EPIDEMIOLOGY — Approximately 148,610 new cases of large bowel cancer are diagnosed each year in the United States, of which 106,680 are colon and the remainder rectal cancers [1]. In 2006, more than 55,000 Americans will die of CRC, accounting for approximately 10 percent of all cancer deaths. In the United States, CRC ranks second to lung cancer as a cause of cancer death, and it is third both in frequency and cause of cancer death among Americans Incidence — Age is a major risk factor for sporadic CRC. It is a rare diagnosis before the age of 40, the incidence begins to increase significantly between the ages of 40 and 50, and age-specific incidence rates increase in each succeeding decade thereafter. The lifetime incidence of CRC in patients at average risk is about 5 percent, with 90 percent of cases occurring after age 50. The incidence is higher in patients with specific inherited conditions that predispose them to the development of CRC In the United States, incidence rates declined slightly (by 3 percent) between 1998 and 2003, after remaining relatively stable 1992 to 1998, following a long-term decline that began in the mid-1980s [3]. During the period from 1996 to 2000, the average annual incidence rates per 100,000 population were 64.2 and 46.7 for men and women, respectively. Despite these data, during the same time period, the incidence rates for cancer of the ascending colon increased, particularly in women. A gradual shift toward right-sided or proximal colon cancers has been observed both in the United States and internationally. As an example, data obtained from the National Cancer Database suggest that the proportion of tumors proximal to the splenic flexure increased from 51 to 55 percent of all colonic lesions between 1988 and 1993. The greatest increase in incidence is in cecal primaries This change in the anatomic distribution of CRCs may be, in part, related to improvements in diagnosis and treatment, and increased screening by flexible sigmoidoscopy with removal of adenomatous polyps in the descending colon, but there also appears to be a true increase in the incidence of ascending colon and cecal cancers. In keeping with this hypothesis, five-year survival rates have improved significantly for left and transverse colon cancers, but not for right-sided tumors Globally, the incidence of CRC varies 10-fold, with the highest incidence rates in North America, Australia, and northern and western Europe; developing countries have lower rates, particularly Africa and Asia. These geographic differences appear to be attributable to differences in dietary and environmental exposures that are imposed upon a background of genetically determined susceptibility. Mortality — Death rates from CRC have declined progressively since the mid-1980s in the United States. This improvement in outcome can be attributed, at least in part, to detection of disease at an earlier stage, and more effective treatments, particular adjuvant therapy. The United States has one of the lowest mortality rates from CRC, despite having a higher incidence than most countries. Data collected by the Surveillance, Epidemiology, and End Results Reporting Program of the United States National Cancer Institute suggest that 61 percent of all patients treated for colorectal cancer (all stages and sites combined) survive five years. In contrast, the lowest five-year survival rates have been reported by China and Eastern Europe (32 and 30 percent, respectively). RISK FACTORS — Environmental and genetic factors can increase the likelihood of developing CRC. Although inherited susceptibility results in the most striking increases in risk, the majority of CRCs are sporadic rather than familial. At least some data supports the view that family history (as well as physical activity level) are stronger contributors to colon cancer as opposed to rectal cancer risk. Nevertheless, here we will consider both entities together. Our understanding of the molecular pathogenesis of CRC (both sporadic and inherited) is evolving rapidly. These findings have led to the identification of several specific genetic disorders, all of which are inherited in an autosomal dominant fashion, that are associated with a very high risk of developing colon cancer. Familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC) are the most common of the familial colon cancer syndromes, but together these two conditions account for fewer than 5 percent of CRC cases Familial adenomatous polyposis — Familial adenomatous polyposis (FAP) and its variants (Gardner's syndrome, Turcot's syndrome, and attenuated adenomatous polyposis coli) account for less than 1 percent of colorectal cancers. In typical FAP, numerous colonic adenomas typically appear during childhood. Symptoms appear at an average age of approximately 16 years and colonic cancer occurs in 90 percent of untreated individuals by age 45. An attenuated form of APC (AAPC) carries a similarly high risk of colon cancer but is characterized