Tipos de Cancer   /   Cánceres Gastrointestinal

NCI/PDQ^® Health professionals: Colorectal Cancer Prevention (PDQ®)

National Cancer Institute
Ultima Vez Modificado: 3 de diciembre del 2012

TABLE OF CONTENTS

• Who is at Risk?

• Overview
  • Factors Associated With Increased Risk of Colorectal Cancer
    • Excessive alcohol use
    • Cigarette smoking
    • Obesity
  • Factors Associated With a Decreased Risk of Colorectal Cancer
    • Physical activity
  • Interventions Associated With Decreased Risk of Colorectal Cancer
    • Nonsteroidal anti-inflammatory drugs
      • Benefits
      • Harms
    • Aspirin
      • Benefits
      • Harms
    • Postmenopausal hormones
      • Benefits
      • Harms
    • Polyp removal
      • Benefits
      • Harms
    • Diet modification
      • A diet low in fat and meat and high in fiber, fruits, and vegetables
        • Benefits
        • Harms
    • Calcium supplementation
      • Benefits
      • Harms
    • Statins
      • Benefits
      • Harms

• Description of the Evidence
  • Background
    • Incidence and mortality
    • Definition of prevention
    • Etiology and pathogenesis of colorectal cancer
    • Factors associated with increased risk of colorectal cancer
      • Excessive alcohol use
      • Cigarette smoking
      • Obesity
    • Factors associated with a decreased risk of colorectal cancer
      • Physical activity
    • Interventions associated with a decreased risk of colorectal cancer: Benefits and harms
      • Nonsteroidal anti-inflammatory drugs
      • Aspirin
      • Postmenopausal female hormone supplements
      • Polyp removal
      • Diet modification
        • Dietary fat and meat intake
        • Bile acids
        • Dietary fiber, vegetables, and fruit
        • Vitamins
        • Calcium
      • Use of statins

• Changes to This Summary (12/03/2012)

• Questions or Comments About This Summary

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
  • Disclaimer
  • Contact Us

• Get More Information From NCI

Who is at Risk?

For the great majority of people, the major factor that increases a person's risk for colorectal cancer (CRC) is increasing age. Risk increases dramatically after age 50 years; 90% of all CRCs are diagnosed after this age. The history of CRC in a first-degree relative, especially if before the age of 55 years, roughly doubles the risk. Other risk factors are weaker than age and family history. People with inflammatory bowel disease have a much higher risk of CRC. A small percentage (<5%) of CRCs occur in people with a genetic predisposition, including familial adenomatous polyposis and hereditary nonpolyposis coli.

Overview

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

Factors Associated With Increased Risk of Colorectal Cancer

Excessive alcohol use

Based on solid evidence from observational studies, excessive alcohol use is associated with an increased risk of colorectal cancer (CRC). 1 2 3

Magnitude of Effect: A pooled analysis of eight cohort studies estimated an adjusted relative risk (RR) of 1.41 (95% confidence interval [CI], 1.161.72) for consumption exceeding 45 g/day. 3

• Study Design: Cohort studies.
• Internal Validity: Fair.
• Consistency: Fair.
• External Validity: Fair.

Cigarette smoking

Based on solid evidence, cigarette smoking is associated with increased incidence and mortality from CRC.

Magnitude of Effect: A pooled analysis of 106 observational studies estimated an adjusted RR (current smokers vs. never smokers) for developing CRC of 1.18 (95% CI, 1.111.25). 4

• Study Design: One-hundred six observational studies.
• Internal Validity: Fair.
• Consistency: Good.
• External Validity: Good.

Obesity

Based on solid evidence, obesity is associated with increased incidence and mortality from CRC.

Magnitude of Effect: In one large cohort study, the adjusted RR for developing colon cancer for women with a body mass index of more than 29 was 1.45 (95% CI, 1.022.07). 5 6 A similar increase in CRC mortality was found in another large cohort study. 7

• Study Design: Large cohort studies.
• Internal Validity: Fair.
• Consistency: Good.
• External Validity: Good.

Factors Associated With a Decreased Risk of Colorectal Cancer

Physical activity

Based on solid evidence, regular physical activity is associated with a decreased incidence of CRC.

