Prostate cancer represents the second most common cancer in men worldwide, and is predicted to substantially rise in developed nations owing to sustained population growth, increased life expectancies and an ageing population [1,2]. Fortunately, the advent and widespread adoption of serological prostate-specific antigen (PSA) screening programmes has notably improved the early detection, diagnosis, treatment and management of prostate cancer, demonstrably improving survival outcomes. Impressively, this has led to an increase in 5-year survival rates from ∼68 to ∼99.7% in recent decades, with a 10 and 15-year survival rate of ∼99 and ∼94%, respectively, when detected early [3,4]. As such, prostate cancer survivorship is an emerging and critically important field of study, focused on the effective management of new, recurrent and persistent symptoms across the disease spectrum to explicitly enhance patient health, wellbeing and quality of life [5,6]. Unfortunately, most studies exploring survivorship focus their attention on the initial years of posttreatment survival, with limited attention given to patient needs later in the disease trajectory [6,7▪] when recurrence, castrate resistance and/or metastatic proliferation inevitably result in progression to advanced prostate cancer, whereby patient needs magnify [7▪].
Advanced prostate cancer is characterized by the recurrence and/or invasion of the primary carcinoma to secondary sites (i.e. nodal, visceral or skeletal metastases) and/or the development of resistance to first-line hormone therapy (androgen deprivation therapy; ADT) whereby androgen independent progression occurs (castrate-resistant prostate cancer; CRPC) . Men with advanced prostate cancer present a significant challenge to clinicians, because of their high disease burden and omnipresent comorbidities, in addition to common treatment-related side-effects stemming from second-line hormone therapies (abiraterone and enzalutamide) , first-line and second-line chemotherapies (docetaxel and cabazitaxel) , radionuclear therapies (strontium-89, samarium-153 and radium-223)  and emergent immunotherapies , the optimal sequencing of which has yet to be determined. Indeed, the vast majority of advanced prostate cancer patients (>80%) will develop bone metastases, which is a currently incurable stage of disease leading to palliation, poor prognoses and numerous clinical complications [13,14▪]. It is therefore a high priority and of significant clinical interest to devise and implement strategies to safely and effectively reduce the disease burden and treatment toxicity profile of advanced prostate cancer patients; particularly, strategies which are inexpensive, noninvasive and able to be widely implemented. Exercise is an emerging and provocative therapy in oncology, inherently aligned with the ‘exercise medicine’ movement [15–17], which shows excellent promise to meet this patient need.
Exercise was first considered a potential therapy for cancer patients and survivors in the mid-1980s [18–20], with only a further ∼25 exercise oncology studies reported in the subsequent two decades . Increasingly, over the last decade, exercise medicine has rapidly ascended as a key field of interest in the prevention  and management  of cancer, while emerging as a potential therapeutic agent to delay disease progression [24▪▪–26▪▪,27,28▪,29] and increase overall survival [29,30,31▪▪,32▪▪,33,34]. Primarily, researchers have focused their attention on the use of exercise in the neoadjuvant and adjuvant settings as a preventive, preparatory and rehabilitative tool for surgery (presurgical and postsurgical programmes) [35,36], and for symptom control during and/or following primary treatments, including radiotherapy, chemotherapy and hormone therapy (particularly ADT) postdiagnosis [37–40]. Collectively, this body of research has produced level 1 evidence , asserting the role of exercise for cancer patients to improve quality of life across several key metrics, including the mitigation of cancer-related fatigue [41▪] and restoration of physical function and exercise capacity [22,42], notably in response to treatment driven changes in body composition . The effectiveness of exercise as a neoadjuvant and adjuvant therapy to minimize, manage and, in some cases, reverse the side-effects of primary therapies has been promising to date [42–46].
Exercise oncology (i.e. the application of exercise medicine in cancer) has also continued to broaden, with several novel avenues being explored through preclinical orthotopic models that have the potential to significantly improve outcomes in advanced prostate cancer patients once translated to human clinical trials [47,48,49▪▪,50▪▪,51–54]. Indeed, the impressive ability of exercise to potentially modulate cancer-specific outcomes is of direct clinical interest and warrants rigorous scientific inquiry. Beyond neoadjuvant and adjuvant applications, exercise is emerging as a synergistic medicine (i.e. increasing the potency or effectiveness of concomitantly applied therapies) and targeted medicine (i.e. exerting its own systemic and localized anticancer effects, independent of other therapies) to underpin delays in disease progression and improvements in survival for advanced cancer patients. For example, synergies between exercise and chemotherapy have been identified [49▪▪,50▪▪,51], with aerobic exercise demonstrating an ability to interfere with tumour-driven dysregulation of angiogenesis; acting to restore and normalize tumour vasculature, thus improving blood supply and tumoral perfusion as mechanisms to enhance chemotherapeutic efficacy [49▪▪,50▪▪,51–55]. This same angiogenic response may also synergistically improve the effectiveness of radiotherapy [51–55], as reversible DNA damage can be stabilized if sufficient oxygen is present (i.e. oxygen enhancing effect of radiotherapy) , which could be optimized through exercise driven provasculature changes, resulting in increased tumour cell death. This is yet another avenue of exploration for future research. When extrapolated, this may also lead to synergistic improvements in the potency of other systemically delivered therapies inclusive of emerging immunotherapies in the prostate cancer treatment mix, or endogenous immune agents produced by various organs in the body that are driven by exercise .
