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Relation
T. Nakamura, H. Ishikawa, T. Sakai et al. Influence of physical fitness on colorectal tumor development in patients with familial adenomatous polyposis.Medicine (Baltimore). 2019;98(38):e17076.
Study objective
The authors evaluated the influence of physical fitness, as measured by exercise testing, on the risk of developing colorectal cancer (CRC) in individuals with familial adenomatous polyposis (FAP).
Draft
This is a double-blind, cross-sectional study of patients who had previously participated in 2 CRC prevention trials (J-FAPP trial and J-FAPP trial II), both of which were double-blind, randomized multicenter trials.
Participant
A total of 119 people (54 men and 65 women) between the ages of 17 and 73 took part in the study. 43 of the participants had a history of CRC, the other 76 did not.
Either clinical symptoms or a parent who had FAP prompted the diagnosis of FAP. In the study, 116 of the 119 participants underwent genetic testing, and 98 of these individuals tested positive for a pathological mutation in their germlineAPCGen. No significant differences in history of CRC were found between groups.
Exercise to reduce the risk of sporadic and genetically induced CRC is an effective treatment beyond its effectiveness.
Since FAP is a hereditary disease, the study included 10 cases involving 2 members of the same family and 7 cases involving 3 members of the same family. The researchers conducted preliminary analyzes by family lineage but found no observable differences in the results.
Study parameters assessed
All participants were exercise tested twice between September 2000 and August 2007, first at the time of recruitment, followed by another test 2 years later. Participants performed the stress test in the form of a postprandial step test at least 2 hours after the last meal and after confirming resting blood lactic acid (LA) levels<1.5 mmol/L. Heart rate (HR) was measured immediately after the step test and predicted maximum oxygen uptake (VO2max) based on the increase in HR as the training load intensity also increased. The intensity levels were adjusted for age, with participants aged 50 and over completing the test with slightly fewer steps per minute.
Primary outcome measures
The authors examined 2 primary endpoints: the development of CRC and the maximum polyp diameter measured during colonoscopies performed up to 3 years before to 2 years after the step test. The authors compared these two results with the participants' VO2max during the exercise test, the surrogate marker for physical fitness.
Key insights
Even after adjustments for age, gender, surgical history, alcohol consumption, and smoking status, the risk of CRC was significantly higher in those with low VO2max compared to those with high VO2max (OR: 3.32; 95% CI: 1.00–11.02). In other words, the risk of developing CRC decreased as physical fitness increased.
In the 40 participants without a history of colectomy, maximum polyp diameter was similarly significantly negatively correlated with VO2maximum (r=–0.44,P<0.01).
Practice implications
The researchers precisely noted that although increasing epidemiological evidence shows the positive effect of exercise on the prevention of sporadic CRC,1-3There are few studies on the effects of exercise on individuals with FAP. This represents a much-needed area of study because almost 100% of individuals with FAP, if left untreated, will eventually develop CRC.4Given this dramatically increased risk of malignancy and the resulting drastic policy of prophylactic colectomy as common practice, chemopreventive treatments represent a critical area of care for this population. To date, agents proven effective in reducing polyp burden and colon adenoma progression in patients with FAP include nonsteroidal ones Anti-inflammatory drugs (NSAIDs, e.g. aspirin5and celecoxib6-8), erlotinib,9.10and curcumin in combination with quercetin.11This publication provides compelling evidence for the inclusion of exercise on this list. This simple lifestyle recommendation may allow more patients with FAP to avoid major surgical procedures while reducing the risk of developing CRC.
Although the mechanism of action of exercise in CRC prevention remains unclear, perhaps due to the variety of biological pathways influenced by physical activity, a number of potential mechanisms have been proposed. Exercise can reduce colon inflammation, a key factor in tumor progression; higher levels of physical activity at baseline are associated with lower concentrations of prostaglandin E2(PG2) in the rectal mucosa as identified by biopsy up to 26 months later.12Another way exercise may influence CRC risk comes from its role in insulin regulation. It is now well known that exercise increases insulin sensitivity and decreases apparent insulin production.13a risk factor in CRC. High insulin levels, associated with a sedentary lifestyle, high body mass, and an increase in abdominal obesity, are a mitogen for both normal and neoplastic colonic epithelial cells.14-15
As the results of this study show, the effects of regular exercise and appropriate physical conditioning may also extend to other forms of CRC in which genetic mutations play a role. This latter effect of exercise on insulin metabolism may provide a clue to the potential impact of exercise on hereditary non-polyposis colorectal cancer (HNPCC). Zečevic et al. (2006) noted a possible association between a mutation in insulin-like growth factor (IGF) and an increased risk of CRC in patients with HNPCC. They showed that variants of the IGF-1 genotype with shorter cytosine-adenine (CA) repeat promoter lengths were strongly associated with the development of malignancy in HNPCC. In fact, the time to onset of CRC decreased with each decrease in CA repeat number (HR = 1.17; 95% CI: 1.05-1.31;P=0.006) and patients with a CA<17 repeat alleles had a statistically significantly higher risk of CRC (HR = 2.36; 95% CI: 1.28–4.36;P=0.006).16This increase in risk is due to the finding that IGF-1 genotypes with shorter CA repeat lengths result in higher IGF-1 expression levels.17The relationship between insulin and IGF-1 is complex, but one of the main interactions between these related hormones is the stimulatory effect of insulin on IGF-1 synthesis.18Therefore, exercise as a modulator of insulin levels may hold promise as a treatment to treat increased IGF-1 production in HNPCC. This theory is promising because recently Kim et al. (2005) discovered that moderate exercise over a long period of time reduces circulating levels of insulin and IGF-1.19Clearly, further research is needed to assess the use of exercise in HNPCC.
Exercise to reduce the risk of sporadic and genetic CRC is an effective treatment that goes beyond its effectiveness, as has been repeatedly explained - it is free and easily accessible to all patients. In the field of medicine, particularly in the field of oncology, the seduction of innovation and technology among both physicians and patients can often lead to simple but effective strategies being overlooked. Nakamura et al. remind us of the crucial importance of primary prevention and illustrate how nature, here a genetic predisposition to CRC, can be influenced by appropriate care.