Trends and risk factors for colorectal cancer

Introduction
Colorectal cancer (CRC) is the third most common cancer in the world, accounting for approximately 9% of new invasive cancer diagnosed worldwide.[1] In British Columbia, incidence rates for CRC are among the highest in the world,[2] being surpassed only by lung, female breast, and prostate cancers. In 1998, 2060 new cases (12.6% of all new cases) and 660 deaths (8.5% of all cancer-related deaths) were estimated for CRC in BC.[3] 

Incidence and mortality trends in BC
At present in BC, one of 17 men and 1 of 19 women can be expected to develop CRC in their lifetime, and 1 of 47 men and 1 of 53 women will die from it. It is estimated that the average annual potential years of life lost due to CRC in BC from 1984 to 1993 was 8400.[4]

The age-specific incidence and mortality rates are higher in men than in women, yet the age-standardized CRC rates for incidence and mortality have declined in both sexes in recent years. The percent changes in rates are most apparent for CRC mortality, with declining rates in both sexes since the mid-1970s. Changes in incidence rate were less consistent in the mid-1980s, with slowly increasing rates in men and stable rates in women. From the mid-1980s, incidence rates for CRC have declined, especially in women. Improvement has also been seen in survival for both sexes since the early-1980s, with significant gains in long-term survivors.[5] 

These trends are seen throughout Canada, with an average annual percent change for men and women in incidence of -0.5% and -1.4%, respectively, from 1986 to 1993, and in mortality of -1.4% and -2.5%, respectively, from 1986 to 1995. Previously, incidence rates in Canada had been steadily increasing in men and relatively stable in women; mortality rates had been declining but at much slower rates.[3] These declines are thought to be the result of early detection, effective treatment for earlier-staged disease, and lifestyle changes such as diet and exercise modification.[1-6] 

Lifestyle and other environmental risk factors
The importance of lifestyle and other environmental factors in CRC is supported by the large international variation in incidence rates and the dramatic change in rates following migration. There are ten-fold differences in international rates for colon cancer and five-fold differences for rectal cancer. Studies of migrants show CRC rates approach those of the adopted country more rapidly than for other cancers, usually within the first generation or after about 20 or more years of residence.[1]

Diet
For many years dietary factors have been considered important both in enhancing and reducing risk of CRC. The relationship between dietary fat, dietary fibre, and bile acid metabolism forms the basis for the dominant dietary hypothesis for CRC.[6] Experimental models have shown that fecal secondary bile acids (which are the product of conversion of primary bile acids by colonic bacteria) stimulate colonic crypt epithelial cell proliferation and promote tumorigenesis.

Dietary fibre is thought to reduce the adverse effects of dietary fat and fecal bile acids by increasing fecal bulk and reducing transit time, physically diluting fecal contents by water absorption, altering metabolic activity and composition of colonic microflora, binding bile acids and bile salts, lowering colonic pH (thus reducing the conversion of primary to secondary bile acids), and facilitating the binding of free fatty acids with calcium and other salts. Insoluble and less fermentable components of fibre are most effective in reducing the adverse effects, and the benefit is seen when administered during the promotion stage of carcinogenesis. This may explain the early changes seen in CRC incidence rates among migrants.

In 1997, a panel of world experts in diet and cancer published new dietary recommendations for the reduction of cancer incidence worldwide.[7] The recommendations are summarized in “Lifestyle recommendations for reducing CRC risk."

Dietary factors associated with increased risk
There is a link between CRC and frequent consumption of red meat.[6] It is not clear whether it is the fat in red meat or the carcinogens produced when red meat is cooked at high temperatures (i.e., heavily browned) that produce the carcinogenic effect.

A number of other dietary factors are suspected of increasing risk. These include obesity (particularly in men), greater adult height, frequent eating, high sugar intake (especially sucrose), high total and saturated fat intake, and frequent consumption of eggs and processed meat.[6] Biological mechanisms have been proposed for each of these possible risk factors. For example, sugar intake may raise blood sugar levels and insulin levels, either of which may directly influence colon cell proliferation and cancer development.

Dietary factors associated with decreased risk
There is convincing evidence that diets high in vegetables decrease the risk of CRC.[1,6] The data is strongest for both raw and green vegetables, which may exert anticancer effects through the vitamins, dietary fibre, and phytochemicals that they contain. There is less consistent evidence for fruit.