Provocative evidence also exists to promote the potential independent role of exercise medicine for advanced prostate cancer patients. Putatively, exercise is thought to alter tumour biology by numerous mechanisms in response to a variety of modes and dosages (Fig. 1) [24▪▪]; however, the direct influence of exercise on tumour biology remains largely unknown, despite many hypothesized mechanical and nonmechanical mechanisms of action [47,48,49▪▪,50▪▪,51–59,60▪]. Specifically, exercise regulates endocrine–paracrine activity, immune system function, blood glucose and cholesterol levels, insulin responses and body composition and may epigenetically modulate tumour cell proliferation, telomere length, telomere enzyme activity, tumour vascularity, oxidative stress capacity, platelet cloaking and platelet adhesion [61–66]. This emerging field of exercise medicine (i.e. biological alterations driven from biomechanical stimuli)  in exercise oncology presents practitioners with unique opportunities to target tumour formation, growth and invasion of primary or secondary prostate carcinomas through exercise interventions. For example, aerobic exercise has been shown to stimulate natural killer cell production, mobilization and infiltration in to tumours, producing an approximate 60% reduction in tumour incidence and growth across several different preclinical tumour models [68▪▪]. Similarly, controlled mechanical compressions of skeletal sites with known bone metastases have been shown to interfere with tumour-driven dysregulation of osteogenesis, producing an approximate 80% reduction in tumour growth rate in osteolytic models, while preserving skeletal integrity by approximately 70% in loaded versus unloaded conditions . Cautiously, these preclinical findings use animal models over disparate time-periods, and require confirmatory human trials, some of which are currently in progress [69▪], though provide promising insights into exercise medicine independent of other therapies.
Epidemiological studies support the role of physical activity (i.e. incidental and/or nonspecific activities requiring bodily movement) and its association with delayed disease progression and increased overall survival [27,28▪,29,30,31▪▪,32▪▪,33,34]. Specifically, prediagnosis physical activity has been linked to tumour vessel normalization, which reduces the propensity of tumours to metastasize (i.e. delay disease progression) and has the potential to produce a 6.6–17.1-fold risk reduction in prostate cancer mortality [70▪▪,71]; whereby postdiagnosis moderate-to-vigorous physical activity has been linked to reductions in all-cause and prostate cancer-specific mortality of between 30 and 60% (pooled risk reduction = 0.62, 95% confidence interval: 0.47–0.82) [31▪▪,32▪▪,33,34,72▪], depending on the type, duration and frequency of physical activity reported. However, these studies provide associations using patient self-reported measures only and do not demonstrate a dose–response or load–adaptation insight into cause and effect between physical activity, disease progression or overall survival. Consequently, studies are yet to explore the role of exercise (i.e. purposeful, prescriptive, programmed and progressive activities of a specific nature; the nomenclature of which is often incorrectly used synonymously with physical activity) on disease-specific endpoints and such interventions would most certainly produce even greater benefits than those analysing self-reported physical activity. To address this need, a Global Action Plan (GAP4) has been funded by the Movember Foundation, with a multinational Phase III exercise trial (INTERVAL-MCRPC: https://clinicaltrials.gov/ct2/show/NCT02730338) launched, and currently underway to directly examine the effects of exercise medicine on disease progression and overall survival in metastatic castrate-resistant prostate cancer patients [73▪].
TREATMENTS, TOXICITIES AND EXERCISE
Exercise and antiandrogen therapies
Endocrine modification therapies are common first-line treatments for prostate cancer (beyond radical prostatectomy and radiation therapy), aiming to suppress testosterone released from the testes and/or to block androgen receptor uptake of testosterone by cancer cells, producing an environment commensurate with castration [74,75]. ADT remains the primary hormonal therapy for local and metastatic prostate cancer patients, proving an extremely successful pharmacological avenue to slow the progression of certain prostate cancers. On the contrary, long-term exposure to ADT inevitably leads to resistance, thus becoming ineffective due to tumour adaptability, desensitization to drug action and systemic acclimatization to the castrate environment [74–77]. This generates a rapid rise in PSA levels and velocity, indicating an advancement of the disease to CRPC. Consequently, extragonadal androgen sources start to sustain tumour growth despite castrate levels of testosterone, requiring second-line therapies to be introduced into the treatment mix [76,77].
