Physical activity after cancer: An evidence review of the international literature

Robert James Thomas, Mea Holm and Ali Al-Adhami

Introduction

The number of individuals surviving cancer is expected to rise by one-third according to estimates from the American Cancer Society and the National Cancer Institute¹. This means that in the UK over 3 million individuals, and in the USA over 18 million individuals, will be living with the consequences of cancer by 2,022. The increase in the number of survivors is attributed to earlier diagnosis, an aging population, better cure rates and more effective systemic therapies to keep patients with metastatic disease alive for longer. To achieve these benefits, patients often have to endure more complex and arduous therapies, frequently leaving them beleaguered with acute and long-term adverse effects. In addition to being unpleasant, these adverse effects result in financial implications for patients and their families, as well as resulting in a greater usage of health resources.

Although the importance of exercise is beginning to be recognised by health professionals, advocacy groups and charities, it still remains an under-utilised resource. This article highlights the evidence that a physically active lifestyle and formal exercise programmes can help relieve many of the common concerns and adverse effects which plague individuals in the cancer survivorship period.

Physical activity improves well-being after cancer

Dozens of interventional studies have tested the feasibility and potential benefits of exercise in cancer survivors^2,3,4. Recent meta-analyses of randomised trials involving exercise interventions after cancer, encouragingly demonstrate that the benefits of exercise spanned across several common cancer types and following a range of treatments including surgery, radiotherapy, chemotherapy, hormones and even the newer biological therapies. The most recent meta-analysis of 34 randomised trials published in the BMJ in 2012 involving patients exercising after cancer, demonstrated a benefit for a number of troublesome symptoms particularly fatigue, mood, anxiety and depression; muscle power, hand grip, exercise capacity and quality of life⁵.

The American College of Sports Medicine also published a comprehensive review of exercise intervention studies in cancer populations which included data from 85 RCT’s of exercise in cancer survivors. Evidence consistently demonstrated that exercise could be performed safely in adjuvant and post-treatment settings. Exercise led to significant improvements in aerobic fitness; increased flexibility and strength; quality of life; anxiety and depression; fatigue, body image, size and composition⁴.

The individual categories of symptoms which commonly afflict cancer survivors are now discussed in more detail:

Cancer related fatigue (CRF) is one of the most distressing symptoms experienced by patients during and after their anti-cancer therapies. It is reported by 60-96% of patients during chemotherapy, radiotherapy or after surgery, and by up to 40% of patients taking long-term therapies such as hormonal or biological therapies⁶. The first step to treating CRF is to correct, if possible, any medical conditions that may aggravate it, such as anaemia, electrolyte imbalance, liver failure and nocturia; or to eliminate drugs such as opiates, anti-histamines and anti-sickness medication⁷. The role of exercise was reviewed in 28 randomised, controlled trials (RCTs) involving 2083 participants in a variety of exercise programmes and showed that exercise improved CRF, although the benefit overall was small⁸. A second review of 18 RCTs involving 1,109 participants, sub-divided the data into types of exercise and demonstrated that supervised exercise programmes had the most impact on CRF⁹. Further meta-analyses and reviews have also showed that supervised exercise programmes had better results, with a greater reduction in CRF amongst breast cancer survivors assigned to exercise programmes compared to home-based programmes^4,5,8,10.

Psychological distress, including anxiety and depression, is common after cancer with reported prevalence rates of 25-30%¹¹. Patients with psychological distress have also been shown to have reduced survival compared to those who are psychologically healthy¹². Exercise may help alleviate this symptom and improve mood, as a number of observational studies have shown that cancer patients who exercise have reduced levels of depression and anxiety, better self-esteem and are happier, especially if they involve group activities¹³. The recent meta-analyses of RCTs also demonstrated a reduction in anxiety and depression among individuals assigned to exercise programmes^4,5.

Quality of life (QOL) is lower in many cancer sufferers and survivors, linked to other physical and psychological symptoms of cancer and its’ treatment. Meta-analyses of studies of exercise intervention programmes have demonstrated an improvement of QOL at all stages of the illness for the common cancer types and following several types of treatment^4,5. For example, in a study involving 1,966 patients with colorectal cancer, patients achieving at least 150 minutes of physical activity per week had an 18% higher QOL score than those who reported no physical activity, as measured by the QOL FACT-C¹⁴. Another study showed similar benefits for breast cancer survivors who had completed surgery, radiotherapy or chemotherapy, and also demonstrated that change in peak oxygen consumption correlated with change in overall QOL¹⁵.

