Exercise improves quality of life in androgen deprivation therapy-treated prostate cancer: systematic review of randomised controlled trials

in Endocrine-Related Cancer
Authors:
Laisa Teleni School of Nursing, Faculty of Health Sciences and Medicine, West Moreton Hospital and Health Service, Department of Pharmacy, Oncology Pharmacy, Department of Nutrition and Dietetics, Department of Urology, Australian Prostate Cancer Research Centre – Queensland, Department of Diabetes and Endocrinology, School of Medicine, Division of Cancer Services, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
School of Nursing, Faculty of Health Sciences and Medicine, West Moreton Hospital and Health Service, Department of Pharmacy, Oncology Pharmacy, Department of Nutrition and Dietetics, Department of Urology, Australian Prostate Cancer Research Centre – Queensland, Department of Diabetes and Endocrinology, School of Medicine, Division of Cancer Services, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia

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Raymond J Chan School of Nursing, Faculty of Health Sciences and Medicine, West Moreton Hospital and Health Service, Department of Pharmacy, Oncology Pharmacy, Department of Nutrition and Dietetics, Department of Urology, Australian Prostate Cancer Research Centre – Queensland, Department of Diabetes and Endocrinology, School of Medicine, Division of Cancer Services, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
School of Nursing, Faculty of Health Sciences and Medicine, West Moreton Hospital and Health Service, Department of Pharmacy, Oncology Pharmacy, Department of Nutrition and Dietetics, Department of Urology, Australian Prostate Cancer Research Centre – Queensland, Department of Diabetes and Endocrinology, School of Medicine, Division of Cancer Services, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia

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Alexandre Chan School of Nursing, Faculty of Health Sciences and Medicine, West Moreton Hospital and Health Service, Department of Pharmacy, Oncology Pharmacy, Department of Nutrition and Dietetics, Department of Urology, Australian Prostate Cancer Research Centre – Queensland, Department of Diabetes and Endocrinology, School of Medicine, Division of Cancer Services, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
School of Nursing, Faculty of Health Sciences and Medicine, West Moreton Hospital and Health Service, Department of Pharmacy, Oncology Pharmacy, Department of Nutrition and Dietetics, Department of Urology, Australian Prostate Cancer Research Centre – Queensland, Department of Diabetes and Endocrinology, School of Medicine, Division of Cancer Services, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia

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Elisabeth A Isenring School of Nursing, Faculty of Health Sciences and Medicine, West Moreton Hospital and Health Service, Department of Pharmacy, Oncology Pharmacy, Department of Nutrition and Dietetics, Department of Urology, Australian Prostate Cancer Research Centre – Queensland, Department of Diabetes and Endocrinology, School of Medicine, Division of Cancer Services, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
School of Nursing, Faculty of Health Sciences and Medicine, West Moreton Hospital and Health Service, Department of Pharmacy, Oncology Pharmacy, Department of Nutrition and Dietetics, Department of Urology, Australian Prostate Cancer Research Centre – Queensland, Department of Diabetes and Endocrinology, School of Medicine, Division of Cancer Services, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia

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Ian Vela School of Nursing, Faculty of Health Sciences and Medicine, West Moreton Hospital and Health Service, Department of Pharmacy, Oncology Pharmacy, Department of Nutrition and Dietetics, Department of Urology, Australian Prostate Cancer Research Centre – Queensland, Department of Diabetes and Endocrinology, School of Medicine, Division of Cancer Services, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
School of Nursing, Faculty of Health Sciences and Medicine, West Moreton Hospital and Health Service, Department of Pharmacy, Oncology Pharmacy, Department of Nutrition and Dietetics, Department of Urology, Australian Prostate Cancer Research Centre – Queensland, Department of Diabetes and Endocrinology, School of Medicine, Division of Cancer Services, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia

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Warrick J Inder School of Nursing, Faculty of Health Sciences and Medicine, West Moreton Hospital and Health Service, Department of Pharmacy, Oncology Pharmacy, Department of Nutrition and Dietetics, Department of Urology, Australian Prostate Cancer Research Centre – Queensland, Department of Diabetes and Endocrinology, School of Medicine, Division of Cancer Services, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
School of Nursing, Faculty of Health Sciences and Medicine, West Moreton Hospital and Health Service, Department of Pharmacy, Oncology Pharmacy, Department of Nutrition and Dietetics, Department of Urology, Australian Prostate Cancer Research Centre – Queensland, Department of Diabetes and Endocrinology, School of Medicine, Division of Cancer Services, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia

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Alexandra L McCarthy School of Nursing, Faculty of Health Sciences and Medicine, West Moreton Hospital and Health Service, Department of Pharmacy, Oncology Pharmacy, Department of Nutrition and Dietetics, Department of Urology, Australian Prostate Cancer Research Centre – Queensland, Department of Diabetes and Endocrinology, School of Medicine, Division of Cancer Services, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
School of Nursing, Faculty of Health Sciences and Medicine, West Moreton Hospital and Health Service, Department of Pharmacy, Oncology Pharmacy, Department of Nutrition and Dietetics, Department of Urology, Australian Prostate Cancer Research Centre – Queensland, Department of Diabetes and Endocrinology, School of Medicine, Division of Cancer Services, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia
School of Nursing, Faculty of Health Sciences and Medicine, West Moreton Hospital and Health Service, Department of Pharmacy, Oncology Pharmacy, Department of Nutrition and Dietetics, Department of Urology, Australian Prostate Cancer Research Centre – Queensland, Department of Diabetes and Endocrinology, School of Medicine, Division of Cancer Services, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia

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Men receiving androgen deprivation therapy (ADT) for prostate cancer (PCa) are likely to develop metabolic conditions such as diabetes, cardiovascular disease, abdominal obesity and osteoporosis. Other treatment-related side effects adversely influence quality of life (QoL) including vasomotor distress, depression, anxiety, mood swings, poor sleep quality and compromised sexual function. The objective of this study was to systematically review the nature and effects of dietary and exercise interventions on QoL, androgen deprivation symptoms and metabolic risk factors in men with PCa undergoing ADT. An electronic search of CINAHL, CENTRAL, Medline, PsychINFO and reference lists was performed to identify peer-reviewed articles published between January 2004 and December 2014 in English. Eligible study designs included randomised controlled trials (RCTs) with pre- and post-intervention data. Data extraction and assessment of methodological quality with the Cochrane approach was conducted by two independent reviewers. Seven exercise studies were identified. Exercise significantly improved QoL, but showed no effect on metabolic risk factors (weight, waist circumference, lean or fat mass, blood pressure and lipid profile). Two dietary studies were identified, both of which tested soy supplements. Soy supplementation did not improve any outcomes. No dietary counselling studies were identified. No studies evaluated androgen-deficiency symptoms (libido, erectile function, sleep quality, mood swings, depression, anxiety and bone mineral density). Evidence from RCTs indicates that exercise enhances health- and disease-specific QoL in men with PCa undergoing ADT. Further studies are required to evaluate the effect of exercise and dietary interventions on QoL, androgen deprivation symptoms and metabolic risk factors in this cohort.

Abstract

Men receiving androgen deprivation therapy (ADT) for prostate cancer (PCa) are likely to develop metabolic conditions such as diabetes, cardiovascular disease, abdominal obesity and osteoporosis. Other treatment-related side effects adversely influence quality of life (QoL) including vasomotor distress, depression, anxiety, mood swings, poor sleep quality and compromised sexual function. The objective of this study was to systematically review the nature and effects of dietary and exercise interventions on QoL, androgen deprivation symptoms and metabolic risk factors in men with PCa undergoing ADT. An electronic search of CINAHL, CENTRAL, Medline, PsychINFO and reference lists was performed to identify peer-reviewed articles published between January 2004 and December 2014 in English. Eligible study designs included randomised controlled trials (RCTs) with pre- and post-intervention data. Data extraction and assessment of methodological quality with the Cochrane approach was conducted by two independent reviewers. Seven exercise studies were identified. Exercise significantly improved QoL, but showed no effect on metabolic risk factors (weight, waist circumference, lean or fat mass, blood pressure and lipid profile). Two dietary studies were identified, both of which tested soy supplements. Soy supplementation did not improve any outcomes. No dietary counselling studies were identified. No studies evaluated androgen-deficiency symptoms (libido, erectile function, sleep quality, mood swings, depression, anxiety and bone mineral density). Evidence from RCTs indicates that exercise enhances health- and disease-specific QoL in men with PCa undergoing ADT. Further studies are required to evaluate the effect of exercise and dietary interventions on QoL, androgen deprivation symptoms and metabolic risk factors in this cohort.

Introduction

Prostate cancer (PCa) is the second most commonly diagnosed cancer in men after lung cancers. According to the International Agency for Research on Cancer, more than 1.1 million cases were diagnosed in 2012, with highest incidence rates in Australia, New Zealand and Northern America followed by Western and Northern Europe (Ferlay et al. 2013).

Managing treatment-related morbidity is increasingly important for men undergoing androgen deprivation therapy (ADT). In hormone-sensitive PCa, androgens can stimulate the growth of cancer cells. These effects can be blocked or reduced through the use of surgical or medical ADT, shrinking the tumour or slowing tumour growth. This therapy is common for the management of metastatic PCa and as an adjuvant therapy in localised PCa. With the exception of primary ADT in men with localised PCa (Sammon et al. 2015), the use rates of ADT in Australia and the USA are rising, with this therapy being offered earlier in the cancer trajectory (Grossmann et al. 2011). Compared with no treatment, ADT is associated with an increased risk in non-cancer mortality in men over 66 years with localised disease (Abdollah et al. 2015). These men are more likely to develop metabolic conditions, such as diabetes, cardiovascular disease and abdominal obesity, or experience further life-limiting morbidities such as osteoporosis. Treatment-related side effects include vasomotor distress, depression and anxiety, mood swings, poor sleep quality and compromised libido and erectile function leading to diminished function and quality of life (QoL; Grossmann et al. 2011).

Evidence indicates that the effects of ADT can be attenuated through specific health behaviours. The current ‘Nutrition and physical activity guidelines for cancer survivors’ (Rock et al. 2012) recommend that for all cancers, nutrition, physical activity, stress and sleep assessment should commence as soon as possible after diagnosis, and account for current and anticipated preferences, symptoms and lifestyle needs. In cancer survivors, exercise has been shown to improve cardiovascular fitness, muscle strength, body composition, fatigue, anxiety, depression and some aspects of QoL (Rock et al. 2012). Similarly, an individualised multidisciplinary approach including dietetics and exercise physiotherapy was recommended in the joint consensus statement from the Endocrine Society of Australia, the Australian and New Zealand Bone and Mineral Society, and the Urological Society of Australia and New Zealand (Grossmann et al. 2011).

In a previous meta-analysis, Chipperfield et al. (2014) evaluated the effect of physical activity on outcomes such as depression, anxiety, cognitive function and QoL while excluding studies of other outcomes or those including dietary interventions. There are no meta-analyses of high level evidence that evaluate the effect of dietary and/or exercise interventions in preventing or ameliorating ADT-related metabolic and other side effects beyond those relating to QoL.

