Colorectal Cancer Prevention (PDQ®): Prevention - Health Professional Information [NCI]

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Colorectal Cancer Prevention

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about colorectal cancer prevention. This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board.

Information about the following is included in this summary:

  • Colorectal cancer incidence and mortality statistics and information about colorectal cancer risk factors.
  • Interventions for colorectal cancer prevention.
  • Benefits and harms of interventions to prevent colorectal cancer.

This summary is intended as a resource to inform clinicians and other health professionals about the currently available information on colorectal cancer prevention. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system in reporting the evidence of benefit and potential harms associated with specific interventions. It does not provide formal guidelines or recommendations for making health care decisions. Information in this summary should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less technical language.

Summary of Evidence

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

Use of Nonsteroidal Anti-Inflammatory Drugs

Benefits

There is inadequate evidence that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of colorectal cancer (CRC). Celecoxib decreases the adenoma burden and may be a useful adjunct in reducing CRC risk associated with adenomatous polyposis of the colon. However, celecoxib does not have a role in reducing the risk of sporadic CRC because its long-term efficacy in preventing CRC has not been shown due to attributed increased risk of cardiovascular events and because there are other effective ways, such as screening, to reduce CRC mortality.[1] Based on solid evidence, NSAIDs reduce the risk of adenomas, but the extent to which this translates into a reduction of CRC is uncertain.

Description of the Evidence

  • STUDY DESIGN: No adequate studies.
  • INTERNAL VALIDITY: N/A.
  • CONSISTENCY: N/A.
  • MAGNITUDE OF EFFECTS OF HEALTH OUTCOMES: N/A.
  • EXTERNAL VALIDITY: N/A.

Harms

Based on solid evidence, harms of NSAID use include upper gastrointestinal bleeding and serious cardiovascular events such as myocardial infarction, heart failure, and hemorrhagic stroke.[2].

Description of the Evidence

  • STUDY DESIGN: Evidence obtained from randomized controlled trials.
  • INTERNAL VALIDITY: Good.
  • CONSISTENCY: Good.
  • MAGNITUDE OF EFFECTS ON HEALTH OUTCOMES: The estimated average excess risk of upper gastrointestinal complications attributable to chronic low-dose aspirin is about five extra cases per 1,000 aspirin users per year. The excess risk varies with the underlying gastrointestinal risk, however, it might exceed ten extra cases per 1,000 person-years in more than 10% of aspirin users.[3]
  • EXTERNAL VALIDITY: Good.

Postmenopausal Hormone Use

Benefits

Based on solid evidence, postmenopausal estrogen plus progesterone hormone use decreases the incidence of CRC, but this benefit is not applicable to estrogen alone use.[4]

Description of the Evidence

  • STUDY DESIGN: Evidence obtained from a randomized controlled trial and meta-analysis of 18 obeservational studies.
  • INTERNAL VALIDITY: Good.
  • CONSISTENCY: One randomized study and a meta-analysis.
  • MAGNITUDE OF EFFECTS ON HEALTH OUTCOMES: In the Women's Health Initiative (WHI), there was a 44% reduction in CRC incidence in the estrogen and progesterone group but not in the estrogen-only group. A meta-analysis of 18 observational studies showed a 20% reduction in colon cancer incidence among women who had ever used hormone replacement therapy (relative risk [RR] = 0.80; 95% confidence interval [CI], 0.74–0.86) compared with nonusers and a 34% reduction among current users (RR = 0.66; 95% CI, 0.59–0.74).[4,5]
  • EXTERNAL VALIDITY: Good.

Harms

Based on solid evidence, harms of postmenopausal combined estrogen plus progestin hormone use include increased risk of breast cancer, coronary heart disease, and thromboembolic events.

Description of the Evidence

  • STUDY DESIGN: Evidence from randomized controlled trials.
  • INTERNAL VALIDITY: Good.
  • CONSISTENCY: Good.
  • MAGNITUDE OF EFFECTS ON HEALTH OUTCOMES: The WHI showed a 26% increase in invasive breast cancer in the combined hormone group, a 29% increase in coronary heart disease events, a 41% increase in stroke rates, and a twofold higher rate of thromboembolic events.[6]
  • EXTERNAL VALIDITY: Fair.

Polyp Removal

Benefits

Based on fair evidence, removal of adenomatous polyps reduces the risk of CRC.

Description of the Evidence

  • STUDY DESIGN: Evidence obtained from cohort studies.
  • INTERNAL VALIDITY: Good.
  • CONSISTENCY: N/A.
  • MAGNITUDE OF EFFECTS ON HEALTH OUTCOMES: Unknown.[7]
  • EXTERNAL VALIDITY: Good.

Harms

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: 35 events per 10,000 procedures.[8]
  • EXTERNAL VALIDITY: Good.

Diet Modification

A DIET LOW IN FAT AND HIGH IN FIBER, FRUITS, AND VEGETABLES

Benefits

There is inadequate evidence to suggest that a diet low in fat and high in fiber, fruits, and vegetables decreases the risk of CRC. However, these studies were powered to detect differences in adenoma incidence and not cancer incidence.

Description of the Evidence

  • STUDY DESIGN: Evidence obtained from randomized controlled trials.
  • INTERNAL VALIDITY: Fair.
  • CONSISTENCY: N/A.
  • MAGNITUDE OF EFFECTS ON HEALTH OUTCOMES: N/A.
  • EXTERNAL VALIDITY: N/A.

Harms

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.

