A number of factors increase the risk of developing colorectal cancer. Recognition of these has impact on screening strategies. However, 75% of all cases occur in people with no known predisposing factors.

A. Age
The incidence of colorectal cancer rises sharply after age 45 years, and 90% of cases occur in persons over the age of 50 years.

B. Family History of Neoplasia
A family history of colorectal cancer is present in 20% of patients with colon cancer. Hereditary factors are believed to contribute to 20-30% of colorectal cancers; however, the genes responsible for most of these cases have not yet been identified. Up to 5% of colorectal cancers are caused by inherited germline mutations resulting in polyposis syndromes or hereditary nonpolyposis colorectal cancer (HNPCC). Approximately 6% of the Ashkenazic Jewish population has a missense mutation in the APC gene (APC I1307K) that confers a modestly increased lifetime risk of developing colorectal cancer (OR 1.4-1.9) but phenotypically resembles sporadic colorectal cancer rather than FAP. Genetic screening is available, and patients harboring the mutation merit intensive screening.

A family history of colorectal cancer or adenomatous polyps is one of the most important risk factors for colorectal cancer. The risk of colon cancer is proportionate to the number and age of affected first-degree family members with colon cancer. People with one first-degree family member with colorectal cancer have an increased risk approximately 2 times that of the general population. However, the relative risk is 3.8 times if the family member’s cancer was diagnosed at < 45 years of age, 2.2 if diagnosed at 45-59 years of age, and only 1.8 if diagnosed at >

59 years of age. Patients with two first-degree relatives have a fourfold - or 25-30% lifetime - risk of developing colon cancer. First-degree relatives of patients with adenomas also are at increased risk for colorectal neoplasia, especially if the adenoma was detected before age 60 years. Cancers arise at an earlier age in patients with a positive family history, meriting screening at an earlier age. The risk of a 40-year-old person with a positive family history is comparable to that of an average-risk 50-year-old person.

C. Inflammatory Bowel Disease
The risk of adenocarcinoma of the colon begins to rise 7-10 years after disease onset in patients with ulcerative colitis and Crohn’s colitis. The cumulative risk approaches 5-10% after 20 years and 20% after 30 years. Chronic treatment with 5-ASA agents and folate is associated with a lower risk of cancer in patients with ulcerative colitis.

D. Dietary Factors and Chemoprevention
In epidemiologic studies, diets rich in fats and red meat are associated with an increased risk of colorectal adenomas and cancer, whereas diets high in fruits, vegetables, and fiber are associated with a decreased risk. However, two prospective, randomized controlled trials failed to demonstrate a risk reduction in the recurrence of adenomas after treatment with a diet low in fat and high in fiber, fruits, and vegetables or with fiber supplementation over a 3- to 4-year period. Although calcium carbonate (3 g/d) and folate therapy have been shown in prospective trials to yield a modest reduction in the relative risk of developing colorectal neoplasia, a recent prospective study of 36,000 women did not show a protective benefit of calcium and vitamin D. The antioxidant vitamins A, C, E, and beta carotene have not been shown to be of benefit in prospective controlled studies.

Cohort and case-control studies show that prolonged regular use of aspirin (at least 325 mg twice weekly) and NSAIDs is associated with a 30-50% decrease in the incidence of colorectal cancer and adenomas. Prospective, blinded clinical trials have shown that daily low-dose aspirin (80-325 mg) reduces the number of recurrent adenomas at 1-3 years in patients with a history of colorectal adenomas or cancer. Because long-term aspirin use is associated with a low incidence of serious complications (gastrointestinal hemorrhage, stroke), it should not be prescribed as a chemopreventive agent in people without polyps or with small adenomas unless there are other medical indications. Long-term administration of low-dose aspirin may be considered in patients with a personal or family history of colorectal cancer or advanced adenomas; however, they do not obviate the need for colonoscopy screening and surveillance. Two recent prospective controlled studies of patients who had adenomas removed by colonoscopy demonstrated a 35-45% reduction in the cumulative rate of new adenomas detected by colonoscopy within 3 years in patients treated with celecoxib (a selective COX-2 inhibitor) versus placebo. However, the risk of serious cardiovascular events was 1.3 to 3.4 times higher among patients treated with celecoxib, which vastly outweighs any potential chemopreventive benefit. Given their increased cardiovascular risk, COX-2 inhibitors should not be used for colon cancer chemoprevention except in patients with inherited polyposis syndromes.

E. Race
The incidence of colon adenocarcinoma is higher in blacks than in whites. It is unclear whether this is due to genetic or socioeconomic factors (eg, diet or reduced access to screening).

Patrick Johnston, Queen’s University Belfast, Belfast, Northern Ireland, U.K.
Eric Van Cutsem, University Hospital Gasthuisberg, Leuven, Belgium

References