Weight gain:45% of women with breast cancer report significant weight gain¹⁶, and in a study of 440 prostate cancer survivors, 53% were overweight or obese¹⁷. For patients with bowel cancer, the CALBG 8980 trial showed that 35% of patients post-chemotherapy were overweight (BMI 25.0–29.9), and 34% were obese (BMI 30.0–34.9) or very obese (BMI >35)¹⁶. The reasons for this are multifactorial, but may include other symptoms of cancer treatment such as fatigue and nausea, causing patients to stop exercising. Regardless of the reasons for weight gain, numerous reviews and a comprehensive meta-analysis of the published literature have demonstrated that individuals who gain weight after cancer treatments have worse survival and more complications¹⁸. Fortunately, supervised exercise programmes have been shown to reduce weight and have significant other benefits on body constitution and fitness, such as improved lean mass indices, bone mineral density, cardiopulmonary function, muscle strength and walking distance^18,19.

Bone mineral density (BMD): Pre-menopausal women who have had breast cancer treatment are at increased risk of osteoporosis, caused by reduced levels of oestrogen brought on by a premature menopause due to chemotherapy, surgery or hormones. Men who receive hormone deprivation therapy for prostate cancer are also at an increased risk of developing osteoporosis. Accelerated bone loss has also been reported for many other cancers, including testicular, thyroid, gastric and CNS cancers, as well as non-Hodgkin’s lymphoma and various haematological malignant diseases^20,21. Lifestyle factors linked to an increase in the risk for developing osteoporosis include a low calcium and vitamin D intake, a diet low in plant-based protein, lack of physical activity, smoking and excessive alcohol intake²². A number of studies have linked regular physical activity with a reduction in the risk of bone mineral loss. Sixty six women with breast cancer were randomized to a control group or an exercise programme. The rate of decline of BMD was -6.23% in the control group, -4.92% in the resistance exercise group, and -0.76% in the aerobic exercise group. The statistically significant benefit was even greater in pre-menopausal women²³. In another RCT of 223 women with breast cancer, it was found that exercise, over 30 minutes 4-7 times a week, helped preserve bone mineral density even when bisphosphonates (risedronate), calcium and vitamin D had already been prescribed²⁴.

Thromboembolism: Those with pelvic involvement, recent surgery and immobility, previous history of varicose veins or thrombosis or receiving chemotherapy, are at higher risk²⁵. Although strategies such as compression stockings, warfarin and low molecular weight heparin are essential, early mobilisation and exercise remains a practical additional aid in reducing this life-threatening complication^18,26.

Constipation caused by immobility, opiate analgesics or anti-emetics during chemotherapy is a significant patient concern. Exercise reduces bowel transit time, and ameliorates constipation and its’ associated abdominal cramps²⁶.

Physical activity improves survival and reduces relapse

In addition to improving the side effects of treatment for cancer, regular physical activity during and after cancer appears to improve overall survival and reduces the probability of relapse. One of the most convincing studies was an RCT in which 2,437 post-menopausal women with early breast cancer were randomised to nutritional and exercise counselling, or no counselling, as part of routine follow-ups¹⁹. In the group receiving counselling, fewer women relapsed and overall survival was greater in the oestrogen-negative subgroup. In another RCT, men with early prostate cancer were randomised to an exercise and lifestyle intervention or standard active surveillance. The average PSA in the intervention group went down, whilst in the control group it went up²⁷. This supports a previous RCT of which the primary end point evaluated a salicylate-based food supplement, but it required men in both arms to receive exercise and lifestyle counselling. Although there was no difference in the primary end point, 34% of men, who’s prostate specific antigen (PSA) was climbing before trial entry, stabilized²⁸.