Novel pharmacological agents which inhibit androgen receptors have recently been developed as second-line hormonal therapies to countenance extragonadal sources of androgen, including derivations from blood and bone marrow, successfully extending overall survival by ∼4–5 months [78,79] in castrate-resistant patients. Specifically, Abiraterone Acetate (Zytiga; Janssen, Beerse, Belgium) and Enzalutamide (Xandti; Astellas, Illinois, USA) are prominent antiandrogen drugs in the standard of care landscape when treating CRPC patients, which act as selective inhibitors to obstruct androgen uptake and utilization by prostate carcinomas regardless of production site (gonadal or extragonadal), thus considered to be very effective at suppressing testosterone in the testes, adrenal glands and the tumour itself, reducing testosterone levels by a further 90% beyond castrate levels [74–80]. Although androgen-deprivation therapies are proving effective in slowing prostate cancer progression, with improvements to survival; observational and longitudinal evidence highlight the burden of treatment to patients, which may be exacerbated by novel antiandrogen therapies [81,82▪] (Fig. 2), yet could potentially be managed through exercise.
ADT induces rapid loss of muscle and bone mass, increased central adiposity and body fat, and is therefore a precursor for the onset of metabolic diseases and other comorbidities such as type II diabetes and/or cardiovascular disease; culminating in physical and functional decline, increased fatigue, heightened fragility, decreased psychosocial health and a reduced quality of life [37–40,41▪,42–46,82▪,83–86]. Given that novel antiandrogen therapies induce an even greater blockade of androgen beyond castration levels (i.e. maximal androgen suppression), these reported side-effects are likely to be more pronounced (Fig. 3), presenting even greater clinical concerns for advanced prostate cancer patients. Although exercise is demonstrably beneficial for patients receiving ADT to prevent, preserve or reverse treatment-related side-effects [45,46], this has yet to be demonstrated in patients receiving maximal antiandrogen suppression. Indeed, exercise is very likely to mitigate fatigue commonly reported by patients on novel antiandrogen therapies [41▪,81], and may synergistically assist in the mitigation of resistance to enzalutamide, with natural killer cells recently implicated in the suppression of androgen receptor splicing variant 7 (ARv7) (i.e. an androgen receptor splicing variant linked to the development of resistance) [87▪▪]. As natural killer cell production and mobilization increases following exercise [68▪▪], by extension, this may aid in the suppression of ARv7; however, further research is required.
Exercise and chemotherapy
Chemotherapies provided to patients with advanced prostate cancer aim to provide symptom control, delay disease progression and increase survival; however, often present with their own clinical challenges and side-effects. Docetaxel remains the mainstay of first-line taxanes, with cabazitaxel established as a second-line taxane in eligible patients (i.e. consideration of bone marrow reserves, bone marrow quality, hepatic function and patient presentation) in favour of mitoxantrone; with cabazitaxel also available as a first-line taxane for patients resistant to docetaxel [10,74]. Owing to the side-effects of cytotoxic therapies, coupled with side-effects of other therapies (i.e. ADT in hormone-sensitive patients), patients may not tolerate full dosages across all cycles of treatment, and in some cases may be ineligible for further chemotherapy treatments if bone marrow and organ function is compromised [88–90]. Further, patients commonly present with high levels of fatigue, physical impairment and develop neutropenia following chemotherapy [91–94] which may lead to patients electing to refuse further chemotherapy dosages or undergo additional courses. Strategies to alleviate treatment toxicities and maintain hepatic and physical function are thus required.
Exercise is well established as a therapy to mitigate cancer-related fatigue [22,41▪], restore physical function and enhance physical fitness [23,42,44,95]; however, exercise may have broader clinical benefits for prostate cancer patients receiving chemotherapy. For example, neoadjuvant exercise may improve patient preparation and physical tolerance of first-line chemotherapy, inclusive of posttherapy recovery, with body composition established as a predictor of chemotherapeutic toxicity [96▪▪]. Furthermore, adjuvant exercise may synergistically increase cytotoxic circulation and intratumoural delivery of chemotherapy, thus increasing therapeutic potency [49▪▪,50▪▪], and may mitigate, restore or reverse side-effects associated with chemotherapy, inclusive of reductions in neutropenia onset, duration and severity of nadir (Fig. 4) following proposed improvements in immune function [97–99]. Neoadjuvant and adjuvant exercise therefore has the potential to assist patients to receive their full individual and aggregate doses of chemotherapy, and coupled with posttherapy exercise, may promote bone marrow quality  and improve patient physical condition to heighten clinical eligibility to receive and tolerate second-line chemotherapy; two clinically meaningful outcomes for advanced prostate cancer patients that are worthy of exploration.
Owing to their variable treatment histories, lifestyle-related and disease-related comorbidities and age-related decline, advanced prostate cancer patients will present with complex clinical cases that will influence the modality, volume, frequency, duration and intensity of exercise prescribed, and the manner in which their exercise programme progresses. Commonly amongst them is bone metastases, a historical barrier to exercise observed in over 80% of advanced cancer patients [100,101]. For patients with bone metastases, it is currently recommended to use exercises that avoid directly loading skeletal regions where metastatic lesions exist (Table 1) . Current studies exploring the safety, feasibility and preliminary efficacy of targeted loading of skeletal sites with bone metastases are currently underway [69▪], with results soon to be released.
