ], i.e., a change in the meaning of one’s self-evaluation of QoL over time as a result of changes in internal standards, values and the conceptualization of QoL [
      • Sprangers M.A.
      • Schwartz C.E.
      Integrating response shift into health-related quality of life research: a theoretical model.
      ]. Third, results may have been contaminated by the adoption of exercise by patients in the control group. The limited information on contamination hampered us to evaluate its influence on the effects. Fourth, our analyses were based on patients participating in RCTs. Median (interquartile range) participation rates in exercise trails were found to be 63% (33–80) of eligible patients [
      • Maddocks M.
      • Mockett S.
      • Wilcock A.
      Is exercise an acceptable and practical therapy for people with or cured of cancer? A systematic review.
      ]. Patients who decline participation may be less motivated for exercise and have lower exercise levels, thus we may not reach patients who may benefit the most. However, studies comparing exercise of participants and non-participants found no differences [
      • Kampshoff C.S.
      • van Mechelen W.
      • Schep G.
      • Nijziel M.R.
      • Witlox L.
      • Bosman L.
      • et al.
      Participation in and adherence to physical exercise after completion of primary cancer treatment.
      ,
      • Gollhofer S.M.
      • Wiskemann J.
      • Schmidt M.E.
      • Klassen O.
      • Ulrich C.M.
      • Oelmann J.
      • et al.
      Factors influencing participation in a randomized controlled resistance exercise intervention study in breast cancer patients during radiotherapy.
      ,
      • van Waart H.
      • van Harten W.H.
      • Buffart L.M.
      • Sonke G.S.
      • Stuiver M.M.
      • Aaronson N.K.
      Why do patients choose (not) to participate in an exercise trial during adjuvant chemotherapy for breast cancer?.
      ]. Nevertheless, demographics may differ between participants and nonparticipants, with the latter more likely to be older [
      • Gollhofer S.M.
      • Wiskemann J.
      • Schmidt M.E.
      • Klassen O.
      • Ulrich C.M.
      • Oelmann J.
      • et al.
      Factors influencing participation in a randomized controlled resistance exercise intervention study in breast cancer patients during radiotherapy.
      ] and to have lower education levels [
      • Kampshoff C.S.
      • van Mechelen W.
      • Schep G.
      • Nijziel M.R.
      • Witlox L.
      • Bosman L.
      • et al.
      Participation in and adherence to physical exercise after completion of primary cancer treatment.
      ,
      • van Waart H.
      • van Harten W.H.
      • Buffart L.M.
      • Sonke G.S.
      • Stuiver M.M.
      • Aaronson N.K.
      Why do patients choose (not) to participate in an exercise trial during adjuvant chemotherapy for breast cancer?.
      ]. Therefore, results may not be fully generalizable to all patients with cancer. Future IPD meta-analyses should also study the moderator effects of baseline QoL, PF and fitness [
      • Wiskemann J.
      • Kuehl R.
      • Dreger P.
      • Schwerdtfeger R.
      • Huber G.
      • Ulrich C.M.
      • et al.
      Efficacy of exercise training in SCT patients–who benefits most?.
      ], and specific symptoms as fatigue and distress [
      • Kalter J.
      • Buffart L.M.
      • Korstjens I.
      • van Weert E.
      • Brug J.
      • Verdonck-de Leeuw I.M.
      • et al.
      Moderators of the effects of group-based physical exercise on cancer survivors’ quality of life.
      ] and the moderator effects on other physical, psychosocial and clinical outcomes, as they may differ [
      • Courneya K.S.
      • McKenzie D.C.
      • Mackey J.R.
      • Gelmon K.
      • Reid R.D.
      • Friedenreich C.M.
      • et al.
      Moderators of the effects of exercise training in breast cancer patients receiving chemotherapy: a randomized controlled trial.
      ,
      • Courneya K.S.
      • Sellar C.M.
      • Stevinson C.
      • McNeely M.L.
      • Friedenreich C.M.
      • Peddle C.J.
      • et al.
      Moderator effects in a randomized controlled trial of exercise training in lymphoma patients.
      ].