References:

1. Arber N, Eagle CJ, Spicak J, et al.: Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 355 (9): 885-95, 2006.
2. Solomon SD, Pfeffer MA, McMurray JJ, et al.: Effect of celecoxib on cardiovascular events and blood pressure in two trials for the prevention of colorectal adenomas. Circulation 114 (10): 1028-35, 2006.
3. Hernández-Díaz S, García Rodríguez LA: Cardioprotective aspirin users and their excess risk of upper gastrointestinal complications. BMC Med 4: 22, 2006.
4. Chlebowski RT, Wactawski-Wende J, Ritenbaugh C, et al.: Estrogen plus progestin and colorectal cancer in postmenopausal women. N Engl J Med 350 (10): 991-1004, 2004.
5. Nelson HD, Humphrey LL, Nygren P, et al.: Postmenopausal hormone replacement therapy: scientific review. JAMA 288 (7): 872-81, 2002.
6. Writing Group for the Women's Health Initiative Investigators.: Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 288 (3): 321-33, 2002.
7. Robertson DJ, Greenberg ER, Beach M, et al.: Colorectal cancer in patients under close colonoscopic surveillance. Gastroenterology 129 (1): 34-41, 2005.
8. Nelson DB, McQuaid KR, Bond JH, et al.: Procedural success and complications of large-scale screening colonoscopy. Gastrointest Endosc 55 (3): 307-14, 2002.

Significance

Incidence and Mortality

Colorectal cancer (CRC) 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 146,970 new cases diagnosed in the United States in 2009 and 49,920 deaths due to this disease.[2] Between 1998 and 2004, CRC incidence rates in the United States declined by 2.3% per year.[3] Over the past 20 years, the mortality rate has been declining. There was a 1.8% decline in mortality rate per year between 1985 and 2002. Between 2002 and 2005, the mortality rate declined by 4.3% per year.[2] The overall 5-year survival rate is 64%. About 6% of Americans are expected to develop the disease within their lifetimes.[4] The risk of CRC begins to increase after the age of 40 years and rises sharply at the ages of 50 to 55 years; 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.[5,6] Hence, effective primary and secondary preventive approaches must be developed to reduce the morbidity and mortality from CRC.

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 effective form of primary prevention.

Etiology and Pathogenesis of Colorectal Cancer

Genetics,[7,8] experimental,[9,10] and epidemiologic [11,12,13] studies suggest that CRC 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.[14] Efforts to identify causes and develop effective preventive measures have led to the hypothesis that adenomatous polyps (adenomas) are precursors for the vast majority of CRCs.[15] While most of these adenomas are polypoid, flat and depressed lesions that 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.[16] In effect, measures that reduce the incidence and prevalence of adenomas may result in a subsequent decrease in the risk of CRC.[17] The finding of an adenoma on flexible sigmoidoscopy may warrant colonoscopy to evaluate the more proximal colon for synchronous neoplasms.[18] Many of the intervention trials employ adenoma recurrence or disappearance as a surrogate endpoint.[19] The evolution of a carcinoma from a small adenoma, however, takes many years.[11]

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 2009. Atlanta, Ga: American Cancer Society, 2009. Also available online. Last accessed January 6, 2010.
3. American Cancer Society.: Cancer Facts and Figures 2008. Atlanta, Ga: American Cancer Society, 2008. Also available online. Last accessed October 1, 2008.
4. 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 December 10, 2009.
5. 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.
6. 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.
7. Willett W: The search for the causes of breast and colon cancer. Nature 338 (6214): 389-94, 1989.
8. Fearon ER, Vogelstein B: A genetic model for colorectal tumorigenesis. Cell 61 (5): 759-67, 1990.
9. 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.
10. 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.
11. Potter JD: Reconciling the epidemiology, physiology, and molecular biology of colon cancer. JAMA 268 (12): 1573-7, 1992 Sep 23-30.
12. Wynder EL, Reddy BS: Dietary fat and fiber and colon cancer. Semin Oncol 10 (3): 264-72, 1983.
13. 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.
14. 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.
15. Hill MJ, Morson BC, Bussey HJ: Aetiology of adenoma--carcinoma sequence in large bowel. Lancet 1 (8058): 245-7, 1978.
16. 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.
17. 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.
18. 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.
19. 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 the two functional isoforms of COX, termed COX-1 and COX-2, but newer second-generation drugs that inhibit primarily COX-2. 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.

Both celecoxib and rofecoxib have been associated with serious cardiovascular events including dose-related death from cardiovascular causes, myocardial infarction, stroke, or heart failure.[2,3,4,5] Four trials that demonstrated this increased risk are summarized in Table 1.

Table 1. Cardiovascular Risks Associated With Celecoxib and Rofecoxib Dose/Drugs

bid = twice a day; CI = confidence interval; HR = hazard ratio; OR = odds ratio; RR = relative risk.
Authors Dose/Trial Drug Risk Indication
[3] Rofecoxib <25 mg/qd; rofecoxib >25 mg/qd OR = 1.47 (0.99–2.17) 3 vs. 58 (1.27–10.17) Nested case-control study all users
[5] Celecoxib 200 mg/qd vs. 400 mg bid 3.4%; HR = 3.4 (95% CI, 1.4–7.8) Sporadic adenoma prevention trial (N = 2,035)
[4] Rofecoxib 25 mg/qd RR = 1.92 (95% CI, 1.19–3.11; P = .008) Chemoprevention sporadic adenoma
[2] Rofecoxib 25 mg/qd RR (estimated) = 2.66 (95% CI, 1.03–6.86; P = .04) Chemoprevention sporadic adenoma median study Rx 7.4 months