Magnitude of Effect: A meta-analysis of 52 observational studies found a statistically significant 24% reduction in CRC incidence (RR = 0.76; 95% CI, 0.720.81). 8

• Study Design: Cohort studies and meta-analysis.
• Internal Validity: Fair.
• Consistency: Good.
• External Validity: Good.

Interventions Associated With Decreased Risk of Colorectal Cancer

Nonsteroidal anti-inflammatory drugs

Benefits

There is inadequate evidence that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of CRC. In people without genetic predisposition but with a prior history of a colonic adenoma that had been removed, three randomized controlled trials (RCT) found that celecoxib 9 10 and rofecoxib 11 decrease the incidence of recurrent adenoma, although follow-up was too short to determine whether the incidence of CRC would have been affected.

Based on solid evidence, NSAIDs reduce the risk of adenomas, but the extent to which this translates into a reduction of CRC is uncertain.

• Study Design: No adequate studies with CRC outcome.
• Internal Validity: Not applicable (N/A).
• Consistency: N/A.
• External Validity: N/A.

Harms

Based on solid evidence, harms of NSAID use are relatively common and potentially serious, and include upper gastrointestinal bleeding, chronic kidney disease, and serious cardiovascular events such as myocardial infarction, heart failure, and hemorrhagic stroke. 12

Magnitude of Effect: The estimated average excess risk of upper gastrointestinal complications in average-risk people attributable to NSAIDs is 4/1,000 to 5/1,000 people per year. 13 14 The excess risk varies with the underlying gastrointestinal risk, however, it likely exceeds ten extra cases per 1,000 people per year in more than 10% of users. 15 Serious cardiovascular events are increased by 50% to 60%. 14

• Study Design: Evidence obtained from RCTs and high quality systematic reviews and meta-analyses. 13 14
• Internal Validity: Good.
• Consistency: Good.
• External Validity: Good.

Aspirin

Benefits

Based on solid evidence, daily aspirin (acetylsalicylic acid [ASA]) for at least 5 years reduces CRC incidence and mortality. This is based on two reports of extended follow-up of two RCTs 16 17 and meta-analysis of observational studies. 16 A third report that adds extended follow-up of an additional two RCTs (with a meta-analysis of all four RCTs) adds certainty to this conclusion. 18

Magnitude of Effect: After 23 years of follow-up, incidence of CRC in the placebo group was 3.8% and in the ASA group 2.5% (hazard ratio [HR] = 0.63; 95% CI, 0.470.85). In the report from all four RCTs, the 20-year risk of death due to CRC in trials that allocated ASA for at least 5 years was reduced by about 40% (HR = 0.60; 95% CI, 0.450.81), absolute risk reduction was from about 3.1% to 1.9%. The primary effect was on mortality from proximal colon cancer.

• Study Design: Extended follow-up of four RCTs.
• Internal Validity: Fair, some data from registries and death certificates, some loss to follow-up; variation in ASA dose; adherence to ASA unknown after end of trials (59 years).
• Consistency: Consistent.
• External Validity: Fair, most data from British men; fewer data from women.

Harms

Based on solid evidence, harms of ASA use include excessive bleeding, including gastrointestinal bleeds and hemorrhagic stroke.

Magnitude of Effect: The estimated average excess risk of upper gastrointestinal complications is 10 to 30 per 1,000 people for a period of 10 years, on the higher end for men and on the lower end for women. Risk increases with age. 19

• Study Design: Evidence obtained from large databases. 15 20
• Internal Validity: Good.
• Consistency: Good.
• External Validity: Good, data from national databases.

Postmenopausal hormones

Benefits

Based on solid evidence, postmenopausal estrogen plus progesterone hormone use, but not estrogen alone, decreases the incidence of CRC. 21

Magnitude of Effect: 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. The absolute reduction in the incidence of CRC was 0.6 cancers per 1,000 women, from 1.6 cancers per 1,000 women to 1.0 cancer per 1,000 women. A meta-analysis of 18 observational studies showed a 20% reduction in colon cancer incidence among women who had ever used hormone therapy (RR = 0.80; 95% CI, 0.740.86) compared with nonusers and a 34% reduction among current users (RR = 0.66; 95% CI, 0.590.74). 21 22

• Study Design: Evidence obtained from a RCT and meta-analysis of 18 observational studies.
• Internal Validity: Good.
• Consistency: Good.
• 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.