      Study strengths are the large number of included RCTs from multiple countries, the consequent large sample size, and the uniform analytical procedures across all studies. Limitations are the following: first, there was considerable publication bias in studies that met our inclusion criteria, overestimating the intervention effects, particularly for studies reporting on QoL. However, no significant differences in effect sizes were found between studies providing data and those that did not, indicating that the 34 RCTs included in the analyses were a representative sample of the published literature. Second, not all RCTs met all quality criteria. In particular, information on exercise adherence and contamination was limited, hampering the ability to check whether adherence was similar across moderator subgroups. However, a previous review on determinants of exercise adherence in patients with cancer concluded that the majority of studies showed no significant association of demographic and clinical factors with adherence [
      • Kampshoff C.S.
      • Jansen F.
      • van Mechelen W.
      • May A.M.
      • Brug J.
      • Chinapaw M.J.
      • et al.
      Determinants of exercise adherence and maintenance among cancer survivors: a systematic review.
      ]. Finally, we focused on short term intervention effects as very few studies have examined maintenance of intervention effects into the long term.
      In conclusion, exercise, and particularly those with a supervised component, effectively improves QoL and PF across subgroups of patients with cancer with different demographic and clinical characteristics, both during and following treatment. Although effect sizes were small, our study provides additional evidence to support the implementation of exercise as part of standard care to improve QoL and PF. Current knowledge on the exercise effects on QoL and PF is primarily based on studies in patients with non-metastasised breast or prostate cancer. Future studies should therefore shift the focus to understanding the exercise effects in understudied and advanced cancer populations; on clinical outcomes including specific symptoms, cancer treatment completion, and survival; and on how to optimize exercise participation, adherence, and prescriptions.

      Funding

      Via “Bas Mulder Award” granted to L.M. Buffart by the Alpe d’HuZes foundation/Dutch Cancer Society (VU 2011-5045).

      Author contributions

      Buffart, Brug, Verdonck-de Leeuw are members of the steering committee of POLARIS. Courneya, Newton, Jacobsen and Aaronson are members of the international advisory board of POLARIS. These authors contributed to the concept and design of the study. Buffart, Kalter and Sweegers gathered, pooled and analyzed the data. Buffart, Brug, Verdonck-de Leeuw drafted the manuscript. Buffart, Courneya, Newton, Aaronson, May, Galvão, Chinapaw, Steindorf, Irwin, Stuiver, Hayes, Griffith, Lucia, Mesters, van Weert, Knoop, Goedendorp, Mutrie, Daley, McConnachie, Bohus, Thorsen, Schulz, Short, James, Plotnikoff, Arbane, Schmidt, Potthoff, van Beurden, Oldenburg, Sonke, van Harten, Garrod, Schmitz, Winters-Stone, Velthuis, Taaffe, van Mechelen, Kersten, Nollet, Wenzel, Wiskemann, Brug are principal investigators of the randomised controlled trials of which the data are pooled for the current study, and have consequently contributed to the study concept, design and conduct of the trial that they were responsible for. All authors have critically revised the manuscript and approved the final version.

      Authors’ disclosures of potential conflicts of interest

      Dr. Steindorf reports personal fees from Lilly Deutschland (Award), outside the submitted work; Dr. Bohus reports grants from Josse Carreras Foundation, during the conduct of the study; Dr. van Mechelen reports to be shareholder-director of VU University Medical Center Amsterdam spin-off company Evalua Nederland B.V. (www.evalua.nl) and non-executive board member of Arbo Unie B.V. (www.arbounie.nl). Both companies are active in the Dutch occupational health care sector.
      Dr. Nollet reports grants from Dutch Cancer Society, during the conduct of the study. Dr. Brug reports grants from Dutch Cancer Society, during the conduct of the study.

      Acknowledgements

      The POLARIS study was supported by the “Bas Mulder Award” granted to L.M. Buffart by the Alpe d’HuZes foundation, part of the Dutch Cancer Society (VU 2011-5045).

      References

        • Torre L.A.
        • Siegel R.L.
        • Ward E.M.
