Does Exercise Improve Survival in Cancer?
When it comes to cancer, a growing body of evidence supports the premise that regular physical activity may play a protective role and decrease the risk for many types of the disease. Exercise may also temper the adverse effects of treatment and help in recovery and rehabilitation when cancer therapy has ended.
But for all of its benefits, does exercise affect cancer outcomes? Do patients who regularly engage in physical activity have a better shot at survival, and do they lower their risk for disease recurrence?
The answer to that question remains up in the air. The jury is definitely still out, with no definitive agreement among the cancer community, as highlighted in a recent “Cross Talk” article published in Cancer World.
The New Chemo?
The role of regular physical activity as a way of reducing cancer risk has been embraced by many experts in the cancer community, as well as organizations such as International Agency for Research on Cancer. The 12-point official guide from the European Union on how to lower your cancer risk puts physical activity in the number 4 slot: “Be physically active in everyday life. Limit the time you spend sitting.”
But as the Cancer World article points out, the benefits of exercise are more controversial for those who already have cancer. While no one is disputing that exercise can be beneficial, there is disagreement as to the strength of current evidence regarding exercise and its role in survival.
One advocate highlighted in the article is Thierry Bouillet, MD, an oncologist at Avicenne Hospital in Paris, France, who feels that physical activity should be prescribed to women with early breast cancer, along with their regular therapeutic regimen.
The premise for this is based in part on the results of an analysis published in April, from the scientific commission of the National Federation Sport and Cancer CAMI in France. This review of 8 studies looked at how physical activity affected survival in patients with localized breast cancer (Crit Rev Oncol Hematol. 2015;94:74-86). Led by Dr Bouillet, the authors reported that “a physical activity higher than 8–9 metabolic equivalent task (MET)-hour per week was associated with a 50% reduction in mortality from both cancer and all causes.”
This translated into a benefit of 4% to 6% in terms of 5-year and 10-year survival, the “same benefit as chemotherapy,” Dr Bouillet told Cancer World.
The studies in the review were observational, but Dr Bouillet still felt that they built a “credible picture” because they were large and accounted for important confounders. He also pointed to randomized controlled trials that suggest exercise helps patients feel and function better, as well as help their social and psychological functioning. Taken together, these factors may affect survival.
The CAMI federation began in 1998, with Dr Bouillet as one of the founding members. It now has almost 60 partner institutions across France that run courses in a variety of different physical activities, everything from the martial arts to modern dance, and the programs are adapted for people with different types of chronic medical conditions. According to the article, the programs are now increasingly being offered by hospitals, such as the Institut Gustave Roussy in Villejuif, France, which now holds dance and karate classes.
The principle of prescribing physical activity that is adapted to the patient’s “pathology, physical abilities and medical risk” was also recently introduced as an amendment into a new piece of health legislation in France, the “Loi de la Santé.” The amendment sets the framework for providing this type of service, including the responsibilities for training physicians in prescribing adequate physical activity.
Cancer World also points to a controversial summary statement that was published in association with the amendment, which refers specifically to breast cancer treatment. While it discusses the more proven benefits of physical activity for counteracting fatigue, it mentions the effect in reducing recurrences and increasing survival chances by more than 50%.
But on the other side of the fence, the feeling is that evidence to promote exercise as a means of improving the odds of survival and preventing recurrence is just not there.
As Cancer World points out, earlier this year the consensus panel of the St Gallen International Breast Cancer Conference found that there was insufficient evidence to include physical activity in adjuvant therapy clinical guidelines for treating patients with early-stage disease. The panel did, however, endorse prescribing both physical activity and weight loss for their general health benefits.
One expert who advocates the need for better evidence is Pam Goodwin, MD, a medical oncologist at the University of Toronto’s Mount Sinai Hospital in Canada, who has conducted a great deal of research on lifestyle factors associated with breast cancer.
Dr Goodwin argues that the evidence for an effect of greater physical activity on cancer outcomes in early breast cancer is “simply not strong enough to tell patients their breast cancer outcomes will be improved if they become more active or lose weight.”
“The St Gallen adjuvant therapy guidelines focus on breast cancer specific survival and reduction in risk of recurrence,” she told Cancer World. “It wasn’t that I or anybody else was opposed to having breast cancer patients who are interested in being physically active be active — there’s no problem with that. The issue is that we don’t have the evidence to tell them that it will improve their breast cancer outcomes.”
