Colon Cancer Prevention

Colon Cancer Prevention 2

Colon Cancer Prevention 3

Colon Cancer Prevention 4

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      Prevention statement for Health professionals

Prevention of Colorectal Cancer

Summary of Evidence

Note: Separate PDQ summaries on Screening for Colorectal Cancer; Colon Cancer Treatment; and Rectal Cancer Treatment are also available.

Use of Nonsteroidal Anti-Inflammatory Drugs

Based on solid evidence, use of nonsteroidal anti-inflammatory drugs, including piroxicam, sulindac, and aspirin, may prevent adenoma formation or cause adenomatous polyps to regress in individuals with prior colorectal cancer or adenomatous polyps and in the setting of familial adenomatous polyposis.

Description of the Evidence

· Study Design: Evidence obtained from randomized controlled trials.

· Internal Validity: Good.

· Consistency: Good.

· Magnitude of Effects of Health Outcomes: Small positive.

· External Validity: Good.

Based on solid evidence, harms of nonsteroidal anti-inflammatory drug use include upper gastrointestinal bleeding and serious cardiovascular events such as myocardial infarction, heart failure, and hemorrhagic stroke.

Description of the Evidence

· Study Design: Evidence obtained from randomized controlled trials.

· Internal Validity: Good.

· Consistency: Good.

· Magnitude of Effects on Health Outcomes: Increased risk, small magnitude.

· External Validity: Good.

Postmenopausal Hormone Use

There is inadequate evidence to determine whether postmenopausal hormone use would decrease the incidence of colorectal cancer.

Description of the Evidence

· Study Design: Evidence obtained from a randomized controlled trial.

· Internal Validity: Fair.

· Consistency: One study.

· Magnitude of Effects on Health Outcomes: Fair.

· External Validity: Fair.

Based on fair evidence, harms of postmenopausal hormone use include increased risk of endometrial cancer, breast cancer, thromboembolic events, and coronary heart disease.

Description of the Evidence

· Study Design: Evidence from randomized controlled trials.

· Internal Validity: Fair.

· Consistency: Fair.

· Magnitude of Effects on Health Outcomes: Negative, small.

· External Validity: Fair.

Diet Modification

A Diet Low in Fat and High in Fiber, Fruits, and Vegetables

There is inadequate evidence to suggest that a diet low in fat and high in fiber, fruits, and vegetables decreases the risk of colorectal cancer.

Description of the Evidence

· Study Design: Evidence obtained from randomized controlled trials.

· Internal Validity: N/A.

· Consistency: N/A.

· Magnitude of Effects on Health Outcomes: N/A.

· External Validity: N/A.

There are no known harms from dietary modification, including reduction of fatty acids and increase in the intake of fiber, fruits, and vegetables.

Description of the Evidence

· Study Design: Multiple types.

· Internal Validity: Good.

· Consistency: Good.

· Magnitude of Effects on Health Outcomes: None known.

· External Validity: Good.

Polyp Removal

Based on solid evidence, removal of adenomatous polyps reduces the risk of colorectal cancer.

Description of the Evidence

· Study Design: Evidence obtained from cohort studies.

· Internal Validity: Good.

· Consistency: N/A.

· Magnitude of Effects on Health Outcomes: Good.

· External Validity: Good.

Based on solid evidence, harms of polyp removal include infrequent perforation of the colon during the procedure as well as bleeding and infection following the procedure.

Description of the Evidence

· Study Design: Evidence obtained from randomized controlled trials and cohort studies.

· Internal Validity: Good.

· Consistency: Good.

· Magnitude of Effects on Health Outcomes: Negative, small.

· External Validity: Good.

Significance

Incidence and Mortality

Colorectal cancer is the third most common malignant neoplasm worldwide [1] and the second leading cause of cancer deaths (irrespective of gender) in the United States. [2] It is estimated that there will be 148,610 new cases diagnosed in the United States in 2006 and 55,170 deaths due to this disease. Between 1998 and 2002, colorectal cancer incidence rates in the United States declined by 1.8% per year. Over the past 15 years, the mortality rate declined by 1.8% per year. [2] The overall 5-year survival rate is 65.6%. About 6% of Americans are expected to develop the disease within their lifetimes. [3] The risk of colorectal cancer begins to increase after the age of 40 and rises sharply at the ages of 50 to 55; the risk doubles with each succeeding decade, and continues to rise exponentially. Despite advances in surgical techniques and adjuvant therapy, there has been only a modest improvement in survival for patients who present with advanced neoplasms. [4] [5] Hence, effective primary and secondary preventive approaches must be developed to reduce the morbidity and mortality from colorectal cancer.

Definition of Prevention

Primary prevention involves the identification of genetic, biologic, and environmental factors that are etiologic or pathogenic in the development of cancer, and subsequent complete or significant interference with their effects on carcinogenesis. Removal of premalignant lesions (adenomas) may also be an ffective form of primary prevention.