Celecoxib reduces the incidence of adenomas; however, celecoxib does not have a role in reducing the risk of sporadic colorectal cancer (CRC). Its long-term efficacy in preventing CRC has not been shown due to increased risk of cardiovascular events, and because there are other effective ways, such as screening to reduce CRC mortality.[6]

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.[7,8] 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.[9] 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 CRC, including a 50% reduction in advanced cases.[10] 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.[11] 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 RR 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.[12] 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.[13] 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.[14] In a subsequent analysis of more than 12 years, both randomized and observational analyses indicated that there was no association between the use of aspirin and the incidence of CRC. The low dose of aspirin and the short treatment period may account for the null findings.[15]

In a randomized study of 635 patients with prior CRC (T1–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 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.[16] 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 RRs 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 the 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.[17] Harms of treatment were similar in the two 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.[18,19] 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.[20]

The NSAID piroxicam, at a dose of 20 mg/day, reduced mean rectal prostaglandin concentration by 50% in individuals with a history of adenomas.[21] Several studies assessing the effect of aspirin or other nonsteroidals on polyp recurrence following polypectomy are in progress.[22] 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.[23]

TABLE 2. 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

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.[24]
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

Postmenopausal female hormone supplements

Several epidemiologic studies have suggested a decreased risk of colon cancer among users of postmenopausal female hormone supplements.[25,26,27,28] For rectal cancer, most studies have observed no association or a slightly elevated risk.[29,30,31]

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 CRCs in the hormone group and 72 in the placebo group (HR = 0.56; 95% CI, 0.38–0.81; P = .003). The invasive CRCs 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).[32]

Use of statins

Overall, evidence indicates that statin use neither increases nor decreases the incidence or mortality of CRC. Although some case-control studies have shown a reduction in risk, neither a large cohort study [33] nor a meta-analysis of four randomized controlled trials [34] 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.[35] 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.[36] In laboratory studies, a high-fat intake increases the incidence of induced colon tumors in experimental animals.[37,38] Several case-control studies have explored the association of colon cancer risk with meat or fat consumption as well as protein and energy intake.[39,40] Although positive associations with meat consumption or with fat intake have been found frequently, the results have not always achieved statistical significance.[41] 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.[42] In Norway, an increased risk for processed meat only was found,[43] a finding that was confirmed in the Netherlands.[44] 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.[45] 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.[46] No increase in risk with meat or fat consumption was seen, however, in two other large prospective studies, the American Cancer Society's Cancer Prevention Study II and the Iowa Women's Health Study.[47,48] 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 (RR for =1 time per week vs. no meat intake = 1.85, 95% CI, 1.19–2.87, P for trend = .01).[49] 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 CRCs 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).[50,51]

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% more than the 8.1 years of follow-up. There was no evidence of reduction in invasive CRCs between intervention and comparison groups with a HR of 1.08 (95% CI, 0.90–1.29).[52] Likewise, there was no benefit of the low-fat diet on all-cancer mortality, overall mortality, or cardiovascular disease.[53]

Explanations for the conflicting results regarding whether dietary fat or meat intake affects risk of CRC [44] 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 [54]); and (d) variability in the consumption of other foods such as vegetables.[55] 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.[56] Although far from clear-cut, the available evidence suggests CRC risk is possibly associated with some interaction of dietary fat, protein, and caloric intake.

Six case-control studies and two cohort studies have explored potential dietary risk factors for colorectal adenomas.[57,58] Three of the eight 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.[59] In a multicenter randomized controlled trial, a diet low in fat (20% of total calories) and high in fiber, fruits, and vegetables did not reduce the risk of recurrence of colorectal adenomas.[60]

Bile acids

A central effect of bile acids in the etiology and pathogenesis of CRC has been claimed.[61] 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.[62] The potential mechanism of action of bile salts in colorectal carcinogenesis is unknown, although it has been suggested that it is mediated by diacylglycerol.[63] 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 CRC is mixed. Most animal and epidemiologic studies show a protective effect of dietary fiber on colon carcinogenesis.[22] 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.[64,65,66] 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.[66] Butyrate has been shown to have anticarcinogenic effects in vitro and is regarded as an important fuel for the colonic epithelium.[67,68] A meta-analysis of 13 case-control studies from nine countries concluded that intake of fiber-rich foods is inversely related to cancers of both the colon and rectum.[69] 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, in men and women, and in 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.[39,69] These substances include phenolic compounds, sulfur-containing compounds, and flavones.[70,71] In a prospective cohort study of a low-risk population, an inverse association was found with legume intake and the risk of CRC (RR for >2 times/week vs. 1 time/week = 0.53; 95% CI, 0.33–0.86, P for trend = .03).[49]

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.[72] 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 CRC 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).[73]

Many epidemiologic studies have examined the relationship between fruit and vegetable intake and the incidence of colon and/or rectal cancer,[74] 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.[75] 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. Associations were not 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 CRC, 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 one 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 CRC 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.[76]

Six case-control studies and three cohort studies have explored potential dietary risk factors for colorectal adenomas.[57,58,73] Four of the nine 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.[73]

High-fiber cereal supplements during a 3-year period did not result in a decrease in adenoma recurrence in a randomized controlled trial of 1,303 individuals.[77] 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 per 1,000 kcal) was not associated with a reduction in risk of recurrence of colorectal adenomas.[60]

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.[78] Indirect effects on bile acid metabolism and a direct effect on colonic epithelial cells are also possible.