The majority of the other published evidence for a reduced relapse rate and improved survival after cancer originates from retrospective analysis or prospective cohort studies. The National Cancer Institute, in a recent meta-analysis, reviewed 45 of these observational studies. The strongest evidence was demonstrated for breast cancer survivors; the next strongest evidence was for colorectal cancer survivors, followed by prostate cancer¹⁰. The most notable are summarised below:

Breast cancer: The five most prominent prospective cohort studies (in aggregate more than 15,000 women), have examined the relationship between physical activity cancer and prognosis:

• Irwin et al. (2008)²⁹ investigated a cohort of 933 breast cancer survivors and found that those who consistently exercised for >2.5 hours per week had a 67% lower risk of all deaths compared to sedentary women.
• Holmes et al. (2005)³⁰ performed a separate evaluation of 2,987 women in the Nurses’ Health Study and found that women walking >3 hours a week had lower recurrence rates, and better overall survival.
• Holick et al. (2008)³¹ performed a prospective observational study of 4,482 breast cancer survivors, and found that women who were physically active for >2.8 hours per week had a 35-49% lower risk of dying from breast cancer.
• Pierce et al. (2007)³² found that the benefits of 3 hours of exercise were even greater if combined with a healthy diet.
• Sternfeld et al. (2009)³³ in the LACE study, evaluated 1,870 women within 39 months of diagnosis. There was a significant difference in overall death rate between the highest and lowest quartile of exercise levels.

Colorectal cancer: The scientific community eagerly awaits the results of the CHALLENGE RCT mentioned above, but a number of retrospective analyses of randomised chemotherapy and cohort trials have been published:

• Haydon et al. (2006)³⁴retrospectively analysed a RCT involving patients with stage III bowel cancer and found a significant association between exercise and a 31% reduction in relapse rate.
• Giles et al. (2002)³⁵found that of 526 patients recruited into the Australian Cohort Study, those participating in recreational sport 1-2 days per week had a 5 year overall survival of 71%, as opposed to 57% in non exercisers.
• Meyerhardt et al. (2006)¹⁶ found in an analysis of the Intergroup CALGB study, that physically active patients with bowel cancer had 35% reduction in relapse rate in after chemotherapy.
• Meyerhardt et al. (2009)³⁶ analysed 668 patients with colorectal cancer within the Health Professionals Study. Men who exercised >27 vs. < 3METS-hours / week had a lower cancer-specific mortality.

Prostate cancer: Three cohort studies have demonstrated a survival benefit for physically active men with prostate cancer:

• Kenfield et al. (2011)³⁷performed a subset analysis of 2,686 men with prostate cancer, within the Health Professional Study, who exercised >30minutes per week or >3 MET-hours of total activity, had a 35% lower risk of overall death, and men who walked at a brisk pace for >90 minutes had a 51% lower risk of overall death.
• Richman et al. (2011)³⁸ reported that 1,455 men with prostate cancer, walking more than 3 hours a week, correlated with an improved survival but only if >3miles/hour.
• Giavannucci (2005)³⁹, within a prospective analysis, reported that men who exercised vigorously had a lower risk for fatal prostate cancer, although this effect was only seen for men over the age of 65.

Quantity and type of exercise recommended for cancer patients

For reduced cancer relapse and improved well-being, most of the cohort studies summarized above suggest moderate exercise of around 2.5 to 3 hours a week for breast cancer survivors. However, for prostate cancer survivors, mortality continues to decrease if the patient walks 4 or more hours per week, and more vigorous activity is also associated with significant further reductions in risk for all-cause mortality³⁷. When the mode of exercise is primarily walking, a pace of at least 3 miles/hour (for >3 hours/week) is recommended for a reduced risk of relapse ³⁸. Therefore, both the pace and duration of exercise affect the survival benefit achievable from exercise, with more vigorous activity generally having a greater benefit (see Table 1). The best results appear to be with programmes including a combination of aerobic and resistance exercises, particularly within a social group.

Table 1: Summary of exercise guidelines for cancer survivors

The precise amount of exercise has to be determined on an individual basis and depends on pre-treatment ability, current disability caused by the cancer itself or the treatment, as well as time proximity to major treatments. An exercise programme supervised by a trained professional has major advantages, as they can design a regimen which starts slowly and gradually builds up to an acceptable and enjoyable pace. In addition, they can help motivate the individual to continue exercising for the short and the long-term, and they can judge the optimal exercise levels to improve fatigue, and not aggravate it.