Etiology and Pathogenesis of Colorectal Cancer

Genetics, [6] [7] experimental, [8] [9] and epidemiologic [10] [11] [12] studies suggest that colorectal cancer results from complex interactions between inherited susceptibility and environmental factors. It has been suggested that dietary factors may be responsible for a significant but poorly quantitated number of cancer cases. [13] Efforts to identify causes and to develop effective preventive measures have led to the hypothesis that adenomatous polyps (adenomas) are precursors for the vast majority of colorectal cancers. [14] While most of these adenomas are polypoid, flat and depressed lesions may be more prevalent than previously recognized. Large flat and depressed lesions are more likely to be severely dysplastic. Specialized techniques may be needed to identify, biopsy, and remove such lesions. [15] In effect, measures that reduce the incidence and prevalence of adenomas may result in a subsequent decrease in the risk of colorectal cancer. [16] The finding of an adenoma on flexible sigmoidoscopy may warrant colonoscopy to evaluate the more proximal colon for synchronous neoplasms. [17] Many of the intervention trials employ adenoma recurrence or disappearance as a surrogate endpoint. [18] The evolution of a carcinoma from a small adenoma, however, takes many years. [10]

References:

1. Shike M, Winawer SJ, Greenwald PH, et al.: Primary prevention of colorectal cancer. The WHO Collaborating Centre for the Prevention of Colorectal Cancer. Bull World Health Organ 68 (3): 377-85, 1990.

2. American Cancer Society.: Cancer Facts and Figures 2006. Atlanta, Ga: American Cancer Society, 2006. Also available online. Last accessed June 12, 2006.

3. Ries LAG, Eisner MP, Kosary CL, et al., eds.: SEER Cancer Statistics Review, 1975-2002. Bethesda, Md: National Cancer Institute, 2005. Also available online. Last accessed May 11, 2006.

4. Moertel CG, Fleming TR, Macdonald JS, et al.: Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 322 (6): 352-8, 1990.

5. Krook JE, Moertel CG, Gunderson LL, et al.: Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 324 (11): 709-15, 1991.

6. Willett W: The search for the causes of breast and colon cancer. Nature 338 (6214): 389-94, 1989.

7. Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 61 (5): 759-67, 1990.

8. Reddy B, Engle A, Katsifis S, et al.: Biochemical epidemiology of colon cancer: effect of types of dietary fiber on fecal mutagens, acid, and neutral sterols in healthy subjects. Cancer Res 49 (16): 4629-35, 1989.
9. Reddy BS, Tanaka T, Simi B: Effect of different levels of dietary trans fat or corn oil on azoxymethane-induced colon carcinogenesis in F344 rats. J Natl Cancer Inst 75 (4): 791-8, 1985.

10. Potter JD: Reconciling the epidemiology, physiology, and molecular biology of colon cancer. JAMA 268 (12): 1573-7, 1992 Sep 23-30.

11. Wynder EL, Reddy BS: Dietary fat and fiber and colon cancer. Semin Oncol 10 (3): 264-72, 1983.

12. Chen CD, Yen MF, Wang WM, et al.: A case-cohort study for the disease natural history of adenoma-carcinoma and de novo carcinoma and surveillance of colon and rectum after polypectomy: implication for efficacy of colonoscopy. Br J Cancer 88 (12): 1866-73, 2003.

13. Doll R, Peto R: The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst 66 (6): 1191-308, 1981.

14. Hill MJ, Morson BC, Bussey HJ: Aetiology of adenoma--carcinoma sequence in large bowel. Lancet 1 (8058): 245-7, 1978.

15. Rembacken BJ, Fujii T, Cairns A, et al.: Flat and depressed colonic neoplasms: a prospective study of 1000 colonoscopies in the UK. Lancet 355 (9211): 1211-4, 2000.

16. Winawer SJ, Zauber AG, Ho MN, et al.: Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 329 (27): 1977-81, 1993.

17. Read TE, Read JD, Butterly LF: Importance of adenomas 5 mm or less in diameter that are detected by sigmoidoscopy. N Engl J Med 336 (1): 8-12, 1997.

18. Vargas PA, Alberts DS: Colon cancer: the quest for prevention. Oncology (Huntingt) 7(11 suppl): 33-40, 1993.

Evidence of Benefit

Chemoprevention

Nonsteroidal Anti-Inflammatory Drugs

The clinical utility of nonsteroidal anti-inflammatory drugs (NSAIDs) results from their ability to inhibit the activity of cyclooxygenase (COX). COX is important in the transformation of arachidonic acid into prostanoids, prostaglandins, and thromboxane A2. NSAIDs include not only aspirin, first-generation nonselective inhibitors of both COX-1 and COX-2, but newer second-generation drugs that inhibit primarily COX-2. The 2 functional isoforms of COX, termed COX-1 and COX-2, play important roles. Normally, COX-1 is expressed in most tissues and primarily plays a housekeeping role, e.g., gastrointestinal mucosal protection and platelet aggregation. COX-2 activity is crucial in stress responses and in mediating and propagating the pain and inflammation that are characteristic of arthritis. [1]