The aim of this review is to examine the effectiveness of dietary and/or exercise in preventing, modifying or managing the effects of ADT in men with PCa. Specifically, the primary objective is to investigate the effect of these interventions on QoL, and the secondary objectives are to evaluate the effects on androgen deprivation symptoms and metabolic risk factors.

Materials and methods

Eligibility criteria

To address the review objectives, we included randomised controlled trials (RCTs) of adult male participants (>18 years of age) with PCa undergoing ADT. Studies with participants not undergoing ADT, and whose data were reported separately, were included. Interventions of interest compared aerobic exercise, resistance exercise and/or dietary counselling with standard care or no treatment. Dietary supplements were compared with matched placebo. Primary outcome measures were health-related QoL (overall physical or mental health) and disease-specific QoL (QoL in the context of PCa) as measured by validated questionnaires. Secondary outcome measures of androgen deprivation symptoms were dual X-ray absorptiometry (DXA) scans of bone mineral density, vasomotor symptoms, insomnia and mood swings, weight gain, depression and anxiety. Secondary outcome measures of metabolic risk factors were fasting glucose, fasting lipid profile and/or fat mass measured by DXA.

Search methods

A search of Medline was undertaken (Table 1) to identify relevant text words and index terms used to describe the articles. A second search of CINAHL, Cochrane CENTRAL, Medline and PsychINFO was conducted using identified text words and index terms. Reference lists of relevant articles were hand searched for additional studies that met the inclusion criteria. Only articles published in the English language between 2004 and 2014 were included.

Table 1

Mesh and keywords used to search for publications in Ovid MEDLINE from 1946 to present

SubjectMeSH and keywords
Prostate cancer‘Prostatic Neoplasms’ (MeSH) or prostate cancer
Dietary interventions‘Diet’ (MeSH) or ‘Diet Therapy’ (MeSH)
Dietary supplements‘Isoflavones’ (MeSH) or isoflavones or ‘Flax’ (MeSH) or flaxseed or ‘Soy Milk’ (MeSH) or ‘Soy Foods’ (MeSH)/or soy or ‘Soybean Proteins’ (MeSH) or ‘Carotenoids’ (MeSH) or ‘Vitamin E’ (MeSH) or lycopene or ‘Folic Acid’ (MeSH) or folate or ‘Dietary Supplements’ (MeSH) or ‘Complementary Therapies’ (MeSH) or ‘Naturopathy’ (MeSH)
Fruit, vegetables and fibre‘Fruit’ (MeSH) or fruit or ‘Vegetables’ (MeSH) or vegetables or ‘Dietary Fiber’ (MeSH) or dietary fibre
Dairy, meat and fat‘Dairy Products’ (MeSH) or dairy or ‘Calcium, Dietary’ (MeSH) or ‘Meat’ (MeSH) or ‘Dietary Fats’ (MeSH)
Exercise interventions‘Exercise’ (MeSH) or ‘physical endurance’ (MeSH) or ‘Exercise Therapy’ (MeSH)
Search limitsEnglish language, 2004–current, all adult (19+ years)

Data collection and extraction

One author (L Teleni) analysed the titles and abstracts from the searches. Full text was sought for studies that both potentially met the eligibility criteria and, where eligibility could not be determined due to insufficient information. Two authors (A L McCarthy and L Teleni) independently assessed eligibility from the full text; any disagreements were resolved by discussion and consensus.

Two review authors (A L McCarthy and L Teleni) independently extracted data from each study using a template developed by the authors for the purpose of the review. Data extracted included descriptions of general study information, methods, participants, intervention and comparator, outcomes and length of follow-up, study results for each outcome and time of assessment. Any discrepancies between review authors were discussed and corrected by consulting the original article. For studies published more than once, data was collated. Where data for an outcome was reported more than once, the data from the publication with the largest study population was used.

Assessment of risk or bias

Two review authors (A L McCarthy and L Teleni) independently assessed the risk of bias of the included studies using the Cochrane Collaboration's tool for assessing risk of bias (Higgins & Green 2011). This tool assesses random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data and selective reporting. Each study was graded according to low, high or unclear risk of bias.

Statistical analysis

Where possible, data were used to calculate the mean difference (MD) using the mean for continuous outcomes with number of participants as the denominator for each outcome. Where different scales were used, the standardised MD (SMD) was calculated. Where the s.d. of the change scores was not given, they were imputed using the s.d. from similar studies (Higgins & Green 2011).

Obvious clinical heterogeneity was assessed by comparing populations, settings, interventions and outcomes before deciding whether it was appropriate to pool studies. Where pooling was undertaken, statistical heterogeneity was assessed with the I2 statistic. Where it was reasonable to assume a single pooled effect (I2<50%), a fixed-effect model was used. Where variation in populations and interventions or substantial heterogeneity (I2≥50%) was evident, a random-effects model was used (DerSimonian & Laird 1986). Review Manager 5.3 was used for statistical analysis (RevMan version 5.3, The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark). Where statistical pooling was not possible, findings are presented in narrative form.

Results

Of the 246 potential articles, 13 met the inclusion criteria (Fig. 1), providing data for nine intervention studies. Intervention characteristics and key findings are summarised in Table 2. The median sample size was 100 (33–121) participants with median intervention duration of 12 (12–24) weeks. Although participant eligibility criteria were similar, cancer stage and treatment varied between studies, as did the depth of information provided about these variables. Only three of the nine studies provided details on the duration of ADT (Fig. 2. As expected for lifestyle-based interventions, the largest risk of bias was lack of blinding of participants.

Figure 1
Figure 1

PRISMA flowchart.