Autoregulation, periodization and exercise selection
Advanced prostate cancer patients may present with numerous treatment side-effects of varying magnitudes at a given exercise session, or across multiple exercise sessions. To accommodate for transient changes and fluctuations in a patient's wellbeing through-out courses of treatment and through-out their disease progression, all exercise programmes should be individualized (i.e. based on a needs analysis and physical assessment) and progressive using autoregulation (i.e. a method in which cancer patients progress at their own pace based on daily and weekly variations in their health, performance capability, recovery capacity or scheduling commitments) [103,104]. Autoregulation is an important concept, allowing patients to consultatively self-determine their capabilities at each session collaboratively with the supervising clinical exercise physiologist, thereby lowering intensity or volume if the patient is fatigued or unwell, or raising intensity or volume if the patient is energetic and motivated. Commensurate with other standard exercise principles, exercise programmes should be periodized (i.e. the systematic planning and phasic organization of exercise volume and intensity, including deloading periods to promote patient recovery), commence conservatively, and include a variety of exercise types and modalities.
Advanced cancer patients should receive medical clearances from either their oncologist (i.e. cancer-specific medications and clearances), cardiologist (i.e. cardiac-specific medication and clearances) and/or general practitioner (i.e. other medications and comorbidity clearances) prior to engaging in an exercise programme, which may limit the modality of exercise permitted. Nevertheless, exercise programmes should ideally involve a multimodal approach with aerobic and resistance exercise of varying intensities and volumes to target the cardiorespiratory and musculoskeletal systems, respectively (Table 2), and to promote various biochemical, hormonal (endocrine–paracrine) and immune responses to disparate modalities. Current clinical exercise guidelines [105–107] recommend achieving a combination of 150 min of moderate, or 75 min of vigorous aerobic exercise coupled with 2–3 resistance exercise sessions for cancer patients and survivors. However, owing to heightened clinical concerns and patient fear of skeletal and other adverse events [69▪], only ∼30% of advanced prostate cancer patients with bone metastases reported meeting aerobic exercise guidelines; with the remaining ∼70% either insufficiently or completely inactive (i.e. performing no aerobic exercise at all) [14▪]. Given the historical safety concerns surrounding resistance exercise in this population (with safety and feasibility recently demonstrated [100,101]), resistance exercise participation would be even lower than those reported for aerobic exercise. Although any activity is better than no activity, it is incumbent upon clinicians to promote patient engagement with exercise physiologists and treat exercise as a medicine for advanced prostate cancer, one which all patients should participate.
Exercise medicine is rapidly evolving as an emerging and provocative therapy in oncology, with excellent promise to meet the broad and magnified needs of advanced prostate cancer patients. This review highlights established clinical evidence, developing preclinical evidence and potential future avenues of novel research pertaining to the role of exercise as an adjuvant, synergistic and targeted therapy. In particular, we highlight the powerful potential of exercise to enhance chemotherapeutic and radiotherapeutic effectiveness, interfere with tumour-driven dysregulation of angiogenesis and osteogenesis and delay disease progression and extend survival. Importantly, due to the complex clinical presentations of advanced prostate cancer patients, this review provides exercise prescription and programming recommendations to ensure that exercise participation is flexible and effective, yet safe and well tolerated by patients. Lastly, we assert the need for future research to focus on translating impressive preclinical outcomes, to patient-focused human clinical trials, to continue to establish exercise as an essential therapy for inclusion into standard of care practices in oncology.
Exercise Medicine Research Institute is a Centre of Research Excellence in Prostate Cancer Survivorship (CRE-PCS) of the National Health and Medical Research Council (NHMRC) of Australia. N.H.H. is Global Exercise Coordinator, R.U.N. is Co-Chair of the Steering Committee, and together with D.A.G. are Principal Investigators for the GAP4 (INTERVAL-MCRPC) trial. Financial support and sponsorship D.A.G. is supported by the Cancer Council of Western Australia's Research Fellowship.
Financial support and sponsorship
D.A.G. is supported by the Cancer Council of Western Australia's Research Fellowship.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
1. Dy GW, Gore JL, Forouzanfar MH, et al. Global burden of urologic cancers, 1990–2013. Eur Urol 2017; 71:437–446.
2. Torre LA, Siegel RL, Ward EM, Jemal A. Global cancer incidence and mortality rates and trends – an update. Cancer Epidemiol Bio Prev 2016; 25:16–27.
3. Miller KD, Siegel RL, Lin CC, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin 2016; 66:271–289.
4. Moyad MA, Newton RU, Tunn UW, Gruca D. Integrating diet and exercise into care of prostate cancer patients on androgen deprivation therapy. Res Rep Urol 2016; 8:133–143.
5. Rosenberg SM, Partidge AH. Looking back, moving forward: the evolution of cancer survivorship care. Lancet Oncol 2017; 18:18–19.