Magnitude of Effect: 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. 23

• Study Design: Evidence from RCTs.
• Internal Validity: Good.
• Consistency: Good.
• External Validity: Fair.

Polyp removal

Benefits

Based on fair evidence, removal of adenomatous polyps reduces the risk of CRC. Much of this reduction likely comes from removal of large (i.e., >1.0 cm) polyps, while the benefit of removing smaller polypswhich are much more commonis unknown. Some but not all observational evidence indicates that this reduction may be greater for left-sided CRC than for right-sided CRC. 24 25 26

Magnitude of Effect: Unknown, probably greater for larger polyps (i.e., >1.0 cm) than smaller ones. 27

• Study Design: Evidence obtained from cohort studies and one RCT of sigmoidoscopy. 25
• Internal Validity: Good.
• Consistency: Consistent.
• External Validity: Good.

Harms

Based on solid evidence, the major harms of polyp removal include perforation of the colon and bleeding.

Magnitude of Effect: Seven to nine events per 1,000 procedures. 28 29 30

• Study Design: Evidence from retrospective cohort studies. 29 30
• Internal Validity: Good.
• Consistency: Good.
• External Validity: Good.

Diet modification

A diet low in fat and meat and high in fiber, fruits, and vegetables

Benefits

Based on fair evidence, a diet low in fat and meat and high in fiber, fruits, and vegetables started as an adult does not reduce the risk of CRC by a clinically important degree.

• Study Design: Evidence obtained from pooled analyses of multiple cohort studies and RCTs.
• Internal Validity: Fair, but measurement error is a potential problem.
• Consistency: Some inconsistency, with one large pooled study 31 finding a reduced risk of distal colon cancer associated with fruit and vegetable intake. RCTs have been consistent.
• External Validity: Good, studies have included large population-based studies.

Harms

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

• Study Design: Cohort and RCT's.
• Internal Validity: Good.
• Consistency: Good.
• External Validity: Good.

Calcium supplementation

Benefits

The evidence is inadequate to determine whether calcium supplementation reduces the risk of CRC.

• Study Design: Pooled and individual prospective cohort studies, meta-analysis of three RCTs with adenoma recurrence as an outcome, and one large individual RCT in women with CRC as an outcome.
• Internal Validity: Good.
• Consistency: Poor; the RCT with CRC as an outcome 32 found no reduction in CRC incidence, while prospective cohort studies found a reduction in CRC incidence between high and low calcium groups; three RCTs found a reduction in adenoma recurrence with calcium supplementation. 33
• External Validity: N/A.

Harms

The evidence is fair that elemental calcium without vitamin D as a supplement in the level of 1,000 to 1,200 mg/day increases the risk of myocardial infarction. Based on fair evidence, calcium supplementation with vitamin D at doses less than 1,000 has few harms.

Magnitude of Effect: In a meta-analysis of RCTs of calcium alone, the risk of myocardial infarction was increased from 4.8% to 5.8% (HR = 1.31; 95% CI, 1.021.67). 34

• Study Design: Pooled and individual prospective cohort studies plus RCTs.
• Internal Validity: Good.
• Consistency: Poor (one meta-analysis of 11 RCTs for calcium alone found increased myocardial infarction; no other individual studies found this). 34
• External Validity: Good.

Statins

Benefits

Based on solid evidence, statins do not reduce the incidence or mortality from CRC.

• Study Design: Meta-analyses of RCTs. 35 36 37
• Internal Validity: Good.
• Consistency: Good.
• External Validity: N/A.

Harms

Based on solid evidence, the harms of statins are small.

• Study Design: Observational studies 38, multiple RCTs, and a review. 39
• Internal Validity: Good.
• Consistency: Good.
• External Validity: Good.