Citation: Endocrine-Related Cancer 23, 2; 10.1530/ERC-15-0456

Table 2

Study characteristics and key findings

ReferencesDesignSampleDuration of ADTIntervention duration and frequencyIntervention form and doseControlKey findings intervention vs control
Bourke et al. (2011)Two-arm50≥6 months12 weeks; supervised 2 days/week (weeks 1–6)–1 day/week (weeks 7–12), unsupervised 1 day/week (weeks 1–6)–2 days/week (weeks 7–12); optional dietary counselling 1 day/fortnight30 min supervised AET at 55–85% predicted MHR or 11–15 Borg Rating of Perceived Exertion Scale+two to four sets supervised RET+30 min unsupervised exercise+optional 15–20 min small group dietary counsellingUsual care↔ HRQoLa

↔ DQoLb

↓ Fatiguec

↔ BW, BMI or WHR

↔ Systolic or diastolic BP
Bourke et al. (2014)Two-arm10033±33 months (intervention), 30±30 months (control)12 weeks; supervised 2 days/week (weeks 1–6)–1 day/week (weeks 7–12), unsupervised 1 day/week (weeks 1–6)–2 days/week (weeks 7–12); dietary counselling 1 day/fortnight30 min supervised AET at 55–75% predicted MHR or 11–13 Borg Rating of Perceived Exertion Scale+two to four sets of 8–12 repetitions of supervised RET (60% 1 RM)+30 min unsupervised exercise+20 min small group dietary counsellingUsual care↑ DQoLb

↑ Fatiguec

↔ BW or BMI

↔ Systolic or diastolic BP
Culos-Reed et al. (2010)Two-arm100≥6 months16 weeks; supervised booster session 1 day/week unsupervised 3–5 days/weekSupervised and unsupervised exercise sessions of walking, stretching, ‘light’ RET. Supervised group sessions of 60 min exercise+30 min education. Unsupervised ‘moderate’ exerciseUsual care↔ QoLd

↔ Fatiguee

↔ Depressionf

↔ Hormone symptomsg

↔ BMI

↓ WC

↔ Systolic or diastolic BP
Galvao et al. (2010) and Cormie et al. (2013)Two-arm57≥2 months12 weeks; supervised 2 days/week+unsupervised 150 min/weekTwo to four sets of supervised RET (12–6 RM) in small groups+15–20 min supervised AET at 65–80% MHR and 11–13 Borg Rating of Perceived Exertion Scale+unsupervised AETUsual care↑ QoLh

↔ Libido, urinary or bowel symptomsi

↔ BW

↑ kg LBMj

↔ kg FM or % FMj

↔ Glucose, TC, TG, LDL or HDL
Galvao et al. (2014)Two-arm100Not reported24 weeks; supervised 2 days/week, unsupervised 2 days/weekSupervised, small group, two to four sets RET (12–16 RM)+20–30 min AET at 70–85% MHR and 11–13 Borg Rating of Perceived Exertion Scale+unsupervised AETUsual care+pedometer and modified educational booklet↔ QoLh

↔ BW or WC

↔ kg LBM, kg FM or % FMj

↓ TC

↑ HDL

↔ Glucose, TG or LDL

↔ Systolic or diastolic BP
Segal et al. (2009) and Alberga et al. (2012)Three-arm121102.9±166.3 days24 weeks; 3 days/weekTwo sets supervised RET, 8–12 repetitions at 60–70% of 1 RM

15–45 min supervised AET at 50–60%–70–75% MHR
Usual careRET:

↔ HRQoLa

↔ DQoLb

↓ Fatiguec

↔ BW or BMI

↓ % FMj

↑ kg LBMj

AET:

↔ HRQoLa

↔ DQoLb

↔ Fatiguec

↔ BW

↓ BMI

↔ kg LBM or % FMj
Sharma et al. (2009) and Napora et al. (2011)Two-arm33≥3 months12 weeks; 1/day20 g powder soy protein 160 mg of total isoflavones (64 mg genistein, 63 mg daidzein and 34 mg glycitein) mixed in beverage20 g powder whole milk↔ HRQoLd

↔ BW or BMI

↔ Libido or erectile functionk,l

↔ Sleep qualitym

↑ Hot flashesn

↔ Glucose, TC, TG and HDL or LDL
Uth et al. (2014)Two-arm57≥6 months12 weeks; 2 days/week (weeks 1–8) and 3 days/week (weeks 9–12)15 min warm up+two to three 15-min football gamesUsual care↑ kg LBMj

↔ kg FM or % FMj

↔ WHR
Vitolins et al. (2013)Four-arm12012 weeks; 1 dayPlacebo venflaxine+20 g powder soy protein (160 mg isoflavones)Placebo venflaxine+20 g milk powder↑ HRQoLa

↑ DQOLb

↔ Hot flashesg

ADT, androgen deprivation therapy; RET, resistance exercise training; AET, aerobic exercise training; RM, repetition maximum; MHR, maximal heart rate; HRQoL, health-related quality of life; DQoL, disease-specific quality of life; BW, body weight; WHR, waist:hip ratio; LBM, lean body mass; FM, fat mass; BP, blood pressure; WC, waist circumference; TC, total cholesterol; TG, triglycerides.

FACT-G, Functional Assessment of Cancer Therapy–general.

FACT-P, FACT–prostate.

FACT-F, FACT–fatigue.

EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer quality of life questionnaire.

FSS, fatigue.

CES-D, Centers for Epidemiologic Studies–Depression.

HFSSS, Hot Flash Symptom Severity Score.

SF-36, 36-Item Short-Form Health Survey, general score.