        • Jemal A.
        Global cancer incidence and mortality rates and trends–an update.
        Cancer Epidemiol Biomarkers Prev. 2016; 25: 16-27
        • Ferlay J.
        • Soerjomataram I.
        • Dikshit R.
        • Eser S.
        • Mathers C.
        • Rebelo M.
        • et al.
        Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012.
        Int J Cancer. 2015; 136: E359-E386
        • Hashim D.
        • Boffetta P.
        • La Vecchia C.
        • Rota M.
        • Bertuccio P.
        • Malvezzi M.
        • et al.
        The global decrease in cancer mortality: trends and disparities.
        Ann Oncol. 2016;
        • Schmitz K.H.
        • Courneya K.S.
        • Matthews C.
        • Demark-Wahnefried W.
        • Galvao D.A.
        • Pinto B.M.
        • et al.
        American College of Sports Medicine roundtable on exercise guidelines for cancer survivors.
        Med Sci Sports Exerc. 2010; 42: 1409-1426
        • Rock C.L.
        • Doyle C.
        • Demark-Wahnefried W.
        • Meyerhardt J.
        • Courneya K.S.
        • Schwartz A.L.
        • et al.
        Nutrition and physical activity guidelines for cancer survivors.
        CA Cancer J Clin. 2012; 62: 243-274
        • Speck R.M.
        • Courneya K.S.
        • Masse L.C.
        • Duval S.
        • Schmitz K.H.
        An update of controlled physical activity trials in cancer survivors: a systematic review and meta-analysis.
        J Cancer Surviv. 2010; 4: 87-100
        • Buffart L.M.
        • Galvao D.A.
        • Brug J.
        • Chinapaw M.J.
        • Newton R.U.
        Evidence-based physical activity guidelines for cancer survivors: current guidelines, knowledge gaps and future research directions.
        Cancer Treat Rev. 2014; 40: 327-340
        • Mishra S.I.
        • Scherer R.W.
        • Geigle P.M.
        • Berlanstein D.R.
        • Topaloglu O.
        • Gotay C.C.
        • et al.
        Exercise interventions on health-related quality of life for cancer survivors.
        Cochrane Database Syst Rev. 2012; 8: CD007566
        • Mishra S.I.
        • Scherer R.W.
        • Snyder C.
        • Geigle P.M.
        • Berlanstein D.R.
        • Topaloglu O.
        Exercise interventions on health-related quality of life for people with cancer during active treatment.
        Cochrane Database Syst Rev. 2012; 8: CD008465
        • Kraemer H.C.
        • Wilson G.T.
        • Fairburn C.G.
        • Agras W.S.
        Mediators and moderators of treatment effects in randomized clinical trials.
        Arch Gen Psychiatry. 2002; 59: 877-883
        • Buffart L.M.
        • Newton R.U.
        • Chinapaw M.J.
        • Taaffe D.R.
        • Spry N.A.
        • Denham J.W.
        • et al.
        The effect, moderators, and mediators of resistance and aerobic exercise on health-related quality of life in older long-term survivors of prostate cancer.
        Cancer. 2015; 121: 2821-2830
        • Kalter J.
        • Buffart L.M.
        • Korstjens I.
        • van Weert E.
        • Brug J.
        • Verdonck-de Leeuw I.M.
        • et al.
        Moderators of the effects of group-based physical exercise on cancer survivors’ quality of life.
        Support Care Cancer. 2015; 23: 2623-2631
        • Courneya K.S.
        • McKenzie D.C.
        • Mackey J.R.
        • Gelmon K.
        • Reid R.D.
        • Friedenreich C.M.
        • et al.
        Moderators of the effects of exercise training in breast cancer patients receiving chemotherapy: a randomized controlled trial.
        Cancer. 2008; 112: 1845-1853
        • Courneya K.S.
        • Sellar C.M.
        • Stevinson C.
        • McNeely M.L.
        • Friedenreich C.M.
        • Peddle C.J.
        • et al.
        Moderator effects in a randomized controlled trial of exercise training in lymphoma patients.
