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Physical Activity Delays Disease Progression and Lowers Risk of Adverse Events in Patients With Metastatic Colorectal Cancer


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Patients who were being treated with chemotherapy for metastatic colorectal cancer and who reported engaging in physical activity had a significantly longer progression-free survival and reduced risk for treatment-related adverse events than did those reporting less physical activity, according to a study published in the Journal of Clinical Oncology.1 Greater physical activity was also associated with longer overall survival, but that finding was not statistically significant.

Brendan J. Guercio, MD

Brendan J. Guercio, MD

“Although our observational study does not offer evidence for causality, it builds on mounting evidence that demonstrates improved colorectal cancer outcomes with greater physical activity and extends this association to colorectal cancer with metastases,” Brendan J. Guercio, MD, and coauthors concluded.

“All patients in our study were receiving chemotherapy for their metastatic colorectal cancer, and so there is no reason to think that physical activity can act as a substitute for standard cancer treatments like chemotherapy,” Dr. Guercio explained to The ASCO Post. “However, our study suggests that the addition of physical activity to standard cancer therapies may be beneficial.” Dr. Guercio was a hospitalist at Brigham & Women’s Hospital in Boston and Instructor of Medicine at Harvard Medical School during the time of the study and is now a hematology and oncology fellow at Memorial Sloan Kettering Cancer Center, New York.

Jeffrey A. Meyerhardt, MD, MPH, FASCO

Jeffrey A. Meyerhardt, MD, MPH, FASCO

“The study findings help justify encouraging patients to exercise and referring patients to physical therapists or programs that do small group training for patients with cancer,” senior author Jeffrey A. Meyerhardt, MD, MPH, FASCO, commented in an interview with The ASCO Post. Dr. Meyerhardt is Clinical Director of the Gastrointestinal Cancer Center and Co-Director of the Colon and Rectal Cancer Center at Dana-Farber Cancer Institute, and Professor of Medicine, Harvard Medical School, Boston. Results of this study and others involving patients receiving chemotherapy show that exercise or physical activity can improve side-effect profiles and quality of life, he added.

Lifestyle Questionnaire

The study involved 1,218 patients enrolled in Cancer and Leukemia Group B (Alliance)/SWOG 80405, a National Cancer Institute–sponsored phase III trial of systemic therapy for metastatic colorectal cancer. Within 1 month of starting therapy, the patients were asked to complete a diet/lifestyle questionnaire, which included reporting average time spent on physical activities during the previous 2 months. Each activity was assigned a metabolic equivalent of task (MET) score.

All trial participants were required to have a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 and adequate bone marrow, renal, and hepatic function. Patients who reported being physically active were less likely to have comorbidities and weight loss and more likely to be younger and male, with a good performance status and lower body mass index and left-sided primary tumors.

“The significance of the association between physical activity and left-sided tumors observed in our study is unclear,” Dr. -Guercio said. “It is possible that the association is real (meaning that it is true for all patients with colorectal cancer), but it is also possible that the association in our study occurred by chance. In recent years, studies have begun to suggest that there are important differences between right-sided and left-sided colon cancers, including different types of genetic patterns and different responses to cancer therapies. Therefore, investigation of a possible association between physical activity and colon cancer sidedness may be of interest in future studies.”

Progression-Free Survival Nearly 20% Higher

At a median follow-up of 6.18 years, “1,056 of the 1,218 patients included in the analysis experienced cancer progression, and 945 subsequently died,” the researchers reported. “An additional 89 patients died without documented progression.” Progression-free survival was almost 20% greater among patients who engaged in 18 or more MET hours per week of physical activity compared to those with had 3 or fewer MET hours per week (hazard ratio [HR] = 0.83).

The study findings help justify encouraging patients to exercise and referring patients to physical therapists or programs that do small group training for patients with cancer.
— Jeffrey A. Meyerhardt, MD, MPH, FASCO

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“The amount of time required to engage in 18 or more MET hours per week would depend in part on the specific type of activity chosen,” Dr. Guercio explained. “For example, brisk walking requires approximately 3 METs per hour, and so 6 hours of brisk walking per week would be equivalent to approximately 18 MET hours in total. On the other hand, heavy yard work or casual bicycling at speeds less than 10 miles per hour require approximately 4 METs per hour, and so 4.5 hours per week spent doing these activities would also be equivalent to 18 MET hours per week.”

Vigorous vs Nonvigorous Activity

Although greater nonvigorous activity was associated with longer overall and progression-free survival, vigorous activity was not significantly associated with patient outcome. Vigorous activity was defined in the study report as “any activity requiring 6 or more METs—for example, running, bicycling, tennis, and aerobic exercises, such as skiing or lap swimming”—and “other activities, such as walking, climbing stairs, or yoga, were defined as nonvigorous.”

“We were surprised by this finding,” Dr. Guercio acknowledged. “More studies will be needed to confirm this finding and to understand why vigorous activity was not associated with longer survival. Notably, most patients in our study did not engage in much vigorous activity. So it is possible that vigorous activity is beneficial and there was not enough vigorous activity going on to see an effect, but we do not yet have data to support that conclusion.”