EORTC QLQ-PR25, EORTC Prostate Cancer-Specific Quality of Life Questionnaire.

DXA, dual X-ray absorptiometry.

Watts questionnaire.

Index of Erectile Function.

Epsworth Sleepiness Scale.

Blatt–Kupperman.

Figure 2
Figure 2

Risk of bias summary. Red (−), high risk of bias; yellow (?), unclear risk of bias; green (+) low risk of bias.

Citation: Endocrine-Related Cancer 23, 2; 10.1530/ERC-15-0456

There were also studies that lacked adequate information for domains of risk of bias assessment. Lack of details pertaining to both random sequence generation and allocation of concealment potentially introduced selection bias. Where studies failed to report blinding of outcome assessors, they introduced potential detection bias. In addition, incomplete outcome data and selective reporting may have increased the risk of attrition and reporting bias.

Interventions

Seven RCTs investigated the effects of exercise on QoL, androgen deprivation symptoms and/or metabolic risk factors in men with PCa (Segal et al. 2009, Culos-Reed et al. 2010, Galvao et al. 2010, 2014, Bourke et al. 2011, 2014, Alberga et al. 2012, Cormie et al. 2013, Uth et al. 2014). Four studies included intervention groups that combined resistance exercise training (RET) and aerobic exercise training (AET) (Galvao et al. 2010, 2014, Bourke et al. 2011, 2014), two studies used only RET (Segal et al. 2009, Culos-Reed et al. 2010, Alberga et al. 2012), one study used AET (Segal et al. 2009, Alberga et al. 2012) and one used football training sessions (Uth et al. 2014). Participants in the interventions involving AET, trained at an intensity ranging from 55 to 85% of maximal heart rate or 11–15 points on the Borg Rating of Perceived Exertion Scale. Most studies of RET did not report exercise intensity. Of those that did, participants trained at 60–70% of one repetition maximum.

Two dietary RCTs of 99 participants investigated the efficacy of 12 weeks of soy supplementation on QoL, androgen deprivation symptoms or metabolic risk factors in men with PCa (Sharma et al. 2009, Napora et al. 2011, Vitolins et al. 2013). One study had four treatment groups randomising venlafaxine and venlafaxine placebo as well as soy and soy placebo (Vitolins et al. 2013). For this review, we only included the treatment groups where venlafaxine placebos were used so as to compare the effects of soy supplementation.

Quality of life

Health-related QoL was reported in five exercise studies of 427 participants (Culos-Reed et al. 2010, Galvao et al. 2010, 2014, Bourke et al. 2011, Alberga et al. 2012). Disease-specific QoL was reported in three exercise studies of 271 participants (Bourke et al. 2011, 2014, Alberga et al. 2012). There was no significant clinical or statistical heterogeneity (I2=0%) and the overall risk of bias was low. Quantitative analysis showed that exercise improved health-related QoL (SMD=0.29; 95% CI=0.10–0.49) and disease-specific QoL (SMD=0.36; 95% CI=0.11–0.61) in men with PCa undergoing ADT (Figs 3 and 4 respectively).

Figure 3
Figure 3

Forest plot of comparison: exercise vs usual care on health-related quality of life.

Citation: Endocrine-Related Cancer 23, 2; 10.1530/ERC-15-0456

Figure 4
Figure 4

Forest plot of comparison: exercise vs usual care on disease-specific quality of life.

Citation: Endocrine-Related Cancer 23, 2; 10.1530/ERC-15-0456

Health-related QoL was reported in both dietary intervention studies. There was no significant clinical or statistical heterogeneity (I2=0%) and the risk of bias was low. Soy supplementation did not significantly improve health-related QoL (SMD=0.01; 95% CI=−0.38 to 0.41). Only Vitolins et al. (2013) evaluated disease-specific QoL, reporting that soy supplementation significantly improved FACT-P global score vs placebo (112.5±6.0 vs 103.8±6.2, P=0.048).

Androgen deprivation symptoms

No exercise intervention evaluated libido, erectile function, sleep quality and insomnia, mood swings, depression or anxiety or bone mineral density. Both dietary intervention studies evaluated the effect of soy supplementation on vasomotor distress. Sharma et al. (2009) reported a significant difference in hot flash scores between groups, but within-group analysis showed no significant improvement in vasomotor distress score in either the placebo or the soy arms due to the imbalance in scores at baseline. Similarly, Vitolins et al. (2013) found soy supplementation did not significantly improve hot flash number, severity or hot flash score vs placebo. One dietary intervention study evaluated libido, erectile function and sleep quality but found no significant improvements with soy supplementation (Sharma et al. 2009, Napora et al. 2011). No dietary studies evaluated insomnia, mood swings, depression, anxiety or bone mineral density.

Metabolic risk factors

Four exercise intervention studies totalling 310 participants evaluated the effect of exercise on body weight. There was no significant clinical or statistical heterogeneity (I2=0%) and the overall risk of bias was low. Quantitative analysis showed that exercise did not significantly improve total body weight (MD=0.26; 95% CI=−2.40 to 2.93; Galvao et al. 2010, 2014, Bourke et al. 2011, 2014). One exercise intervention study evaluated waist:hip ratio, but showed no differences between the intervention and control groups (Bourke et al. 2011). Similarly, exercise did not significantly improve waist circumference measures, which were reported in two studies with a combined total of 200 participants (MD=−0.38; 95% CI=2.97 to 2.22; Culos-Reed et al. 2010, Galvao et al. 2014). Body composition, as measured by DXA, was reported in seven exercise intervention studies. There was no significant clinical or statistical heterogeneity (I2=0%) and the overall risk of bias was low. Exercise did not significantly improve any body composition measure including lean body mass (MD=−0.20; 95% CI=−1.72 to 1.32; Galvao et al. 2010, 2014, Alberga et al. 2012, Uth et al. 2014), total fat mass (MD=−0.61; 95% CI=−2.48 to 1.26; Galvao et al. 2010, 2014, Uth et al. 2014) or percentage fat mass (MD=−0.71; 95% CI=−1.96 to 0.55; Galvao et al. 2010, 2014, Alberga et al. 2012, Uth et al. 2014).