Dr Goodwin also doesn’t put much faith in large series of observational studies because the results often don’t pan out. She uses the example of hormone replacement therapy, for which observational studies showed that the benefits outweighed the risks. But when randomized studies were done, they showed an increase in breast cancer risk and “a lot of the added benefits we thought existed didn’t.”
Julie Gaillot, from the French National Cancer Institute INCa, says that there is still uncertainty about the effect on survival. As for the amendment to the Loi de la Santé, she stated that INCa was not consulted and that, on the basis of current evidence, it is incorrect to suggest that physical activity can lead to a 50% reduction in mortality risk.
But Gaillot backs the general principle that physicians should be encouraging patients to be more active and that a change of mentality is needed. “It’s hard for doctors to introduce physical activity because they are not trained and educated about the benefits of exercise for people who are ill, whether it’s cancer or other chronic illnesses, or in the general population,” she told Cancer World.
INCa has the responsibility to provide advice to the public, she noted, but will provide only information that is based on validated evidence. This primarily means evidence that comes from randomized controlled trials on the benefits on fatigue, quality of life, body composition, and fitness — and not just about participation in sports but more generally adopting a less sedentary lifestyle. At the current time, they will not be endorsing any specific benefit on cancer survival because more solid evidence is needed.
More solid data may be on the way, as Cancer World notes that several randomized controlled trials that are ongoing or about to start will scrutinize the effect of physical activity and weight loss on cancer prognosis.
One is the CHALLENGE trial, led by the National Cancer Institute of Canada, which is investigating the effect of exercise on recurrence in colon cancer. Another that is about to be launched will investigate the effect of weight loss on breast cancer outcomes. That study will be led by Jennifer Ligibel at the Dana-Farber Cancer Institute in Boston. While these studies will take time to show results, the hope is that they will generate more reliable evidence.
More Support for Further Evidence
Medscape Medical News also spoke with two experts about this issue, and both agree that more evidence is needed as far as a survival benefit.
“I would take the same position as Pam Goodwin,” said Kerry S. Courneya, PhD, professor and Canada Research Chair in Physical Activity and Cancer, University of Alberta, Edmonton, Canada.
“There is good evidence for benefits both during and after treatments for several symptoms and some aspects of quality of life,” he noted, “but there is insufficient evidence that exercise will improve cancer outcomes.”
Anne McTiernan, MD, PhD, from the Fred Hutchinson Cancer Research Center, Seattle, Washington, agrees with the St Gallen recommendations.
“Many studies have shown that cancer survivors who are physically active have improved prognosis,” Dr McTiernan told Medscape Medical News. “However, the observational data from which these results come cannot control for potential confounding factors, such as presence of undetected micrometastases, which can cause fatigue and impact exercise levels.”
So with that in mind, it might not be the low exercise levels that cause poorer prognosis, but rather the biology that’s causing both lower exercise and lower prognosis. “The best way to clarify this is with a randomized controlled trial where survivors are randomly assigned to exercise or a control condition and followed long-term to determine effect on recurrence and survival,” she said.
Dr McTiernan explained that she and her group have proposed this sort of study to the US National Institutes of Health, but it was declined because of cost.
Several trials show that in the short term (over several months), exercise programs in survivors improve fatigue and quality of life. “So that’s where the recommendation comes that exercise can improve quality of life in survivors — and most studies were in breast cancer,” she said. “There are very few data on long-term exercise effects on survivors.”
However, Dr McTiernan pointed to an important issue that has not been adequately addressed even in the small trials of exercise or weight loss in cancer survivors: Are there adverse effects for survivors? While other trials looking at cancer treatments always measure adverse effects as part of the overall picture of therapeutic effects, exercise and weight loss trials generally don’t provide that information.
“So we can’t say weight loss or exercise is completely safe,” she explained. “For example, patients who have been treated with cardiotoxic drugs could have arrhythmias induced by more vigorous activity. Weight loss in health persons lowers white blood cell counts, and while this is safe for healthy people, for cancer patients/survivors with immune system depression from treatment, it might not be safe.”