References:

1. 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. [PUBMED Abstract]
2. Gapstur SM, Potter JD, Folsom AR: Alcohol consumption and colon and rectal cancer in postmenopausal women. Int J Epidemiol 23 (1): 50-7, 1994. [PUBMED Abstract]
3. Cho E, Smith-Warner SA, Ritz J, et al.: Alcohol intake and colorectal cancer: a pooled analysis of 8 cohort studies. Ann Intern Med 140 (8): 603-13, 2004. [PUBMED Abstract]
4. Botteri E, Iodice S, Bagnardi V, et al.: Smoking and colorectal cancer: a meta-analysis. JAMA 300 (23): 2765-78, 2008. [PUBMED Abstract]
5. Martínez ME, Giovannucci E, Spiegelman D, et al.: Leisure-time physical activity, body size, and colon cancer in women. Nurses' Health Study Research Group. J Natl Cancer Inst 89 (13): 948-55, 1997. [PUBMED Abstract]
6. Giovannucci E, Ascherio A, Rimm EB, et al.: Physical activity, obesity, and risk for colon cancer and adenoma in men. Ann Intern Med 122 (5): 327-34, 1995. [PUBMED Abstract]
7. Calle EE, Rodriguez C, Walker-Thurmond K, et al.: Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348 (17): 1625-38, 2003. [PUBMED Abstract]
8. Wolin KY, Yan Y, Colditz GA, et al.: Physical activity and colon cancer prevention: a meta-analysis. Br J Cancer 100 (4): 611-6, 2009. [PUBMED Abstract]
9. Bertagnolli MM, Eagle CJ, Zauber AG, et al.: Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 355 (9): 873-84, 2006. [PUBMED Abstract]
10. 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. [PUBMED Abstract]
11. Lanas A, Baron JA, Sandler RS, et al.: Peptic ulcer and bleeding events associated with rofecoxib in a 3-year colorectal adenoma chemoprevention trial. Gastroenterology 132 (2): 490-7, 2007. [PUBMED Abstract]
12. 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. [PUBMED Abstract]
13. Rostom A, Dubé C, Lewin G, et al.: Nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors for primary prevention of colorectal cancer: a systematic review prepared for the U.S. Preventive Services Task Force. Ann Intern Med 146 (5): 376-89, 2007. [PUBMED Abstract]
14. Kearney PM, Baigent C, Godwin J, et al.: Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 332 (7553): 1302-8, 2006. [PUBMED Abstract]
15. Hernández-Díaz S, García Rodríguez LA: Cardioprotective aspirin users and their excess risk of upper gastrointestinal complications. BMC Med 4: 22, 2006. [PUBMED Abstract]
16. Flossmann E, Rothwell PM; British Doctors Aspirin Trial and the UK-TIA Aspirin Trial.: Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet 369 (9573): 1603-13, 2007. [PUBMED Abstract]
17. Rothwell PM, Wilson M, Elwin CE, et al.: Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 376 (9754): 1741-50, 2010. [PUBMED Abstract]
18. Rothwell PM, Fowkes FG, Belch JF, et al.: Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet 377 (9759): 31-41, 2011. [PUBMED Abstract]
19. US Preventive Services Task Force.: Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 150 (6): 396-404, 2009. [PUBMED Abstract]
20. Hernández-Díaz S, Rodríguez LA: Incidence of serious upper gastrointestinal bleeding/perforation in the general population: review of epidemiologic studies. J Clin Epidemiol 55 (2): 157-63, 2002. [PUBMED Abstract]
21. 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. [PUBMED Abstract]
22. Nelson HD, Humphrey LL, Nygren P, et al.: Postmenopausal hormone replacement therapy: scientific review. JAMA 288 (7): 872-81, 2002. [PUBMED Abstract]
23. 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. [PUBMED Abstract]
24. Brenner H, Hoffmeister M, Arndt V, et al.: Protection from right- and left-sided colorectal neoplasms after colonoscopy: population-based study. J Natl Cancer Inst 102 (2): 89-95, 2010. [PUBMED Abstract]
25. Atkin WS, Edwards R, Kralj-Hans I, et al.: Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial. Lancet 375 (9726): 1624-33, 2010. [PUBMED Abstract]
26. Brenner H, Chang-Claude J, Seiler CM, et al.: Protection from colorectal cancer after colonoscopy: a population-based, case-control study. Ann Intern Med 154 (1): 22-30, 2011. [PUBMED Abstract]
27. Robertson DJ, Greenberg ER, Beach M, et al.: Colorectal cancer in patients under close colonoscopic surveillance. Gastroenterology 129 (1): 34-41, 2005. [PUBMED Abstract]
28. Nelson DB, McQuaid KR, Bond JH, et al.: Procedural success and complications of large-scale screening colonoscopy. Gastrointest Endosc 55 (3): 307-14, 2002. [PUBMED Abstract]
29. Levin TR, Zhao W, Conell C, et al.: Complications of colonoscopy in an integrated health care delivery system. Ann Intern Med 145 (12): 880-6, 2006. [PUBMED Abstract]
30. Warren JL, Klabunde CN, Mariotto AB, et al.: Adverse events after outpatient colonoscopy in the Medicare population. Ann Intern Med 150 (12): 849-57, W152, 2009. [PUBMED Abstract]
31. Koushik A, Hunter DJ, Spiegelman D, et al.: Fruits, vegetables, and colon cancer risk in a pooled analysis of 14 cohort studies. J Natl Cancer Inst 99 (19): 1471-83, 2007. [PUBMED Abstract]
32. 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. [PUBMED Abstract]
33. Shaukat A, Scouras N, Schí¼nemann HJ: Role of supplemental calcium in the recurrence of colorectal adenomas: a metaanalysis of randomized controlled trials. Am J Gastroenterol 100 (2): 390-4, 2005. [PUBMED Abstract]
34. Bolland MJ, Avenell A, Baron JA, et al.: Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 341: c3691, 2010. [PUBMED Abstract]
35. Baigent C, Keech A, Kearney PM, et al.: Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366 (9493): 1267-78, 2005. [PUBMED Abstract]
36. Dale KM, Coleman CI, Henyan NN, et al.: Statins and cancer risk: a meta-analysis. JAMA 295 (1): 74-80, 2006. [PUBMED Abstract]
37. Browning DR, Martin RM: Statins and risk of cancer: a systematic review and metaanalysis. Int J Cancer 120 (4): 833-43, 2007. [PUBMED Abstract]
38. Hippisley-Cox J, Coupland C: Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database. BMJ 340: c2197, 2010. [PUBMED Abstract]
39. Joy TR, Hegele RA: Narrative review: statin-related myopathy. Ann Intern Med 150 (12): 858-68, 2009. [PUBMED Abstract]