One dietary intervention study evaluated body weight and BMI but found no significant improvements with soy supplementation (Sharma et al. 2009, Napora et al. 2011). Neither dietary intervention evaluated the effect of soy supplementation on body composition.

Three intervention studies with a combined total of 300 participants reported that exercise did not significantly improve systolic blood pressure (MD=1.72; 95% CI=−2.47 to 5.90; Culos-Reed et al. 2010, Galvao et al. 2010, Bourke et al. 2014). Similarly, exercise did not significantly improve blood glucose levels (MD=0.13; 95% CI=−0.16 to 0.43), total cholesterol (MD=0.13; 95% CI=−0.18 to 0.44), triglycerides (MD=−0.06; 95% CI=−0.27 to 0.15), LDL cholesterol (MD=0.06; 95% CI=−0.20 to 0.32) or HDL cholesterol (MD=0.06; 95% CI=−0.05 to 0.16).

Only one dietary intervention study evaluated the effect of soy supplementation on lipid profile. Soy supplementation did not significantly improve total cholesterol, triglycerides, LDL cholesterol or HDL cholesterol. Neither dietary supplement studies evaluated the effect of soy on glucose levels.

Discussion

Exercise

Exercise interventions conducted over 12–24 weeks and which consisted of two to three days per week of combined aerobic and resistance exercise, were associated with significant improvements in health- and disease-specific QoL in men with PCa receiving ADT. Despite these improvements, the magnitude of effect of exercise on these outcomes was small to moderate. The majority of included studies implemented resistance and aerobic exercise as a combined intervention, so it was not possible to determine whether this improvement was attributable to the one type of exercise or the synergy of both. These results are consistent with the meta-analysis by Chipperfield et al. (2014) who reported preliminary data indicating that physical activity significantly improved QoL. However, in the present analysis there were no corresponding improvements in any secondary outcomes. A possible explanation lies in the studies' designs. Exercise intervention studies are often at much greater risk of performance bias compared with other randomised trial designs due to the use of usual care or waitlist control groups, as well as the logistical inability to blind participants and interventionists. Moreover, those in the exercise groups had longer and more intense contact with interventionists, a degree of health professional contact that could have improved perceptions of QoL independent of the effect of exercise. Therefore, improvements in these outcomes may have been masked by a variability in the types of exercise, intensity of the intervention and the duration of the interventions.

Bone fracture is a major risk factor for increased mortality. Depleted testosterone and oestrogen levels in men with PCa undergoing ADT can lead to bone loss (Higano 2004). These changes increase bone resorption and suppress bone formation, increasing the risk of fracture (Higano 2008, Michaud 2010). Despite the well-established effect of ADT on bone mineral density, there were a notable lack of studies evaluating the effect of exercise on this outcome. Similarly, other androgen deficiency symptoms including hot flashes, sexual function, sleep quality, depression and anxiety were often not reported as outcomes. These findings are consistent with Chipperfield et al. (2014) who also identified no studies evaluating the effect of physical activity on anxiety and depression.

Although ADT is associated with reduced PCa-specific mortality, its association with increased risk of non-cancer mortality, metabolic parameters and body composition could lead to the development of metabolic syndrome. Metabolic syndrome is a cluster of cardiovascular risk factors including insulin resistance, increased triglycerides and fasting glucose, low HDL, increased waist circumference and hypertension. It is implicated in the development of diabetes and cardiovascular disease. In addition to metabolic syndrome, large cohort analyses have demonstrated that serum cholesterol is independently associated with cardiovascular mortality (Stamler et al. 1986, Lewington et al. 2007).

Interestingly, although associated with the development of diabetes (Saylor & Smith 2009), the effect of ADT on the risk of developing cardiovascular disease is unclear. ADT increases a number of cardiovascular risk factors, including elevated fasting insulin; decreased insulin sensitivity; worsened lipid profile (Whitsel et al. 2001, Isidori et al. 2005, Laughlin et al. 2008, Traish et al. 2009); hypertension (Svartberg et al. 2004) and abdominal obesity (Marin et al. 1993). In a large meta-analysis of observational studies, Zhao et al. (2014) reported a non-significant 10% increase in cardiovascular disease risk (hazard ratio (HR)=1.10; 95% CI=1.00–1.21; P=0.06) but a significant association with cardiovascular mortality (HR=1.17; 95% CI=1.04–1.32; P=0.01). Conversely, in a meta-analysis of RCTs (Nguyen et al. 2011), the relative risk of cardiovascular death for men undergoing ADT for PCa vs control was not significant (risk ratio (RR)=0.93; 95% CI=0.79–1.10; P=0.41). The discrepancy between these two analyses could be explained by differences in risk. Compared with patients with more advanced disease, low risk patients have a higher life expectancy and are less likely to die of their cancer and therefore live long enough for cardiovascular disease to become a problem.

We found that exercise did not significantly improve lipid profiles, blood glucose levels, blood pressure, body weight or body composition. It is possible that too few studies were included in the current meta-analysis, thereby providing insufficient data or sample size to identify any ameliorative effect of exercise on these outcomes.