6. Johnson M. Tailored prostate cancer survivorship: one size does not fit all. Br J Urol Int 2016; 118:343–344.
7▪. Bernat JK, Wittman DA, Hawley ST, et al. Symptom burden and information needs in prostate cancer survivors: a case for tailored long-term survivorship care. Br J Urol Int 2016; 118:372–378.
8. Hoang DT, Iczkowski KA, Kilari D, et al. Androgen receptor-dependent and -independent mechanisms driving prostate cancer progression: opportunities for therapeutic targeting from multiple angles. Oncotarget 2017; 8:3724–3745.
9. Guo C, Yeh S, Niu Y, et al. Targeting androgen receptor versus targeting androgens to suppress castration resistant prostate cancer. Cancer Lett 2017; 397:133–143.
10. Saad F. The evolving role of chemotherapy in prostate cancer. Curr Opin Support Palliat Care 2016; 10:262–265.
11. Nilsson S. Radionuclide therapies in prostate cancer: integrating radium-223 in the treatment of patients with metastatic castration-resistant prostate cancer. Curr Oncol Rep 2016; 18:14.
12. Silvestri I, Cattarino S, Giantulli S, et al. A perspective of immunotherapy for prostate cancer. Cancers 2016; 8:64.
13. McDougall JA, Bansal A, Goulart BH, et al. The clinical and economic impacts of skeletal-related events among medicare enrollees with prostate cancer metastatic to bone. Oncologist 2016; 21:320–326.
14▪. Zopf EM, Newton RU, Taaffe DR, et al. Associations between aerobic exercise levels and physical and mental health outcomes in men with bone metastatic prostate cancer: a cross-sectional investigation. Eur J Cancer Care 2016; PMID: 27647712. [Epub ahead of print].
15. Newton RU, Galvão DA, Hart NH, et al. Endogenous exercise medicine: mechanisms influencing prostate cancer biology. Br J Urol Int 2016; 118:10.
16. MacAuley D, Bauman A, Frémont P. Exercise: not a miracle cure, just good medicine. BMJ 2015; 50:h1416.
17. Sallis RE. Exercise is medicine and physicians need to prescribe it. Br J Sports Med 2009; 43:3–4.
18. Garabrant DH, Peters JM, Mack TM, Bernstein L. Job activity and colon cancer risk. Am J Epidemiol 1984; 119:1005–1014.
19. Winningham ML, MacVicar MG, Burke CA. Exercise for cancer patients: guidelines and precautions. Phys Sportsmed 1986; 14:125–134.
20. Cunningham AJ, Morris G, Cheney CL. Effects of resistance exercise on skeletal muscle in marrow transplant recipients receiving total parental nutrition. J Parenter Enteral Nutr 1986; 10:558–563.
21. Galvão DA, Newton RU. Review of exercise intervention studies in cancer patients. J Clin Oncol 2005; 24:899–909.
22. Shephard RJ. Physical activity and prostate cancer: an updated review. Sports Med 2017; 47:1055–1073.
23. Bourke L, Smith D, Steed L, et al. Exercise for men with prostate cancer: a systematic review and meta-analysis. Eur Urol 2016; 69:693–703.
24▪▪. Galvão DA, Taaffe DR, Spry N, et al. Enhancing active surveillance of prostate cancer: the potential of exercise medicine. Nat Rev Urol 2016; 13:258–265.
25▪▪. Thomas RJ, Kenfield SA, Jimenez A. Exercise-induced biochemical changes and their potential influence on cancer: a scientific review. Br J Sports Med 2017; 51:640–644.
26▪▪. Ashcraft KA, Peace RM, Betof AS, et al. Efficacy and mechanisms of aerobic exercise on cancer initiation, progression, and metastasis: a critical systematic review of in vivo preclinical data. Cancer Res 2016; 76:4032–4050.
27. Richman EL, Kenfield SA, Stampfer MJ, et al. Physical activity after diagnosis and risk of prostate cancer progression: data from the cancer of the prostate strategic urologic research endeavor. Cancer Res 2011; 71:3889–3995.
28▪. Peisch SF, Van Blarigan EL, Chan JM, et al. Prostate cancer progression and mortality: a review of diet and lifestyle factors. World J Urol 2016; PMID: 27518576. [Epub ahead of print].
29. Kenfield SA, Batista JL, Jahn JL, et al. Development and application of a lifestyle score for prevention of lethal prostate cancer. J Natl Cancer Inst 2016; 108:djv39.
30. Newton RU, Galvão DA. Accumulating evidence for physical activity and prostate cancer survival: time for a definitive trial of exercise medicine? Eur Urol 2016; 70:586–587.
31▪▪. Friedenreich CM, Wang Q, Neilson HK, et al. Physical activity and survival after prostate cancer. Eur Urol 2016; 70:576–585.
32▪▪. Gunnell A, Joyce S, Tomlin S, et al. Physical activity and survival among long-term cancer survivor and noncancer cohorts. Front Public Health 2017; 5:19.
33. Bonn SE, Sjölander A, Lagerros YT, et al. Physical activity and survival among men diagnosed with prostate cancer. Cancer Epidemiol Biomarkers Prev 2015; 24:57–64.