Nonselective COX inhibitors include indomethacin (Indocin); sulindac (Clinoril); piroxicam (Feldene); diflunisal (Dolobid); ibuprofen (Advil, Motrin); ketoprofen (Orudis); naproxen (Naprosyn); and naproxen sodium (Aleve, Anaprox). Selective COX-2 inhibitors include celecoxib (Celebrex), rofecoxib (Vioxx), and valdecoxib (Bextra). Rofecoxib and valdecoxib are no longer marketed because of an associated increased risk of serious cardiovascular events. In a nested case-control study of 8,143 cases of coronary heart disease (27% fatal) and 31,496 age- and gender-matched controls, multivariate adjusted odds ratios (OR) for rofecoxib (all doses) versus celecoxib was 1.59 (95% CI, 1.10–2.32); for rofecoxib 25 mg/day or less, the OR was 1.47 (0.99–2.17). [2] In a sporadic adenoma chemoprevention trial comparing rofecoxib 25 mg with placebo, rofecoxib administration was associated with a relative (RR) of 1.92 (95% CI, 1.19–3.11; P = .008) of serious cardiovascular events. The number of patients in the trial was 2,586 and its duration was 3 years. Forty-six of 1,287 in the rofecoxib group (1.50 events per 100 patient years) had a serious adverse cardiovascular event compared with 26 of 1,299 in the placebo group (0.78 events per 100 patient years).

[3]
Celecoxib administration was associated with a dose-related increase in death from cardiovascular cause, myocardial infarction, stroke, or heart failure in a sporadic adenoma prevention trial (N = 2,035) that extended over 3 years and compared 2 doses of celecoxib, 200 mg or 400 mg twice daily, with placebo. Seven of 679 patients in the placebo group (1.0%) as compared with 16 of 685 patients receiving 200 mg of celecoxib twice a day (2.3%; HR, 2.3; 95% CI, 0.9–5.5) and 23 of 671 patients receiving 400 mg of celecoxib twice a day (3.4%; HR, 3.4; 95% CI, 1.4–7.8) had a severe cardiovascular adverse event.

[4]
Several, but not all, epidemiological studies have reported a reduction in colon cancer incidence associated with the use of aspirin. Several cohort studies suggest a preventive effect of aspirin. Among a group of more than 600,000 adults enrolled in an American Cancer Society study, mortality in regular users of aspirin was about 40% lower for cancers of the colon and rectum. [5] [6] In a study of more than 11,000 men and women in Sweden with rheumatoid arthritis (and presumably ingesting NSAIDs), colon cancer incidence was 37% lower and rectal cancer was 28% lower than predicted from cancer registry data. [7] In a report from the Health Professionals Follow-up Study of 47,000 males, regular use of aspirin (at least 2 times per week) was associated with a 30% overall reduction in colorectal cancer, including a 50% reduction in advanced cases. [8] In a Women's Health Study randomized 2 x 2 factorial trial of 100 mg of aspirin every other day for an average of 10 years, similar rates of breast, colorectal, or other site-specific cancers were observed in both the aspirin and placebo arms. [9] In a report from the Nurses’ Health Study involving 82,911 women followed for 20 years, the multivariate RR for colon cancer was 0.77 (95% CI, 0.67–0.88) among women who regularly used aspirin (=2 standard 325 mg tablets per week) compared with nonregular use. Significant risk reduction was not observed, however, until more than 10 years of use. The benefit appeared to be dose-related (e.g., women who used more than 14 aspirin per week for longer than 10 years had a multivariate RR for cancer of 0.47 [95% CI, 0.31–0.71]). A similar dose-response relationship was observed for nonaspirin NSAIDs. The incidence of reported major gastrointestinal bleeding events also appeared to be dose-related. [10] A population-based retrospective cohort study of nonaspirin NSAID use among individuals aged 65 years and older was also associated with lower risk, particularly with increasing durations of use. [11] In the Physicians’ Health Study, 22,000 men aged 40 to 84 years were randomly assigned to receive placebo or aspirin (325 mg every other day) for 5 years. There was no reduction in invasive cancers or adenomas at a median follow-up of 4.5 years. [12] In a subsequent analysis over a 12-year period, both randomized and observational analyses indicated that there was no association between the use of aspirin and the incidence of colorectal cancer. The low dose of aspirin and the short treatment period may account for the null findings. [13]