The underlying mechanisms of the potential anti-cancer effects of exercise

The body’s chemical environment significantly changes after exercise, best demonstrated in the Ornish study, which found that serum from prostate cancer patients who exercised, had an almost eight times greater inhibitory effect on the growth of cultured androgen dependent prostate cancer cells compared to serum from patients in the control group²⁷. The precise chemical mechanism, which the anti-cancer effect remains incompletely understood, but one of the most likely mechanisms involving growth factors such as insulin-like growth factor (IGF-1) and its’ binding proteins insulin-like growth factor binding proteins (IGFBPs), due to the central role of these proteins in the regulation of cell growth (see Table 2). After binding to its receptor tyrosine kinase, IGF-1 activates several signalling pathways including the AKT pathway, leading to the inhibition of apoptosis and the promotion of cell growth and angiogenesis^34,40,41. An inverse relationship of cancer risk with IGFBP3 levels has also been shown, although this effect has not been confirmed in all studies⁴². Exercise has been shown to increase the levels of IGFBP3, and this was associated with a 48% reduction of cancer-specific deaths in a large prospective cohort study of 41,528 participants⁴³. Decreased levels for IGF-1 in physically active patients have been reported with an associated survival benefit⁴⁴.

Table 2: Summary of the potential biochemical pathways of the anticancer effects of exercise

Exercise has also been shown to have a large impact on gene expression, although the mechanisms through which the patterns of gene expression are affected remain to be determined. In a recent study of the mechanisms through which exercise impacts prostate cancer survival, it was found that 184 genes are differentially expressed between prostate cancer patients who engage in vigorous activity, and those who do not ³⁷. Amongst the genes that were more highly expressed in men who exercise were BRCA1 and BRCA2, both of which are involved in DNA repair processes.

Another neuropeptide which changes after exercise is Vasoactive Intestinal Protein (VIP). Breast and prostate cancer patients have been found to have higher VIP titres compared to individuals who regularly exercise, and who have increased production of natural anti-VIP antibodies⁴⁵. In hormone-related cancers such as cancers of the breast, ovaries, prostate and testes, the association between high levels of circulating sex hormones and cancer risk is well established⁴⁶. Another mechanism through which exercise may affect cancer, is through decreasing the serum levels of these hormones. For breast cancer survivors, the link between exercise and lower levels of oestrogen has been shown^13,34,47. An indirect, related mechanism is that exercise helps reduce adiposity, and adiposity in turn influences the production and availability of sex hormones⁴⁸. In addition, greater adiposity leads to higher levels of Leptin, a neuropeptide cytokine with has cancer promoting properties^49,50.

Other pathways include the modulation of immunity, such as improvements in NK cell cytolytic activity 11; the modulation of apoptotic pathways through impacting on a key regulator, p53⁵¹, and an exciting recent discovery, the messenger protein irisin, which is produced in muscle cells in response to exercise and is found is to be an important molecule in linking exercise to the health benefits⁵² , However, we are only beginning to scratch the surface with these and the other mechanisms discussed here, and much more research needs to be done to in this area.

Incorporating exercise into mainstream cancer management

The challenge for health professionals is how to encourage and motivate individuals with cancer to increase their exercise levels. Some, of course, are motivated to increase physical activity or remain active after cancer. However, a recent survey of 440 men with prostate cancer found that only 4% of patients exercised for more than the 3 hours a week recommended by the WCRF¹⁷. Macmillan Cancer Relief has produced a series of helpful booklets and web-based patient information materials designed to inform and motivate individuals to exercise as part of its ‘Move More’programme. The Cancernet website has a facility to search for local exercise facilities by postcode, which can be an aid for health professionals when counselling patients. It highlights activities that men will hopefully find feasible and enjoyable such as golf, exercise groups and walking groups, and are encouraged to attend in addition to work place activity and gardening.