        Cancer Epidemiol Biomarkers Prev. 2009; 18: 2600-2607
        • Carmack Taylor C.L.
        • de Moor C.
        • Basen-Engquist K.
        • Smith M.A.
        • Dunn A.L.
        • Badr H.
        • et al.
        Moderator analyses of participants in the Active for Life after cancer trial: implications for physical activity group intervention studies.
        Ann Behav Med. 2007; 33: 99-104
        • Tierney J.F.
        • Vale C.
        • Riley R.
        • Smith C.T.
        • Stewart L.
        • Clarke M.
        • et al.
        Individual participant data (IPD) meta-analyses of randomised controlled trials: guidance on their use.
        PLoS Med. 2015; 12: e1001855
        • Riley R.D.
        • Lambert P.C.
        • Abo-Zaid G.
        Meta-analysis of individual participant data: rationale, conduct, and reporting.
        BMJ. 2010; 340: c221
        • Teramukai S.
        • Matsuyama Y.
        • Mizuno S.
        • Sakamoto J.
        Individual patient-level and study-level meta-analysis for investigating modifiers of treatment effect.
        Jpn J Clin Oncol. 2004; 34: 717-721
        • Fisher D.J.
        • Copas A.J.
        • Tierney J.F.
        • Parmar M.K.
        A critical review of methods for the assessment of patient-level interactions in individual participant data meta-analysis of randomized trials, and guidance for practitioners.
        J Clin Epidemiol. 2011; 64: 949-967
        • Buffart L.M.
        • Kalter J.
        • Chinapaw M.J.
        • Heymans M.W.
        • Aaronson N.K.
        • Courneya K.S.
        • et al.
        Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS): rationale and design for meta-analyses of individual patient data of randomized controlled trials that evaluate the effect of physical activity and psychosocial interventions on health-related quality of life in cancer survivors.
        Syst Rev. 2013; 2: 75
        • Stewart L.A.
        • Clarke M.
        • Rovers M.
        • Riley R.D.
        • Simmonds M.
        • Stewart G.
        • et al.
        Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data: the PRISMA-IPD Statement.
        JAMA. 2015; 313: 1657-1665
        • Courneya K.S.
        • Segal R.J.
        • Gelmon K.
        • Reid R.D.
        • Mackey J.R.
        • Friedenreich C.M.
        • et al.
        Predictors of supervised exercise adherence during breast cancer chemotherapy.
        Med Sci Sports Exerc. 2008; 40: 1180-1187
        • Kampshoff C.S.
        • van Mechelen W.
        • Schep G.
        • Nijziel M.R.
        • Witlox L.
        • Bosman L.
        • et al.
        Participation in and adherence to physical exercise after completion of primary cancer treatment.
        Int J Behav Nutr Phys Act. 2016; 13: 100
        • Steins Bisschop C.N.
        • Courneya K.S.
        • Velthuis M.J.
        • Monninkhof E.M.
        • Jones L.W.
        • Friedenreich C.
        • et al.
        Control group design, contamination and drop-out in exercise oncology trials: a systematic review.
        PLoS One. 2015; 10: e0120996
        • Ahmed I.
        • Sutton A.J.
        • Riley R.D.
        Assessment of publication bias, selection bias, and unavailable data in meta-analyses using individual participant data: a database survey.
        BMJ. 2012; 344: d7762
        • Duval S.
        • Tweedie R.
        Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis.
        Biometrics. 2000; 56: 455-463
        • Kampshoff C.S.
        • Chinapaw M.J.
        • Brug J.
        • Twisk J.W.
        • Schep G.
        • Nijziel M.R.
        • et al.
        Randomized controlled trial of the effects of high intensity and low-to-moderate intensity exercise on physical fitness and fatigue in cancer survivors: results of the Resistance and Endurance exercise After ChemoTherapy (REACT) study.
        BMC Med. 2015; 13: 275
        • Courneya K.S.
        • Friedenreich C.M.
        Physical activity and cancer control.
        Semin Oncol Nurs. 2007; 23: 242-252
        • American Collega of Sports Medicine
        ACSM’s guidelines for exercise testing and prescription.
