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Collaborative Review – Prostatic Disease

Exercise for Men with Prostate Cancer: A Systematic Review and Meta-analysis

By: Liam Bourkea , Dianna Smithb, Liz Steedc, Richard Hooperc, Anouska Cartera, James Cattod, Peter C. Albertsene, Bertrand Tombalf, Heather A. Payneg and Derek J. Rosarioh

European Urology, Volume 69 Issue 4, April 2016, Pages 693-703

Published online: 01 April 2016

Keywords: Exercise, Prostate cancer, Quality of life, Fatigue, Adverse effects

Abstract Full Text Full Text PDF (1,1 MB) Patient Summary

Abstract

Context

Exercise could be beneficial for prostate cancer survivors. However, no systematic review across cancer stages and treatment types addressing potential benefits and harms exists to date.

Objective

To assess the effects of exercise on cancer-specific quality of life and adverse events in prostate cancer trials.

Evidence acquisition

We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, AMED, CINAHL, PsycINFO, SPORTDiscus, and PEDro. We also searched grey literature databases, including trial registers. Searches were from database inception to March 2015. Standardised mean differences (SMDs) were calculated for meta-analysis.

Evidence synthesis

We included 16 randomised controlled trials (RCTs) involving 1574 men with prostate cancer. Follow-up varied from 8 wk to 12 mo. RCTs involved men with stage I–IV cancers. A high risk of bias was frequently due to problematic intervention adherence. Seven trials involving 912 men measured cancer-specific quality of life. Pooling of the data from these seven trials revealed no significant effect on this outcome (SMD 0.13, 95% confidence interval [CI] –0.08 to 0.34, median follow-up 12 wk). Sensitivity analysis of studies that were judged to be of high quality indicated a moderate positive effect estimate (SMD 0.33, 95% CI 0.08–0.58; median follow-up 12 wk). Similar beneficial effects were seen for cancer-specific fatigue, submaximal fitness, and lower body strength. We found no evidence of benefit for disease progression, cardiovascular health, or sexual function. There were no deaths attributable to exercise interventions. Other serious adverse events (eg, myocardial infarction) were equivalent to those seen in controls.

Conclusions

These results support the hypothesis that exercise interventions improve cancer-specific quality of life, cancer-specific fatigue, submaximal fitness, and lower body strength.

Patient summary

This review shows that exercise/physical activity interventions can improve quality of life, fatigue, fitness, and function for men with prostate cancer.

Take Home Message

Data from randomised controlled trials in this review indicate that exercise interventions improve cancer-specific quality of life, cancer-specific fatigue, submaximal fitness, and lower body strength. We found no evidence of benefit for disease progression, cardiovascular health, or sexual function outcomes.

Keywords: Exercise, Prostate cancer, Quality of life, Fatigue, Adverse effects.

1. Introduction

Prostate cancer is the primary cause of years lived with cancer disability in the Americas, Northwest Europe, Australia, New Zealand, and much of sub-Saharan Africa [1]. Management of prostate cancer ranges from no intervention (active surveillance or watchful waiting) to radical local treatment (prostatectomy and radiation therapy) with or without combined androgen deprivation therapy (ADT), ADT alone, to taxane-based chemotherapy for progressive castration-resistant disease [2] and second-line hormone agents [3] and [4]. First-line radical treatment for prostate cancer can negatively impact quality of life (eg, erectile dysfunction, incontinence, radiation proctitis), as can ADT (eg, loss of muscle mass, fatigue, psychological morbidity, higher risk of cardiovascular disease and bone fracture) [5] and [6]. Direct symptoms for advanced or metastatic cancer (eg, pain, hypercalcaemia, spinal cord compression, pathological fractures) can also adversely affect health [7] and [8].

Several recent systematic reviews have examined the effects of exercise in cancer survivors in terms of quality of life [9] and [10], exercise behaviour [11], and fatigue [12]. These reviews cover an amalgamation of heterogeneous primary cancers. Most evidence comes from trials in breast cancer and thus cannot be generalised to men with prostate cancer. Furthermore, exercise therapy appears to be beneficial in the short term, but little is known about dose, duration, and longer-term effects of such therapy, including adverse effects over extended follow-up. Finally, despite the potential health benefits for men with prostate cancer, few clinicians are aware of the role of exercise, and in many cases it goes unprescribed. The aim of this review was primarily to evaluate the effect of exercise interventions on cancer-specific quality of life after prostate cancer diagnosis and to assess adverse effects.

2. Evidence acquisition

Methods for this systematic review have been described in detail elsewhere [13]. In brief, the primary review outcomes were quality of life and adverse events. Secondary outcomes include effects on fatigue, disease progression, cardiovascular health, physical fitness and function, and sexual function.

