Colorectal Cancer: Epidemiology, Etiology, and Molecular Basis

Fig. 38.1

Age-adjusted colorectal cancer incidence and death rates in the USA 1975–2006

CRC in the USA over a lifetime is 5.5 % in men and 5.1 % in women.

The risk of CRC continues to increase with age (Fig. 38.2).

Fig. 38.2

Age-specific SEER incidence rates in the USA 1992–2006

Overall, the incidence of CRC in men is 61 per 100,000 males as compared to 45 per 100,000 females.

In addition, the ratio of colon to rectal cancer differs by sex; the ratio of colon to rectal cases for women is 3:1 as compared to 2:1 for males.

Ashkenazi Jewish individuals appear to be at a slightly increased risk of CRC. At least part of this increased incidence may be due to a higher prevalence of the I1307K mutation of the adenomatous polyposis gene (APC), a mutation that confers an increased risk of CRC development (18–30 % lifetime risk).

In the USA, the incidence of CRC is higher in African Americans of either sex as compared to white Americans. Asian American/Pacific Islanders, Native Americans, and Hispanic Americans experience a lower incidence of CRC than Caucasians (Table 38.1).

Table 38.1

Incidence and mortality rates for CRC by site, race, and ethnicity, USA 2001–2005

		White	African American	Asian American and Pacific Islander	American Indian/Alaska Native	Hispanic/Latino
Incidence	Male	58.9	71.2	48.0	46.0	47.3
Incidence	Female	43.2	54.5	35.4	41.2	32.8
Mortality	Male	22.1	31.8	14.4	20.5	16.5
Mortality	Female	15.3	22.4	10.2	14.2	10.8

Adapted from Jemal A, Siegal R, Ward E, Hao Y, Xu J, Ward E, and Thun MJ; American Cancer Society. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225–249. Table 11 DOI:10.1007/_11. Incidence and mortality rates for by site, race and ethnicity, USA, 2001–2005. Pg 242

Incidence and mortality rates per 100,000 age-adjusted to the 2000 US standard population

According to the American Cancer Society, between 1996 and 2004 for all patients diagnosed with CRC, 40 % of patients were diagnosed with localized disease, 36 % with regional disease, and 19 % with metastatic disease. Five percent of patients were not staged. As a proportion of total cases, African Americans were more likely to present with advanced disease; 24 % of African Americans have metastatic disease at presentation (Table 38.2).

Table 38.2

Stage at diagnosis (USA 1996–2004)

	Whites (%)	African Americans (%)
Localized	40	35
Regional	36	34
Distant	19	24
Unstaged	5	7

Adapted from Jemal A, Siegal R, Ward E, Hao Y, Xu J, Ward E, and Thun MJ; American Cancer Society. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225–249. Figure 9. Incidence and mortality rates for by site, race and ethnicity, USA, 2001–2005. Pg 246

There is substantial geographic variation in the incidence of CRC, with relatively high rates in North America, Western Europe, and Australia and relatively low rates in Africa and Asia (Fig. 38.3).

Fig. 38.3

(a) Age-standardized (to the world population) incidence rates of cancer of the large bowel among females. (b) Age-standardized (to the world population) incidence rates of cancer of the large bowel among males

Environmental factors (most prominently dietary factors) are still considered to have a major role in this disease.

Interestingly, there is less variation in the incidence of rectal cancer between countries as compared to the incidence of colon cancer.

Mortality from CRC is declining in the USA (Fig. 38.1 and Table 38.1).

However, for those who develop CRC, no improvement in case fatality has been identified since 1986 indicating that the trends in mortality are likely complex.

African Americans suffer the highest mortality rate from CRC in the USA (Table 38.1).

Because CRC is a survivable cancer, with a 5-year survival rates adjusted for life expectancy of 64 %, the prevalence of people living with a diagnosis of CRC in the population is substantial. In total, over one million Americans alive in 2006 have had a diagnosis of CRC.

Etiology

Dietary Constituents and Supplements

The relationship between diet and CRC risk is at best unclear.

Dietary Fat

Dietary fat, particularly saturated animal fat, has been implicated in carcinogenesis of the colon and rectum.
Countries with populations eating a high-fat diet had higher CRC rates than countries with populations eating a lower fat diet, making ecological comparisons between countries subject to a substantial risk of confounding.
Over 13 case–control studies evaluating the relationship between dietary fat intake and the risk of CRC were quantitatively summarized by Howe et al. and include 5,287 cases with CRC and 10,470 controls.
Overall, there was no evidence for any association of total dietary fat intake and development of CRC.
In addition, at least six cohort studies have been conducted to evaluate the relationship between dietary fat and CRC.