        9th ed. Lippincot Williams and Wilkins, Philadelphia2014
        • Korstjens I.
        • May A.M.
        • van Weert E.
        • Mesters I.
        • Tan F.
        • Ros W.J.
        • et al.
        Quality of life after self-management cancer rehabilitation: a randomized controlled trial comparing physical and cognitive-behavioral training versus physical training.
        Psychosom Med. 2008; 70: 422-429
        • Duijts S.F.
        • van Beurden M.
        • Oldenburg H.S.
        • Hunter M.S.
        • Kieffer J.M.
        • Stuiver M.M.
        • et al.
        Efficacy of cognitive behavioral therapy and physical exercise in alleviating treatment-induced menopausal symptoms in patients with breast cancer: results of a randomized, controlled, multicenter trial.
        J Clin Oncol. 2012; 30: 4124-4133
        • Goedendorp M.M.
        • Peters M.E.
        • Gielissen M.F.
        • Witjes J.A.
        • Leer J.W.
        • Verhagen C.A.
        • et al.
        Is increasing physical activity necessary to diminish fatigue during cancer treatment? Comparing cognitive behavior therapy and a brief nursing intervention with usual care in a multicenter randomized controlled trial.
        Oncologist. 2010; 15: 1122-1132
        • Courneya K.S.
        • Segal R.J.
        • Mackey J.R.
        • Gelmon K.
        • Reid R.D.
        • Friedenreich C.M.
        • et al.
        Effects of aerobic and resistance exercise in breast cancer patients receiving adjuvant chemotherapy: a multicenter randomized controlled trial.
        J Clin Oncol. 2007; 25: 4396-4404
        • Hayes S.C.
        • Rye S.
        • Disipio T.
        • Yates P.
        • Bashford J.
        • Pyke C.
        • et al.
        Exercise for health: a randomized, controlled trial evaluating the impact of a pragmatic, translational exercise intervention on the quality of life, function and treatment-related side effects following breast cancer.
        Breast Cancer Res Treat. 2013; 137: 175-186
        • Short C.E.
        • James E.L.
        • Girgis A.
        • D’Souza M.I.
        • Plotnikoff R.C.
        Main outcomes of the Move More for Life Trial: a randomised controlled trial examining the effects of tailored-print and targeted-print materials for promoting physical activity among post-treatment breast cancer survivors.
        Psychooncology. 2015; 24: 771-778
        • Segal R.J.
        • Reid R.D.
        • Courneya K.S.
        • Sigal R.J.
        • Kenny G.P.
        • Prud’Homme D.G.
        • et al.
        Randomized controlled trial of resistance or aerobic exercise in men receiving radiation therapy for prostate cancer.
        J Clin Oncol. 2009; 27: 344-351
        • van Waart H.
        • Stuiver M.M.
        • van Harten W.H.
        • Geleijn E.
        • Kieffer J.M.
        • Buffart L.M.
        • et al.
        Effect of low-intensity physical activity and moderate- to high-intensity physical exercise during adjuvant chemotherapy on physical fitness, fatigue, and chemotherapy completion rates: results of the PACES randomized clinical trial.
        J Clin Oncol. 2015; 33: 1918-1927
        • Zhang J.
        • Gan L.
        • Wu Z.
        • Yan S.
        • Liu X.
        • Guo W.
        The influence of marital status on the stage at diagnosis, treatment, and survival of adult patients with gastric cancer: a population-based study.
        Oncotarget. 2016;
        • Aizer A.A.
        • Chen M.H.
        • McCarthy E.P.
        • Mendu M.L.
        • Koo S.
        • Wilhite T.J.
        • et al.
        Marital status and survival in patients with cancer.
        J Clin Oncol. 2013; 31: 3869-3876
        • Jones L.W.
        • Demark-Wahnefried W.
        Diet, exercise, and complementary therapies after primary treatment for cancer.
        Lancet Oncol. 2006; 7: 1017-1026
        • Baumann F.T.
        • Zopf E.M.
        • Bloch W.
        Clinical exercise interventions in prostate cancer patients–a systematic review of randomized controlled trials.