Several pilot schemes have been started throughout the UK with the aim to incorporate exercise programmes into standard oncology practice. The difficulty with small schemes is that they tend to be poorly funded, often poorly attended and are unlikely to be sustainable in the longer term. Many agree that the gold standard model would be similar to the cardiac rehabilitation programme⁵³. This would involve a hospital scheme run by a physiotherapist or an occupational therapist, supervising patients immediately after surgery, radiotherapy and even during chemotherapy. This is followed by refering the patient to a community-based scheme for the longer term. Unfortunately, this type of scheme is expensive and unlikely to be funded at present, despite the obvious savings by preventing patient relapsing and ultilising health care facilities to help late effects of cancer treatment⁵⁴. However, expanding existing services, such as the National Exercise Referral Scheme, is a practical solution. The National Exercise Referral Scheme exists for other chronic conditions such as cardiac rehabilitation, obesity and lower back pain. The national standards for the scheme to be expanded to include cancer rehabilitation were written and accepted in 2010. Training providers have now developed training courses for exercise professionals set against these standards. Trainers completing the course gain a Register of Exercise Professionals (REPs) Level Four qualification, allowing them to receive referrals from GPs and other health professionals.

Conclusion

There are a wealth of well-conducted studies which have demonstrated an association between regular exercise and lower risk of side effects after cancer, as well as reasonable prospective data for a lower relapse rates and better overall survival. However, as there are several overlapping lifestyle factors, which are difficult to investigate on their own, there remain some concerns that exercisers may do better in these studies because they are less likely to be over-weight, more likely to have better diets and to be non-smokers. Although the existing RCTs provide encouraging evidence that exercise intervention programmes are beneficial, further large RCTs are needed, particularly in terms of cost-effectiveness, before commissioner’s start investing more in this area.