In a randomized study of 635 patients with prior colorectal cancer (T1 to T2 N0 M0) who had undergone curative resection, aspirin intake at 325 mg/day was associated with a decrease in the adjusted RR of any recurrent adenoma as compared with the placebo group (0.65; 95% CI, 0.46–0.91) after a median duration of treatment of 31 months. The time to the detection of a first adenoma was longer in the aspirin group than in the placebo group (HR for the detection of a new polyp, 0.54; 95% CI, 0.43–0.94, P = .022). Harms of treatment included upper gastrointestinal hemorrhage and hemorrhagic stroke. [14] In a study of 1,121 patients with a recent history of colorectal adenomas, after a mean duration of treatment of 33 months, the unadjusted relative risks of any adenoma (as compared with the placebo group) were 0.81 in the 81-mg aspirin group (95% CI, 0.69–0.96) and 0.96 in 325-mg aspirin group (95% CI, 0.81–1.13). For advanced neoplasms (adenomas measuring at least 10.0 mm in diameter or with tubulovillous or villous features, severe dysplasia or invasive cancer), the RRs were 0.59 (95% CI, 0.38–0.92) in the 81-mg aspirin group, and 0.83 (95% CI, 0.55–1.23) in the 325-mg aspirin group. [15] Harms of treatment were similar in the 2 groups and included upper gastrointestinal bleeding and hemorrhagic stroke.
Several studies conducted in a rigorous manner have demonstrated the effectiveness of sulindac in reducing the size and number of adenomas in familial polyposis. [16] [17] In a randomized double-blind placebo-controlled study of 77 patients with familial adenomatous polyposis, patients receiving 400 mg of celecoxib twice a day had a 28.0% reduction in the mean number of colorectal adenomas (P = .003 for the comparison with placebo) and a 30.7% reduction in the polyp burden (sum of polyp diameters; P = .001) as compared with reductions of 4.5% and 4.9%, respectively, in the placebo group. The reductions in the group receiving 100 mg of celecoxib twice a day were 11.9% (P = .33 for the comparison with placebo) and 14.6% (P = .09), respectively. The incidence of adverse events was similar among the groups. [18]
The NSAID piroxicam, at a dose of 20 mg/day, reduced mean rectal prostaglandin concentration by 50% in individuals with a history of adenomas. [19] Several studies assessing the effect of aspirin or other nonsteroidals on polyp recurrence following polypectomy are in progress. [20] In several of these studies, mucosal prostaglandin concentration is being measured.

The potential for the use of NSAIDs as a primary prevention measure is being studied. There are, however, several unresolved issues that mitigate against making general recommendations for their use. These include a paucity of knowledge about the proper dose and duration for these agents, and concern about whether the potential preventive benefits such as a reduction in the frequency or intensity of screening or surveillance could counterbalance long-term risks such as gastrointestinal ulceration and hemorrhagic stroke for the average-risk individual. [21]

Table 1: Ongoing Phase II/III and Phase III Chemoprevention Trials in Colorectal Neoplasia
Phase II/III Trials

Investigator/Institution Patient Population Interventions Status of Patient Accrual
P. Lynch/Univ. of Texas M.D. Anderson Cancer Center Prephenotypic FAP Celecoxib vs. placebo Open
F. Meyskens/Univ. of California-Irvine Prior sporadic adenoma Sulindac + eflornithine vs. placebo Open
P. Lynch/Univ. of Texas M.D. Anderson Cancer Center Phenotypic FAP Celecoxib + eflornithine vs. celecoxib Open

R. Bresalier/Univ. of Texas M.D. Anderson Cancer Center Individuals with ACF Sulindac vs. aspirin vs. ursodiol vs. placebo Closed

Phase III Trials
Investigator/Institution Patient Population Interventions Status of Patient Accrual
D. Alberts/Univ. of Arizona Prior sporadic adenoma Ursodeoxycholic acid vs. placebo Closed
M. Bertagnolli/Multicenter Prior sporadic adenoma Celecoxib vs. placebo Closed
Women’s Health Initiative/National Institutes of Health Postmenopausal women Low-fat diet vs. calcium + vitamin D vs. HRT vs. placebo Closed
J. Burn/CAPP-1, Univ. of Newcastle Prephenotypic FAP Aspirin vs. resistant starch vs. both vs. placebo Closed
uk-CAP/Cancer Research U.K. Prior sporadic adenoma Aspirin vs. folate vs. both vs. placebo Closed
P. Lance/Univ. of Arizona Prior sporadic adenoma Celecoxib vs. selenium vs. both vs. placebo Open selenium vs. placebo only
J. Baron/Dartmouth Univ. Prior sporadic adenoma Aspirin ± folate vs. placebo; also, folate arm is ongoing Closed
H. Berkel/Hipple Cancer Research Center Prior sporadic adenoma Piroxicam vs. calcium carbonate vs. both vs. placebo Closed
E. Giovannucci/Harvard Prior sporadic adenoma Folate vs. placebo Closed
J. Burn/CAPP-2, Univ. of Newcastle HNPCC patients or mutation carriers Aspirin vs. resistant starch vs. both vs. placebo Closed
FAP = familial adenomatous polyposis; ACF = aberrant crypt foci; HRT = hormone replacement therapy; CAPP = Concerted Action Polyposis Prevention Study; uk-CAP = United Kingdom Colorectal Adenoma Prevention Study; HNPCC = hereditary nonpolyposis colorectal cancer.
Also see Umar et al. [22]

Postmenopausal Female Hormone Supplements

Several epidemiologic studies have suggested a decreased risk of colon cancer among users of postmenopausal female hormone supplements. [23] [24] [25] [26] For rectal cancer, most studies have observed no association or a slightly elevated risk. [27] [28] [29]