We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, AMED, CINAHL, PsycINFO, SPORTDiscus, and PEDro databases from inception to March 31, 2015. We expanded the database search by attempting to identify unpublished studies and references in the grey literature (via the OpenGrey database). We also searched the World Health Organization (WHO) trials page, the ISRCTN meta-register of controlled trials (www.isrctn.com), and ClinicalTrials.gov.

2.1. Inclusion and exclusion criteria

We included only randomised controlled trials (RCTs) involving adults in which trial participants had been diagnosed with prostate cancer. Only interventions that included a component targeted at increasing aerobic exercise and/or resistance exercise behaviour compared with a usual care or waiting-list control group with at least 6 wk of follow-up (from trial baseline assessment) were considered in the review. We excluded trials addressing recovery of continence only. Only studies that reported the frequency, duration, and intensity of aerobic exercise behaviour, or the frequency, intensity, type, sets, and repetitions of resistance exercise behaviour as prescribed in the intervention were included in the review.

2.2. Data extraction

After extraction piloting, three review authors (L.B., D.S., and A.C.) worked independently to screen all titles and abstracts to identify records that met the inclusion criteria or that could not be safely excluded without assessment of the full text (eg, when no abstract was available). Disagreements at this stage were resolved by discussion with another review author (D.J.R.). Full-text articles for these records were retrieved. After training to ensure a consistent approach to study assessment and data abstraction, three review authors (L.B., D.S., and A.C.) worked independently to assess the full-text articles retrieved. The selection process is documented in a Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow diagram (Figure 1) [14].

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Fig. 1 Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow diagram. RCT = randomised controlled trial.

The review authors did not conduct data extraction for any primary studies for which they were listed as an author. Data were entered into the statistical software of The Cochrane Collaboration Review Manager (RevMan 5) for calculation of meta-analyses. Where appropriate, we contacted study authors to request information that was missing from reports for the studies included.

The risk of bias was assessed using The Cochrane Collaboration tool [15]. Two of three review authors (L.B., D.S., and A.C.) applied the risk-of-bias tool independently to each study. Differences were resolved by discussion or by appeal to a third review author (D.J.R.). Review authors did not assess the risk of bias for any studies for which they were an author. The results are summarised in Figure 2.

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Fig. 2 Risk of bias for the trials included.

2.3. Data synthesis

If the data available were sufficient and if it was appropriate to do so, we performed a meta-analysis using Review Manager software. I2 calculations were performed in STATA. If statistical heterogeneity was noted, meta-analysis was performed using a random-effects model. Fixed-effect models were used only if no significant statistical heterogeneity was present. We noted the time points at which outcomes were collected and reported. If adverse effects data were insufficient or if meta-analysis was not appropriate, we provide a narrative synthesis.

For continuous outcomes (eg, cancer-specific quality of life), we extracted the point estimate for the measure of central tendency for the final value of the outcome of interest and the number of participants assessed at stated follow-up in each treatment arm to estimate the standardised mean difference (SMD) between treatment arms and its 95% confidence interval (CI).

2.4. Unit of analysis

We did not include crossover trials in this review because of the difficulty involved in washing out interventions to change behaviour. For trials with multiple intervention groups, we first eliminated groups for which the intervention did not meet the criteria for inclusion in the review. We then combined all relevant intervention groups to create a single pairwise comparison with the control group.

2.5. Assessment of heterogeneity

We used clinical expertise to judge whether it was appropriate to combine trials in a meta-analysis. Consistency of results was assessed using the I2 statistic and its 95% CI. Data were analysed using RevMan and Stata 12.

2.6. Sensitivity analysis

Results of meta-analyses were interpreted in light of the findings with respect to risk of bias. Risk of bias was assessed for each follow-up. For sensitivity analysis, we used the longest follow-up for which there was a low risk of bias. Where appropriate, we contacted study authors for additional information or for further clarification of study methods if any doubt arose regarding sources of bias.

2.7. Subgroup analysis

If a sufficient number of studies were identified and if the reporting resolution was adequate, we performed subgroup analyses for anticancer treatment received, cancer stage, obesity, previous physical activity at baseline, and explanatory (efficacy) versus pragmatic (effectiveness) trial designs. We categorised interventions according to the theoretical basis, the behaviour change techniques, and categorisation using the Coventry, Aberdeen & London-Refined (CALO-RE) taxonomy [14].

