In the last decades, more efforts are focused on the prevention and treatment of malignant diseases, given the increase in all cancers incidence A lifestyle change, including healthy eating habits and regular physical activity, has significantly impacted colorectal cancer prevention. The effect of dose-dependent physical activity on mortality and recurrence rates of colorectal carcinoma has been unequivocally demonstrated in observational studies. However, clear recommendations are not available on the frequency, duration, and intensity of exercise in patients with colorectal cancer due to the lack of evidence in randomized clinical trials. Regarding pathophysiological mechanisms, the most plausible explanation appears to be the influence of physical activity on reducing chronic inflammation and insulin resistance with a consequent positive effect on insulin growth factor 1 signaling pathways.

Colorectal cancer (CRC) is the fourth most common cancer worldwide, with increasing incidence due to lifestyle, environmental changes, and aging demographics; it is estimated to rise to 2.2 million new cases and 1.1 million deaths by 2030[1,2]. Forty-four percent of new CRC diagnoses are older patients, and 20%-25% of CRC is diagnosed at the advanced stage[3]. Five-year overall survival for CRC ranges from 58.4% to 65%[4,5]. CRC screening programs have led to a 16% decline in overall mortality rate without affecting incidence[6]. Thus, strategies that could prevent or decrease the burden of CRC are of major importance.

Sedentary behavior (both viewed through the prism of reduced physical activity and/or time spent on sitting) is emerging as an independent risk factor for chronic diseases such as diabetes, hypertension, obesity, and cardiovascular disease and can directly increase mortality. According to objectively assessed measurements, adults spend 50% to 60% of the day being physically inactive, in sedentary behaviors[7].

Cancer is a leading cause of death in many modern societies, although largely preventable through healthy lifestyle choices[8]. A meta-analysis of 43 observational studies recently linked the sedentary lifestyle to the development of three specific types of cancers; lung, endometrial, and colon. For the later, authors reported an 8% increase of risk in case of each 2-h increase in sitting time[9]. Another meta-analysis, which included 17 prospective studies, reported the associations between sedentary behavior and some cancer types, including CRC [relative risk, 1.30; 95% confidence interval (CI), 1.12-1.49][10].

The Reasons for Geographic and Racial Differences in Stroke study, which included a cohort of 8002 adults aged ≥ 45 years in the United States and prospectively followed them by accelerometry for a mean of 5.7 years, reported an association between greater sedentary time with greater risk of cancer mortality. Moreover, the authors found that replacing 30 min of sedentary time with physical activity (either light or moderate-vigorous) can reduce the cancer mortality for 8% and 31%, respectively[11]. Analysis of cancer risk in relation to the level of leisure-time physical activity involving more than 1.44 million adults showed that a high level of activity provides protection against 13 cancers. For the cancer protection effects, the hazard rates (HR) of cancers in gastrointestinal tracts, namely esophagus, gastric cardia, colon and rectum, are shown to be reduced to 0.58, 0.78, 0.84 and 0.87 respectively with corresponding 95%CI values being 0.37-0.89, 0.64-0.95, 0.77-0.91 and 0.80-0.95. Other cancer protection by elevated physical activities pertains to liver, lungs, kidney, endometrium, breast, bladder, head and neck, and two hematological malignancies (myeloma and myeloid leukemia), with HR in a range of 0.73-0.90. It is noteworthy that these protection effects are irrespective of patients’ body mass index or previous physical fitness. Overall, the higher the physical activity level, the lower the total cancer risk[12]. Similarly, a recently published umbrella review evaluating physical activity and cancer risk showed that regular physical activity might prevent seven types of cancers (colon, breast, endometrium, lung, esophagus, pancreas, and meningioma)[13].

Physical activity offers the protection against colorectal precancerous polyps[14]. There was an exercise duration-related lower prevalence of colon adenomas and polyps in persons who exercised for ≥ 1 h per week as opposed to those who exercised less than an hour weekly[15]. Moreover, the risk for polyp development was decreased throughout the colon, regardless of its specific part. Another study reported the exercise-related decrease in the total number of intestinal polyps, and more specifically in the development of large polyps by 67%[16]. Animal studies suggest preventing of colorectal polyp formation through pro-inflammatory cytokine interleukin-6, which is decreased after treadmill running[17].

Despite the treatment advances, new therapies have a limited impact on cure rates and colon cancer patients’ survival. Therefore, adjuvant treatment strategies, among which lifestyle interventions, are needed. Several observational studies have demonstrated the anti-cancer effects of exercise and its dose-dependent effect on decreasing cancer recurrence mortality and risk. More specifically, physical activity may prevent approximately 15% of colon cancer[18]. A systematic review by Des Guetz and colleagues[19] analyzed six observational studies involving over 7500 CRC survivors and reported that higher post-diagnosis physical activity was associated with a lower risk of CRC-specific mortality (HR, 0.61; 95%CI, 0.44-0.86) and a lower risk of all-cause mortality (HR, 0.62; 95%CI, 0.54-0.71). Despite noticed benefits, no randomized controlled trials have been published exploring the beneficial association between physical activity and survival after CRC treatment. The Challenge Trial[20] is the first prospective randomized controlled trial evaluating the effects (improvements of 3-year disease-free survival, QoL) of structured physical activity on the survival of stage 2 and 3 CRC survivors.

Randomized exercise trials and longitudinal studies initially suggested the link between the preventive role of physical activity on cancer through primarily weight reduction and/or prevention of weight gain[21-23], but nowadays, the association seems more direct and straightforward. There is data suggesting preventive effects even when physical activity lacked the weight loss or maintenance of healthy weight^[24J. Potential mechanisms might include a reduction in insulin resistance and inflammation that have been directly linked to colorectal carcinogenesis, or stimulation of digestion and intestinal motility (Figure 1). Moreover, physical activity might directly influence the molecular and genetic pathways involved in colorectal carcinogenesis and improve patient survival[25]. According to available data, physical activity increases the expression of P27 and cyclooxygenase-2 (COX-2) and decreases that of insulin receptor substrate 1 and B-catenin, which correlates to improved cancer-specific survival[26-30]. Another plausible mechanism in need of further exploration is the effect of physical activity on soluble intercellular adhesion molecule, which is known to affect early death and disease recurrence[31].

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Figure 1 Potential explanatory mechanisms of the association between physical activity and prevention of colorectal cancer.

According to the American Cancer Society guidelines, it is important not only to avoid inactivity but also to be engaged in minimally 150 min cumulative moderate or 75 min vigorous-intensity aerobic exercise weekly, and perform at least two days per week of strength exercises in order to prevent the development of CRC or to have a favorable prognosis[52,53]. The recommendation is to increase the amount of exercise to achieve 300 min of aerobic exercise weekly if possible. Generally, no specific precautions need to be taken if participation in physical activity is incorporated slowly, when time and intensity slowly upgrade. In older individuals or those with known cardiovascular disease, sometimes a medical clearance before engaging in physical activity is needed. Similarly, if patients are on cardiotoxic chemotherapy, a cardiologist’s consult might be prudent[25]. Finally, physical activity improves the patients’ quality of life, functional status, muscle strength, depression, and decreases the risk of CRC recurrence and cancer-specific and overall mortality[54,55].