In the Women’s Health Initiative Trial, 16,608 postmenopausal women aged 50 to 79 years were randomly assigned to a combination of conjugated equine estrogens (0.625 mg/day) plus medroxyprogesterone (2.5 mg/day) or placebo. There were 43 invasive colorectal cancers in the hormone group and 72 in the placebo group (HR 0.56; 95% CI, 0.38–0.81, P = .003). The invasive colorectal cancers in the hormone group were similar in histologic features and grade to those in the placebo group but with a greater number of positive lymph nodes (mean ± standard deviation 3.24 ± 4.1 vs. 0.8 ± 1.7; P = .002) and were more advanced (regional or metastatic disease; 76.2% vs. 48.5%; P = .004). [30]

Use of Statins

Overall, evidence indicates that statin use neither increases nor decreases the incidence or mortality of colorectal cancer. Although some case-control studies have shown a reduction in risk, neither a large cohort study [31] nor a meta-analysis of 4 randomized controlled trials [32] found any effect of statin use.

Dietary Factors

The studies reviewed below include those on adenomas; special note is made if a study applies to adenomas only.

Dietary Fat and Meat Intake

Colon cancer rates are high in populations with high total fat intakes and are lower in those consuming less fat. [33] On average, fat comprises 40% to 45% of total caloric intake in high-incidence Western countries; in low-risk populations, fat accounts for only 10% of dietary calories. [34] In laboratory studies, a high-fat intake increases the incidence of induced colon tumors in experimental animals. [35] [36] Several case-control studies have explored the association of colon cancer risk with meat or fat consumption as well as protein and energy intake. [37] [38] Although positive associations with meat consumption or with fat intake have been found frequently, the results have not always achieved statistical significance. [39] A number of prospective cohort studies have been conducted in the United States and abroad. In Japan, an increased risk of colon cancer with increased frequency of meat consumption was observed in the group with infrequent vegetable consumption among a group of 265,000 men and women. [40] In Norway, an increased risk for processed meat only was found, [41] a finding that was confirmed in the Netherlands. [42] A clearly defined gradient in risk for frequency of meat and poultry consumption was not observed in a population of Seventh Day Adventists that included a large proportion of vegetarians. [43] A prospective study among female nurses showed an increased risk of colon cancer associated with red meat consumption (beef, pork, lamb, and processed meat) and also with the intake of saturated and monounsaturated fat, predominantly derived from animals. [44] No increase in risk with meat or fat consumption was seen, however, in 2 other large prospective studies, the American Cancer Society’s Cancer Prevention Study II and the Iowa Women’s Health Study. [45] [46] In a prospective cohort study of a low-risk population of non-Hispanic white members of the Adventist Health Study, a positive association between meat (both red and white) intake and colon cancer was observed (relative risk [RR] for =1 time per week vs. no meat intake = 1.85, 95% confidence interval [CI], 1.19–2.87, P for trend = .01). [47] It has been hypothesized that the heterocyclic amines (HCAs) formed when meat and fish are cooked at high temperatures may contribute to the increased risk of colorectal cancers associated with meat consumption that has been observed in epidemiologic studies. A population-based case-control study in Sweden, however, found no evidence of increased risk associated with total HCA intake; for colon cancer the RR was 0.6 (95% CI, 0.4–1.0), and for rectal cancer it was 0.7 (95% CI, 0.4–1.1). [48] [49]

A randomized controlled dietary modification study was undertaken among 48,835 postmenopausal women aged 50 to 79 years who were also enrolled in the Women's Health Initiative. The intervention promoted a goal of reducing total fat intake by 20%, while increasing daily intake of vegetables, fruits, and grains. The intervention group accomplished a reduction of fat intake of approximately 10% over the 8.1 years of follow-up. There was no evidence of reduction in invasive colorectal cancers between intervention and comparison groups with a hazard ratio (HR) of 1.08 (95% CI, 0.90–1.29). [50] Likewise, there was no benefit of the low-fat diet on all cancer mortality, overall mortality, or cardiovascular disease. [51]

Explanations for the conflicting results regarding whether dietary fat or meat intake affects risk of colorectal cancer [42] include (a) validity of dietary questionnaires used; (b) differences in the average age of the population studied; (c) variations in methods of meat preparation (in some instances, mutagenic and carcinogenic HCAs could have been released at high temperatures [52]); and (d) variability in the consumption of other foods such as vegetables. [53] In addition, some epidemiological studies have reported lower incidence rates of colon cancer in populations with high intakes of both fat and fiber, compared with populations with high levels of fat but low levels of fiber consumption. [54] Although far from clear-cut, the available evidence suggests colorectal cancer risk is possibly associated with some interaction of dietary fat and protein and caloric intake.