3. Evidence synthesis

3.1. Search results

Figure 1 shows the results for the literature searches and screening process for the review. We identified 4356 unique records from database searches and 22 manuscripts through grey literature and hand checking of references for studies included and related systematic reviews [16] and [17]. After reviewing by title and abstract, we evaluated the full text for 91 records, after which 67 studies were excluded from the review. All full-text manuscripts were available in English. We sent 31 emails requesting further information on published manuscripts and received four responses (only one of which provided new data).

3.2. Studies included

We included 16 RCTs [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], and [33] (Table 1) involving 1574 men with prostate cancer (sample size 20–423). We also found eight linked manuscripts with secondary analysis [34], [35], [36], [37], [38], [39], [40], and [41]. All studies were randomised at the patient level. Follow-up varied from 8 wk to 12 mo. RCTs involved men with stage I–IV cancers, but we found no trials for men exclusively undergoing chemotherapy (two trials included a small proportion of men who had chemotherapy) [26] and [33]. Exercise interventions were supervised [22], [27], [29], [30], and [31], home-based [21], [24], and [32], a mix of supervised and home-based [18], [23], [25], and [33], or supervised with suggested home-based activity [19] and [20]; two were unclear [26] and [28]. Exercise behaviour (dose) was monitored using objective [22], [29], [30], [31], and [32], subjective [24] and [26], or a mixture of objective or subjective methods [18], [23], [25], and [33], was not monitored [21], or was unclear [19], [20], [27], and [28]. All trials included a usual care comparator. Two trials supplemented usual care with standard exercise advice for cancer survivors [23] and [26]. Our previous Cochrane review [11] demonstrated that simple advice is highly unlikely to improve exercise behaviour, so we judged these studies eligible for inclusion.

