Prevention of colorectal cancer

Colorectal cancer is a preventable disease. When people migrate from low-incidence countries, such as Japan or Africa, to a high-incidence country such as the United States, the rates of disease among their offspring increase to those of their adopted country. This indicates that there is something in the environment that is responsible. If we could identify and modify these environmental factors, we could prevent colorectal cancer.

Diet. There have been a large number of studies of diet and colon cancer. Unfortunately, it has been difficult to draw firm conclusions about the association between diet and colorectal cancer.

Red meat. The majority of studies have shown an increased risk of colorectal cancer with high intakes of red meat. Heterocyclic amines and polyaromatic hydrocarbons are produced when red meat is cooked at high temperature. These compounds may be carcinogenic.

Fiber. Burkett advanced the hypothesis that fiber prevents colorectal cancer almost 40 years ago. Although the hypothesis is appealing, recent studies indicate that it may not be correct. A large, carefully conducted cohort study found no protective effect of fiber from any source – cereals, fruits, or vegetables. Two randomized trials of fiber in post-polypectomy patients did not show that fiber prevented new adenomas during the 3-year study period.

Fruits and vegetables. These are a large number of studies of fruits and vegetables in connection with colorectal cancer, and virtually all of them demonstrate a moderate protective effect. One exception is a report from the Nurses’ Health Study, which did not find a protective effect against colon or rectal cancer. While the mechanism for protection by vegetables is not known, there are a large number of chemicals from the plant kingdom that have been found to be anticarcinogenic or antimutagenic in test systems. These chemicals operate at a number of different sites in the carcinogenic pathway.

Calcium. A large randomized controlled trial has shown that 1200mg per day of calcium, in the form of calcium carbonate, resulted in a 19 percent reduction in the development of new adenomas and a 24 percent reduction in the number of new adenomas in comparison with a placebo. The end point in the study was adenomas, rather than cancer, but because virtually all cancers are thought to arise from adenomas, the protective effect is thought to extend to cancer. The mechanism for protection by calcium is not known.

Selenium. Trace metals, such as selenium, zinc, iron, and fluoride may be capable of influencing the risk of colorectal cancer. A large randomized trial of selenium administration to prevent skin cancer found that colorectal cancer deaths were 60 percent less frequent in individuals who were assigned to the selenium group. These results are quite surprising and need to be confirmed.

Micronutrients. Because fruits and vegetables are associated with a lower risk of colorectal cancer, one might speculate that the protective effect might be due to vitamins, particularly the antioxidant vitamins A. C. and E. Antioxidants can inhibit free-radical reactions and thereby prevent oxidative damage to DNA. Unexpectedly, clinical trials of antioxidant vitamins have not shown an effect against colonic neoplasms. In large Nurses’ Cohort, women who tool multivitamins that contained folic acid for at least 15 years were about 75 percent less likely to develop colon cancer than women who never took multivitamins. Protection required vitamin use for 15 years of more; a shorter duration of use conferred no protection. The protective effect seen in the Nurses’ study was primarily due to the folic acid component of the multivitamin, rather than the antioxidant vitamins.

Smoking and alcohol. The majority of studies demonstrate an increased risk of colorectal cancer and adenomas with cigarette smoking. Alcohol has been linked with an increased risk for both adenomas and cancer. The data are more consistent for adenomas, but the majority of studies also support an association between alcohol and cancer, The effect of alcohol may relate to its antagonism of methyl group metabolism, and the effect appear to be increased by low levels of the folic acid, a methyl donor.

Physical activity. Physical activity has consistently been show to protect against colorectal cancer. Both leisure-time and occupational activities appear to be important.

Obesity. The amount of food, rather than the type, may be important. Obesity has been linked to colon cancer in both men and women. Recent cohort studies have shown that obese women were 50 percent more likely to develop colon cancer, and obese men 80 percent more likely.

Constipation. There has long been speculation that constipation might be responsible for large bowel cancer, due to more prolonged contact with the mucosa by carcinogenic substances in feces. Howerver, neither constipation nor the use of laxatives appears to be an important risk factor for colorectal cancer.

NSAIDs. Aspirin and nosteroidal anti-inflammatory drugs appear to be protective against colorectal neoplasia, based on evidence from a variety of different types of studies. In a randomized trial of polyposis patients, sulindac has been shown to result in polyp regression. The mechanism is not known, but it could be related to increased apoptosis in transformed mucosa. There has been speculation that the effect could be due to inhibition of the cyclooxygenase-2 pathway to prostaglandin production, since Cox-2 is up-regulated in colon tumors. Celecoxib has been shown to decrease the numbers of polyps in polyposis patients. Three recent randomized controlled trials have shown that daily aspirin can decrease the risk of recurrent colorectal adenomas. Taken together, the three studies, along with extensive observational studies, show that aspirin is an effective chemopreventive agent.

Despite the compelling evidence of a protective effect of aspirin and conventional NSAIDs, these drugs have well-known adverse effects. Drugs in this class can increase the risk of hemorrhagic strokes and gastrointestinal bleeding. Because of an unfavorable cost-benefit ratio, these drugs should not be recommended for routine prevention in low-risk individuals.

Hormone use. Postmenopausal hormones have been shown to be associated with a decreased risk of colorectal cancer. A meta-analysis has shown that postmenopausal women who has taken hormone replacement were 20 percent less likely to develop colon cancer. A recent study showed that hormone replacement reduces that overall risk of colon cancer.

Practical recommendations. Sensible modification in diet and lifestyle could have a favorable impact on the development of colorectal cancer. At the same time, it is important to recognize that the benefits of screening for colorectal cancer completely overshadow the effects of primary prevention. In discussing strategies for cancer prevention with out patients, it is very important to make it clear that the most important strategy is screening.

Practical, evidence-based recommendations for primary prevention might include the following:

• Eat a sensible diet, high in vegetables and fruits; limit red meat (less than two servings per week)

• Avoid obesity (body mass index <26kg/m2)

• Take regular exercise — 30min/day, moderate or vigorous.

• Consider supplements with calcium (1200mg/day) and folic acid (1mg).

• Limit alcohol consumption; don’t smoke.

• Participate in regular screening.

• Avoid health claims and fads based on weak data.