Description of the Evidence

Background

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 143,460 new cases diagnosed in the United States in 2012 and 51,690 deaths due to this disease. 2 Between 2004 and 2008, CRC incidence rates in the United States declined by 2.5% per year in women, and by 2.7% per year in men. 2 For 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. However, in adults younger than 50 years, CRC incidence rates have been increasing by about 1.7% per year since 1992 in men and women. 2 The overall 5-year survival rate is 64%. About 5% of Americans are expected to develop the disease within their lifetimes. 2 3 The risk of CRC begins to increase after the age of 40 years and rises sharply at ages 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. 4 5 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 use of medications or other interventions before the clinical appearance of CRC with the intent of preventing clinical CRC and CRC mortality.

Etiology and pathogenesis of colorectal cancer

Genetics, 6 7 experimental, 8 9 and epidemiologic 10 11 12 studies suggest that CRC results from complex interactions between inherited susceptibility and environmental factors. The exact nature and contribution of these factors to CRC incidence and mortality is the subject of ongoing research.

Factors associated with increased risk of colorectal cancer

Excessive alcohol use

There is evidence of an association of CRC with alcoholic beverage consumption. In a meta-analysis of eight cohort studies, the relative risk (RR) for consumption of 45 g/day (i.e., about three standard drinks/day) compared with nondrinkers was 1.41 (95% confidence interval [CI], 1.161.72). 13 Case-control studies suggest a modest-to-strong positive relationship between alcohol consumption and large bowel cancers. 14 15 A meta-analysis found that the association did not vary by sex or location within the large bowel. 16

Five studies have reported a positive association between alcohol intake and colorectal adenomas. 17 A case-control study of diet, genetic factors, and the adenoma-carcinoma sequence was conducted in Burgundy. 18 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. 18

A large cohort study found a dose-response relationship between alcohol intake and death from CRC, with a RR of 1.2 (95% CI, 1.01.5) for four or more drinks per day compared with nondrinkers. 19