Table 1 Description of studies included in the review

StudyN randomisedFollow-upParticipants and treatmentInterventionReview outcome measures
Bourke et al [18]Exercise n = 50
Usual care n = 50
Baseline, 3 mo, 6 moTumour stage: T3–4
Current PCa treatment: ADT
Metastatic disease: 11 in the exercise and 9 in the usual care group
Aerobic frequency: 3 times/wk
Aerobic intensity: 55–75% of age-predicted HRmax or 11–13 on the Borg rating of perceived exertion scale
Aerobic duration: 30 min
Resistance frequency: 3 times/wk
Resistance sets: 2–4
Resistance reps: 8–12
Resistance load: 60% of 1 RM
PCa-specific QoL: FACT-P
Adverse events: reported
PCa-specific fatigue: FACT-F
CV health: systolic and diastolic BP
Physical function: aerobic exercise tolerance by submaximal treadmill test
Cormie et al [19]Exercise n = 10
Usual care n = 10
Baseline, 12 wkTumour stage: not clear
Current PCa treatment: unclear; all men had previous ADT
Metastatic disease: all men
Aerobic frequency: unclear
Aerobic intensity: unclear
Aerobic duration: 150 min/wk
Resistance frequency: twice/wk
Resistance sets: 2–4
Resistance reps: 8–12
Resistance load: 8–12 RM
Adverse events: reported
PCa-specific fatigue: Multidimensional Fatigue Symptom Inventory-Short Form questionnaire
Physical function: (1) one repetition max in leg extension (2) 400-m walk, (3) usual and fast-pace 6-m walk, (4) timed ‘up and go’ test
Cormie et al [20]Exercise n = 32
Usual care n = 31
Baseline, 3 moTumour stage(s): not clear
Current PCa treatment: ADT, RT
Metastatic disease: none
Aerobic frequency: twice/wk
Aerobic intensity: target intensity ∼70–85% of estimated HRmax
Aerobic duration: 20–30 min
Resistance frequency: twice/wk
Resistance sets: 1–4
Resistance reps: 6–12
Resistance load: 60–85% of 1 RM
PCa-specific QoL: QLQ-PR25
Adverse events: reported
PCa-specific fatigue: FACT-F
Disease progression: PSA
CV health: systolic and diastolic BP
Physical function: 400-m walk, leg press, chest press, seated row
Sexual function: QLQ-PR25 sexual domain
Dieperink et al [21]Intervention n = 79
Control n = 82
12 wk before RT, before intervention (4 wk after RT), and 21–22 wk thereafterTumour stage: T1–3
Current PCa treatment: RT and ADT
Metastatic disease: n = 3 in each group received pelvic RT for metastatic lymph nodes
Aerobic frequency: 7 d/wk
Aerobic intensity: lower limit for moderate-intensity physical exercise corresponds to walking at an average speed of 4 km/h
Aerobic duration:30 min/d
PCa-specific QoL: EPIC questionnaire
Sexual function: EPIC questionnaire sexual sum score
Galvão et al [22]Exercise n = 29
Usual care n = 28
Baseline, 12 wkTumour stage: unclear
Current PCa treatment: RT + ADT
Nodal metastases: n = 2 in exercise and n = 3 in usual care group
Aerobic frequency: twice/wk
Aerobic intensity: 65–80% HRmax and perceived exertion 11–13 (6- to 20-point Borg scale)
Aerobic duration: 15–20 min of CV exercisesa
Resistance frequency: twice/wk
Resistance sets: 2–4
Resistance reps: 6–12
Resistance load: 6–12 RM
PCa-specific QoL: QLQ-C30 and QLQ-PR25
Adverse events: reported
PCa-specific fatigue: QLQ-C30 fatigue domain
Disease progression: PSA
Physical function: 400-m walk, dynamic strength for upper and lower body
Sexual function: QLQ-PR25
Galvão et al [23]Exercise n = 50
Usual care n = 50
Baseline, 6 mo, 12 moTumour stage: T2–4
Current PCa treatment: none (previous ADT + RT + bisphosphonate
Metastatic disease: excluded from trial
Aerobic frequency: 4 times/wk
Aerobic intensity: 70–85% HRmax and perceived exertion at 11–13 (6- to 20-point Borg scale)
Aerobic duration: 20–30 min of CV exercises
Resistance frequency: twice/wk
Resistance sets: 2–4
Resistance reps: 6–12
Resistance load: 6–12 RM
Adverse events: reported
Disease progression: PSA
CV health: BP
Physical function: submaximal exercise tolerance, chair rise test
Hebert et al [24]Exercise n = 29
Control n = 25
Baseline, 3 mo, 6 moTumour stage: unclear
Current PCa treatment: previous surgery, RT, or both
Metastatic disease: unclear
Aerobic frequency: 5 times/wk
Aerobic intensity: 3.0–6.0 MET min or 4–7 kcal/min
Aerobic duration: ≥30 min
Adverse events: unclear
Disease progression: PSA
Jones et al [25]Exercise n = 25
Usual care n = 25
Baseline, 6 moTumour stage: T1–2
Current PCa treatment: previous bilateral nerve-sparing RP
Metastatic disease: none
Aerobic frequency: five sessions/wk
Aerobic intensity: 55–100% of VO2 peak
Aerobic duration: 30–45 min/session
PCa-specific QoL: FACT-G and FACT-P
Adverse events: reported
PCa-specific fatigue: FACT-F
CV health: BP
Physical function: VO2 peak
Sexual function: IIEF questionnaire
McGowan et al [26]Physical activity guidelines n = 141