        Support Care Cancer. 2012; 20: 221-233
        • Courneya K.S.
        • McKenzie D.C.
        • Mackey J.R.
        • Gelmon K.
        • Friedenreich C.M.
        • Yasui Y.
        • et al.
        Effects of exercise dose and type during breast cancer chemotherapy: multicenter randomized trial.
        J Natl Cancer Inst. 2013; 105: 1821-1832
        • The World Health Organization Quality of Life Assessment
        (WHOQOL): development and general psychometric properties.
        Soc Sci Med. 1998; 46: 1569-1585
        • Gerlich C.
        • Schuler M.
        • Jelitte M.
        • Neuderth S.
        • Flentje M.
        • Graefen M.
        • et al.
        Prostate cancer patients’ quality of life assessments across the primary treatment trajectory: ‘True’ change or response shift?.
        Acta Oncol. 2016; 1–7
        • Anota A.
        • Bascoul-Mollevi C.
        • Conroy T.
        • Guillemin F.
        • Velten M.
        • Jolly D.
        • et al.
        Item response theory and factor analysis as a mean to characterize occurrence of response shift in a longitudinal quality of life study in breast cancer patients.
        Health Qual Life Outcomes. 2014; 12: 32
        • Sprangers M.A.
        • Schwartz C.E.
        Integrating response shift into health-related quality of life research: a theoretical model.
        Soc Sci Med. 1999; 48: 1507-1515
        • Maddocks M.
        • Mockett S.
        • Wilcock A.
        Is exercise an acceptable and practical therapy for people with or cured of cancer? A systematic review.
        Cancer Treat Rev. 2009; 35: 383-390
        • Gollhofer S.M.
        • Wiskemann J.
        • Schmidt M.E.
        • Klassen O.
        • Ulrich C.M.
        • Oelmann J.
        • et al.
        Factors influencing participation in a randomized controlled resistance exercise intervention study in breast cancer patients during radiotherapy.
        BMC Cancer. 2015; 15: 186
        • van Waart H.
        • van Harten W.H.
        • Buffart L.M.
        • Sonke G.S.
        • Stuiver M.M.
        • Aaronson N.K.
        Why do patients choose (not) to participate in an exercise trial during adjuvant chemotherapy for breast cancer?.
        Psychooncology. 2015;
        • Wiskemann J.
        • Kuehl R.
        • Dreger P.
        • Schwerdtfeger R.
        • Huber G.
        • Ulrich C.M.
        • et al.
        Efficacy of exercise training in SCT patients–who benefits most?.
        Bone Marrow Transplant. 2014; 49: 443-448
        • Kampshoff C.S.
        • Jansen F.
        • van Mechelen W.
        • May A.M.
        • Brug J.
        • Chinapaw M.J.
        • et al.
        Determinants of exercise adherence and maintenance among cancer survivors: a systematic review.
        Int J Behav Nutr Phys Act. 2014; 11: 80
        • Arbane G.
        • Tropman D.
        • Jackson D.
        • Garrod R.
        Evaluation of an early exercise intervention after thoracotomy for non-small cell lung cancer (NSCLC), effects on quality of life, muscle strength and exercise tolerance: randomised controlled trial.
        Lung Cancer. 2011; 71: 229-234
        • Cadmus L.A.
        • Salovey P.
        • Yu H.
        • Chung G.
        • Kasl S.
        • Irwin M.L.
        Exercise and quality of life during and after treatment for breast cancer: results of two randomized controlled trials.
        Psychooncology. 2009; 18: 343-352
        • Cormie P.
        • Galvao D.A.
        • Spry N.
        • Joseph D.
        • Chee R.
        • Taaffe D.R.
        • et al.
        Can supervised exercise prevent treatment toxicity in patients with prostate cancer initiating androgen-deprivation therapy: a randomised controlled trial.
        BJU Int. 2015; 115: 256-266
        • Courneya K.S.
        • Friedenreich C.M.
        • Quinney H.A.
        • Fields A.L.
        • Jones L.W.
        • Fairey A.S.
        A randomized trial of exercise and quality of life in colorectal cancer survivors.