34. Kenfield SA, Stampfer MJ, Giovannucci E, Chan JM. Physical activity and survival after prostate cancer diagnosis in the health professionals’ follow-up study. J Clin Oncol 2011; 29:726–732.
35. Singh F, Newton RU, Galvão DA, et al. A systematic review of presurgical exercise intervention studies with cancer patients. Surg Oncol 2013; 22:92–104.
36. van Zutphen M, Winkels RM, van Duijnhoven FJ, et al. An increase in physical activity after colorectal cancer surgery is associated with improved recovery of physical functioning: a prospective cohort study. BMC Cancer 2017; 17:74.
37. Galvão DA, Spry NA, Denham J, et al. A multicentre year-long randomised controlled trial of exercise training targeting physical function in men with prostate cancer previously treated with androgen suppression and radiation from TROG 03.04 RADAR. Eur Urol 2014; 65:856–864.
38. Lipsett A, Barrett S, Haruna F, et al. The impact of exercise during adjuvant radiotherapy for breast cancer on fatigue and quality of life: a systematic review and meta-analysis. Breast 2017; 32:144–155.
39. Teleni T, Chan RJ, Chan A, et al. Exercise improves quality of life in androgen deprivation therapy-treated prostate cancer: systematic review of randomised controlled trials. Endocr Relat Cancer 2016; 23:101–112.
40. Farris MS, Kopciuk KA, Courneya KS, et al. Associations of postdiagnosis physical activity change from prediagnosis physical activity with quality of life in prostate cancer survivors. Cancer Epidemiol Biomarkers Prev 2017; 14:55.
41▪. Taaffe DR, Newton RU, Spry N, et al. Effects of different exercise modalities on fatigue in prostate cancer patients undergoing androgen deprivation therapy: a year-long randomised controlled trial. Eur Urol 2017; PMID: 28249801. [Epub ahead of print].
42. Moe EL, Chadd J, McDonagh M, et al. Exercise interventions for prostate cancer survivors receiving hormone therapy: systematic review. Transl J Am Coll Sports Med 2017; 2:1–9.
43. Gardner JR, Livingston PM, Fraser SF. Effects of exercise on treatment-related adverse effects for patients with prostate cancer receiving androgen-deprivation therapy: a systematic review. J Clin Oncol 2013; 32:335–346.
44. Newton RU, Galvão DA. Exercise medicine for prostate cancer. Eur Rev Aging Phys Act 2013; 10:41–45.
45. Galvão DA, Taaffe DR, Spry N, et al. Combined resistance and aerobic exercise program reverses muscle loss in men undergoing androgen suppression therapy for prostate cancer without bone metastases: a randomized controlled trial. J Clin Oncol 2010; 28:340–347.
46. Galvao DA, Taaffe DR, Spry N, Newton RU. Exercise can prevent and even reverse adverse effects of androgen suppression treatment in men with prostate cancer. Prostate Cancer Prostatic Dis 2007; 10:340–346.
47. Lynch ME, Fischbach C. Biomechanical forces in the skeleton and their relevance to bone metastasis: biology and engineering considerations. Adv Drug Deliv Rev 2014; 79–80:119–134.
48. Lynch ME, Brooks D, Mohanan S, et al. In vivo tibial compression decreases osteolysis and tumor formation in a human metastatic breast cancer model. J Bone Miner Res 2013; 28:2357–2367.
49▪▪. Schadler KL, Thomas NJ, Galie PA, et al. Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy. Oncotarget 2016; 7:65429–65440.
50▪▪. Betof AS, Lascola CD, Weitzel DH, et al. Modulation of murine breast tumor vascularity, hypoxia, and chemotherapeutic response by exercise. J Natl Cancer Inst 2015; 107:1–6.
51. Betof AS, Dewhirst MW, Jones LW. Effects and potential mechanisms of exercise training on cancer progression: a translational perspective. Brain Behav Immun 2013; 30:S75–S87.
52. McCullough DJ, Stabley JN, Siemann DW, Behnke BJ. Modulation of blood flow, hypoxia, and vascular function in orthotopic prostate tumors during exercise. J Natl Cancer Inst 2014; 106:dju036.
53. McCullough DJ, Nguyen LM, Siemann DW, Behnke BJ. Effects of exercise training on tumor hypoxia and vascular function in the rodent preclinical orthotopic prostate cancer model. J Appl Physiol 2013; 115:1846–1854.
54. Jones LW, Antonelli J, Masko EM, et al. Exercise modulation of the host-tumor interaction in an orthotopic model of murine prostate cancer. J Appl Physiol 2012; 113:263–272.
55. Jordan BF, Sonveaux P. Targeting tumor perfusion and oxygenation to improve the outcome of anticancer therapy. Front Pharmacol 2012; 3:94.
56. Hoffman P. Exercise training, tumour metabolism, tumour–host interaction and lactate shuttle theory. Front Pharmacol 2014; doi:10.3389/conf.fphar.2014.61.00022.