Self-administered implementation intention n = 141
Telephone-assisted implementation intention n = 141
Baseline, 1 mo, 3 moTumour stage: unclear
Current PCa treatment: watchful waiting, surgery, RT, ADT, CTx, PCa recurrence
Metastatic disease: 1.9% of the cohort
Aerobic frequency: unclear
Aerobic intensity [22]: ∼500–1000 MET min/wk
Aerobic duration: 150–300 min/wk, or increase physical activity by at least 60 min/wk if already meeting the guidelines
PCa-specific QoL: FACT-P
PCa-specific fatigue: FACT-F
Monga et al [27]Unclear (n = 30 randomised in total)Baseline, 8 wkTumour stage: unclear
Current PCa treatment: RT
Metastatic disease: unclear
Aerobic frequency: 3 times/wk
Aerobic intensity: target HR calculated as [0.65 × (HRmax – resting HR)] + resting HR
Aerobic duration: 30 min of walking on a treadmill
PCa-specific QoL: FACT-P
PCa-specific fatigue: Piper fatigue scale
Physical function: submaximal fitness (Bruce treadmill protocol) and timed five reps of chair sit-to-stand test
Park et al [28]Exercise n = 33
Usual care n = 33
Week before RP, before exercise (3 wk after RP), after exercise (15 wk after RP)Tumour stage: pT2a–3a
Current PCa treatment: post RP
Metastatic disease: unclear
Aerobic frequency: 2 times/wk
Aerobic intensity: 45–75% of HR reserve maximum and 9–13 rated perceived exertion
Aerobic duration: 60 min
Adverse events: reported
Physical function: sit-ups, chair stand, dominant grip strength, adduction ability, back lift, and knee lift performed for 2 min
Segal et al [29]Exercise n = 82
Control n = 73
Baseline, 12 wkTumour stage: I–IV
Current PCa treatment: ADT
Metastatic disease: unclear
Resistance frequency: 3 times/wk
Resistance sets: 2
Resistance reps: 8–12
Resistance load: 60–70% of 1 RM
PCa-specific QoL: FACT-P
PCa-specific fatigue: FACT-F
Disease progression: PSA
Physical function: dynamic muscle endurance for upper and lower body
Segal et al [30]Resistance exercise n = 40
Aerobic exercise n = 40
Control n = 41
Baseline, 12 wk, 24 wkTumour stage: I–IV
Current PCa treatment: RT and ADT (61% of cohort on ADT)
Metastatic disease: none (excluded from trial)
Aerobic frequency: 3 times/wk
Aerobic intensity: up to 60% of predetermined VO2 peak for weeks 1–4, progressing to 70–75% for weeks 5–24
Aerobic duration: starting at 15 min, increased by 5 min every 3 wk to reached 45 min
Resistance frequency: 3 times/wk
Resistance sets: 2
Resistance reps: 8–12
Resistance load: 60–70% of estimated 1 RM
PCa-specific QoL: FACT-P
Adverse events: reported
PCa-specific fatigue: FACT-F
Disease progression: PSA
Physical function: VO2 peak, dynamic strength for upper and lower body
Uth et al [31]Exercise n = 29
Usual care n = 28
Baseline, 12 wkTumour stage: unclear
Current PCa treatment: ADT (previous RT)
Metastatic disease: nodal metastases, 14% of exercise and 35% of usual care group; bone metastases, 24% of exercise and 15% of usual care group
Aerobic frequency: 2–3 times/wk
Aerobic intensity: 70–100% HRmax
Aerobic duration: in weeks 1–4, football training consisted of two weekly sessions, starting with 15 min of warm-up exercises (running, dribbling, passing, shooting, balance, and muscle strength) followed by two 15-min 5–7-a-side games; in weeks 5–8, each session increased to three 15-min games after warming up; in weeks 9–12, there were three weekly training sessions of the same duration
Adverse events: reported
Physical function: VO2 peak, knee-extensor maximal strength, chair sit-to-stand test
Windsor et al [32]Exercise n = 33
Control n = 33
Baseline, 4 wk, 8 wkTumour stage: T1–2 for 51/65
Current PCa treatment: RT for all; adjuvant hormone therapy for high-risk tumours in19/66, including 10/33 in the control and 9/33 in the exercise group
Metastatic disease: unclear
Aerobic frequency: at least 3 d/wk during RT
Aerobic intensity: 60–70% of calculated HRmax
Aerobic duration: 30 min
PCa-specific fatigue: Brief Fatigue Inventory questionnaire
Winters-Stone et al [33]Exercise n = 29
Control n = 22
Baseline, 6 mo, 12 moTumour stage: unclear
Current PCa treatment: ADT for all; 45% of exercise and 50% of control group received RT; 7% of exercise and 14% of control group received CTx
Metastatic disease: 27.6% of exercise and 13.6% of control group
Resistance frequency: 3 times/wk
Resistance sets: displacement 1–10, lower body 1–2, upper body 1–2
Resistance reps: displacement 10, lower body 8–12, upper body 8–14
Resistance load: lower body and displacement 0–15% of body weight; upper body 10–15 RM
Adverse events: reported
PCa-specific fatigue: Schwartz fatigue scale
Physical function: bench press 1 RM, leg press 1 RM, chair stand, 4-m fast walk

