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Originally published as JCO Early Release 10.1200/JCO.2006.06.6548 on July 5 2006 © 2006 American Society of Clinical Oncology.
Cancer Survival: Time to Get Moving? Data Accumulate Suggesting a Link Between Physical Activity and Cancer SurvivalSchool of Nursing and Department of Surgery, Duke University Medical Center, Durham, NC Last year, an article by Holmes et al1 rocked the research community involved in cancer survivorship. The article reported a significant protective association between increased physical activity that occurred after the diagnosis of breast cancer and recurrence, cancer-related mortality, and overall mortality among a cohort of 2,987 stage I to III breast cancer survivors nested within the Nurse's Health Study. This year, Meyerhardt et al2,3 add to this growing body of research with findings from two separate studies that appear in this issue of the Journal of Clinical Oncology. Both of these prospective studies focused on colorectal cancer and each found a protective association with postdiagnosis physical activity. One of these studies closely paralleled the previous work of Holmes et al1 as it explored the association between physical activity undertaken after diagnosis and its relationship to mortality (overall and cancer specific) using the same cohort, the same survey instrument to assess physical activity, the same exclusionary criteria, and a similar analysis plan.2 Given the lower incidence of colorectal cancer, as compared with breast cancer, far fewer cases of colorectal cancer (573 v 2,987) were identified within the Nurse's Health Study cohort. Even with fewer cases, the study by Meyerhardt et al2 found significant protective associations with increasing levels of physical activity. Both studies found reductions in overall risk of mortality with 9+ metabolic equivalent task (MET) -hours per week of physical activity; however, although significant benefits were observed for breast cancer–specific mortality at the 9+ MET-hours per week cut point, for colorectal cancer–specific mortality, the cut point was 18+ MET-hours per week. In translating this information into useful clinical guidelines, 9 MET-hours per week is roughly equivalent to four to five weekly 30-minute sessions of brisk walking, whereas 18 MET-hours per week assumes exercise sessions that are double in duration or frequency, or more strenuous in nature (see Table 2 in Meyerhardt et al3). In this report, Meyerhardt et al2 present additional analyses and evidence that distinguishes that these protective associations are independent of premorbid levels of physical activity. Indeed, the research team is to be applauded for their careful work, which clearly suggests that it is physical activity that occurs postdiagnosis that is associated with an improved prognosis, rather than exercise habits established before disease. Such data have obvious import for clinical practice, as do the confirmatory findings of the second study by Meyerhardt et al3 appearing in this journal. This study was performed on a cohort of 832 patients participating in the Cancer and Leukemia Group B adjuvant therapy trial sponsored by the National Cancer Institute comparing weekly fluorouracil (FU) and leucovorin versus weekly irinotecan, FU, and leucovorin (CALGB 89803) in stage III colon cancer.3 One of this study's primary strengths was its reliance on the clinical trial framework. As such, the effects of confounding may have been minimized, given that the sample was composed solely of individuals who underwent a complete surgical resection and were found to have regional lymph node metastases (no evidence of distant metastases), and who had received one of two specified chemotherapeutic regimens. In addition, physical activity assessments were specifically timed in relation to treatment course (6 months post-therapy) and standardized methods were used for follow-up of cancer-related end points. Indeed, this study provides a successful example of how clinical research can augment classic epidemiologic studies to answer research questions. One approach relies on well-defined, circumscribed samples and assessing outcomes specifically in relation to disease or treatment course, and the other approach relies on broad-based samples to obtain results that are more readily generalizable. Findings of this clinical study indicated significantly lower rates of recurrence and increased disease-free survival with 18+ MET-hours per week of physical activity, with data showing relative reductions in risk of recurrence that approached 50% in both crude and adjusted analyses—associations that were durable even after the exclusion of participants who may have had underlying occult disease (such as those who had died or were found to have recurrences within 6 months of physical activity assessment). Associations with overall survival were not as strong and 95% CIs were much broader; nevertheless, the association was still significant in adjusted analyses. From the article, it is not known whether these other causes of death were from diseases where proven associations with physical activity exist, such as cardiovascular disease, or from other causes of mortality not traditionally linked to exercise. The results of this clinical study corroborate the epidemiologic findings of Holmes et al1 and Meyerhardt et al2 reviewed in the preceding paragraphs and suggest reduced relative risks that approximate 50% to 60% for both recurrence and overall mortality among those who reported higher levels of physical activity, as compared with those who were sedentary.3 Again, it should be noted that although all three studies employed a designated referent of less than 3 MET-hours per week to define those with sedentary lifestyles, significant benefits for breast cancer survivors were observed at 9+ MET-hours per week, whereas for colorectal and colon cancer patients, physical activity of at least 18 MET-hours per week was needed before significant benefits were observed. It is unknown whether this difference relates to issues inherent in study sample, power, or design, or whether different physical activity thresholds exist for different cancers. Indeed, this is an area that requires additional research. It is of particular interest that in the study of breast cancer by Holmes et al,1 the greatest