A number of other dietary factors have also been associated with lower risk of CRC, including diets high in starch, fibre (non-starch polysaccharides), and carotenoids.[6] The evidence for dietary fibre is inconsistent. Case-control studies have generally shown a reduced risk with higher dietary fibre consumption, whereas cohort studies have not.[8,9] This may be due to differences in dietary data collection methods, the relevant timing of exposure, different biases associated with case-control and cohort studies, or the diverse nature of dietary fibre, to name a few possible reasons.[9] It is unclear whether it is dietary fibre per se, or the other constituents of fruits, vegetables, cereals, pulses, and seeds that exert the anticancer effects.

Epidemiologic studies have been inconsistent in showing a protective effect for supplemental dietary calcium or vitamin D.[1,6] Experimental animal studies have shown that supplemental calcium suppresses the proliferation of aberrant colonic epithelium. Etiologic comparisons demonstrate a gradient of increasing CRC mortality with higher latitudes, supporting a vitamin D effect through its link with UV radiation exposure.[10] The findings, however, are inconsistent from epidemiologic analytic studies, both for colorectal adenomas and cancer.

Certain phytochemicals found in plant foods are known to exert cancer chemopreventive effects in experimental animals. One of these phytochemicals, the soybean isoflavonoid genistein, is of current interest because it has been observed that consumption of soybean-rich diets is linked to a decreased risk of CRC. A recent study of the effect of genistein on azoxymethane-induced colon carcinogenesis, however, showed tumor enhancement.[11] Hence genistein supplements are not recommended.

There is insufficient evidence to support a role in CRC development for a number of other dietary factors. These include resistant starch (defined as starch that resists digestion) found in such foods as whole grains, pulses, breads, bananas, and cooled cooked potatoes and rice, as well as vitamin C, vitamin E, folate, methionine, selenium, iron, cereals, coffee, and fish.

Alcohol
High rates of alcohol consumption may also increase risk of CRC. It appears that the total alcohol intake, rather than type of drink, is most strongly associated with risk. Although beer consumption has been associated with rectal cancer, the findings are weak and inconsistent for both colon cancer and precursor adenomas. Alcohol may exert its carcinogenic effect by a direct solvent or cytotoxic effect, by inducing microsomal enzymes that convert procarcinogens to more active forms, or indirectly by promoting a number of vitamin and mineral deficiencies.[1,6] 

Tobacco
Cigarette smoking has been consistently associated with adenomatous polyps but the effect is modest and conflicting for CRC. It has been speculated that tobacco triggers an early event prior to neoplastic transformation.[1,6] 

Exercise and sociodemographic factors
CRC is not considered to be an occupational disease,[1] although there is an increased risk associated with sedentary jobs.[12] There is convincing evidence that regular physical activity reduces the risk of colon cancer; the evidence for rectal cancer is limited and inconsistent.[1,6] Regular exercise stimulates peristalsis, thereby decreasing transit time for carcinogenic substances in the colon. Additionally, regular physical activity favorably affects cells of the immune system. CRC is not uniformly associated with socioeconomic status; however, the risk is elevated in urban areas, with higher incomes, and with greater number of years of education.

Other diseases
Several diseases are associated with CRC. Inflammatory bowel disease (ulcerative colitis and Crohn’s disease) increase risk and advance the age at diagnosis of CRC.[1] Risk of CRC is dependent upon the age at diagnosis of inflammatory bowel disease, the duration of symptoms, the extent of mucosal involvement, and the presence of multicentric foci of dysplasia in flat mucosa or adenomatous polyps. The precursor neoplastic lesion may be either an adenomatous polyp or nonpolypoid flat mucosa with epithelial dysplasia. The malignant potential of an adenoma is dependent upon its size (i.e., 1 cm or larger), the presence of high-grade dysplasia, and the predominance of villous features.

Several cancers also increase risk of CRC, including ovarian, endometrial, and breast cancer.[1] Increase in risk is more likely if the first primary is diagnosed at an early age.

NSAIDS
The non-steroidal anti-inflammatory drugs (NSAIDS) include aspirin, ibuprofen, sulindac, indomethacin, and piroxicam. They have been associated with a lower risk of colorectal adenomas and cancer, both from experimental animal studies and epidemiologic analytic studies.[1,6] NSAIDS may act by inhibiting cyclooxygenase activity, prostaglandin synthesis, and the cascade of arachidonic acid metabolites, which are involved in cell transformation, tumor growth, and metastasis.

Acknowledgments
We thank Ms Heather Roscoe and Ms Judi Gray for preparing the manuscript, Dr Andrew Coldman for reviewing the manuscript, and Mr Norman Phillips for preparing the figures.

Dr Hislop is an epidemiologist in Cancer Control Research at the BC Cancer Agency and a clinical professor in the department of Health Care and Epidemiology at the University of British Columbia. Ms Hobenshield is a registered dietitian/nutritionist at the BC Cancer Agency.