        Eur J Cancer Care (Engl). 2003; 12: 347-357
        • Courneya K.S.
        • Mackey J.R.
        • Bell G.J.
        • Jones L.W.
        • Field C.J.
        • Fairey A.S.
        Randomized controlled trial of exercise training in postmenopausal breast cancer survivors: cardiopulmonary and quality of life outcomes.
        J Clin Oncol. 2003; 21: 1660-1668
        • Courneya K.S.
        • Sellar C.M.
        • Stevinson C.
        • McNeely M.L.
        • Peddle C.J.
        • Friedenreich C.M.
        • et al.
        Randomized controlled trial of the effects of aerobic exercise on physical functioning and quality of life in lymphoma patients.
        J Clin Oncol. 2009; 27: 4605-4612
        • Daley A.J.
        • Crank H.
        • Saxton J.M.
        • Mutrie N.
        • Coleman R.
        • Roalfe A.
        Randomized trial of exercise therapy in women treated for breast cancer.
        J Clin Oncol. 2007; 25: 1713-1721
        • Galvao D.A.
        • Taaffe D.R.
        • Spry N.
        • Joseph D.
        • Newton R.U.
        Combined resistance and aerobic exercise program reverses muscle loss in men undergoing androgen suppression therapy for prostate cancer without bone metastases: a randomized controlled trial.
        J Clin Oncol. 2010; 28: 340-347
        • Galvao D.A.
        • Spry N.
        • Denham J.
        • Taaffe D.R.
        • Cormie P.
        • Joseph D.
        • et al.
        A multicentre year-long randomised controlled trial of exercise training targeting physical functioning in men with prostate cancer previously treated with androgen suppression and radiation from TROG 03.04 RADAR.
        Eur Urol. 2014; 65: 856-864
        • Griffith K.
        • Wenzel J.
        • Shang J.
        • Thompson C.
        • Stewart K.
        • Mock V.
        Impact of a walking intervention on cardiorespiratory fitness, self-reported physical function, and pain in patients undergoing treatment for solid tumors.
        Cancer. 2009; 115: 4874-4884
        • Herrero F.
        • San Juan A.F.
        • Fleck S.J.
        • Balmer J.
        • Perez M.
        • Canete S.
        • et al.
        Combined aerobic and resistance training in breast cancer survivors: a randomized, controlled pilot trial.
        Int J Sports Med. 2006; 27: 573-580
        • Irwin M.L.
        • Varma K.
        • Alvarez-Reeves M.
        • Cadmus L.
        • Wiley A.
        • Chung G.G.
        • et al.
        Randomized controlled trial of aerobic exercise on insulin and insulin-like growth factors in breast cancer survivors: the Yale Exercise and Survivorship study.
        Cancer Epidemiol Biomarkers Prev. 2009; 18: 306-313
        • Mehnert A.
        • Veers S.
        • Howaldt D.
        • Braumann K.M.
        • Koch U.
        • Schulz K.H.
        Effects of a physical exercise rehabilitation group program on anxiety, depression, body image, and health-related quality of life among breast cancer patients.
        Onkologie. 2011; 34: 248-253
        • Mutrie N.
        • Campbell A.M.
        • Whyte F.
        • McConnachie A.
        • Emslie C.
        • Lee L.
        • et al.
        Benefits of supervised group exercise programme for women being treated for early stage breast cancer: pragmatic randomised controlled trial.
        BMJ. 2007; 334: 517
        • Newton R.U.
        • Taaffe D.R.
        • Spry N.
        • Gardiner R.A.
        • Levin G.
        • Wall B.
        • et al.
        A phase III clinical trial of exercise modalities on treatment side-effects in men receiving therapy for prostate cancer.
        BMC Cancer. 2009; 9: 210
        • Ohira T.
        • Schmitz K.H.
        • Ahmed R.L.
        • Yee D.
        Effects of weight training on quality of life in recent breast cancer survivors: the Weight Training for Breast Cancer Survivors (WTBS) study.
        Cancer. 2006; 106: 2076-2083
        • Persoon S.