Several [79,80,81,82] but not all [58,83] 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 [84] and some but not all human studies [85,86,87,88] have described a decrease in colonic epithelial cell proliferation after the administration of calcium citrate. Human studies using the labeling index are dependent on a complex methodology.[89] 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.[90] The primary endpoint was the proportion of patients (72% of whom were male) in whom at least one adenoma was detected following a first and/or second follow-up endoscopy. A modest decrease in risk was found for both developing at least one 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 could not determine the effect of calcium on risk of the first adenoma, nor was it large enough or of sufficient duration to examine the risk of invasive CRC. After calcium supplementation is stopped, the lower risk may persist up to 5 years.[91] The results of other ongoing adenoma recurrence studies are awaited with interest (refer to Table 2). 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 CRC (HR = 1.08; 95% CI, 0.86–1.34; P = .051).[92] The relatively short duration of follow-up, considering the latency period of CRC 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.[93]

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).[94] The Women's Health Study, however, showed no relationship between CRC in women and the use of 600 IU of vitamin E every other day.[95] 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.[96] A systematic review of published observational studies that provide sufficient data to calculate the dose-response relationship of serum 25-hydroxyvitamin D or oral intake of vitamin D with risk of CRC was conducted. The results suggested that a daily intake of 1,000 IU of vitamin D—half the safe upper limit for intake established by the National Academy of Sciences—and a concentration of serum 25-hydroxyvitamin D of 33 ng/mL were each associated with 50% lower risk of CRC.[97] In a population-based case-control study, an inverse relationship between vitamin D intake and risk of CRC was found.[98]

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 CRC, aspirin use, smoking, body mass, physical activity, and intakes of red meat, alcohol, methionine, and fiber.[99] In a double-blind, placebo-controlled, two-factor, phase III randomized clinical trial (Aspirin/Folate Polyp Prevention Study) involving 1,021 men and women with a recent history of colorectal adenoma, folic acid (1 mg/day) was associated with higher risks of developing at least one advanced adenoma (11.6% for folic acid [n = 35]); 6.9% for placebo [n = 21]; unadjusted RR = 1.67; 95% CI, 1.00–2.80; P = .05). Folic acid ingestion was associated with higher risks of having three or more adenomas and of non-CRCs. There was no effect modification by sex, age, smoking, alcohol use, body mass index, baseline plasma folate, or aspirin use. There was no apparent effect on overall adenoma incidence (44.1% for folic acid [n = 221]); 42.4% for placebo [n = 206]; unadjusted use ratio 1.04; 95% CI, 0.9–1.20; P = .58).[100]

Ongoing studies of dietary and other interventions in the chemoprevention of colorectal neoplasia are listed in Table 2.

Other Factors

Polyp removal

The National Polyp Study showed a reduction of more than 75% in the subsequent incidence of CRC after colonoscopic polypectomy compared with three nonconcurrent, external control groups.[101]

Physical activity

A sedentary lifestyle has been associated in some [102,103] but not all [104] studies with an increased risk of CRC. There are numerous observational studies that have examined the relationship between physical activity and colon cancer risk.[105] Most of these studies have shown an inverse relationship between level of physical activity and colon cancer incidence. The average RR 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 CRC 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.[106] Further, the association between CRC 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 [104] and with CRC in men in Sweden.[107] 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.[28]

Obesity is associated with a twofold increase in the risk of CRC in premenopausal women.[108]

Alcohol consumption

There is evidence of an association of CRC with alcoholic beverage consumption. In a meta-analysis, this association was weak.[109] 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.[110] Subsequently published case-control studies suggest a modest-to-strong positive relationship between alcohol consumption and large bowel cancers.[111,112]

Five studies have reported a positive association between alcohol intake and colorectal adenomas.[113] A case-control study of diet, genetic factors, and the adenoma-carcinoma sequence was conducted in Burgundy.[114] 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.[114]

Cigarette smoking

Most case-control studies of cigarette exposure and adenomas have found an elevated risk for smokers.[57] In addition, a significantly increased risk of adenoma recurrence following polypectomy has been associated with smoking in both men and women.[57] In the Nurses' Health Study, the minimum induction period for cancer appears to be at least 35 years.[115] 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 CRC.[116] In the Cancer Prevention Study II (CPS II), a large nationwide cohort study, multivariate-adjusted CRC mortality rates were highest among current smokers, intermediate among former smokers, and lowest in nonsmokers, with increased risk observed after 20 or more years of smoking in men and women combined.[117] On the basis of CPS II data, it was estimated that 12% of CRC 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 threefold increased risk of developing colon cancer, though subsite analysis found a statistically significant effect only for rectal but not colon cancer.[118] 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.[119] However, a 28-year follow-up of 57,000 Finns showed no association between the development of CRC and baseline smoking status, though there was a 57% to 71% increased risk in persistent smokers.[120] 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.[121]

Fecal occult blood testing

The Minnesota randomized trial of fecal occult blood tests investigated reduction in incidence of CRC. Nearly 85% of patients 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 CRC was reduced by 20% in the annually screened arm and 17% in the biennially screened arm.[122]

References:

1. Hinz B, Brune K: Cyclooxygenase-2--10 years later. J Pharmacol Exp Ther 300 (2): 367-75, 2002.
2. Kerr DJ, Dunn JA, Langman MJ, et al.: Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer. N Engl J Med 357 (4): 360-9, 2007.
3. Graham DJ, Campen D, Hui R, et al.: Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 365 (9458): 475-81, 2005.
4. Bresalier RS, Sandler RS, Quan H, et al.: Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 352 (11): 1092-102, 2005.
5. Solomon SD, McMurray JJ, Pfeffer MA, et al.: Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 352 (11): 1071-80, 2005.
6. Arber N, Eagle CJ, Spicak J, et al.: Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 355 (9): 885-95, 2006.
7. Thun MJ, Namboodiri MM, Heath CW Jr: Aspirin use and reduced risk of fatal colon cancer. N Engl J Med 325 (23): 1593-6, 1991.
8. Thun MJ, Namboodiri MM, Calle EE, et al.: Aspirin use and risk of fatal cancer. Cancer Res 53 (6): 1322-7, 1993.
9. Gridley G, McLaughlin JK, Ekbom A, et al.: Incidence of cancer among patients with rheumatoid arthritis. J Natl Cancer Inst 85 (4): 307-11, 1993.
10. Giovannucci E, Rimm EB, Stampfer MJ, et al.: Aspirin use and the risk for colorectal cancer and adenoma in male health professionals. Ann Intern Med 121 (4): 241-6, 1994.
11. Cook NR, Lee IM, Gaziano JM, et al.: Low-dose aspirin in the primary prevention of cancer: the Women's Health Study: a randomized controlled trial. JAMA 294 (1): 47-55, 2005.
12. Chan AT, Giovannucci EL, Meyerhardt JA, et al.: Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer. JAMA 294 (8): 914-23, 2005.
13. Smalley W, Ray WA, Daugherty J, et al.: Use of nonsteroidal anti-inflammatory drugs and incidence of colorectal cancer: a population-based study. Arch Intern Med 159 (2): 161-6, 1999.
14. Gann PH, Manson JE, Glynn RJ, et al.: Low-dose aspirin and incidence of colorectal tumors in a randomized trial. J Natl Cancer Inst 85 (15): 1220-4, 1993.
15. Stürmer T, Glynn RJ, Lee IM, et al.: Aspirin use and colorectal cancer: post-trial follow-up data from the Physicians' Health Study. Ann Intern Med 128 (9): 713-20, 1998.
16. Sandler RS, Halabi S, Baron JA, et al.: A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med 348 (10): 883-90, 2003.
17. Baron JA, Cole BF, Sandler RS, et al.: A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med 348 (10): 891-9, 2003.
18. Labayle D, Fischer D, Vielh P, et al.: Sulindac causes regression of rectal polyps in familial adenomatous polyposis. Gastroenterology 101 (3): 635-9, 1991.
19. Giardiello FM, Hamilton SR, Krush AJ, et al.: Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 328 (18): 1313-6, 1993.
20. Steinbach G, Lynch PM, Phillips RK, et al.: The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 342 (26): 1946-52, 2000.
21. Earnest DL, Hixson LJ, Fennerty MB, et al.: Inhibition of prostaglandin synthesis: potential for chemoprevention of human colon cancer. Cancer Bull 43(6): 561-568, 1991.
22. Vargas PA, Alberts DS: Colon cancer: the quest for prevention. Oncology (Huntingt) 7(11 suppl): 33-40, 1993.
23. Imperiale TF: Aspirin and the prevention of colorectal cancer. N Engl J Med 348 (10): 879-80, 2003.
24. Umar A, Viner JL, Richmond E, et al.: Chemoprevention of colorectal carcinogenesis. Int J Clin Oncol 7 (1): 2-26, 2002.
25. Calle EE, Miracle-McMahill HL, Thun MJ, et al.: Estrogen replacement therapy and risk of fatal colon cancer in a prospective cohort of postmenopausal women. J Natl Cancer Inst 87 (7): 517-23, 1995.
26. Newcomb PA, Storer BE: Postmenopausal hormone use and risk of large-bowel cancer. J Natl Cancer Inst 87 (14): 1067-71, 1995.
27. Grodstein F, Newcomb PA, Stampfer MJ: Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. Am J Med 106 (5): 574-82, 1999.
28. Terry MB, Neugut AI, Bostick RM, et al.: Risk factors for advanced colorectal adenomas: a pooled analysis. Cancer Epidemiol Biomarkers Prev 11 (7): 622-9, 2002.
29. Risch HA, Howe GR: Menopausal hormone use and colorectal cancer in Saskatchewan: a record linkage cohort study. Cancer Epidemiol Biomarkers Prev 4 (1): 21-8, 1995 Jan-Feb.
30. Gerhardsson de Verdier M, London S: Reproductive factors, exogenous female hormones, and colorectal cancer by subsite. Cancer Causes Control 3 (4): 355-60, 1992.
31. Prihartono N, Palmer JR, Louik C, et al.: A case-control study of use of postmenopausal female hormone supplements in relation to the risk of large bowel cancer. Cancer Epidemiol Biomarkers Prev 9 (4): 443-7, 2000.
32. Chlebowski RT, Wactawski-Wende J, Ritenbaugh C, et al.: Estrogen plus progestin and colorectal cancer in postmenopausal women. N Engl J Med 350 (10): 991-1004, 2004.
33. Jacobs EJ, Rodriguez C, Brady KA, et al.: Cholesterol-lowering drugs and colorectal cancer incidence in a large United States cohort. J Natl Cancer Inst 98 (1): 69-72, 2006.