Red Meat

Red meat is high in iron, a pro-oxidant. Dietary iron may increase free-radical production in the colon, and these free radicals may cause chronic mucosal damage or promote other carcinogens.
Alternatively, dietary heme, present in red meat, may have a cytotoxic effect on colonic surface epithelium, resulting in rebound inhibition of apoptosis and crypt hyperplasia.
A large number of epidemiologic studies and three meta-analyses have been published. The pooled estimate for the increase in the risk of CRC due to red meat consumption was similar; odds of development of CRC in the highest meat consuming groups as compared to the lowest was 1.14–1.28. It is therefore difficult to rule out the possibility that the apparent effect of red meat on the development of CRC may be confounded or modified by other dietary or lifestyle factors.
Genetics may also play a role. In the Fukuoka Colorectal Cancer Study, colon cancer risk was increased in relation to red meat intake only in individuals with a specific polymorphism of Cytochrome P450 2E1 (CYP2E1).

Fruit and Vegetable Intake

Fruits and vegetables are a source of antioxidants, including carotenoids and ascorbate.
Results from 22 case–control studies and four prospective cohort studies have provided substantial support for the hypothesis that vegetable intake reduces the risk of CRC while intake of fruit did not seem to have an effect.
Other studies, however, did not demonstrate a convincing link between vegetable or fruit intake and a reduced risk of CRC.
In four large prospective cohort studies (the Nurse’s Health Study of 121,700 women, the Health Professionals Follow-up Study of 51,529 men, the Netherlands Cohort Study on Diet and Cancer including 120,852 men and women, and the Cancer Prevention Study II Nutrition Cohort, including 133,163 men and women), fruit and vegetable intake was not statistically significantly associated with a reduced risk of CRC.
More recent studies have reported conflicting results. A pooled analysis of 14 cohort studies, including 756,217 men and women followed between 6 and 20 years also did not find a significantly reduced risk of CRC in the highest consumers of total fruits and vegetables, total vegetables, or total fruits.
Finally, the recently reported European Prospective Investigation into Cancer and Nutrition (EPIC) study, involving a cohort of 452,755 men and women followed an average of 8.8 years, reported a significant inverse relationship between total fruit and vegetable consumption and the risk of colon cancer (RR = 0.76; 95 % CI, 0.63–0.91).
The Polyp Prevention Trial randomized 2,079 people with a history of colorectal adenomas to either intensive dietary counseling with assignment to a diet low in fat and high in fruits, vegetables, and fiber, or to a control group (no dietary change). No difference in adenoma recurrence rate was found in the intervention group as compared to the control group. However, follow-up of 34,467 women participating in the Nurses’ Health Study found an inverse relationship for total consumption of fruit, but not vegetables, on the risk of colorectal adenomas.
Overall, the evidence for an association between fruit and vegetable intake and the risk of CRC is inconsistent.

Fiber

Dietary fiber was one of the first dietary components thought to have a protective role in carcinogenesis.
A number of mechanisms have been proposed for the protective effects of fiber; fiber may increase intestinal transit and therefore reduce the length of exposure of the colon to carcinogens, or fiber may dilute or absorb various potential carcinogens, particularly bile salts.
Surprisingly, two large American cohort studies, the Nurses’ Health study and the Health Professionals’ Follow-up Study found no evidence of benefit of fiber on CRC risk.
However, more recent studies have reopened the debate. In the PLCO Cancer Screening Trial, a nested case–control study of over 37,508 people undergoing flexible sigmoidoscopy was performed using food frequency questionnaires. People who reported the highest amounts of fiber in their diets had the lowest risk of colorectal adenomas – 27 % risk reduction compared to people who ate the least amount of fiber.
A meta-analysis in which the data from 13 prospective cohort studies were reanalyzed. Although dietary fiber intake was inversely associated with the risk of CRC in age-adjusted analyses, this association did not hold when adjusted for other dietary risk factors.
A meta-analysis has evaluated the effect of five intervention trials. These studies randomized a total of 4,349 individuals to some form of fiber supplementation or high-fiber dietary intervention. When the data were combined, there was no difference between the intervention and control groups for the number of subjects developing at least one adenoma (RR = 1.04; 95 % CI, 0.95–1.13). The authors concluded that there is currently no evidence from randomized studies to suggest that increased dietary fiber intake reduces the incidence or recurrence of adenomatous polyps within a 2–4-year period.