Cigarette smoking

Most case-control studies of cigarette exposure and adenomas have found an elevated risk for smokers. 20 In addition, a significantly increased risk of adenoma recurrence following polypectomy has been associated with smoking in both men and women. 20 In the Nurses' Health Study, the minimum induction period for cancer appears to be at least 35 years. 21 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. 22 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. 23 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. 24 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. 25 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. 26 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. 27

A meta-analysis of 106 observational studies found a RR (ever smokers compared with nonsmokers) for CRC incidence of 1.18 (95% CI, 1.111.25), with an absolute risk increase of 10.8 cases per 100,000 person-years (95% CI, 7.913.6). There was a statistically significant dose-response effect. In 17 studies with data on CRC mortality, cigarette smoking was associated with CRC death, with a RR (ever smokers vs. never smokers) of 1.25 (95% CI, 1.141.37), and an absolute increase in the death rate of 6.0 deaths per 100,000 person-years. For both incidence and mortality, the association was stronger for rectal cancer than for colon cancer. 28

Obesity

At least three large cohort studies have found an association between obesity and CRC incidence or mortality. 29 30 31 The Nurses' Health Study found that women with a body mass index (BMI) of more than 29, compared with women with a BMI of less than 21, had an adjusted RR for CRC incidence of 1.45 (95% CI ,1.022.07). 29 In the CPS II 31, men and women with a BMI of 30 to 34.9 had an adjusted RR for CRC mortality (compared with people with a BMI of 18.524.9) of 1.47 (95% CI, 1.301.66), with a statistically significant dose-response effect. 31 The effects were similar in men and women.

Factors associated with a decreased risk of colorectal cancer

Physical activity

A sedentary lifestyle has been associated in some 32 33 but not all 34 studies with an increased risk of CRC. Numerous observational studies that have examined the relationship between physical activity and colon cancer risk. 35 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%. Large U.S. cohort studies have found statistically significant adjusted RR of 0.54 (95% CI, 0.330.90) 29 and 0.53 (95% CI, 0.320.88) 30 when comparing people with high versus low average energy expenditure. A meta-analysis of 52 observational studies found an overall adjusted RR of 0.76 (95% CI, 0.720.81), with similar results for men and women. 36

Interventions associated with a decreased risk of colorectal cancer: Benefits and harms

Nonsteroidal anti-inflammatory drugs

One large cohort study (301,240 people with 3,894 colorectal cancer cases) found an association between daily or weekly nonaspirin (nonacetylsalicylic acid [non-ASA]) nonsteroidal anti-inflammatory drug (NSAID) use and reduced 10-year incidence of proximal and distal colon cancer, but not rectal cancer, with a hazard ratio (HR) of 0.67 (95% CI, 0.580.77) for daily use for colon cancer. Because exposure to non-ASA NSAIDs was assessed only once, assessment was by self-report, and there is no information on dose or duration of use, the certainty of this single study must be rated low. Further research is needed before this finding can be accepted. 37

Although evidence is currently inadequate to determine whether NSAIDs reduce CRC incidence, proponents suggest that any effect of these drugs 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 (acetylsalicylic acid [ASA]) (which is considered separately here) and other, first-generation nonselective inhibitors of the two functional isoforms of COX, termed COX-1 and COX-2, but also 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. 38

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. 39 40 41 42 Four trials that demonstrated this increased risk are summarized in the Table. In addition, a network meta-analysis of all large scale (RCTs) comparing any NSAID to any other NSAID or placebo found that there is little evidence to suggest that any of the investigated drugs are safe in cardiovascular terms. Naproxen seemed least harmful. 43

Other major harms from all NSAIDs are gastrointestinal bleeding and renal impairment. The incidence of reported major gastrointestinal bleeding events appears to be dose-related. 44

Celecoxib reduces the incidence of adenomas; however, celecoxib does not have a clinical role in reducing the risk of sporadic 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. 45 A population-based retrospective cohort study of nonaspirin NSAID use among individuals aged 65 years and older was associated with lower risk of CRC, particularly with longer durations of use. 46

Several studies conducted in a rigorous manner have demonstrated the effectiveness of sulindac in reducing the size and number of adenomas in familial polyposis. 47 48 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. 49