Weight gain in men undergoing ADT for PCa over 12–24 weeks would likely be minimal. Seible et al. (2014) reported that even one year after ADT initiation, weight gain was clinically insignificant (1.32±4 kg, P=0.0005). Contrary to traditional beliefs about risk groups, Seible et al. (2014) has previously reported that the independent predictors of weight gain in this population include a non-obese BMI and a relatively young age (i.e. <30 kg/m2 and <65 years old respectively). The mean sample ages of the studies analysed in this review were over 65 years, with most centring around 70 years. The inclusion of studies of older populations could have unintentionally obfuscated any larger weight alterations in the younger participants, resulting in smaller mean weight changes.

It is also possible that any losses in fat mass may have been obscured by gains in lean tissue. In men undergoing ADT, significant weight and body composition changes tend to occur within the first few months of treatment initiation and continue for 1–2 years. In an observational study, Smith et al. (2002) reported that men undergoing 48 weeks of ADT experienced significant increases in percentage body fat (9.4±1.7%, P<0.001) and significant decreases in percentage lean body mass (2.7±0.5%, P<0.001). In the current study, despite most studies' eligibility criteria including men who had been undergoing ADT for at least 2–6 months, exercise did not significantly improve fat mass or lean body mass. However, similar to weight changes, it is possible that too few studies were included in the current analysis to capture such small changes or that intervention periods were too short to capture the effect of exercise on body composition.

Diet

The precise contribution of sex steroid deprivation to the adverse effects of ADT is unclear. Low testosterone has been implicated in diminished QoL, androgen-deficiency symptoms and metabolic risk factors in men with PCa on ADT; however, these men also have low oestradiol levels (Sharma et al. 2009). It is hypothesised that due to the structural similarity of isoflavones (soy protein) to oestrogen, soy could induce a weak oestrogenic effect, minimising these adverse effects. In this review, soy supplementation did not significantly improve health-related QoL and there were insufficient data to quantitatively address disease-specific QoL. There were also insufficient data to evaluate the effect of soy on androgen deficiency symptoms, with the exception of vasomotor distress. Consistent with previous trials, soy supplementation did not significantly improve vasomotor distress. In breast cancer, soy has been shown to have no effect on the menopausal symptoms of postmenopausal women (Quella et al. 2000, Van Patten et al. 2002, MacGregor et al. 2005). There were insufficient data to evaluate the effect of soy on metabolic risk factors.

Strengths and limitations

This systematic review includes a quantitative analysis of RCTs, the highest level of evidence for interventions. Where studies were combined, there was minimal clinical and statistical heterogeneity. Data extraction and risk of bias assessment was conducted independently by two reviewers and almost all studies were found to have a low risk of bias.

The findings of this review were limited, however, by the lack of dietary intervention studies, particularly those using dietary counselling. Exercise interventions could not be evaluated by exercise type (i.e. resistance vs aerobic) so any significant results should be considered preliminary and attributed to combined modality.

Conclusion

There are significant gaps in the literature with regards to dietary and exercise interventions for the management of QoL, androgen deficiency symptoms and metabolic risk factors in men receiving ADT for PCa. Although the effects of exercise interventions on QoL are apparent, it is unclear whether these improvements are attributable to increased interventionist contact, aerobic exercise, resistance exercise or the combination of all three. More studies are required that control for interventionist contact as well as exercise type (i.e. aerobic or resistance), intensity and duration.

There is also a clear gap in the literature as to the effect of dietary counselling on QoL, androgen deficiency symptoms and metabolic risk factors in men undergoing ADT. No dietary studies addressing the effects of dietary counselling on ADT symptom management were identified for this review. It is possible that either the dietary counselling studies are addressing outcomes which have little relevance to ADT symptom management or they do not exist.

Despite the findings of this review, interventions that are effective in this population are still needed to ameliorate or manage the adverse effects of ADT. This is particularly important for decreasing this risk of cardiovascular disease and diabetes through managing metabolic risk factors and addressing bone mineral density.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This work was supported by the New Professor Grant, Queensland University of Technology.

Author contribution statement

A L McCarthy conceptualised the systematic review. A L McCarthy and L Teleni designed the systematic review and collected the data. L Teleni, A L McCarthy and R J Chan performed the initial analysis and interpretation and wrote the manuscript. All authors reviewed the analysis, interpretation and critically reviewed the manuscript. All authors have read and approved the version of the manuscript being submitted.

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    • Search Google Scholar
    • Export Citation
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  • Collapse
  • Expand
  • PRISMA flowchart.

  • Risk of bias summary. Red (−), high risk of bias; yellow (?), unclear risk of bias; green (+) low risk of bias.

  • Forest plot of comparison: exercise vs usual care on health-related quality of life.

  • Forest plot of comparison: exercise vs usual care on disease-specific quality of life.