34. Dale KM, Coleman CI, Henyan NN, et al.: Statins and cancer risk: a meta-analysis. JAMA 295 (1): 74-80, 2006.
35. Rose DP, Boyar AP, Wynder EL: International comparisons of mortality rates for cancer of the breast, ovary, prostate, and colon, and per capita food consumption. Cancer 58 (11): 2363-71, 1986.
36. Reddy BS: Dietary fat and its relationship to large bowel cancer. Cancer Res 41 (9 Pt 2): 3700-5, 1981.
37. Reddy BS, Narisawa T, Vukusich D, et al.: Effect of quality and quantity of dietary fat and dimethylhydrazine in colon carcinogenesis in rats. Proc Soc Exp Biol Med 151 (2): 237-9, 1976.
38. Nauss KM, Locniskar M, Newberne PM: Effect of alterations in the quality and quantity of dietary fat on 1,2-dimethylhydrazine-induced colon tumorigenesis in rats. Cancer Res 43 (9): 4083-90, 1983.
39. Potter JD: Reconciling the epidemiology, physiology, and molecular biology of colon cancer. JAMA 268 (12): 1573-7, 1992 Sep 23-30.
40. Potter JD, McMichael AJ: Diet and cancer of the colon and rectum: a case-control study. J Natl Cancer Inst 76 (4): 557-69, 1986.
41. Bingham SA: Diet and large bowel cancer. J R Soc Med 83 (7): 420-2, 1990.
42. Hirayama T, Tannenbaum SR, Reddy BS, et al.: A large-scale cohort study on the relationship between diet and selected cancers of the digestive organs. In: Bruce WR, Correa P, Lipkin M, et al., eds.: Gastrointestinal cancer: endogenous factors. [Cold Spring Harbor, NY]: Cold Spring Harbor Laboratory, 1981, Branbury Report 7, 409-429.
43. Bjelke E: Epidemiology of colorectal cancer, with emphasis on diet. Int Congr Ser 484: 158-174, 1980.
44. Goldbohm RA, van den Brandt PA, van 't Veer P, et al.: A prospective cohort study on the relation between meat consumption and the risk of colon cancer. Cancer Res 54 (3): 718-23, 1994.
45. Phillips RL, Snowdon DA: Dietary relationships with fatal colorectal cancer among Seventh-Day Adventists. J Natl Cancer Inst 74 (2): 307-17, 1985.
46. Willett WC, Stampfer MJ, Colditz GA, et al.: Relation of meat, fat, and fiber intake to the risk of colon cancer in a prospective study among women. N Engl J Med 323 (24): 1664-72, 1990.
47. Thun MJ, Calle EE, Namboodiri MM, et al.: Risk factors for fatal colon cancer in a large prospective study. J Natl Cancer Inst 84 (19): 1491-500, 1992.
48. Bostick RM, Potter JD, Sellers TA, et al.: Relation of calcium, vitamin D, and dairy food intake to incidence of colon cancer among older women. The Iowa Women's Health Study. Am J Epidemiol 137 (12): 1302-17, 1993.
49. Singh PN, Fraser GE: Dietary risk factors for colon cancer in a low-risk population. Am J Epidemiol 148 (8): 761-74, 1998.
50. Augustsson K, Skog K, Jägerstad M, et al.: Dietary heterocyclic amines and cancer of the colon, rectum, bladder, and kidney: a population-based study. Lancet 353 (9154): 703-7, 1999.
51. Forman D: Meat and cancer: a relation in search of a mechanism. Lancet 353 (9154): 686-7, 1999.
52. Beresford SA, Johnson KC, Ritenbaugh C, et al.: Low-fat dietary pattern and risk of colorectal cancer: the Women's Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 295 (6): 643-54, 2006.
53. Howard BV, Van Horn L, Hsia J, et al.: Low-fat dietary pattern and risk of cardiovascular disease: the Women's Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 295 (6): 655-66, 2006.
54. Sugimura T: Carcinogenicity of mutagenic heterocyclic amines formed during the cooking process. Mutat Res 150 (1-2): 33-41, 1985 Jun-Jul.
55. Lee HP, Gourley L, Duffy SW, et al.: Colorectal cancer and diet in an Asian population--a case-control study among Singapore Chinese. Int J Cancer 43 (6): 1007-16, 1989.
56. Reddy BS, Hedges AR, Laakso K, et al.: Metabolic epidemiology of large bowel cancer: fecal bulk and constituents of high-risk North American and low-risk Finnish population. Cancer 42 (6): 2832-8, 1978.
57. Neugut AI, Jacobson JS, DeVivo I: Epidemiology of colorectal adenomatous polyps. Cancer Epidemiol Biomarkers Prev 2 (2): 159-76, 1993 Mar-Apr.
58. Kampman E, Giovannucci E, van 't Veer P, et al.: Calcium, vitamin D, dairy foods, and the occurrence of colorectal adenomas among men and women in two prospective studies. Am J Epidemiol 139 (1): 16-29, 1994.
59. Neugut AI, Garbowski GC, Lee WC, et al.: Dietary risk factors for the incidence and recurrence of colorectal adenomatous polyps. A case-control study. Ann Intern Med 118 (2): 91-5, 1993.
60. Schatzkin A, Lanza E, Corle D, et al.: Lack of effect of a low-fat, high-fiber diet on the recurrence of colorectal adenomas. Polyp Prevention Trial Study Group. N Engl J Med 342 (16): 1149-55, 2000.
61. Cheah PY: Hypotheses for the etiology of colorectal cancer--an overview. Nutr Cancer 14 (1): 5-13, 1990.
62. Reddy BS, Engle A, Simi B, et al.: Effect of dietary fiber on colonic bacterial enzymes and bile acids in relation to colon cancer. Gastroenterology 102 (5): 1475-82, 1992.