The NSAID piroxicam, at a dose of 20 mg/day, reduced mean rectal prostaglandin concentration by 50% in individuals with a history of adenomas. 50 Several studies assessing the effect of ASA or other nonsteroidals on polyp recurrence following polypectomy are in progress. 51 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. 52

Aspirin

The preponderance of evidence from both observational studies and long-term follow-up of RCTs indicates that daily ASA for at least 5 years reduces the incidence of CRC. Among a group of more than 600,000 adults enrolled in an American Cancer Society study, mortality in regular users of ASA was about 40% lower for cancers of the colon and rectum. 53 54 In a report from the Health Professionals Follow-up Study of 47,000 males, regular use of ASA (at least 2 times per week) was associated with a 30% overall reduction in CRC, including a 50% reduction in advanced cases. 55 In a Women's Health Study of a randomized 2 x 2 factorial trial of 100 mg of ASA every other day for an average of 10 years, similar rates of breast, colorectal, or other site-specific cancers were observed in both the ASA and placebo arms. 56 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, 0.670.88) among women who regularly used ASA (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 ASA per week for longer than 10 years had a multivariate RR for cancer of 0.47 [95% CI, 0.310.71]).

A systematic review of 46 observational studies of ASA and CRC in 2007 found a reduction in CRC (OR for any use 0.80 [0.730.87]). 57 A large cohort study (301,240 people with 3,894 colorectal cancer cases) published after this systematic review found an association between weekly or daily ASA use and reduced 10-year incidence of distal and rectal (but not proximal) colorectal cancer, with an HR of 0.76 (95% CI, 0.640.90) for rectal cancer for daily use. However, use was assessed at only one time, and there is no information about dose or duration of use. 37

In the Physicians' Health Study, 22,000 men aged 40 to 84 years were randomly assigned to receive placebo or ASA (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. 58 In a subsequent analysis of more than 12 years, both randomized and observational analyses indicated that there was no association between the use of ASA and the incidence of CRC. The low dose of ASA and the short treatment period may account for the null findings. 59

In a randomized study of 635 patients with prior CRC (T1T2 N0 M0) who had undergone curative resection, ASA 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, 0.460.91) after a median duration of treatment of 31 months. The time to detection of a first adenoma was longer in the ASA group than in the placebo group (HR for the detection of a new polyp, 0.54; 95% CI, 0.430.94, P = .022). Harms of treatment included upper gastrointestinal hemorrhage and hemorrhagic stroke. 60 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 ASA group (95% CI, 0.690.96) and 0.96 in the 325-mg ASA group (95% CI, 0.811.13). 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, 0.380.92) in the 81-mg ASA group, and 0.83 (95% CI, 0.551.23) in the 325-mg ASA group. 61 Harms of treatment were similar in the two groups and included upper gastrointestinal bleeding and hemorrhagic stroke.

Four reports in 2007, 2010, 2011, and 2012 57 62 63 64 have analyzed long-term follow-up of RCTs of daily ASA versus the control. The 2007 analysis reported on two RCTs with reliable follow-up of more than 20 years. This report found that the use of 300 mg or more of ASA per day for at least 5 years reduced the incidence of CRC after a latency of 10 years (RR at 1019 years [0.60; 95% CI, 0.42-0.87]). The 2010 analysis analyzed long-term follow-up data from four RCTs, finding that allocation to ASA for 5 or more years reduced the 20-year incidence and mortality of proximal colon cancer (adjusted incidence HR = 0.35; 95% CI, 0.200.63; adjusted mortality HR = 0.24; 95% CI, 0.110.52) and also reduced the 20-year risk of rectal cancer (RR = 0.58; 95% CI, 0.360.92) but not distal colon cancer. There was no increase in benefit at doses more than 75 mg/day. The absolute 20-year risk reduction in fatal CRC was 1.76% (95% CI, 0.612.91).