by fewer adenomas and an older average age of cancer diagnosis of 54 years. An APC mutation occurring in approximately 6 percent of the Ashkenazi Jewish population has been associated with a 20 to 30 percent risk of colon cancer without the associated polyposis FAP is caused by germline mutations in the adenomatosis polyposis coli (APC) gene which is located on chromosome 5 . The same gene is involved, but the sites of the APC gene mutations are different, in the attenuated form of FAP Hereditary nonpolyposis colorectal cancer — Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant syndrome, which is more common than FAP, and accounts for approximately 2 to 6 percent of all colonic adenocarcinomas HNPCC is currently divided into two subgroups:
Both have similar colon cancer manifestations, characterized by early age of onset and predominant involvement of the right colon. The mean age at initial cancer diagnosis is 48 years, with some patients presenting in their 20s. Nearly 70 percent of first lesions arise proximal to the splenic flexure, and approximately 10 percent will have synchronous (simultaneous onset of two or more distinct tumors separated by normal bowel) or metachronous (nonanastomotic new tumors developing at least six months after the initial diagnosis) cancers [16]. Lynch syndrome II is differentiated by a high risk of extracolonic tumors, the most common of which is endometrial carcinoma which develops in up to 40 percent of female gene carriers in affected families. Other sites at increased risk of neoplasm formation include the ovary, stomach, small bowel, hepatobiliary system, and renal pelvis or ureter . However, the distinction between Lynch syndromes I and II is becoming less clear as more families are studied [ Personal or family history of sporadic cancers or adenomatous polyps — Patients with a personal history of CRC or adenomatous polyps are at risk for the development of a future large bowel cancer. In patients undergoing resection of a single CRC, metachronous primary cancers develop in 1.5 to 3 percent of patients in the first five years postoperatively. A personal history of large (>1 cm) adenomatous polyps and polyps with villous or tubulovillous histology also increase the risk of CRC, particularly if multiple. The relative risk ranges from approximately 3.5 to 6.5 in such patients. On the other hand, as a group, patients with an isolated small (<1 cm) tubular adenoma do not appear to be at increased risk Family history is also an important risk factor in sporadic disease, with a single affected first-degree relative (parent, sibling, or child) increasing the risk 1.7-fold of that in the general population. Risk is further increased if two first-degree relatives have colon cancer or if the index case is diagnosed below 55 years of age. The presence of a family history of a colonic adenoma appears to carry the same significance as a positive family history of colorectal cancer. Colonoscopic surveillance should be considered in the latter two situations, beginning at age 40, or 10 years earlier than the youngest cancer in the family Inflammatory bowel disease — There is a well documented association between chronic ulcerative colitis and colonic neoplasia, with the extent and duration of disease being the primary determinants. Pancolitis confers a 5- to 15-fold increase in risk compared to the expected incidence in the general population, and left-sided disease is associated with about a threefold relative risk; in comparison, the risk does not appear to be significantly increased with proctitis alone. A reasonable estimate of the colon cancer incidence is about 0.5 percent per year for subjects with disease duration between 10 and 20 years, then 1 percent per year thereafter. Most reports suggest that the co-occurrence of ulcerative colitis and primary sclerosing cholangitis or pericholangitis identifies a subset of these patients with an even greater risk The increase in risk of colon cancer begins about 10 years after the initial diagnosis of pancolitis, and at 15 to 20 years for colitis limited to the left colon. The probability of developing cancer then increases with disease duration and by the fourth decade of disease it reaches as high as 30 percent in patients with pancolitis]. Although there is much less data, it appears that Crohn's colitis is associated with a similar relative risk of colon malignancy as ulcerative colitis Systemic inflammation by itself may be a risk factor for colon cancer, possibly explaining at least some of the protective effect of nonsteroidal antiinflammatory drugs). In one case-control study, elevated C-reactive protein levels (a measure of inflammation) were associated with an increase in the risk of colorectal cancer among "average risk" patients. However, this relationship has not been found by others Diabetes mellitus and insulin resistance — Increasing evidence suggests that diabetes mellitus is associated with an elevated risk of colon cancer. A