Six case-control studies and 2 cohort studies have explored potential dietary risk factors for colorectal adenomas. [55] [56] Three of the 8 studies found that higher fat consumption was associated with increased risk. High fat intake has been found to increase the risk of adenoma recurrence following polypectomy. [57] In a multicenter randomized controlled trial, a diet low in fat (20% of total calories) and high in fiber and fruits and vegetables did not reduce the risk of recurrence of colorectal adenomas. [58]

Bile Acids

A central effect of bile acids in the etiology and pathogenesis of colorectal cancer has been claimed. [59] An increased bile acid concentration in the intestinal tract accompanies a high-fat diet because bile acids are released from the gallbladder after fat ingestion. The concentration of bile acids in the colon is heavily influenced by the amount and type of fat in the diet. [60] The potential mechanism of action of bile salts in colorectal carcinogenesis is unknown, although it has been suggested that it is mediated by diacylglycerol. [61] The conversion of dietary phospholipids to diacylglycerol by intestinal bacteria is enhanced by a high-fat diet. It is proposed that diacylglycerol enters the cell directly, stimulating protein kinase C, which is involved in intracellular signal transduction.

Dietary Fiber, Vegetables, and Fruit

The evidence on whether dietary fiber exerts a protective role in reducing the incidence of colorectal cancer is mixed. Most animal and epidemiologic studies show a protective effect of dietary fiber on colon carcinogenesis. [20] The term fiber is used to describe a complex mixture of compounds, including insoluble fiber (typified by wheat bran and cellulose) and soluble fiber (usually dried beans). Ingestion of fiber could modify carcinogenesis in the large bowel by a number of potential mechanisms. [62] [63] [64] These mechanisms include binding to bile acids, increasing fecal water and possibly diluting carcinogens, and decreasing transit time (not an obvious factor). Fiber may act as a substrate for bacterial fermentation with a resultant increase in bacterial mass and the production of short-chain fatty acids, typified by butyrate. [64] Butyrate has been shown to have anticarcinogenic effects in vitro and is regarded as an important fuel for the colonic epithelium. [65] [66] A meta-analysis of 13 case-control studies from 9 countries concluded that intake of fiber-rich foods is inversely related to cancers of both colon and rectum. [67] The analysis did not include fiber supplements. The inverse association with fiber was observed in 12 of the 13 studies and was similar in magnitude for left-sided and right-sided colon and rectal cancers, men and women, and different age groups. It has been suggested that the inverse association with fiber may be reflective of some other closely associated dietary constituents, such as the anticarcinogens found in vegetables, fruits, legumes, nuts, and grains. [37] [67] These substances include phenolic compounds, sulfur-containing compounds, and flavones. [68] [69] In a prospective cohort study of a low-risk population, an inverse association was found with legume intake and the risk of colorectal cancer (RR for >2 times/week vs. 1 time/week = 0.53; 95% CI, 0.33–0.86, P for trend = .03). [47]

Other studies have corroborated the effects of dietary fiber. One study used a supplement of 10 g/day of wheat bran, cellulose, and oat bran and found a decreased mutagenic activity of fecal contents in those receiving wheat bran and cellulose supplementation, although no measurable inhibition was observed during oat bran supplementation. [70] Fecal-total and secondary bile acid excretion increased during oat fiber supplementation.

Despite the evidence from case-control studies of a protective effect, results from the large prospective Nurses’ Health Study found no difference in risk of colorectal cancer between women in the highest compared with lowest quintile group with respect to dietary fiber, after adjusting for age, known risk factors, and total energy intake (RR = 0.95; 95% CI, 0.73–1.25). [71]

Many epidemiologic studies have examined the relationship between fruit and vegetable intake and the incidence of colon and/or rectal cancer, [72] with considerable variation in findings. Perhaps the most definitive analysis to date is a prospective study that examined dietary intake data based on food frequency questionnaires from 88,764 women in the Nurses' Health Study and 47,325 men in the Health Professionals Follow-up Study. [73] The study included a total of 1,743,645 person-years of follow-up, 937 cases of colon cancer, and 244 cases of rectal cancer. On the basis of analyses adjusted for numerous covariates, the authors found no association in women or men between overall fruit and vegetable consumption and risk of colon or rectal cancer. Neither were associations observed when the data were examined for subgroups of fruits or vegetables (with the exception of legumes, which were associated with an increased risk of colon cancer in women) or individual fruits or vegetables (with the exception of prunes, which were associated with an increased risk of colon cancer in men). Results did not change when data were examined by vitamin use status, smoking status, or family history of colorectal cancer, nor were elevated risks seen when individuals with very low levels of fruit and vegetable consumption were compared with those having the highest levels. For women and men combined, the covariate-adjusted RR of colon cancer associated with 1 additional serving of fruits and vegetables per day was 1.02 (95% CI, 0.98–1.05); the comparable RR for rectal cancer was 1.02 (95% CI, 0.95–1.09).