“I don’t want the messaging to be that you shouldn’t do vigorous activity,” Dr. Meyerhardt remarked. “It is not as if someone who can run and does run is not going to benefit. I view it more that modest activity still can be beneficial. I think that is an important take home.”

Reducing Adverse Events

During the median follow-up of 6.18 years, 795 patients experienced 1 or more grade 3 or higher treatment-related adverse events, but patients participating in 9 or more MET hours per week of physical activity had a significantly lower rate of treatment-related events (HR = 0.73). These effects included lower rates of neutropenia, anemia, diarrhea, dehydration, vomiting, anorexia, nausea, and fatigue.

“Total physical activity equivalent to 30 or more minutes of moderate daily activity was associated with a 27% reduction in severe treatment-related toxicities,” according to Dr. Guercio. That 30 or more minutes of moderate daily activity works out to about 9 or more MET hours. “For example, if a patient chose to go for a brisk walk for 30 minutes on 6 days of a given week, that would be a total of 3 hours of brisk walking, which is approximately equal to 9 MET hours per week,” Dr. Guercio explained.

Potential Mechanisms

In addition to reducing treatment-related toxicities, the study report notes that physical activity may improve cancer outcomes by reducing hyperinsulinemia, oxidative damage, and inflammation. “There is some evidence for each of these effects,” Dr. Guercio said. “I personally find the evidence around the effects of hyperinsulinemia on cancer outcomes to be of particular interest, as it is also supported by studies showing that type 2 diabetes and unhealthy diets that promote high insulin levels are associated with worse outcomes for patients with colorectal cancer.”

“There are studies that have shown that exercise can lower inflammatory markers, and inflammation can also lead to growth of certain cancer cells,” Dr. Meyerhardt noted. Exercise that includes resistance training “could affect body composition and particularly build muscle mass and lean body mass. There are an increasing number of studies showing how lean body mass and muscle mass can be associated with outcome in patients with cancer.”

Beyond Observational Studies

A recent article in JAMA Oncology reviewing the development of exercise as an interception therapy for cancer noted, “the existing evidence base supporting the antitumor activity of exercise is confined predominantly to observational data—studies that use self-reported methods to measure physical activity or exercise exposure, with limited confirmatory data from preclinical or clinical studies.”2 These preclinical and clinical studies can provide insight into how an intervention works and how it should be used. Both Dr. Guercio and Dr. Meyerhardt consider it important to continue both clinical and observational studies.

“Future studies, ideally of a nonobservational design, are still very important,” Dr. Guercio said. “It is important to note that, because our study was observational by design, we can use it to show associations between exercise and survival, but we cannot use it to prove that those associations are causal. In order to truly prove that physical activity can lengthen patient survival, we would ultimately need one or more randomized clinical trials, which can be much more challenging but are not limited in the same way that observational studies are.”

“The most important thing,” Dr. Meyerhardt noted, “is, if we do intervene—if we change what people are doing—is that really going to change their outcome? That is why randomized studies are important. There is one randomized study in colon cancer, the Challenge study, being conducted in Canada. “Patients with high-risk stage II and III colon cancer will be randomly assigned to an exercise intervention vs usual care for 3 years after their diagnosis. That study is currently accruing patients toward a goal of 950.”

The CALGB Connection

The study by Dr. Guercio and colleagues and other studies concerning physical activity and healthier eating among patients with colorectal cancer were embedded in a CALGB (Alliance)/SWOG study. Another ongoing CALGB/SWOG combined effort is looking at whether adding celecoxib, a COX-2 inhibitor, would be beneficial to patients with stage III colon cancer. Researchers have collected questionnaires from about 2,000 patients, “and that will give us more power to be able to look at some of these issues. There have not yet been enough events to release the data,” Dr. Meyerhardt said.

“We are also going to embed these questions in a study of pancreatic cancer,” he added. Questionnaires will be used to collect data on exercise and diet among patients who have resectable pancreatic cancer. That study has been approved by the National Cancer Institute. “The hope is that it will open to accrual sometime in 2020.” 

DISCLOSURE: Dr. Guercio has received institutional research funding from Bristol-Myers Squibb, Eli Lilly and Company, Genentech, Pfizer, and Sanofi. Dr. Meyerhardt has received honoraria from Cota Healthcare, Ignyta, and Taiho Pharmaceutical; has served in a consulting or advisory role for Array BioPharma; and has received institutional research funding from Boston Biomedical.

REFERENCES

1. Guercio BJ, Zhang S, Ou FS, et al: Associations of physical activity with survival and progression in metastatic colorectal cancer: Results from Cancer and Leukemia Group B (Alliance)/SWOG 80405. J Clin Oncol. August 13, 2019 (early release online).

2. Iyengar NM, Jones LW: Development of exercise as interception therapy for cancer: A review. JAMA Oncol. August 22, 2019 (early release online).


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