But the bottom line, according to Dr McTiernan, is that exercise improves fatigue and quality of life in cancer survivors in the short term. “Cancer survivors, especially those who have undergone chemotherapy, should start an exercise program at a lower level than they were used to before cancer, and progress slowly, to reduce chances of injury,” she added. “Strength training appears to be safe even in people with lymphedema, but should be done under the supervision of someone who knows how to work with cancer survivors.”
Another recent paper, published online in the Journal of Clinical Oncology, presents a strategy for investigating exercise as a treatment for cancer.
In this commentary, Lee W. Jones, PhD, from Memorial Sloan Kettering Cancer Center, New York, New York, has put together a modified framework that uses a “precision oncology approach,” which can help researchers investigate exercise as a candidate anticancer treatment.
He notes that promising epidemiologic discovery data have led to the provocative hypothesis that exercise treatment may be able to improve cancer outcomes. This has in turn stepped up the call for larger phase 3 trials to definitively test this question.
“Emerging epidemiologic data suggest that the potential efficacy of exercise differs on the basis of tumor subtype,” he writes. “The heterogeneity in response creates the strong hypothesis that a precision oncology approach is required to optimize the benefit and safety of exercise as a candidate antitumor strategy.”
Therefore, he proposes a “potential translational framework that may facilitate these efforts.”
Instead of the “one size fits all generic version of exercise,” the physical activity should instead be matched to the patient, based on the molecular profile of the tumor and the patient’s genotype. Dr Jones tackles this approach by dividing it into seven steps: discovery, evaluation of causality (epidemiology), molecular epidemiology, preclinical testing, safety and tolerability clinical trials, early signal-seeking/biomarker driven clinical trials, and definitive clinical trials.
The Seven Steps
- Discovery: the initial discovery of a correlation between the exposure and the clinical disease end point of interest. An example would be if self-reported higher exposure to exercise after diagnosis were associated with a reduced risk for recurrence and cancer death in non small-cell lung cancer.
- Evaluation of causality (epidemiology): consensus of epidemiologic data showing a consistent relationship between exposure to treatment and the clinical disease end point of interest meeting the Bradford-Hill criteria. An example would be that higher exposure to (self-reported) postdiagnosis exercise is consistently associated with a reduced risk for recurrence and cancer death in non-small cell lung cancer in a dose-dependent manner, after adjustment for important clinical covariates and treatment.
- Molecular epidemiology: the application of -omic-based platforms to elucidate whether certain patient subtypes might be more responsive to exercise exposure than others. This information can be used to guide patient selection. Continuing on with the two examples above, this would indicate that not only would recurrence and death be reduced in non small-cell lung cancer (in a dose-dependent manner), but these associations appear to be confined to tumors expressing a certain molecular marker (eg, HER1/EGFR-overexpressing tumors).
- Preclinical testing: consensus of data showing that the treatment exposure causes inhibition and/or modulation of tumor end points in relevant animal models. An example would be forced treadmill running that is associated with inhibition of tumor growth in a genetically engineered mouse model or patient-derived xenograft of HER1/EGFR-overexpressing non-small cell lung cancer.
- Safety and tolerability clinical trials: the initial first-in-human studies that are needed to show the safety and tolerability of the planned exercise treatment dose in the target population and setting of interest. Preliminary information on treatment efficacy should also be obtained at this time. An example is supervised aerobic training that consists of five walking sessions per week at 55% to 80% of exercise capacity for 30 to 60 minutes per session for 16 weeks found to be safe (no adverse events) and tolerable and associated with improvements in exercise capacity in HER1/EGFR-overexpressing non-small cell lung cancer.
- Signal-seeking/ biomarker-driven clinical trials: a preliminary single-arm or randomized phase 2 trials to investigate initial clinical activity of the treatment in the target oncology population and setting of interest, which will make the decision on whether to further pursue the line of investigation. An example is supervised aerobic training that is associated with a favorable improvement in clinical response rate with a numeric improvement in progression-free survival as compared with usual care. A somatic mutation in the HER1/EGFR tyrosine kinase domain correlated with response to exercise treatment.
- Definitive clinical trials: large-scale, definitive, randomized controlled phase 3 trials that are adequately powered to detect clinically important differences on accepted clinical end points (eg, progression-free survival, overall survival) in the target setting. An example is supervised aerobic training for 16 weeks that improves progression-free survival and overall survival in HER1/ EGFR-overexpressing non-small cell lung cancer.
J Clin Oncol. Published online October 12, 2015. Full text