63. Morotomi M, Guillem JG, LoGerfo P, et al.: Production of diacylglycerol, an activator of protein kinase C, by human intestinal microflora. Cancer Res 50 (12): 3595-9, 1990.
64. Steinmetz KA, Potter JD: Vegetables, fruit, and cancer. I. Epidemiology. Cancer Causes Control 2 (5): 325-57, 1991.
65. Steinmetz KA, Potter JD: Vegetables, fruit, and cancer. II. Mechanisms. Cancer Causes Control 2 (6): 427-42, 1991.
66. Jacobs LR: Fiber and colon cancer. Gastroenterol Clin North Am 17 (4): 747-60, 1988.
67. Roediger WE: The effect of bacterial metabolites on nutrition and function of the colonic mucosa: symbiosis between man and bacteria. In: Kasper H, Goebell H, eds.: Colon and Nutrition. Lancaster, Pa: Lancaster Press. Falk Symposium 32, 1981, pp 11-25.
68. Jacobs LR: Relationship between dietary fiber and cancer: metabolic, physiologic, and cellular mechanisms. Proc Soc Exp Biol Med 183 (3): 299-310, 1986.
69. Howe GR, Benito E, Castelleto R, et al.: Dietary intake of fiber and decreased risk of cancers of the colon and rectum: evidence from the combined analysis of 13 case-control studies. J Natl Cancer Inst 84 (24): 1887-96, 1992.
70. Potter JD: Epidemiology of diet and cancer: evidence of human maladaptation. In: Micozzi MS, Moon TE, eds.: Macronutrients: Investigating their Role in Cancer. New York: Marcel Dekker, 1992, pp 55-84.
71. Kritchevsky D: Dietary guidelines. The rationale for intervention. Cancer 72 (3 Suppl): 1011-4, 1993.
72. 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.
73. Fuchs CS, Giovannucci EL, Colditz GA, et al.: Dietary fiber and the risk of colorectal cancer and adenoma in women. N Engl J Med 340 (3): 169-76, 1999.
74. World Cancer Research Fund., American Institute for Cancer Research.: Food, Nutrition and the Prevention of Cancer: A Global Perspective. Washington, DC: The Institute, 1997.
75. Michels KB, Edward Giovannucci, Joshipura KJ, et al.: Prospective study of fruit and vegetable consumption and incidence of colon and rectal cancers. J Natl Cancer Inst 92 (21): 1740-52, 2000.
76. Terry P, Giovannucci E, Michels KB, et al.: Fruit, vegetables, dietary fiber, and risk of colorectal cancer. J Natl Cancer Inst 93 (7): 525-33, 2001.
77. Alberts DS, Martínez ME, Roe DJ, et al.: Lack of effect of a high-fiber cereal supplement on the recurrence of colorectal adenomas. Phoenix Colon Cancer Prevention Physicians' Network. N Engl J Med 342 (16): 1156-62, 2000.
78. Wargovich MJ, Eng VW, Newmark HL, et al.: Calcium ameliorates the toxic effect of deoxycholic acid on colonic epithelium. Carcinogenesis 4 (9): 1205-7, 1983.
79. Slattery ML, Sorenson AW, Ford MH: Dietary calcium intake as a mitigating factor in colon cancer. Am J Epidemiol 128 (3): 504-14, 1988.
80. Kune S, Kune GA, Watson LF: Case-control study of dietary etiological factors: the Melbourne Colorectal Cancer Study. Nutr Cancer 9 (1): 21-42, 1987.
81. Yang CY, Chiu HF: Calcium and magnesium in drinking water and risk of death from rectal cancer. Int J Cancer 77 (4): 528-32, 1998.
82. Zheng W, Anderson KE, Kushi LH, et al.: A prospective cohort study of intake of calcium, vitamin D, and other micronutrients in relation to incidence of rectal cancer among postmenopausal women. Cancer Epidemiol Biomarkers Prev 7 (3): 221-5, 1998.
83. Manousos O, Day NE, Trichopoulos D, et al.: Diet and colorectal cancer: a case-control study in Greece. Int J Cancer 32 (1): 1-5, 1983.
84. Wargovich MJ, Baer AR: Basic and clinical investigations of dietary calcium in the prevention of colorectal cancer. Prev Med 18 (5): 672-9, 1989.
85. Lipkin M, Newmark H: Effect of added dietary calcium on colonic epithelial-cell proliferation in subjects at high risk for familial colonic cancer. N Engl J Med 313 (22): 1381-4, 1985.
86. Buset M, Lipkin M, Winawer S, et al.: Inhibition of human colonic epithelial cell proliferation in vivo and in vitro by calcium. Cancer Res 46 (10): 5426-30, 1986.
87. Wargovich MJ, Isbell G, Shabot M, et al.: Calcium supplementation decreases rectal epithelial cell proliferation in subjects with sporadic adenoma. Gastroenterology 103 (1): 92-7, 1992.
88. Bostick RM, Potter JD, Fosdick L, et al.: Calcium and colorectal epithelial cell proliferation: a preliminary randomized, double-blinded, placebo-controlled clinical trial. J Natl Cancer Inst 85 (2): 132-41, 1993.
89. Konishi H, Steinbach G, Hittelman WN, et al.: Cell kinetic analysis of intact rat colonic crypts by confocal microscopy and immunofluorescence. Gastroenterology 111 (6): 1493-500, 1996.
90. Baron JA, Beach M, Mandel JS, et al.: Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group. N Engl J Med 340 (2): 101-7, 1999.
91. Grau MV, Baron JA, Sandler RS, et al.: Prolonged effect of calcium supplementation on risk of colorectal adenomas in a randomized trial. J Natl Cancer Inst 99 (2): 129-36, 2007.
