Exercise and physical activity are beneficial along the spectrum of care in cancer patients. However, much more research is needed to better understand this association and guide recommendations for patients.
Until a decade ago, when cancer patients asked their oncologists whether exercise would be helpful as part of their treatment for cancer, the likely response was terse and/or dismissive. Oncology providers were doubtful of patients’ ability to exercise or participate in physical activity (PA) during therapy and likely did not consider that exercise and PA would impact their cancer outcomes. However, there is now a burgeoning body of literature consistently reporting the positive association of exercise and PA on cancer prevention, tolerance to cancer-directed therapies (radiation and chemotherapy), reduction in recurrence, and improvement in survival.[1,2] As a result, many health organizations, including the American Cancer Society and American College of Sports Medicine, recommend exercise for cancer survivors.[1,3] However, the type, intensity, and duration of exercise remain uncertain and it is not known whether the effects of exercise impact all types of cancer and treatments.
In this issue of ONCOLOGY, Lemanne et al have elegantly summarized the effect of exercise and PA at various points on the cancer survivorship continuum, including cancer risk, treatment side effects, early survivorship, and advanced cancer. They address some of the potential molecular mechanisms through which exercise may exert an effect on tumor progression, such as mammalian target of rapamycin (mTOR)/Akt, phosphatidylinositide 3 (PI3)-kinases, and phosphatase and tensin homolog (PTEN). Their conclusions and caveats are supported by a growing body of literature, including numerous meta-analyses and systemic reviews. Among the many benefits of exercise and PA on cancer, most oncologists and cancer patients may be most interested in exercise and PA effects on survival.
Do we have enough evidence to say that the exercise is good for cancer patients through both the treatment and survival periods? The answer is that there is reasonably good evidence of an exercise/PA benefit in patients with some types of cancers (eg, breast and colorectal) but not enough evidence for many others. Recently, Ballard-Barbash et al performed a systematic review of 45 articles that were related to PA, cancer survival, and biomarkers potentially relevant to cancer survivors. They reported that PA was associated with reduced all-cause, breast cancer–specific, and colorectal cancer–specific mortality. However, how much PA is needed to elicit the beneficial influence on survival? As discussed by Lemanne and colleagues, some studies in colorectal cancer suggest that at least 18 metabolic equivalent tasks (MET) hours per week of PA is needed.[6,7] We have also recently performed a meta-analysis of prospective cohort studies which investigated the association between PA and cancer survival in colorectal cancer. Our meta-analysis showed that a relatively modest level of PA, on the order of 9 MET hours per week or more, was associated with improvements in mortality rates among colorectal cancer patients, compared with less than 3 MET hours per week. In breast cancer patients, 9 MET hours per week or more of PA was associated with significantly reduced cancer-specific and all-cause mortality as well. However, all of these studies are observational in nature and all create categories of exercise levels in order to generate hazard ratios for analyses, therefore defining the cutoff for benefit is neither straightforward nor precise.
Although a positive association between PA and survival of cancer patients have been identified consistently in breast and colorectal cancer, evidence of an association between PA and survival is still lacking for other cancers, such as stomach, prostate, and endometrium cancer. Further, to date, all studies on exercise, PA, and cancer recurrence and/or mortality are observational in nature. This has led to a debate about whether a randomized trial is needed in breast and colorectal cancer to prove causation. The challenges are many in a randomized trial of exercise. First, as stated, the minimum level of intensity and total duration of a particular exercise needed in order to see an effect are not defined. Second, the question of how to change one’s level of exercise and sustain those changes in exercise for the number of patients required for such a trial to have sufficient statistical power is not clear. Supervised exercise sessions are preferred by some investigators but difficult to institute on a large scale. Telephone-based or web-based counseling has been used in other behavioral trials, but it is unclear that such approaches will increase and sustain the level of exercise and PA for the needed sample size to have adequate power to test for impact on recurrences and/or survival. Other issues like drop-in rates (control-arm patients increasing their exercise levels) and drop-out rates are of greater concern in such behavioral studies than in most drug trials.