a Participants were encouraged to supplement with exercise at home to reach 150 min/wk.

FACT-P = Functional Assessment of Cancer Therapy-Prostate; FACT-G = FACT-General; FACT-F = FACT-Fatigue; QLQ-C30 = European Organisation for Research and Treatment of Cancer (EORTC) core QoL questionnaire; QLQ-PR25 = EORTC prostate-specific module; EPIC = Expanded Prostate Cancer Index composite; IIEF = International Index of Erectile Function; CV = cardiovascular; MET = metabolic equivalent; VO2 peak = peak oxygen consumption; RM = repetition maximum; HR = heart rate; QoL = quality of life; PCa = prostate cancer; PSA = prostate-specific antigen; RT = radiation therapy; BP = blood pressure; RP = radical prostatectomy; CTx = chemotherapy.

The behaviour change techniques used primarily focused on instruction on how to perform behaviour, with practice and goals set by trainers. Three trials [18], [21], and [26] reported a more psychological approach to changing behaviours by incorporating techniques such as problem solving, social support, and client-set goals. Of interest in comparison to our previous review, significantly more studies reported that they taught generalisation of behaviour; however, association with outcome was not possible in this review owing to the small number of studies per outcome. All studies were conducted in countries categorised as high income by WHO.

3.3. Risk of bias and quality

Figure 2 shows risk-of-bias judgements made for the studies included. Supplementary File 1 describes these judgements in detail. All trials were judged to have a high risk of bias for blinding of participants given that it is not possible to blind the participant in an exercise intervention. However, we did not judge that this necessarily compromised study quality. The most common issues around high risk of bias that would impact on study quality were level of study attrition during at least one follow-up point, poor intervention adherence, lack of investigator blinding, and selective reporting bias.

3.4. Effects of interventions on primary review objectives

Seven trials involving 912 men measured cancer-specific quality of life using a tool that gave an overall/summary score that could used in a meta-analysis [18], [22], [25], [26], [27], [29], and [30]. No significant effect on this outcome was found from pooling the data from these seven trials (SMD 0.13, 95% CI –0.08 to 0.34). No statistical heterogeneity was observed (I2 46%, 95% CI 0–76%). Sensitivity analysis of studies that were judged to be of high quality [18], [22], and [30] (note that 3-mo follow-up data were used from the study by Bourke et al [18]) indicated a moderate positive effect estimate (SMD 0.33, 95% CI 0.08–0.58) with no significant heterogeneity (I2 0%, 95% CI 0–73%). Figure 3 shows a forest plot of the results.

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Fig. 3 Forest plot of (A) quality-of-life outcomes for the trials included and (B) sensitivity analysis. SD = standard deviation; SMD = standardised mean difference; CI = confidence interval; df = degrees of freedom.

Ten studies reported information on adverse events involving 685 men. Four studies reported no adverse events [20], [22], [28], and [33]. Two studies reported deaths, one due to lung cancer [23] and one in the control arm of the trial [18]. One incident of acute myocardial infarction (MI) in a participant with no previous cardiac history required hospitalisation and resuscitation after only the third day of the aerobic training protocol [30]. In the 2014 trial by Galvão et al [23], one participant in the control group with no previous history of cardiac disease had a nonfatal MI during the second half of the study, but made a full recovery. One study reported adverse electrocardiograph changes during exercise testing in terms of significant ST segment depression in three patients [25]. One study reported two fibula fractures in the intervention group [31], one of which revealed underlying peripheral neuropathy. In one study, one man in the exercise group fell while dressing at home and suffered a fractured rib [19] but was able to complete the final 2 wk of the intervention with a modified prescription. Three studies reported mixed musculoskeletal complications from pre-existing back and knee pain [23], training-induced leg cramps or back pain [25], and three minor tendon/ligament/quadriceps injuries [31] with exercise.

3.5. Secondary review outcomes

Positive beneficial effects were observed for cancer-specific fatigue, lower body strength, and aerobic fitness. Supplementary File 2 describes the meta-analysis for secondary review outcomes. No effects on cardiovascular health or disease progression outcomes were observed. A borderline positive effect on sexual activity was evident (p = 0.05) but there was no effect on sexual function.

3.6. Planned subgroup analysis and CALO-RE taxonomy for behaviour change technique

Supplementary File 3 describes planned subgroup outcomes and results for the CALO-RE taxonomy data.

3.7. Discussion

Sixteen trials involving 1574 men with prostate cancer were included in the review. From sensitivity analysis, we found high quality evidence that exercise interventions can improve cancer specific quality of life and cancer specific fatigue in men with prostate cancer at up to 6 mo of follow-up (with moderate beneficial effect estimate). There were no deaths attributable to exercise interventions. Other serious adverse events as a result of exercise (eg, MI) were equivalent to those seen in controls. In one trial that used a competitive contact sport as the intervention (football) a high rate of lower limb fracture was seen in the intervention arm. More frequently, soft tissue complications such as minor musculoskeletal sprains and strains were reported for intervention groups in more controlled settings. No effect on cardiovascular health or disease progression outcomes was observed. Positive beneficial effects were evident for lower body strength and aerobic fitness. A borderline positive effect for sexual activity should be viewed with caution as the data were taken from two small trials.

We specifically selected only trials that reported key metrics for exercise prescription to support reproducibility. In doing so, we synthesised data for 11 more RCTs than a recent systematic review [17]. Furthermore, to the best of our knowledge, this is the first review to report a quantified meta-analysis of effect estimates for key patient outcomes such as cancer-specific quality of life and fatigue. Our review offers the most up-to-date evidence on adverse effects systematically gathered from an exhaustive review of RCTs. Our meta-analysis of improvements in sexual activity is unique but should be interpreted with caution as the data are taken from just two available trials.