meta-analysis of 15 studies (six case-control and nine cohort) including a total of 2,593,935 participants estimated that the risk of colorectal cancer among diabetics was approximately 30 percent higher than nondiabetics (RR 1.30) One possible explanation linking diabetes to colon cancer is hyperinsulinemia because insulin is an important growth factor for colonic mucosal cells and stimulates colonic tumor cells. Plasma concentrations of insulin-like growth factor (IGF-I) and IGF binding protein-3 (IGFBP-3) were found to influence the risk of colorectal cancer in a cohort of 14,916 men who were followed prospectively. Subjects with values of IGF-I in the highest quintiles were more likely to develop colorectal cancer compared to those with values in the lowest quintiles (relative risk 2.51); in contrast, increased plasma concentrations of IGFBP-3 were protective (relative risk 0.28). A similar relationship between serum levels of C-peptide (an indicator of insulin production) and colorectal cancer risk was reported in a cohort of individuals followed in the Physicians' Health Study, independent of IGF-I or IGFBP-3 levels
Chronic insulin therapy may also increase the risk of colorectal
cancer in diabetics. A nested case control trial estimated that the age-
and sex-adjusted risk of colorectal cancer associated with
Cholecystectomy — A relationship between cholecystectomy and right-sided colon cancer has been described in some reports. As an example, in a study of 278,460 patients followed for up to 33 years after surgery, patients who had undergone cholecystectomy had a slightly increased risk of right-sided colon cancer (standardized incidence ratio 1.16), but not more distal colon cancers. Several meta-analyses have confirmed this association with proximal colon cancers, although discordant data have also been reported Alcohol — An association between alcohol consumption and an increased risk of colorectal cancer has been observed in several studies. A pooled analysis of eight cohort studies estimated that the risk was increased modestly, particularly in those whose alcohol consumption exceeded 45 g/d (adjusted relative risk 1.41, 95% CI 1.16-1.72). The amount of alcohol in a 12 oz beer, 4 oz glass of wine, and 1.5 oz shot of 80-proof liquor was estimated to be 13, 11, and 14 g, respectively, The risk was increased to a lesser degree in those with daily alcohol consumption in the range of 30 to 45 g/d (RR 1.16). The risk may be related to interference of folate absorption by alcohol and decreased folate intake Obesity — Two large prospective cohort studies have shown that being obese confers an approximately 1.5-fold increased risk of developing colon cancer relative to being normal weight (body mass index 18.5 to 24.9 kg/m2) [60,61]. Furthermore, obesity also increases the likelihood of dying from colorectal cancer [ Other risk factors — Several other risk factors for colon cancer have been studied:
PROTECTIVE FACTORS — In addition to the risk factors for colorectal cancer described above, certain protective factors have been identified. These include a diet high in fruits and vegetables, regular physical activity, the regular use of aspirin or nonsteroidal antiinflammatory drugs (NSAIDs), and hormone replacement therapy in postmenopausal women. Diet — Many epidemiologic studies have shown an association between the intake of a diet high in fruits and vegetables and protection from colorectal cancer. The relative risk of colorectal cancer is approximately 0.5 comparing groups with the highest intake to those with the lowest. Whether this protective effect is due to the fiber, antioxidant vitamins, folic acid, minerals such as selenium, other micronutrients, or phytochemicals (flavones) in vegetables or is due to some other constituent(s) is not known. However, discordant data have also been published. The link between consumption of produce and colorectal cancer was challenged in a prospective study that combined subjects from the Nurses' Health Study (88,764 women) and the Health Professionals' Follow-up Study (47,325 men). There was no significant association between the consumption of fruits, vegetables, or fruits and vegetables on the incidence of either colon or rectal cancer, independent of vitamin supplement use or smoking habits. Some reports suggest that a diet low in red meat, animal fat and/or cholesterol may also be protective. In one study of nearly 10,000 men and women, for example, subjects in the highest quartile of cholesterol consumption had a significantly higher risk of colorectal cancer compared to the lowest quartile (relative risk 3.26), even after adjusting for fruit and vegetable consumption and other relevant factors . Large epidemiologic studies have found an increased risk of distal colon cancer with long-term consumption of red meat or processed meats ] while other studies (with shorter follow-up periods) have failed to find a significant relationship between meat intake and risk of colorectal