Tuesday, January 6, 2009

Exercise and Cancer Prevention

The observations were compelling, to say the least. First it was breast cancer, then colorectal cancer: 40 to 50 percent reductions in the risk of cancer-related death and cancer recurrence.The apparent cause was not a new targeted agent or a novel combination therapy, but rather, frequent trips back and forth in heavily chlorinated water, regular bouts with yard mulch and garden weeds, striding through the neighborhood for 30 minutes every morning. In other words, old-fashioned exercise.

Five large observational studies have now linked reports of regular post-treatment physical activity with superior outcomes compared with patients who remained sedentary after treatment. And now the first prospective, randomized clinical trial is nearly set to test whether physical activity can indeed influence cancer's course after treatment.

Results from the observational studies "are certainly compelling enough to warrant a randomized trial of physical activity," says Dr. Kerry Courneya, of the University of Alberta, who will lead the trial in patients who have been treated for colon cancer.

The trial represents a shift of sorts, because most cancer-related physical activity research to this point has not focused on recurrence or survival.

Studies That Got the Ball Rolling Physical activity and survival after colorectal cancer diagnosis - Meyerhardt et al., Journal of Clinical Oncology, August 2006  Impact of physical activity on cancer recurrence and survival in patients with stage III colon cancer - Meyerhardt et al., Journal of Clinical Oncology, August 2006Physical activity and survival after breast cancer diagnosis - Holmes et al., JAMA, May 2005

"There is extensive evidence [from prospective studies] that post-treatment activity improves cancer patient-reported outcomes such as quality of life or fatigue," explains Dr. Rachel Ballard-Barbash, associate director of the Applied Research Program in NCI's Division of Cancer Control and Population Sciences. Although there isn't much evidence to indicate which specific types of activities might be most beneficial from a recurrence or survival standpoint, Dr. Ballard-Barbash continues, "We do have good evidence on how to get cancer patients physically active."

The level of activity required for a measurable benefit varied, but the cancer mortality risk reductions reported from the large observational studies of physical activity - two of which came from the long-running Nurses' Health Study - have been fairly consistent.

"It's certainly intriguing data," says Dr. Wendy Demark-Wahnefried, from the Department of Behavioral Science at the University of Texas M.D. Anderson Cancer Center, who has been studying the impact of diet and exercise on long-term cancer survivors for more than a decade. "One of the questions now is whether the clinical trials [of physical activity] can be done, because I think there is tremendous interest."

NCI sponsored a workshop 2 years ago on how best to design such trials, notes Dr. Ballard-Barbash, and NCI has been fielding proposals to conduct them.

Dr. Lee W. Jones, director of the Tug McGraw Research Center at the Duke University Medical Center, says data to help inform optimal trial design (e.g., type of activity, intervention delivery strategies, etc.) is coming, as well as data on the potential biological mechanisms by which exercise may inhibit tumor growth.

Researchers, Dr. Jones says, have speculated that physical activity might influence post-treatment outcomes in breast cancer patients by dampening levels of estrogen or insulin, elevated levels of which are associated with poor outcomes. Several studies involving breast cancer patients, for instance, have consistently found a threefold increased risk of death among women with the highest insulin levels.

Meanwhile, studies involving patients with a range of problems, including diabetes and heart disease, have shown that physical activity can reduce insulin levels. Last year, researchers from Dana-Farber Cancer Institute (DFCI), led by Dr. Jennifer Ligibel, showed that a regimen of cardiovascular and strength training lowered insulin levels in sedentary women who had completed adjuvant therapy for early stage breast cancer.

"We're very interested in what happens biologically with physical activity," explains Dr. Ligibel, from DFCI's Breast Cancer Program. "We think it has to be modification of hormone levels.…And the data suggest that estrogen is not the whole story." The data, however, are far from consistent.

"In our preclinical studies, we've found that the hypoxia/angiogenic pathways are really upregulated with exercise, but that insulin doesn't change much," says Dr. Jones. (This does not necessarily mean that exercise doesn't alter insulin signaling in the tumor, he cautions.) And in one animal model study of prostate cancer, Dr. Jones adds, voluntary exercise actually accelerated tumor growth.

The trial Dr. Courneya is leading, dubbed CHALLENGE, is set to launch by the end of this year in Canada, and will investigate whether increased physical activity can improve disease-free survival (DFS) in patients treated for high-risk stage II and III colon cancer. (Another Canadian clinical trial that is already underway, called LISA, is testing whether a dietary and physical activity regimen focused on weight loss can improve DFS in overweight or obese women who have been treated for early stage breast cancer.)

The physical activity intervention in the trial follows from a similar - and highly successful - trial, the Diabetes Prevention Program. "The activity in this trial will be a mix," Dr. Courneya explains. "The literature doesn't point to a specific type of exercise that has the most benefit. So we're going to promote aerobic exercise, assuming that most participants will walk, but expecting that others will do things like biking or swimming."

The physical activity component will include in-person or phone-based meetings with exercise consultants for 3 years, with more frequent meetings for the first year. "This isn't like taking a drug," Dr. Courneya acknowledges. "These types of lifestyle interventions are difficult and have to be delivered over a longer period of time."

Dr. Ligibel agrees that delivery of the intervention is a challenge. "The data suggest there is better compliance with dietary modifications than physical activity modifications," she says. Even so, small studies and trials of the influence of exercise on cancer outcomes are multiplying and expanding to other cancer types. Dr. Jones' group at Duke, for example, has been conducting studies in patients before and after lung cancer surgery, as well as in patients with primary brain tumors.

"I'm very confident that anybody, regardless of where they are in the cancer survivorship continuum, can exercise," Dr. Jones says. "It's just a matter of what type of exercise, the frequency, and the intensity."

SOURCE: National Cancer Institute's Report - Some Exercise a Day May Keep Cancer at Bay by Carmen Phillips

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