Much of the uncertainty in judging trial bias came from poor reporting around randomisation procedures in terms of both sequence generation and allocation concealment; however, no trial was judged to be at high risk of bias. As for other systematic reviews undertaken by our group evaluating exercise in cancer populations [11], we did not penalise trials for being at high risk of performance bias for blinding of participants. Furthermore, bias is not likely because trials with poor adherence to the exercise intervention commonly have no effect on clinical outcomes [24] and [26]. It is not possible to blind participants to taking part in an exercise intervention. Some trials have suggested this should be addressed by sham exercise conditions. However, given that aerobic exercise recommendation guidelines for survivors are freely available on the Internet (eg, from the American Cancer Society) and are often positively promoted by care providers and cancer support charities (eg, Macmillan), the legitimacy of any sham condition seems dubious.

As for any behaviour change intervention, requiring participants to maintain an increase in exercise behaviour can be very challenging. Poor adherence to the intervention prescription means that the intended dose of the intervention was not received. This creates obvious problems when trying to understand the true effect of the intervention on trial outcomes. The major reasons why trials were judged to have a high risk of bias were attrition and adherence biases, which we judged would have a substantial impact on the quality of evidence. Selective reporting bias—particularly with regard to adverse events—was the other most prevalent issue.

Three studies reported data over up to 12 mo of follow-up [23], [25], and [33], but all were judged to be at high risk of bias. Thus, for harmonisation with other high-quality evidence where possible, we only extracted 6-mo data for use in meta-analyses. Therefore, the long-term durability of some of the key findings of this review is uncertain. The studies reported here involved a mixture of T-stage cancers, with some studies including men with T1–4 disease [29] and [30]. This limits the certainty for recommendations stratified by disease stage (indeed we were not able to conduct planned subgroup analyses). This is also true for treatment type, although several meta-analyses of high-quality studies are largely representative of men on ADT. High-quality studies are required for men with earlier disease stages undergoing radical treatment. No evidence was found for men undergoing chemotherapy (apart from a very small minority of the cohort in two trials [26] and [33]). Furthermore, the value of exercise interventions among men on newer hormone treatments such as enzalutamide is not clear. In addition, we did not find any evidence for men undergoing more recent radical innovations such as high-intensity focused ultrasound.

All the studies were taken from peer-reviewed journals as we were unable to locate any unpublished results, despite contacting internationally recognised experts in the field. We found some evidence that exercise might have a beneficial impact on sexual activity, but in the absence of concurrent improvements in sexual function, the value of this finding to patients is uncertain. It should also be noted that the majority of these interventions took place in a controlled environment.

All the studies were conducted in countries classified as high income by WHO. No evidence was derived from developing countries, and it is uncertain whether the resources and/or infrastructure required for some of the interventions included in this review would be available in these parts of the world. Very few trials reported baseline ethnicity data, but the data available seem to indicate that the large majority of studies involved Caucasian men. Given that prostate cancer disproportionately affects other ethnic groups (eg, black men), it should be noted that these men are underrepresented in these trials. We were not able to identify any trials that satisfied our pragmatic design criteria, so these data should be considered to address the efficacy of the interventions rather than the effectiveness of health services. Our review objective to assess the effect of exercise interventions on disease progression was difficult to achieve. We were only able to undertake a synthesis of prostate-specific antigen data measured as a secondary outcome in underpowered trials. This finding should be viewed with much caution. Trials that evaluate the impact of exercise on dichotomous outcomes such as progression-free survival or overall mortality would be an excellent addition to the field.

The mechanisms by which exercise interventions improve cancer-specific quality of life remain speculative. Any formal analysis of such mechanisms was beyond the scope of this review. Improvements in fatigue, lower limb function, and exercise capacity potentially occur because of well-established adaptations associated with exercise training, such as improvements in cardiac output, metabolic adaptations, and recruitment of skeletal muscle motor units. Exercise has also been linked to improvements in negative physiological changes associated with advanced cancer, such as cachexia [42]. To what extent this contributes to improved physical functioning and quality of life is uncertain. A substantive psychological benefit related to empowerment and self-efficacy could be a factor. Formal mediator and moderator studies would be useful to address this uncertainty. A number of studies included dietary interventions as part of a lifestyle intervention. Although not formally analysed, a minimal impact on dietary outcomes was reported in most studies, suggesting that the predominant effector in the intervention was the exercise component.