Recent studies shed more light on the mechanisms that may account for the associations between exercise/PA and cancer survival, suggesting that exercise may have both direct and indirect effects on tumors. First, exercise and PA may directly have effects on tumor development and progression mediated through altering procarcinogens such as insulin, insulin like growth factor (IGF)-1, IGF binding proteins, estradiol,[13,14] sex hormone binding globulin (SHBG),[13,14] dehydroepiandrosterone sulphate (DHEAS), colonic bile acid, inflammatory markers, rs2665802 polymorphism, and promoter hypermethylation of tumor suppressor genes. We have also recently reported that, in stage II/III colorectal cancer patients who completed adjuvant therapies, 12 weeks of participation in a home-based exercise program significantly reduced levels of fasting insulin and tumor necrosis factor alpha but increased adiponectin levels. We have observed significantly increased IGF-1 levels in patients after participation in the exercise program, but IGFBP-3 levels also increased, resulting in no change in the IGF-1/IGFBP-3 ratio. Secondly, the indirect effects of exercise on tumor could be associated with the general health status and immune function of cancer patients, which are important factors that may help cancer patients to successfully complete adjuvant therapy and treatment with different lines of chemotherapies.
Therefore, we agree with Lemanne and colleagues that exercise and PA are beneficial along the spectrum of care in cancer patients. However, much more research is needed to better understand this association and guide recommendations for patients.
Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Rock CL, Doyle C, Demark-Wahnefried W, et al. Nutrition and physical activity guidelines for cancer survivors. CA Cancer J Clin. 2012;62:243-74.
2. Kushi LH, Doyle C, McCullough M, et al. American Cancer Society Guidelines on nutrition and physical activity for cancer prevention: reducing the risk of cancer with healthy food choices and physical activity. CA Cancer J Clin . 2012;62:30-67.
3. Schmitz KH, Courneya KS, Matthews C, et al. American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Med Sci Sports Exerc. 2010;42:1409-26.
4. Lemanne D, Cassileth B, Gubili J. The role of physical activity in cancer prevention, treatment, recovery, and survivorship. Oncology. 2013;27:580-85.
5. 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;104:815-40.
6. Meyerhardt JA, Heseltine D, Niedzwiecki D, et al. Impact of physical activity on cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803. J Clin Oncol. 2006;24:3535-41.
7. Meyerhardt JA, Giovannucci EL, Ogino S, et al. Physical activity and male colorectal cancer survival. Arch Intern Med. 2009;169:2102-8.
8. Je Y, Jeon JY, Giovannucci EL, Meyerhardt JA. Association between physical activity and mortality in colorectal cancer: a meta-analysis of prospective cohort studies. Int J Cancer. 2013 Apr 12. [Epub ahead of print]
9. Holmes MD, Chen WY, Feskanich D, et al. Physical activity and survival after breast cancer diagnosis. JAMA 2005;293:2479-86.
10. Meyerhardt JA, Giovannucci EL, Holmes MD, et al. Physical activity and survival after colorectal cancer diagnosis. J Clin Oncol. 2006;24:3527-34.
11. Ligibel JA, Campbell N, Partridge A, et al. Impact of a mixed strength and endurance exercise intervention on insulin levels in breast cancer survivors. J Clin Oncol. 2008;26:907-12.
12. 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;18:306-13.
13. 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;28:1458-66.
14. van Gils CH, Peeters PH, Schoenmakers MC, et al. Physical activity and endogenous sex hormone levels in postmenopausal women: a cross-sectional study in the Prospect-EPIC Cohort. Cancer Epidemiol Biomarkers Prev. 2009;18:377-83.
15. Wertheim BC, Martinez ME, Ashbeck EL, et al. Physical activity as a determinant of fecal bile acid levels. Cancer Epidemiol Biomarkers Prev. 2009;18:1591-8.
16. Friedenreich CM, Neilson HK, Woolcott CG, et al. Inflammatory marker changes in a yearlong randomized exercise intervention trial among postmenopausal women. Cancer Prev Res (Phila). 2012;5:98-108.
17. Khoury-Shakour S, Gruber SB, Lejbkowicz F, et al. Recreational physical activity modifies the association between a common GH1 polymorphism and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev. 2008;17:3314-8.
18. Coyle YM, Xie XJ, Lewis CM, et al. Role of physical activity in modulating breast cancer risk as defined by APC and RASSF1A promoter hypermethylation in nonmalignant breast tissue. Cancer Epidemiol Biomarkers Prev. 2007;16:192-6.
19. Lee DH, Kim JY, Lee MK, et al. Effects of a 12-week home-based exercise program on the level of physical activity, insulin, and cytokines in colorectal cancer survivors: a pilot study. Support Care Cancer. 2013 May 2. [Epub ahead of print]