  • Abdollah F, Sammon JD, Reznor G, Sood A, Schmid M, Klett DE, Sun M, Aizer AA, Choueiri TK & Hu JC et al. 2015 Medical androgen deprivation therapy and increased non-cancer mortality in non-metastatic prostate cancer patients aged ≥66 years. European Journal of Surgical Oncology 41 15291539. (doi:10.1016/j.ejso.2015.06.011).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Alberga AS, Segal RJ, Reid RD, Scott CG, Sigal RJ, Khandwala F, Jaffey J, Wells GA & Kenny GP 2012 Age and androgen-deprivation therapy on exercise outcomes in men with prostate cancer. Supportive Care in Cancer 20 971981. (doi:10.1007/s00520-011-1169-x).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bourke L, Doll H, Crank H, Daley A, Rosario D & Saxton JM 2011 Lifestyle intervention in men with advanced prostate cancer receiving androgen suppression therapy: a feasibility study. Cancer Epidemiology, Biomarkers & Prevention 20 647657. (doi:10.1158/1055-9965.EPI-10-1143).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Bourke L, Gilbert S, Hooper R, Steed LA, Joshi M, Catto JWF, Saxton JM & Rosario DJ 2014 Lifestyle changes for improving disease-specific quality of life in sedentary men on long-term androgen-deprivation therapy for advanced prostate cancer: a randomised controlled trial. European Urology 65 865872. (doi:10.1016/j.eururo.2013.09.040).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Chipperfield K, Brooker J, Fletcher J & Burney S 2014 The impact of physical activity on psychosocial outcomes in men receiving androgen deprivation therapy for prostate cancer: a systematic review. Health Psychology 33 12881297. (doi:10.1037/hea0000006).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Cormie P, Newton RU, Taaffe DR, Spry N, Joseph D, Akhlil Hamid M & Galvao DA 2013 Exercise maintains sexual activity in men undergoing androgen suppression for prostate cancer: a randomized controlled trial. Prostate Cancer and Prostatic Diseases 16 170175. (doi:10.1038/pcan.2013.22).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Culos-Reed SN, Robinson JW, Lau H, Stephenson L, Keats M, Norris S, Kline G & Faris P 2010 Physical activity for men receiving androgen deprivation therapy for prostate cancer: benefits from a 16-week intervention. Supportive Care in Cancer 18 591599. (doi:10.1007/s00520-009-0694-3).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • DerSimonian R & Laird N 1986 Meta-analysis in clinical trials. Controlled Clinical Trials 7 177188. (doi:10.1016/0197-2456(86)90046-2).

  • Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D & Bray F 2013 GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. Lyon, France: IARC. (available at: http://globocan.iarc.fr).

    • PubMed
    • Export Citation
  • Galvao DA, Taaffe DR, Spry N, Joseph D & Newton RU 2010 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. Journal of Clinical Oncology 28 340347. (doi:10.1200/JCO.2009.23.2488).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Galvao DA, Spry N, Denham J, Taaffe DR, Cormie P, Joseph D, Lamb DS, Chambers SK & Newton RU 2014 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. European Urology 65 856864. (doi:10.1016/j.eururo.2013.09.041).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Grossmann M, Hamilton EJ, Gilfillan C, Bolton D, Joon DL & Zajac JD 2011 Bone and metabolic health in patients with non-metastatic prostate cancer who are receiving androgen deprivation therapy. Medical Journal of Australia 194 301306.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Higano CS 2004 Understanding treatments for bone loss and bone metastases in patients with prostate cancer: a practical review and guide for the clinician. Urologic Clinics of North America 31 331352. (doi:10.1016/j.ucl.2004.01.001).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Higano CS 2008 Androgen-deprivation-therapy-induced fractures in men with nonmetastatic prostate cancer: what do we really know? Nature Clinical Practice. Urology 5 2434. (doi:10.1038/ncpuro0995).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savović J, Schulz KF, Weeks L & Sterne JAC 2011 The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. British Medical Journal 343 d5928. (doi:10.1136/bmj.d5928).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Isidori AM, Giannetta E, Greco EA, Gianfrilli D, Bonifacio V, Isidori A, Lenzi A & Fabbri A 2005 Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clinical Endocrinology 63 280293. (doi:10.1111/j.1365-2265.2005.02339.x).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Laughlin GA, Barrett-Connor E & Bergstrom J 2008 Low serum testosterone and mortality in older men. Journal of Clinical Endocrinology and Metabolism 93 6875. (doi:10.1210/jc.2007-1792).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, Halsey J, Qizilbash N, Peto R & Collins R 2007 Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 370 18291839. (doi:10.1016/S0140-6736(07)61778-4).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • MacGregor CA, Canney PA, Patterson G, McDonald R & Paul J 2005 A randomised double-blind controlled trial of oral soy supplements versus placebo for treatment of menopausal symptoms in patients with early breast cancer. European Journal of Cancer 41 708714. (doi:10.1016/j.ejca.2005.01.005).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Marin P, Holmang S, Gustafsson C, Jonsson L, Kvist H, Elander A, Eldh J, Sjostrom L, Holm G & Bjorntorp P 1993 Androgen treatment of abdominally obese men. Obesity Research 1 245251. (doi:10.1002/j.1550-8528.1993.tb00618.x).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Michaud LB 2010 Managing cancer treatment-induced bone loss and osteoporosis in patients with breast or prostate cancer. American Journal of Health-System Pharmacy 67 S20S30.(quiz S31–S23) (doi:10.2146/ajhp100078).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Napora JK, Short RG, Muller DC, Carlson OD, Odetunde JO, Xu X, Carducci M, Travison TG, Maggio M & Egan JM et al. 2011 High-dose isoflavones do not improve metabolic and inflammatory parameters in androgen-deprived men with prostate cancer. Journal of Andrology 32 4048. (doi:10.2164/jandrol.110.010983).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Nguyen PL, Je Y, Schutz FA, Hoffman KE, Hu JC, Parekh A, Beckman JA & Choueiri TK 2011 Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. Journal of the American Medical Association 306 23592366. (doi:10.1001/jama.2011.1745).

    • PubMed
    • Search Google Scholar
    • Export Citation
  • Quella SK, Loprinzi CL, Barton DL, Knost JA, Sloan JA, LaVasseur BI, Swan D, Krupp KR, Miller KD & Novotny PJ 2000 Evaluation of soy phytoestrogens for the treatment of hot flashes in breast cancer survivors: A North Central Cancer Treatment Group Trial. Journal of Clinical Oncology 18 10681074.

    • PubMed
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