The key recommendations from this review are that treating clinicians and guideline bodies should be aware of the level 1 evidence that exercise interventions are efficacious in improving cancer-specific quality of life, fatigue, and exercise capacity in men with prostate cancer. Much of the high-quality evidence comes from trials involving men on ADT. There is very early evidence (that should be interpreted with caution owing to limited number of trials) that exercise could also be useful in improving sexual activity. Trials are ongoing to look at these outcomes [43]. Any exercise programme should be individually tailored with consideration of the individual's physical capabilities and limitations [11]. The treating clinician should play a role in directly advocating the benefits of exercise to men with prostate cancer and leading the multidisciplinary team in the referral process. Where possible, men should be directed to relevant exercise referral schemes, for example in the community. Ideally, support for behavioural change should also be offered to maximise adherence and should include periodic re-evaluation of exercise prescription in terms of either tapering or progression. Effectiveness and cost-effectiveness data for these interventions when integrated into health care services would be informative.

4. Conclusions

There is level 1 evidence that exercise interventions are efficacious in improving cancer-specific quality of life, fatigue, and exercise capacity in men with prostate cancer. The high-quality evidence comes mainly from men with advanced disease on ADT. Adverse events such as minor soft-tissue injuries (sprains and strains) can be expected in a minority of men but can also be mitigated by properly tailored exercise prescription and progression around individual capabilities and existing comorbidities. We found no evidence that exercise improved cardiovascular health but we were limited to synthesising evidence for blood pressure only. Effectiveness and cost-effectiveness data for these interventions when integrated into health care services would be informative.


Author contributions: Liam Bourke had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Bourke, Rosario.

Acquisition of data: Bourke, Amed.

Analysis and interpretation of data: Bourke, Smith, Steed, Hooper, Rosario.

Drafting of the manuscript: Bourke.

Critical revision of the manuscript for important intellectual content: Bourke, Smith, Steed, Hooper, Carter, Catto, Albertsen, Tombal, Payne, Rosario.

Statistical analysis: Bourke, Hooper.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: None.

Other: None.

Financial disclosures: Liam Bourke certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Peter C. Albertsen has received support from the Blue Cross Blue Shield Technology Assessment Committee for reviewing items related to urology; support from Ferring Pharmaceuticals to review data; payment for expert testimony for cases involving prostate cancer and general urology; National Institutes of Health grant support for studies related to prostate cancer; support for serving as a critique panel member at Jackson Hole Seminars in 2014; and support for participating in the 8th Engadin Prostate Cancer Symposium. Liam Bourke and Derek J. Rosario receive funding from Cancer Research UK and the National Institute for Health Research to evaluate the role of exercise in men with prostate cancer. Richard Hooper receives funding from Cancer Research UK to evaluate the role of exercise in men with prostate cancer. Heather A. Payne has received consultancy and lecturer fees from AstraZeneca, Astellas, Janssen, Ferring, Ipsen, Takeda, Sanofi Aventis, and Sandoz; review preparation fees from AstraZeneca, Janssen, Astellas, and Ipsen; payment for development of educational presentations from AstraZeneca, Astellas, Janssen, Ferring, Ipsen, Sandoz, and Sanofi Aventis; and travel/accommodation/meeting expenses from Astellas, Ferring, AstraZeneca, Janssen, and Takeda. Liz Steed has received grant support from the National Institute for Health Research (RP-PG-0609-10181) and Health Technology Assessments, and book royalties from Open University Press. Bertrand Tombal has received grant support from Ferring, Astellas, and AstraZeneca, and consulting fees or honorarium support from Ferring and AstraZeneca; consultancy fees from Amgen, Sanofi, and Bayer; support for expert testimony from Dendreon; and investigator or advisor fees from Medivation. James Catto, Dianna Smith, and Anouska Carter have nothing to disclose.

Funding/Support and role of the sponsor: None.

Acknowledgments: The team would like to thank Mediah Amed for her hard work in devising the strategy for the database searches and adapting the Medline search to other search engines. We would also like to thank the Cochrane Urology editorial group for their assistance in developing the protocol.

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Footnotes

a Health and Wellbeing Research Institute, Centre for Sport and Exercise Science, Sheffield Hallam University, Sheffield, UK

b Geography & Environment, University of Southampton, Southampton, UK

c Centre for Primary Care and Public Health, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

d Academic Urology Unit and Institute for Cancer Studies, The Medical School, University of Sheffield, Sheffield, UK

e Department of Surgery, Division of Urology, University of Connecticut Health Center, Farmington, CT, USA

f University Clinics Saint Luc/Catholic University of Louvain, Brussels, Belgium

g Department of Oncology, University College London Hospitals, London, UK

h Department of Oncology, University of Sheffield, Sheffield, UK

Corresponding author. Health and Wellbeing Research Institute, Centre for Sport and Exercise Science, Sheffield Hallam University, Sheffield S10 2BP, UK. Tel. +44 114 2252374; Fax: +44 12345678.

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