In a population-based prospective cohort study of 61,463 women in Sweden, individuals who consumed very low amounts of fruits and vegetables (<1.5 servings of fruit and vegetables/day) had a RR for developing colorectal cancer of 1.65 (95% CI, 1.23–2.2; P trend = .001) as compared with those individuals who consumed more than 2.5 servings. There was little evidence, however, of a benefit for higher as compared with moderate consumption (more than vs. fewer than 3.5 servings). Limitations of this study are that dietary intake during the study period was not reassessed over time, and the influence of physical activity could not be accurately determined. In addition, the conclusion about very low amounts of intake of fruits and vegetables is based on a retrospective subdivision of the lowest quartile of consumption, and its strength has not been adjusted for other potential confounding factors. [74]

Six case-control studies and 3 cohort studies have explored potential dietary risk factors for colorectal adenomas. [55] [56] [71] Four of the 9 found an association of fiber, carbohydrates, and/or vegetables with reduced risk. In one study, cases with moderate or severe dysplasia had a significantly lower intake of cruciferous vegetables than those with mild dysplasia. No significant effect of dietary fiber on colorectal adenoma was found in the large cohort study of U.S. nurses. [71]

High-fiber cereal supplements over a 3-year period did not result in a decrease in adenoma recurrence in a randomized controlled trial of 1,303 individuals. [75] In a multicenter randomized controlled trial, a diet low in fat (20% of total calories) and high in fiber (18 g of dietary fiber/1,000 kcal) and fruits and vegetables (3.5 servings/1,000 kcal) was not associated with a reduction in risk of recurrence of colorectal adenomas. [58]

Calcium

It has been hypothesized that orally ingested calcium lowers colon cancer risk by binding bile acids and fatty acids, thereby reducing exposure to toxic intraluminal compounds. [76] Indirect effects on bile acid metabolism and a direct effect on colonic epithelial cells are also possible.

Several [77] [78] [79] [80] but not all [56] [81] epidemiologic studies have observed an inverse relationship between calcium intake and cancer risk. Interpretation of these studies can be quite complex. For example, in Utah, an inverse relationship between colon cancer and calcium was observed in a study that compared members of the Church of Jesus Christ of Latter-Day Saints (Mormons) and Seventh Day Adventists with a group from the U.S. population at large. Both study groups have higher calcium intakes, mainly milk and dairy products, than the national average. Unlike the Seventh Day Adventists, however, the Mormon group had a consumption of meats and fat similar to that of the general population.

Experimental studies in rodents [82] and some but not all human studies [83] [84] [85] [86] have described a decrease in colonic epithelial cell proliferation after the administration of calcium citrate. Human studies using labeling index are dependent on a complex methodology. [87] A randomized placebo-controlled trial tested the effect of calcium supplementation (3 g calcium carbonate daily [1,200 mg elemental calcium]) on the risk of recurrent adenoma. [88] The primary endpoint was the proportion of subjects (72% of whom were male) in whom at least 1 adenoma was detected following a first and/or second follow-up endoscopy. A modest decrease in risk was found for both developing at least 1 recurrent adenoma (adjusted risk ratio [ARR] = 0.81; 95% CI, 0.67–0.99) and in the average number of adenomas (ARR = 0.76; 95% CI, 0.60–0.96). The investigators found the effect of calcium was similar across age, sex, and baseline dietary intake categories of calcium, fat, or fiber. The study was limited to individuals with a recent history of colorectal adenomas and so could not determine the effect of calcium on risk of first adenoma, nor was it large enough or of sufficient duration to examine risk of invasive colorectal cancer. The results of other ongoing adenoma recurrence studies are awaited with interest (Table 1). It is important to note that the dose of calcium salt administered may be important; the usual daily doses in trials have ranged from 1,250 to 2,000 mg of calcium.

In a randomized, double-blind, placebo-controlled trial involving 36,282 postmenopausal women, the administration of 500 mg of elemental calcium and 200 IU of vitamin D3 twice daily for an average of 7.0 years was not associated with a reduction in invasive colorectal cancer (HR 1.08; 95% CI, 0.86–1.34; P = 0.051). [89] The relatively short duration of follow-up, considering the latency period of colorectal cancer of 10 to 15 years and suboptimal doses of calcium and vitamin D, may account for the negative effects of this trial, though other factors may also be responsible. [90]

Vitamins

In a prospective cohort study of 35,215 Iowa women, an inverse association between the risk of colon cancer and vitamin E intake was found; the RR for the highest compared with the lowest quartile was 0.3 (95% CI, 0.19–0.54). [91] The Women's Health Study, however, showed no relationship between colorectal cancer in women and the use of 600 IU of vitamin E every other day. [92] In a meta-analysis of 14 randomized trials of supplemental antioxidant vitamins encompassing 170,025 individuals, no evidence of prevention of colorectal adenomas or cancer or other gastrointestinal tumors was found. [93]

In a population-based case-control study, an inverse relationship between vitamin D intake and risk of colorectal cancer was found. [94] A prospective cohort study observed that higher energy-adjusted folate intake in the form of multivitamins containing folic acid was related to a lower risk for colon cancer (RR = 0.69; 95% CI, 0.52–0.93) for intake of more than 400 µg/day compared with intake of 200 µg/day or less after controlling for age, family history of colorectal cancer, aspirin use, smoking, body mass, physical activity, and intakes of red meat, alcohol, methionine, and fiber. [95]

Ongoing studies of dietary and other interventions in the chemoprevention of colorectal neoplasia are listed in Table 1.