References

1. American Cancer Society (ACS); Cancer treatment & survivorship facts & figures 2012-2013. Available from: www.cancer.org/Research/CancerFactsFigures/index.
2. Markes M, Brockow T, Resch K (2006): Exercise for women receiving adjuvant therapy for breast cancer.Cochrane Database of systemic reviews: art no.CD005001. Doi 10.1002/14651858.CD005001.pub2.;
3. McNeeley M, Campbell K, Rowe B et al (2006) Effects of exercise on breast cancer patients and survivours: A systemic review and meta-analysis. Canadian Medical Association Journal 175:34-41.
4. Schmitz KH, Courneya KS, Matthews C et al. (2010) American College of Sports Medicine roundtable on exercise guidelines for cancer survivours. Med Sci Sports Exercise 42: 1409-26
5. Fong DYT, Ho JWT, Hui BPH, et al.; Physical activity for cancer survivors: meta-analysis of randomised Controlled Trials. Br Med J 2012; 344: e70.
6. Wagner LI, Cella D.; Fatigue and cancer: causes, prevalence and treatment approaches. Brit J Cancer 2004; 91: 822-828.
7. Thomas R; Anaemia fatigue and epoeitin in oncology. British Journal of Cancer Management 2005; 2(4): 12-15.
8. Cramp F, Daniel J; Exercise for the management of cancer-related fatigue in adults. Cochrane Database Syst Rev 2008; 2: CD006145.
9. Velthuis MJ, Agasi-Idenburg SC, Aufdemkampe G, et al.; The effect of physical exercise on cancer-related fatigue during cancer treatment: A meta-analysis of randomized controlled trials. Clin Oncol 2010; 2(3): 208-221.
10. Ballard-Barbash R, Friedenreich CM, Courneya KS, et al.; Physical Activity, Biomarkers, and Disease Outcomes in Cancer Survivors: A Systematic Review. J Natl Cancer Inst 2012; 104(11): 815-840.
11. Drouin JS, Armstrong H, Krause S, et al.; Effects of aerobic exercise training on peak aerobic capacity, fatigue, and psychological factors during radiation for breast cancer. Rehabil Oncol 2005; 23: 11­17.
12. Kadan-Lottick NS, Venderwerker LC, Block SD, et al.; Psychiatric disorders and mental health service use in patients with advanced cancer. Cancer 2005; 104(12): 2872-2881.
13. Mock V, Picket M, Ropka ME, et al.; Fatigue and quality of life outcomes of exercise during cancer treatment. Cancer Pract. 2001; 9(3): 119-127.
14. Lynch B, Cerin E, Owen N, et al.; Prospective relationships of physical activity with quality of life among colorectal cancer survivors. J Clin Oncol 2008; 26(27): 4480-4487.
15. Courneya KS, Segal RJ, Mackey JR, et al.; Effects of aerobic and resistance exercise in breast cancer patients receiving adjuvant chemotherapy: A multicenter randomized controlled trial. J Clin Oncol 2007; 25(28): 4396-4404.
16. Meyerhardt JA, Heseltine D, Niedzwiecki D, et al.; The impact of physical activity on patients with stage III colon cancer: Findings from Intergroup trial CALGB 89803. J Clin Oncol 2006; 24(22): 3535-3341.
17. Thomas R, Holm MM, Williams M, et al.; Lifestyle habits during and after prostatic radiotherapy influences the risk of late toxicity. 7th NCRI Cancer Conference; 2011; Liverpool, UK. (full paper in print Clinical Oncology for 2013).
18. Knols R, Aaronson NK, Uebelhart D, et al.; Physical exercise in cancer patients during and after medical treatment: A systemic review of randomized controlled trials. J Clin Oncol 2005; 23(16): 3830-3842.
19. Chlebowski R, Aiello E, McTiernan A; Weight loss in breast cancer patient management. J Clin Oncol 2002; 20(4): 1128-1143.
20. Brown JK, Byers T, Doyle C, et al.; Diet and physical activity during and after cancer treatment: An American cancer society guide for informed choices. CA Cancer J Clin 2003; 53(5): 268-291
21. Saad F, Adachi JD, Brown JP et al. Cancer Treatment – Induced Bone Loss in Breast Cancer and Prostate Cancer. J Clin Oncol 2008;26:5465-76.
22. Weikert C, Hoffmann K, Dierkes J, et al.; Homocysteine metabolism related dietary pattern and the risk of coronary heart disease in two independent German study populations. J Nutr 2005; 135: 1981–1988.
23. Waltman NL, Twiss JJ, Ott CD, et al.; The effect of weight training on bone mineral density and bone turnover in postmenopausal breast cancer survivors with bone loss: A 24-month randomized controlled trial. Osteoporos Int 2010; 21(8): 1361-1369.
24. Schwartz AL, Winters-Stone K, Gallucci B.; Exercise effects on bone mineral density in women with breast cancer receiving adjuvant chemotherapy. Oncol Nurs Forum 2007; 34(3): 627-633.
25. Galster H, Kolb G, Kohsytorz A, et al.; The pre-, peri-, and postsurgical activation of coagulation and the thromboembolic risk for different risk groups. Thromb Res 2000; 100(5): 381-388.
26. Davis N, Bateman L, Thomas R Exercise and lifestyle after cancer – evidence review 2011 British Journal of Cancer vol 105 pp 52-73.
27. Ornish D, Weidner G, Fair WR, et al.; Intensive lifestyle changes may affect the progression of prostate cancer. J Urol 2005; 174: 1065-1070.
