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Understanding the Mechanisms of Exercise as a Medicine to Increase Survival of Men with Prostate Cancer - Beyond the Abstract

The association between increased cancer specific survival, amount and intensity of physical activity is well-established across a range of cancers including for men with cancer of the prostate.1 If patients with cancer are more physically active, then it is hardly surprising that their all-cause mortality will be reduced simply because regular physical activity reduces risk and slows progression of all chronic diseases in particular of the cardiovascular system.2 What is less understood and requires urgent research focus is the relationship between physical activity and cancer specific mortality. In somewhat of a landmark study, Kenfield et al1 reported a 61% lower risk of prostate cancer death in men that did three or more hours per week of vigorous physical activity. This provided important new insight suggesting that it is not just any physical activity but that the intensity is a relevant factor in the survival benefit.

Physical activity is defined as any bodily movement produced by skeletal muscles that result in energy expenditure. Exercise is a subset of physical activity that is planned, structured, and repetitive and has as a final, or an intermediate objective, the improvement or maintenance of physical fitness and health.3 Exercise medicine is the assessment of patient health and fitness specifically for the prescription of exercise as a therapy to treat specific illnesses. In the context of cancer care this field is termed exercise oncology. Current recommendations from several national associations4,5  are that people with cancer should avoid being sedentary and accumulate 75 minutes of vigorous or 150 minutes of moderate physical activity each week or an equivalent combination of the intensities. Each minute of vigorous activity is equivalent to two minutes of moderate activity. In addition, people with cancer should complete at least two sessions of resistance training each week. While this generic recommendation has been very important in dispelling the myth that people with cancer should rest, such a prescription is only feasible in patients that are relatively well and could not be considered the optimal prescription in terms of greatest benefit for the least amount of time and effort. A much better approach would be to tailor the exercise prescription to address those health issues which are causing the greatest morbidity and risk of mortality for the individual patient.4 Fortunately, optimal exercise prescription is well-established for most of the conditions impacting the patient above and beyond the disease of cancer. For example, an appropriate dosage of resistance training is effective for preventing or reversing sarcopenia.6 A high volume of aerobic exercise in combination with dietary restriction and resistance training is effective for fat loss and muscle maintenance in obese men with prostate cancer.7 However, the specifics of exercise prescription to slow the progression of prostate cancer are currently unknown.

While the relationship between physical activity and cancer survival is well demonstrated by numerous retrospective studies with quite large numbers of patients, they do not prove causality. It could be that patients who are doing better live longer and they also happen to be more physically active. To address this gap in knowledge an international trial has been established with a randomized controlled design to specifically investigate whether targeted exercise medicine will extend survival in men with stage IV prostate cancer.8 Incorporated into this research is an extensive examination of the underlying biological mechanisms by which exercise influences tumor biology. There have been a range of mechanisms proposed9 including cytokine signaling, enhanced immune function, hormone receptor adaptation, reduced systemic inflammation and oxidative stress, changes in tumor vascularization, modulated gene and epigenetic expression, telomere alterations, and modulation of other circulating factors such as insulin and growth factors.

From this trial, our team recently published a paper in which we reported that 6 months of vigorous exercise elevated the concentration of myokines in the systemic circulation and the serum from these patients produced a 21% suppression of prostate cancer cell growth.10 Myokines are cytokines produced by skeletal muscle cells and those that we investigated have been demonstrated to signal cancer cells to reduce growth rate and increase phagocytosis.11 In addition to this direct signaling these myokines also work in tandem with the immune system to increase the surveillance and activity of cytotoxic T cells to identify and destroy both in situ and circulating cancer cells. We have also established that there is a relationship between increase in muscle mass over a three-month exercise intervention and the concentration of myokines.12 This is a highly important finding as maintaining or increasing muscle mass is further consolidated as an important goal in the management of prostate cancer. Such a hypothesis is supported by another of our publications in which we reported that overall survival in men with prostate cancer is associated with muscle mass.13 This new knowledge elucidates the significance of exercise medicine specificity and the importance of tailoring the exercise prescription to the individual patient. It is becoming increasingly clear that exercise is not a single medicine and how it is dosed in terms of volume, intensity, timing, duration, and periodization has impact on cancer specific outcomes.