benefits of physical activity were observed among women with stage III breast cancer (for 9+ MET-hours per week of physical activity, relative risk = 0.36; 95% CI, 0.19 to 0.71). Thus, in taking all three of studies together,1-3 we see a protective association with increased physical activity after diagnosis and firm, cancer-specific outcomes—findings that suggest favorable effects across the spectrum of cancer, from early-stage cancer to later stage disease. As clinicians, researchers, and policy makers, we have long awaited such confirmatory findings. To date, our exercise interventions, as well as the current guidelines for cancer survivors,4 and what we ultimately tell our patients, is that exercise may be beneficial, with guidance based largely on proven associations that exist between physical activity and specific comorbid conditions (such as heart disease or osteoporosis) to which cancer survivors are especially prone, or associations between physical activity and other factors, such as quality of life, functional decline, and fatigue. Given the high-risk nature of cancer survivors and the fact that they are high users of health care who have a profound impact on the health economy at large, the benefits of exercise or a healthy diet on outcomes other than those that are cancer specific are still important and cannot be discounted.5,6 Nor can we discount the several biologic mechanisms that are influenced by physical activity and that may play a potent role in hindering neoplasia.7,8 However, what we, as clinicians or interventionists, truly want to be able to say—and what cancer patients truly want to hear—is the following: "Through exercise you may be able to prevent progression or recurrence of your cancer." Unfortunately, the science is still not quite there—yet. While exceptionally valuable, it must be remembered that the findings of Meyerhardt et al,2,3 as well as those of Holmes et al,1 are observational in nature. Therefore, cause and effect cannot be assumed. Furthermore, many questions still remain regarding the effects of physical activity among cancer survivors. Is increased physical activity safe, especially among groups of survivors in which cardiotoxicity is frequently reported? What effort is required for benefit? What types of exercise are most beneficial? Does exercise exert its effects independently of or through weight control? What are the characteristics of cancer patients most responsive to exercise, based on cancer type, stage, receptor status, and so forth? Indeed, the only way that we will be able truly to assess whether increased physical activity can reduce recurrence or deaths due to cancer is to pursue studies that lead up to and include randomized controlled clinical trials that ultimately are able to answer whether or not physical activity is beneficial for cancer control. Data from these three observational studies suggest a reduced risk of recurrence of 50% to 60%.1-3 Such an effect parallels that of trastuzumab for HER-2–positive breast cancer patients,9,10 an agent heralded by the oncologic care community and by the Director of the National Cancer Institute, Andrew C. von Eschenbach, MD, as "a major advance and turning point in eliminating suffering and death from cancer."11 To be sure, behavioral interventions are complex and have a host of barriers in that they are difficult to deliver and require careful attention to issues of adherence; perhaps the largest barrier of all is the lack of industry funding. There is no doubt that the pharmaceutical industry would back an agent with potential to reduce cancer recurrence by at least 50%, but who will back a trial that evaluates the potential benefit of sneakers and sweatpants? Would Nike "Just do it?" Perhaps, and indeed, it would be a magnificent gesture of goodwill. But likely, this is a research question that will require a large multisite trial and fall on the shoulders of the government to support. Every 1.5 minutes, another person in the United States is diagnosed with either breast or colon cancer; indeed, it is these individuals, as well as the more than 4 million survivors of these cancers,12 who would benefit from the answer. It's time to get moving! Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. ACKNOWLEDGMENTS Supported by National Institutes of Health Grants No. CA81191, CA85740, CA106919, and AR52186, and the American Institute for Cancer Research. REFERENCES
1. Holmes MD, Chen WY, Feskanich D, et al: Physical activity and survival after breast cancer diagnosis. JAMA 293:2479-2486, 2005 2. Meyerhardt JA, Giovannucci EL, Holmes MD, et al: Physical activity and survival after colorectal cancer diagnosis. J Clin Oncol 24:3527-3534, 2006 3. Meyerhardt JA, Heseltine D, Niedzwiecki D, et al: The impact of physical activity on cancer recurrence and survival in patients with stage III colon cancer: Findings from CALGB 89803. J Clin Oncol 24:3535-3541, 2006 4. Brown JK, Byers T, Doyle C, et al: Nutrition and physical activity during and after cancer treatment: An American Cancer Society guide for informed choices. CA Cancer J Clin 53:268-291, 2003 5. Yabroff KR, Lawrence WF, Clauser S, et al: Burden of illness in cancer survivors: Findings from a population-based national sample. J Natl Cancer Inst 96:1322-1330, 2004 6. Demark-Wahnefried W, Aziz N, Rowland J, et al: Riding the crest of the teachable moment: Promoting long-term health after the diagnosis of cancer. J Clin Oncol 23:5814-5830, 2005 7. McTiernan A: Physical activity after cancer: Physiologic outcomes. Cancer Invest 22:68-81, 2004[CrossRef][Medline] 8. Schmitz KH, Holtzman J, Courneya KS, et al: Controlled physical activity trials in cancer survivors: Systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev 14:1588-1595, 2005 9. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659-1672, 2005 10. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673-1684, 2005 11. National Cancer Institute: Herceptin combined with chemotherapy improves disease-free survival for patients with early-stage breast cancer. http://www.cancer.gov/newscenter/pressreleases/HerceptinCombination2005 12. American Cancer Society: Cancer Facts and Figures–2006 http://www.cancer.org/downloads/STT/CAFF2006PWSecured.pdf Related Articles
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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