        • Kersten M.J.
        • Chinapaw M.J.
        • Buffart L.M.
        • Burghout H.
        • Schep G.
        • et al.
        Design of the EXercise Intervention after Stem cell Transplantation (EXIST) study: a randomized controlled trial to evaluate the effectiveness and cost-effectiveness of an individualized high intensity physical exercise program on fitness and fatigue in patients with multiple myeloma or (non-) Hodgkin’s lymphoma treated with high dose chemotherapy and autologous stem cell transplantation.
        BMC Cancer. 2010; 10: 671
        • Schmidt M.E.
        • Wiskemann J.
        • Armbrust P.
        • Schneeweiss A.
        • Ulrich C.M.
        • Steindorf K.
        Effects of resistance exercise on fatigue and quality of life in breast cancer patients undergoing adjuvant chemotherapy: a randomized controlled trial.
        Int J Cancer. 2015; 137: 471-480
        • Speck R.M.
        • Gross C.R.
        • Hormes J.M.
        • Ahmed R.L.
        • Lytle L.A.
        • Hwang W.T.
        • et al.
        Changes in the Body Image and Relationship Scale following a one-year strength training trial for breast cancer survivors with or at risk for lymphedema.
        Breast Cancer Res Treat. 2010; 121: 421-430
        • Steindorf K.
        • Schmidt M.E.
        • Klassen O.
        • Ulrich C.M.
        • Oelmann J.
        • Habermann N.
        • et al.
        Randomized, controlled trial of resistance training in breast cancer patients receiving adjuvant radiotherapy: results on cancer-related fatigue and quality of life.
        Ann Oncol. 2014; 25: 2237-2243
        • Thorsen L.
        • Skovlund E.
        • Stromme S.B.
        • Hornslien K.
        • Dahl A.A.
        • Fossa S.D.
        Effectiveness of physical activity on cardiorespiratory fitness and health-related quality of life in young and middle-aged cancer patients shortly after chemotherapy.
        J Clin Oncol. 2005; 23: 2378-2388
        • Travier N.
        • Velthuis M.J.
        • Steins Bisschop C.N.
        • van den Buijs B.
        • Monninkhof E.M.
        • Backx F.
        • et al.
        Effects of an 18-week exercise programme started early during breast cancer treatment: a randomised controlled trial.
        BMC Med. 2015; 13: 121
        • van Vulpen J.K.
        • Velthuis M.J.
        • Steins Bisschop C.N.
        • Travier N.
        • VDB B.J.
        • Backx F.J.
        • et al.
        Effects of an exercise program in colon cancer patients undergoing chemotherapy.
        Med Sci Sports Exerc. 2016; 48: 767-775
        • Winters-Stone K.M.
        • Dobek J.
        • Bennett J.A.
        • Nail L.M.
        • Leo M.C.
        • Schwartz A.
        The effect of resistance training on muscle strength and physical function in older, postmenopausal breast cancer survivors: a randomized controlled trial.
        J Cancer Surviv. 2012; 6: 189-199
        • Winters-Stone K.M.
        • Dobek J.
        • Nail L.M.
        • Bennett J.A.
        • Leo M.C.
        • Torgrimson-Ojerio B.
        • et al.
        Impact + resistance training improves bone health and body composition in prematurely menopausal breast cancer survivors: a randomized controlled trial.
        Osteoporosis Int. 2013; 24: 1637-1646
        • Winters-Stone K.M.
        • Dobek J.C.
        • Bennett J.A.
        • Dieckmann N.F.
        • Maddalozzo G.F.
        • Ryan C.W.
        • et al.
        Resistance training reduces disability in prostate cancer survivors on androgen deprivation therapy: evidence from a randomized controlled trial.
        Arch Phys Med Rehabil. 2015; 96: 7-14
        • Wiskemann J.
        • Dreger P.
        • Schwerdtfeger R.
        • Bondong A.
        • Huber G.
        • Kleindienst N.
        • et al.
        Effects of a partly self-administered exercise program before, during, and after allogeneic stem cell transplantation.
        Blood. 2011; 117: 2604-2613