Other Factors

Polyp Removal

The National Polyp Study showed a reduction of more than 75% in the subsequent incidence of colorectal cancer after colonoscopic polypectomy compared with 3 nonconcurrent, external control groups. [96]

Physical Activity

A sedentary lifestyle has been associated in some [97] [98] but not all [99] studies with an increased risk of colorectal cancer. There are numerous observational studies that have examined the relationship between physical activity and colon cancer risk. [100] Most of these studies have shown an inverse relationship between level of physical activity and colon cancer incidence. The average relative-risk reduction is reportedly 40% to 50%. It is not known, however, whether or to what degree the observed association is due to confounding variables such as diet or a genetic predisposition to colon cancer. In a population-based case-control study of colorectal cancer among Chinese men and women in Western North America and China, colon and rectal cancer risk was elevated among men employed in sedentary occupations on both continents. [101] Further, the association between colorectal cancer risk and saturated fat was stronger among the sedentary than among the active population. Perhaps related to physical activity, body mass was found to be correlated with rectal cancer in men in an Australian study [99] and with colorectal cancer in men in Sweden. [102] One study showed that physical activity in men, 2 hours or more per week, was more strongly associated with reduced risk for advanced adenomas (adenomas =10.0 mm in diameter, a villous adenoma, or an adenoma with high-grade dysplasia) versus nonadvanced adenomas. [26]

Obesity is associated with a 2-fold increase in the risk of colorectal cancer in premenopausal women. [103]
Alcohol Consumption

There is evidence of an association of colorectal cancer with alcoholic beverage consumption. In a meta-analysis, this association was weak. [104] In another review, statistically significant elevations of risk were found in males, particularly in regard to beer consumption and rectal cancer. It is hypothesized that alcohol may act to stimulate mucosal cell proliferation, to activate intestinal procarcinogens and possibly provide a source of unabsorbed carcinogens that can reach the distal large bowel. [105] Subsequently published case-control studies suggest a modest-to-strong positive relationship between alcohol consumption and large bowel cancers. [106] [107]

Five studies have reported a positive association between alcohol intake and colorectal adenomas. [108] A case-control study of diet, genetic factors, and the adenoma-carcinoma sequence was conducted in Burgundy. [109] It separated adenomas smaller than 10.0 mm in diameter from larger adenomas. A positive association between current alcohol intake and adenomas was found to be limited to the larger adenomas, suggesting that alcohol intake could act at the promotional phase of the adenoma-carcinoma sequence. [109]

Cigarette Smoking

Most case-control studies of cigarette exposure and adenomas have found an elevated risk for smokers. [55] In addition, a significantly increased risk of adenoma recurrence following polypectomy has been associated with smoking in both men and women. [55] In the Nurses’ Health Study, the minimum induction period for cancer appears to be at least 35 years. [110] Similarly, in the Health Professionals Follow-up Study, a history of smoking was associated with both small and large adenomas and with a long induction period of at least 35 years for colorectal cancer. [111] In the Cancer Prevention Study II (CPS II), a large nationwide cohort study, multivariate-adjusted colorectal cancer mortality rates were highest among current smokers, intermediate among former smokers, and lowest in never smokers, with increased risk observed after 20 or more years of smoking in men and women combined. [112] On the basis of CPS II data, it was estimated that 12% of colorectal cancer deaths in the U.S. population in 1997 were attributable to smoking. A large population-based cohort study of Swedish twins found that heavy smoking of 35 or more years' duration was associated with a nearly 3-fold increased risk of developing colon cancer, though subsite analysis found a statistically significant effect only for rectal but not colon cancer. [113] Another large population-based case-control study supports the view that current tobacco use and tobacco use within the last 10 years is associated with colon cancer. A 50% increase in risk was associated with smoking more than a pack a day relative to never smoking. [114] However, a 28-year follow-up of 57,000 Finns showed no association between the development of colorectal cancer and baseline smoking status, though there was a 57% to 71% increased risk in persistent smokers. [115] No relationship was found between cigarette smoking, even smoking of long duration, and recurrence of adenomas in a population followed for 4 years after initial colonoscopy. [116]

Fecal Occult Blood Testing

The Minnesota randomized trial of fecal occult blood tests investigated reduction in incidence of colorectal cancer. Nearly 85% of subjects with a positive test underwent diagnostic procedures that included colonoscopy or double-contrast barium enema plus flexible sigmoidoscopy. After 18 years of follow-up, the incidence of colorectal cancer was reduced by 20% in the annually screened arm and 17% in the biennially screened arm. [117]

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· PDQ® Cancer Information Summaries: Supportive Care
o Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.

· PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer)
o Tests or procedures that detect specific types of cancer.

· PDQ® Cancer Information Summaries: Prevention
o Risk factors and methods to increase chances of preventing specific types of cancer.

· PDQ® Cancer Information Summaries: Genetics
o Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.

· PDQ® Cancer Information Summaries: Complementary and Alternative Medicine
o Information about complementary and alternative forms of treatment for patients with cancer.

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
Date last modified: 2006-05-22

http://www.meb.uni-bonn.de/cancer.gov/CDR0000062763.html