57. Jones LW, Dewhirst MW. Therapeutic properties of aerobic training after a cancer diagnosis: more than a one-trick pony? J Natl Cancer Inst 2014; 106:1–3.
58. Jones LW, Fels DR, West M, et al. Modulation of circulating angiogenic factors and tumor biology by aerobic training in breast cancer patients receiving neoadjuvant chemotherapy. Cancer Prev Res 2013; 6:925–937.
59. Wolff G, Balke JE, Andras IE, et al. Exercise modulates redox-sensitive small GTPase activity in the brain microvasculature in a model of brain metastasis formation. PLoS One 2014; 9:1–8.
60▪. Glass OK, Inman BA, Broadwater G, et al. Effect of aerobic training on the host systemic milieu in patients with solid tumours: an exploratory correlative study. Br J Cancer 2015; 112:825–831.
61. Garland SN, Johnson B, Palmer C, et al. Physical activity and telomere length in early stage breast cancer survivors. Breast Cancer Res 2014; 16:413–422.
62. Shammas MA. Telomeres, lifestyle, cancer, and aging. Curr Opin Clin Nutr Metab Care 2011; 14:8–34.
63. Ludlow AT, Zimmerman JB, Witkowski S, et al. Relationship between physical activity level, telomere length, and telomerase activity. Med Sci Sports Exerc 2008; 40:1764–1771.
64. Heber S, Volf I. Effects of physical (in)activity on platelet function. BioMed Res Int 2015; 14:1–11.
65. Sharma D, Brummel-Ziedins KE, Bouchard BA, Holmes CE. Platelets in tumor progression: a host factor that offers multiple potential targets in the treatment of cancer. J Cell Physiol 2014; 229:1005–1015.
66. Egan K, Cooke N, Kenny D. Living in shear: platelets protect cancer cells from shear induced damage. Clin Exp Metastasis 2014; 31:697–704.
67. Wang J, Lu D, Mao D, Long M. Mechanomics: an emerging field between biology and biomechanics. Protein Cell 2014; 5:518–531.
68▪▪. Pedersen L, Idorn M, Olofsson GH, et al. Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution. Cell Metab 2016; 23:554–562.
69▪. Hart NH, Newton RU, Spry NA, et al. Can exercise suppress tumour growth in advanced prostate cancer patients with sclerotic bone metastases? A randomised, controlled study protocol examining feasibility, safety and efficacy. BMJ Open 2017; 7:e014458.
70▪▪. Van Blarigan EL, Gerstenberger JP, Kenfield SA, et al. Physical activity and prostate tumor vessel morphology: data from the health professionals follow-up study. Cancer Prev Res 2015; 8:962–967.
71. Mucci LA, Powolny A, Giovannucci E, et al. Prospective study of prostate tumor angiogenesis and cancer-specific mortality in the health professionals follow-up study. J Clin Oncol 2009; 27:5627–5633.
72▪. Friedenreich CM, Neilson HK, Farris MS, Courneya KS. Physical activity and cancer outcomes: a precision medicine approach. Clin Cancer Res 2016; 22:4766–4775.
73▪. Saad F, Kenfield SA, Chan JM, et al. INTense Exercise foR surviVAL for men with Metastatic Castrate Resistant Prostate Cancer (INTERVAL-MCRPC): a Movember funded multicentre, randomized, controlled phase III study. J Clin Oncol 2016; 34:TPS5092.
74. Karantanos T, Corn PG, Thompson TC. Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches. Oncogene 2013; 32:5501–5511.
75. Toren PJ, Gleave ME. Evolving landscape and novel treatments in metastatic castrate-resistant prostate cancer. Asian J Androl 2013; 15:342–349.
76. Cheng HH, Gulati R, Azad A, et al. Activity of enzalutamide in men with metastatic castration-resistant prostate cancer is affected by prior treatment with abiraterone and/or docetaxel. Prostate Cancer Prostatic Dis 2015; 18:122–127.
77. Ryan CJ, Smith MR, De Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. New Engl J Med 2013; 368:138–148.
78. De Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. New Engl J Med 2011; 364:1995–2005.
79. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367:1187–1197.
80. Attard G, Reid AH, Auchus RJ, et al. Clinical and biochemical consequences of CYP17A1 inhibition with abiraterone given with and without exogenous glucocorticoids in castrate men with advanced prostate cancer. J Clin Endocrinol Metab 2011; 97:507–516.
81. Pezaro C, Mukherji D, Tunariu N, et al. Sarcopenia and change in body composition following maximal androgen suppression with abiraterone in men with castration-resistant prostate cancer. Br J Cancer 2013; 109:325–331.
82▪. Glass OK, Ramalingam S, Harrison MR. Resistance exercise training in patients with genitourinary cancers to mitigate treatment-related skeletal muscle loss. Clin Adv Hematol Oncol 2016; 14:436–446.
83. Owen PJ, Daly RM, Livingston PM, Fraser SF. Lifestyle guidelines for managing adverse effects on bone health and body composition in men treated with androgen deprivation therapy for prostate cancer: an update. Prostate Cancer Prostatic Dis 2017; 20:137–145.