Mechanistic research in exercise oncology is relatively in its infancy. It is analogous to the 1950s when the life-saving benefits of chemotherapy were first realized however the field was completely in the dark as to which types of drugs, dosage, and timing would be optimal for a given patient with cancer. Presently we do not even know whether the broad modes of aerobic versus resistance exercise training have differential effects on the tumor microenvironment and biology. We have no confirmation of the effects of different dosages and intensities of exercise medicine influencing the mechanisms listed above and subsequently creating a cancer suppressive environment. It is unequivocal that being physically active will be of benefit for patients with cancer and targeted exercise will have an even greater influence on the quality and quantity of life. With further research and a greater understanding of the mechanisms by which different exercise prescriptions impact cancer progression more optimal exercise programs can be designed for the individual patient. Such knowledge will also prove invaluable in developing exogenous drug therapies which enhance the exercise effects or exercise enhances drug efficacy.

The best recommendation for our patients is to try and be active on most if not every day, regardless of cancer stage and even when undergoing difficult treatments. Ideally, patients should receive exercise assessment and prescription from a qualified professional such as a clinical exercise physiologist or physiotherapist so that the most beneficial and safe exercise medicine can be provided. Improved quality of life and reduced all-cause mortality is almost assured and cancer specific survival likely increased; although we are still unsure of how this actually works.

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Written by: Robert U. Newton, PhD, DSc,1,2,3 Jin-Soo Kim, PhD,1,2 and Fred Saad, MD4

  1. Exercise Medicine Research Institute, Edith Cowan University, Perth, WA, Australia
  2. School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, 6027, Australia
  3. School of Human Movement and Nutrition Sciences, The University of Queensland, QLD, Brisbane, Australia
  4. Department of Urology, Centre Hospitalier de l'Université de Montréal, Montréal, QC, H2X 3E4, Canada

References:

  1. Kenfield, S.A., et al., Physical activity and survival after prostate cancer diagnosis in the health professionals follow-up study. Journal of clinical oncology: official journal of the American Society of Clinical Oncology, 2011. 29(6): p. 726-32.
  2. Kraus, W.E., et al., Physical Activity, All-Cause and Cardiovascular Mortality, and Cardiovascular Disease. Med Sci Sports Exerc, 2019. 51(6): p. 1270-1281.
  3. Caspersen, C.J., K.E. Powell, and G.M. Christenson, Physical activity, exercise, and physical fitness: definitions and distinctions for health-related research. Public Health Rep, 1985. 100(2): p. 126-31.
  4. Hayes, S.C., et al., The Exercise and Sports Science Australia position statement: Exercise medicine in cancer management. Journal of Science and Medicine in Sport, 2019. 22(11): p. 1175-1199.
  5. Campbell, K.L., et al., Exercise Guidelines for Cancer Survivors: Consensus Statement from International Multidisciplinary Roundtable. Med Sci Sports Exerc, 2019. 51(11): p. 2375-2390.
  6. Lopez, P., et al., Resistance Training Load Effects on Muscle Hypertrophy and Strength Gain: Systematic Review and Network Meta-analysis. Medicine and Science in Sports and Exercise, 2021. 53(6): p. 1206-1216.
  7. Wilson, R.L., et al., Weight Loss for Obese Prostate Cancer Patients on Androgen Deprivation Therapy. Medicine and science in sports and exercise, 2021. 53(3): p. 470-478.
  8. Newton, R.U., et al., Intense Exercise for Survival among Men with Metastatic Castrate-Resistant Prostate Cancer (INTERVAL-GAP4): A multicentre, randomised, controlled phase III study protocol. BMJ Open, 2018. 8(5).
  9. Galvão, D.A., et al., Enhancing active surveillance of prostate cancer: The potential of exercise medicine. Nature Reviews Urology, 2016. 13(5): p. 258-265.
  10. Kim, J.S., et al., Exercise in advanced prostate cancer elevates myokine levels and suppresses in-vitro cell growth. Prostate Cancer and Prostatic Diseases, 2022.
  11. Kim, J.S., et al., Exercise-induced myokines and their effect on prostate cancer. Nature Reviews Urology, 2021. 18(9): p. 519-542.
  12. Kim, J.S., et al., Myokine Expression and Tumor-Suppressive Effect of Serum after 12 wk of Exercise in Prostate Cancer Patients on ADT. Medicine and science in sports and exercise, 2022. 54(2): p. 197-205.
  13. Lopez, P., et al., Associations of fat and muscle mass with overall survival in men with prostate cancer: a systematic review with meta-analysis. Prostate Cancer and Prostatic Diseases, 2021.

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