92. Wactawski-Wende J, Kotchen JM, Anderson GL, et al.: Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 354 (7): 684-96, 2006.
93. Forman MR, Levin B: Calcium plus vitamin D3 supplementation and colorectal cancer in women. N Engl J Med 354 (7): 752-4, 2006.
94. Bostick RM, Potter JD, McKenzie DR, et al.: Reduced risk of colon cancer with high intake of vitamin E: the Iowa Women's Health Study. Cancer Res 53 (18): 4230-7, 1993.
95. Lee IM, Cook NR, Gaziano JM, et al.: Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial. JAMA 294 (1): 56-65, 2005.
96. Bjelakovic G, Nikolova D, Simonetti RG, et al.: Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. Lancet 364 (9441): 1219-28, 2004.
97. Gorham ED, Garland CF, Garland FC, et al.: Vitamin D and prevention of colorectal cancer. J Steroid Biochem Mol Biol 97 (1-2): 179-94, 2005.
98. Pritchard RS, Baron JA, Gerhardsson de Verdier M: Dietary calcium, vitamin D, and the risk of colorectal cancer in Stockholm, Sweden. Cancer Epidemiol Biomarkers Prev 5 (11): 897-900, 1996.
99. Giovannucci E, Stampfer MJ, Colditz GA, et al.: Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study. Ann Intern Med 129 (7): 517-24, 1998.
100. Cole BF, Baron JA, Sandler RS, et al.: Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 297 (21): 2351-9, 2007.
101. 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.
102. White E, Jacobs EJ, Daling JR: Physical activity in relation to colon cancer in middle-aged men and women. Am J Epidemiol 144 (1): 42-50, 1996.
103. Slattery ML, Schumacher MC, Smith KR, et al.: Physical activity, diet, and risk of colon cancer in Utah. Am J Epidemiol 128 (5): 989-99, 1988.
104. Kune GA, Kune S, Watson LF: Body weight and physical activity as predictors of colorectal cancer risk. Nutr Cancer 13 (1-2): 9-17, 1990.
105. Friedenreich CM: Physical activity and cancer prevention: from observational to intervention research. Cancer Epidemiol Biomarkers Prev 10 (4): 287-301, 2001.
106. Whittemore AS, Wu-Williams AH, Lee M, et al.: Diet, physical activity, and colorectal cancer among Chinese in North America and China. J Natl Cancer Inst 82 (11): 915-26, 1990.
107. Gerhardsson de Verdier M, Hagman U, Steineck G, et al.: Diet, body mass and colorectal cancer: a case-referent study in Stockholm. Int J Cancer 46 (5): 832-8, 1990.
108. Terry PD, Miller AB, Rohan TE: Obesity and colorectal cancer risk in women. Gut 51 (2): 191-4, 2002.
109. Longnecker MP, Orza MJ, Adams ME, et al.: A meta-analysis of alcoholic beverage consumption in relation to risk of colorectal cancer. Cancer Causes Control 1 (1): 59-68, 1990.
110. Kune GA, Vitetta L: Alcohol consumption and the etiology of colorectal cancer: a review of the scientific evidence from 1957 to 1991. Nutr Cancer 18 (2): 97-111, 1992.
111. Newcomb PA, Storer BE, Marcus PM: Cancer of the large bowel in women in relation to alcohol consumption: a case-control study in Wisconsin (United States). Cancer Causes Control 4 (5): 405-11, 1993.
112. Meyer F, White E: Alcohol and nutrients in relation to colon cancer in middle-aged adults. Am J Epidemiol 138 (4): 225-36, 1993.
113. Boutron MC, Faivre J: Diet and the adenoma-carcinoma sequence. Eur J Cancer Prev 2 (Suppl 2): 95-8, 1993.
114. Boutron MC, Faivre J: Alcohol, tobacco and the adenoma-carcinoma sequence: a case-control study in Burgundy, France. [Abstract] Gastroenterology 104 (Suppl 4): A-390, 1993.
115. Giovannucci E, Colditz GA, Stampfer MJ, et al.: A prospective study of cigarette smoking and risk of colorectal adenoma and colorectal cancer in U.S. women. J Natl Cancer Inst 86 (3): 192-9, 1994.
116. Giovannucci E, Rimm EB, Stampfer MJ, et al.: A prospective study of cigarette smoking and risk of colorectal adenoma and colorectal cancer in U.S. men. J Natl Cancer Inst 86 (3): 183-91, 1994.
117. Chao A, Thun MJ, Jacobs EJ, et al.: Cigarette smoking and colorectal cancer mortality in the cancer prevention study II. J Natl Cancer Inst 92 (23): 1888-96, 2000.
118. Terry P, Ekbom A, Lichtenstein P, et al.: Long-term tobacco smoking and colorectal cancer in a prospective cohort study. Int J Cancer 91 (4): 585-7, 2001.
119. Slattery ML, Potter JD, Friedman GD, et al.: Tobacco use and colon cancer. Int J Cancer 70 (3): 259-64, 1997.
120. Knekt P, Hakama M, Järvinen R, et al.: Smoking and risk of colorectal cancer. Br J Cancer 78 (1): 136-9, 1998.
121. Baron JA, Sandler RS, Haile RW, et al.: Folate intake, alcohol consumption, cigarette smoking, and risk of colorectal adenomas. J Natl Cancer Inst 90 (1): 57-62, 1998.
122. Mandel JS, Church TR, Bond JH, et al.: The effect of fecal occult-blood screening on the incidence of colorectal cancer. N Engl J Med 343 (22): 1603-7, 2000.

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