84. Hamrick MW, McGee-Lawrence ME, Frechette DM. Fatty infiltration of skeletal muscle: mechanisms and comparisons with bone marrow adiposity. Front Endocrinol 2016; 7:69.
85. Chang D, Joseph DJ, Ebert MA, et al. Effect of androgen deprivation therapy on muscle attenuation in men with prostate cancer. J Med Imaging Radiat Oncol 2014; 58:223–228.
86. Cheung AS, Zajac JD, Grossmann M. Muscle and bone effects of androgen deprivation; current and emerging therapies. Endocr Relat Cancer 2014; 21:371–394.
87▪▪. Lin SJ, Chou FJ, Li L, et al. Natural killer cells suppress enzalutamide resistance and cell invasion in the castration resistant prostate cancer via targeting the androgen receptor splicing variant 7 (ARv7). Cancer Lett 2017; 398:62–69.
88. Grigorian A, O’Brien CB. Hepatotoxicity secondary to chemotherapy. J Clin Transl Hepatol 2014; 2:95–105.
89. Lucas D, Scheiermann C, Chow A, et al. Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration. Nature Med 2013; 19:695–703.
90. Aksentijevich I, Flinn I. Chemotherapy and bone marrow reserve: lessons learned from autologous stem cell transplantation. Cancer Biother Radiopharm 2002; 17:399–403.
91. Saad F, Miller K. Treatment options in castration-resistant prostate cancer: current therapies and emerging docetaxel-based regimens. Urol Oncol 2014; 32:70–79.
92. Ho M, Mackey J. Presentation and management of docetaxel-related adverse effects in patients with breast cancer. Cancer Manag Res 2014; 6:253–259.
93. Meisel A, Von Felten S, Vogt DR, et al. Severe neutropenia during cabazitaxel treatment is associated with survival benefit in men with metastatic castration-resistant prostate cancer (mCRPC): a posthoc analysis of the TROPIC phase III trial. Eur J Cancer 2016; 56:93–100.
94. Paller CJ, Antonarakis ES. Cabazitaxel: a novel second-line treatment for metastatic castration-resistant prostate cancer. Drug Des Dev Ther 2011; 5:117–124.
95. Mustian KM, Cole CL, Lin PJ, et al. Exercise recommendations for the management of symptoms clusters resulting from cancer and cancer treatments. Semin Oncol Nurs 2016; 32:383–393.
96▪▪. Shachar SS, Deal AM, Weinberg M, et al. Body composition as a predictor of toxicity in patients receiving anthracycline and taxane based chemotherapy for early stage breast cancer. Clin Cancer Res 2017; PMID: 28143874. [Epub ahead of print].
97. Karvinen KH, Esposito D, Raedeke TD, et al. Effect of an exercise training intervention with resistance bands on blood cell counts during chemotherapy for lung cancer: a pilot randomized controlled trial. SpringerPlus 2014; 3:15.
98. Kruijsen-Jaarsma M, Révész D, Bierings MB, et al. Effects of exercise on immune function in patients with cancer: a systematic review. Exerc Immunol Rev 2013; 19:120–143.
99. Liu M, Timmons BW. The effect of acute exercise on neutrophil reactive oxygen species production and inflammatory markers in healthy prepubertal and adult males. Pediatr Exerc Sci 2016; 28:55–63.
100. Cormie P, Newton RU, Spry N, et al. Safety and efficacy of resistance exercise in prostate cancer patients with bone metastases. Prostate Cancer Prostatic Dis 2013; 16:328–335.
101. Cormie P, Galvão DA, Spry N. Functional benefits are sustained after a program of supervised resistance exercise in cancer patients with bone metastases: longitudinal results of a pilot study. Support Care Cancer 2014; 22:1537–1548.
102. Galvão DA, Taaffe DR, Cormie P, et al. Efficacy and safety of a modular multimodal exercise program in prostate cancer patients with bone metastases: a randomized controlled trial. BMC Cancer 2011; 11:517–524.
103. Mann JB, Thyfault JP, Ivey PA, Sayers SP. The effect of autoregulatory progressive resistance exercise vs. linear periodization on strength improvement in college athletes. J Strength Cond Res 2010; 24:1718–1723.
104. Ardali G. A daily adjustable progressive resistance exercise protocol and functional training to increase quadriceps muscle strength and functional performance in an elderly homebound patient following a total knee arthroplasty. Physiother Theory Pract 2014; 30:287–297.
105. Segal R, Zwaal C, Green E, et al. Exercise for people with cancer: a clinical practice guideline. Curr Oncol 2017; 24:40–46.
106. Wolin KY, Schwartz AL, Matthews CE, et al. Implementing the exercise guidelines for cancer survivors. J Support Oncol 2012; 10:171–177.
107. Hayes SC, Spence RR, Galvão DA, Newton RU. Australian association for exercise and sport science position stand: optimising cancer outcomes through exercise. J Sci Med Sport 2009; 12:428–434.