cancer. Fiber — A number of laboratory, nutritional and epidemiologic studies have identified a role for dietary fiber in the pathogenesis of colorectal cancer. However, the degree to which dietary fiber protects against the development of colorectal cancer is uncertain since discordant results have been published in a growing number of studies. In the Nurses' Health study, for example, no relationship was noted between fiber intake and the risk of colorectal cancer or adenoma. Furthermore, in two randomized controlled studies from the United States, fiber supplementation had no significant protective effect for the development of recurrent colorectal adenomas ]. Similarly, the Women's Health Initiative Trial found no protective effect of a modest low fat, increased fiber and increased fruit and vegetable dietary intervention on colorectal cancer incidence . A systematic review of five studies involving a total of 4349 patients concluded that there was no definitive evidence that increased dietary fiber reduces the incidence or recurrence of adenomatous polyps within a two- to four-year period . Similarly, a pooled analysis of 13 prospective cohort studies (involving 725,628 men and women followed for 6 to 20 years) found that dietary fiber intake was inversely associated with the risk of colorectal cancer but the association was no longer apparent after accounting for other dietary risk factors In contrast, a decreased risk of colonic adenomas and colorectal cancer was observed in three large epidemiologic studies. While multiple potential explanations may account for the differences among studies , the degree of protection from dietary fiber, if any, will remain unsettled until prospective intervention studies are done. The potential importance of the issue is underscored by the conclusions from one of the large studies that showed a protective effect ; the authors estimated that in populations with low average intake of dietary fiber, an approximate doubling of total fiber intake from foods could reduce the risk of colorectal cancer by 40 percent. Folic acid — Data from animal and human studies have demonstrated that folic acid inhibits pathogenesis of cancer in a number of tissues including the colon . The Nurses' Health study provided observational evidence in support of a protective effect from folic acid supplementation: women who used multivitamins containing folic acid (400 µg/day) significantly reduced their chance of developing colorectal cancer (relative risk 0.25) . This benefit was only evident after 15 years of use. Others suggest that the protective effect of folates is limited to dietary (food) rather than supplemental intake. The protective effect may also depend upon an individual's particular genotype for methylenetetrahydrofolate reductase, an enzyme involved in folate metabolism Vitamin B6 (pyridoxine) — The Nurses' Health study found a protective effect of vitamin B6 (pyridoxine)]. There was an inverse association between plasma concentrations of pyridoxal 5'-phosphate and risk for colon cancer (RR 0.42, 95% CI 0.21 to 0.85 when comparing the highest versus the lowest quartiles). Furthermore, total vitamin B6 intake was inversely related to colon cancer risk (RR 0.51, 95% CI 0.27 to 0.97).
Calcium — Another possible
protective factor is increased dietary calcium or calcium supplementation.
The association between calcium intake and colon cancer risk was examined
in two prospective cohorts from the Nurses' Health Study (n = 87,998
women) and the Health Professionals' Follow-up Study (n = 47344 men). When
both groups were combined, higher calcium intake (>1250 mg daily versus
A similar degree of benefit was noted in a
pooled analysis of individual data on 534,536 individuals from 10 cohort
studies that assessed dietary intake]. The RR for CRC in the highest as
compared to the lowest quartile of calcium intake was 0.86 (95% CI
0.78-0.95). Compared to the lowest category of milk intake (<70 g/day),
individuals ingesting
At least three controlled trials have evaluated the efficacy of calcium supplementation in prevention of recurrence of colorectal adenomas ]. A meta-analysis of these data (including a total of 1485 subject) concluded that the risk of recurrence was significantly lower in patients randomized to calcium (RR 0.80, 95% CI 0.68-0.93) Despite these benefits in adenoma prevention trials, whether calcium supplementation reduces the risk of colorectal cancer is unproven. The only large controlled trial to evaluate this issue included 36,282 post-menopausal women who were randomly assigned to the combination of calcium plus vitamin D or placebo. No significant difference in the rate of invasive colorectal cancer was observed during a mean follow-up of seven years. The study is continuing to determine whether a benefit might be observed with longer follow-up. Other data suggest that the protective effect of calcium may depend upon an individual's genotype for the vitamin D receptor. A controlled trial