28. Thomas R, Blades M, Williams M. Can dietary and lifestyle intervention alter prostate cancer progression 2007.. Nutrition & Food Science, 2007 vol 37, no.1 pp 24-36.
29. Irwin ML, Wilder Smith A, McTiernan A, et al.; Influence of Pre- and Postdiagnosis Physical Activity on Mortality in Breast Cancer Survivors: The Health, Eating, Activity, and Lifestyle Study. J Clin Oncol 2008; 26(24): 3958-3964.
30. Holmes M, Chen WY, Feskanich D, et al.; Physical activity and survival after breast cancer diagnosis. JAMA 2005; 293: 2479-2486.
31. Holick C, Newcomb PA, Trentham-Dietz A, et al.; Physical Activity and Survival after Diagnosis of Invasive Breast Cancer. Cancer Epidemiological Biomarkers Prev 2008; 17: 379-386.
32. Pierce JP, Natarajan L, Caan BJ; Influence of a diet very high in vegetables, fruit, and fiber and low in fat on prognosis following treatment for breast cancer. JAMA. 2007 Jul 18;298(3):289-98.
33. Sternfeld B, Gunderson E;Life After Cancer Epidemiology (LACE) Study: a cohort of early stage breast cancer survivors (United States). Cancer Causes Control. 2005 Jun;16(5):545-56.
34. Haydon AM, McInnis RJ, English DR, et al.; The effect of physical activity and body size on survival after diagnosis with colorectal cancer. Gut 2006; 55(1): 62-67.
35. Giles GG, English DR. The Melbourne Collaborative Cohort Study IARC Sci Publ, 2002. 156: p. 69-70.
36. Meyerhardt LA, Giovannucci EL, Ogino S et al. (2009) Physical activity and male colorectal cancer survival. Arch Intern Med 169:2102-8.
37. Kenfield SA, Stampfer MJ, Giovannucci E, et al.; Physical Activity and Survival After Prostate Cancer Diagnosis in the Health Professionals Follow-Up Study. J Clin Oncol 2011; 29(6): 726-732.
38. 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(11): 1-7.
39. Giavannucci EL, Liu Y, Leitzmann MF, et al.; A prospective study of physical activity and incident and fatal prostate cancer. Arch Intern Med. 2005;165(9): 1005-1010.
40. Palmqvist R, Halmans G, Rinaldi S, et al., Plasma insulin-like growth factor, insulin-like growth factor binding protein, and colorectal cancer: a prospective study in northern Sweden. Gut 2002; 50: 642-646.
41. Yu H, Rohan T; Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst 2000; 92: 1472–1489.
42. Ma J, Pollak MN, Giovannucci E, et al. Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst 1999; 91(7): 620-625.
43. Haydon AM, McInnis RJ, English DR, et al.; Physical activity, insulin-like growth factor 1, insulin-like growth factor binding protein 3, and survival from colorectal cancer. Gut 2006; 55(5): 689-94.
44. Irwin ML, Varma K, Alvarez-Reeves M, et al.; Randomized controlled trial of aerobic exercise on insulin and insulin-like growth factors in breast cancer survivors: the Yale Exercise and Survivorship study. Cancer Epidemiol Biomarkers Prev 2009; 18(1): 306-313.
45. Velijkovic M, Branch DR, Dopsaj V et al Can Natural Antibodies to VIP facilitate prevention and supportive treatment of breast Cancer? Med Hypothesis 2011 77 (3) 404-8
46. Kaaks R, Lukanova A; Effects of weight control and physical activity in cancer prevention: role of endogenous hormone metabolism. Ann NY Acad Sci 2002; 963: 268-281.
47. Folkert E, Dowset M; Influence of sex hormones on cancer progression. J Clin Oncol 2010; 28(26): 4034-4044.
48. Friedenreich CM, Woolcott CG, McTiernan A, et al.; Alberta physical activity and breast cancer prevention trial: Sex hormone changes in a year-long exercise intervention among postmenopausal women. J Clin Oncol 2010; 28(9): 1458-1466.
49. Hoffmann-Goetz, Apter D, Demark-Wahnefried W, et al.; Possible mechanisms mediating an association between physical activity and breast cancer. Cancer 1998; 83(3): S621-S628.
50. Surmacz E; Obesity hormone leptin; a new target for breast cancer? Breast Cancer Res 2007; 9(1): 301.
51. Sharafi, Rahimi; The Effect of Resistance Exercise on p53, Caspase-9, and Caspase-3 in Trained and Untrained Men. J Strength & Cond Res 2012; 26(4): 1142–1148.
52. BostrÖm P, Wu J, Jedrychowski MP, Korde A et al. Irisin induces brown fat of white adipose tissue in vivo and protects against diet-induced obesity and diabetes. Nature (2012) 481, 463-468 doi:10.1038/natutre10777.
53. Jolliffe JA, Rees K, Taylor RS, et al.;Exercise-based rehabilitation for coronary heart disease, Cochrane Database Syst Rev 2003. Abstract available at: http://www.cochrane.org/colloquia/abstracts/ capetown/capetownPC01.html
54. Thomas R, R Oakes, J Gordon, S Russell, M Blades and M Williams (2009) A randomised double-blind phase II study of lifestyle counselling and salicylate compounds in patients with progressive prostate cancer. (2009) Nutrition & Food Science, 39(3):295 – 305.

The above article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.