suggested that calcium supplementation was beneficial only in patients with normal vitamin D levels. Calcium supplementation has been recommended for the primary or secondary prevention of colonic adenomas by the American College of Gastroenterology Magnesium — Animal studies suggest that dietary magnesium may influence colorectal cancer development. A population based study from Sweden found an inverse association between magnesium intake and the risk of colorectal cancer in women . Compared with women in the lowest quintile of magnesium intake, the risk was reduced by approximately 40 percent (RR 0.59, 95% CI 0.40-0.87) in women with the highest quintile of intake. The inverse association was observed for both colon and rectal cancer. Physical activity — Substantial observational data suggest that regular physical activity, either occupational or leisure time, appears to be associated with protection from colorectal cancer, an effect that may be synergistic with high energy intake and obesity . In one study of a cohort of male smokers, for example, subjects who engaged in light occupational activity had a decreased risk of colorectal cancer compared to sedentary workers (relative risk 0.60). Those engaged in moderate or heavy activity had an even lower risk (relative risk 0.45). There was no significant independent relationship between leisure activity and colon cancer, but the lowest risk was found in men who were most active at work and during leisure time (relative risk 0.33) . The mechanism for the apparent protective effect of physical activity is not known. Aspirin and NSAIDs — A substantial body of evidence supports a protective effect of aspirin and other nonsteroidal antiinflammatory drugs on the development of colon cancer. How long-term aspirin or NSAID therapy might protect against colon cancer is not well understood. Proposed explanations are increased apoptosis and impairment of tumor cell growth by inhibition of cyclooxygenase-2. Hormone replacement therapy — Several studies have suggested that postmenopausal hormone use may reduce the risk of colorectal cancer. In the largest epidemiologic study (the Women's Health Study), in women taking combined hormone therapy the risk was reduced by almost 40 percent (hazard ratio [HR] 0.56) In contrast, no significant differences were found in rates of colorectal cancer for unopposed CEE vs placebo use (HR 1.08). Moreover, the National Polyp Prevention Trial (a randomized dietary intervention study of individuals with colorectal adenomas) found no overall reduction in adenoma recurrence in patients taking HRT (either unopposed estrogen or combined therapy) . HRT are not routinely recommended for chemoprevention of colon cancer in women because of the associated long-term risks Statins — Emerging data suggest that HMG-CoA reductase inhibitors (statins) may have a protective effect against several cancers, including colon cancer, although the data are conflicting. In experimental animal models, statins reduce carcinogen-induced colon cancer by up to 65 percent, and they induce apoptosis in colorectal cancer cell lines. Furthermore, a modest reduction in the incidence of colon cancer was observed in two large clinical trials evaluating the benefit of pravastatin and simvastatin for coronary artery disease A reduced risk of colorectal cancer was also observed in the Molecular Epidemiology of Colorectal Cancer (MECC) study, a population-based case-control study in which data regarding personal and family history of cancer, medical conditions, medication use, physical activity, and nutrition were collected from 1953 patients diagnosed with colorectal cancer and 2015 population-based controls matched for age, gender and ethnicity. Use of statins for at least five years was associated with a significant reduction in the risk of colorectal cancer (OR 0.53, 95% CI 0.38-0.74) after adjustment for use of aspirin and other NSAIDs, physical activity, hypercholesterolemia, vegetable consumption, and family history. A potential confounding factor is that the cancer population and the controls were drawn from two different databases. Other case-control studies have failed to document a protective benefit of statin use against colon cancer. The explanation for these conflicting results is unclear. However, there is no consistent evidence that statins increase or decrease the risk of any form of cancer. Antioxidants — Several interventional trials have evaluated the efficacy of antioxidants in the prevention of colorectal adenomas. A meta-analysis of eight controlled trials found no convincing evidence that antioxidant supplements had a significant beneficial effect on primary or secondary prevention of colorectal adenomas |
1
year of insulin use was 2.1 (95% CI 1.2-3.4)
500
mg daily) was associated with a significant reduction in the risk of
distal colon cancers (relative risk [RR] 0.65, 95 percent confidence
interval [CI], 0.43 to 0.98) but not proximal cancers (RR 1.14, 95% CI,
0.72-1.81).