The 2011 analysis examined data from eight RCTs, seven of which provided individual patient data and three of which provided 20-year follow-up data. In trials with allocation to ASA of at least 5 years, the 20-year HR for CRC mortality was 0.60 (95% CI, 0.450.81). Six RCTs, including five from the United Kingdom, were included in a meta-analysis in which patients were randomly assigned to receive either aspirin or placebo and mean scheduled duration of trial treatment was 4 years or more. Individual patient data for all in-trial cancer deaths were obtained. In the three United Kingdom trials, cancer deaths after completion of the trials were obtained via death certification and cancer registration, taking the follow-up to 20 years after randomization. Based on meta-analysis of odds ratios from each trial rather than on more sensitive actuarial analysis of the individual patient data, allocation to aspirin in the RCTs reduced the 20-year risk of death due to colorectal (and esophageal) cancer. Odds ratios for 'maximum aspirin use' were 0.55 for colorectal cancer risk (95% CI, 0.410.76) and 0.47 for esophageal cancer risk (95% CI, 0.270.81) and for 'any aspirin use' were 0.58 for colorectal cancer risk (95% CI, 0.440.78) and 0.51 for esophageal cancer (95% CI, 0.310.83).

In a large cohort study, an association between recent daily aspirin use and lower-cancer mortality in the gastrointestinal tract (RR = 0.61; 95% CI, 0.470.78), liver (RR = 0.52; 95% CI, 0.300.93), and bladder (RR = 0.52; 95% CI, 0.280.97) were observed among the 100,139 analysis-eligible participants from the Cancer Prevention Study II Nutrition Cohort established by the American Cancer Society in 1982. The analysis excluded participants who had a history of cancer in the baseline year or whose records contained incomplete information on aspirin use or smoking, and was based on follow-up questionnaires mailed to participants in 1997 (the baseline year for the analysis), 1999, 2001, and 2003. Mortality follow-up continued through Dec 31, 2008 via automated linkage to the National Death Index vital status and cause of death codes (ICD-10); death certificates were obtained for 99.3% of known deaths. 65

Postmenopausal female hormone supplements

Several observational studies have suggested a decreased risk of colon cancer among users of postmenopausal female hormone supplements. 66 67 68 69 For rectal cancer, most studies have observed no association or a slightly elevated risk. 70 71 72

In the Women's Health Initiative (WHI) 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, 0.380.81; 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). 73

Polyp removal

An analysis of data from the National Polyp Study (NPS), with external, historical controls, has commonly been cited to show a reduction of 76% to 90% in the subsequent incidence of CRC after colonoscopic polypectomy compared with three nonconcurrent, historical control groups. 74 This study may be biased in several ways that inflate the apparent efficacy of polyp removal; the main problem is that potential enrollees in the National Polyp Study were excluded if they had CRC at their baseline examination. Because no such exclusions (or baseline colonoscopy examinations) were done in the three comparison groups, persons who had CRC at baseline would be counted as having incident CRC in subsequent follow-up. Although adjustments were attempted, it is not possible to know the magnitude of the impact of this problem on the result because it is not known how long CRC may be present without causing symptoms.

A long-term follow-up study (median follow-up period, 15.8 years; maximum, 23 years) of the NPS cohort suggested an approximately 53% reduction in CRC mortality due to polypectomy (not just exclusion of persons with CRC at initial exam). However, the degree of reduction must be viewed with caution because this study did not have a direct comparison group, relying mainly on comparison to expected data from the Surveillance, Epidemiology and End Results Program. Further, details are not clear about exactly what the program of colonoscopy was that may have led to decreased mortality. Patients in the NPS were assigned to colonoscopy at years 1 and 3; colonoscopy was also offered to one of the two comparison groups at year 1; all participants were offered colonoscopy at year 6. However, following year 6, the exact surveillance that patients may have undergone and how that surveillance might have been associated with decreased CRC mortality were not clear. 75

It is expected that further follow-up in the United Kingdom Flexible Sigmoidoscopy Screening Trial will be able to provide more detail about the long-term effect of polypectomy, at least on the left side of the colon. 75

Other evidence about the benefit of sigmoidoscopy screening (at which time both polyps and early cancer would be removed) suggests that the impact of endoscopic screening, at least on the left side of the colon, is substantial and prolonged. In an RCT, 170,000 persons were randomly assigned to one-time sigmoidoscopy versus usual care. At sigmoidoscopy, polyps were removed and cancer was detected and referred for treatment. Based on sigmoidoscopy findings, persons were considered to have low risk if they had normal exams or only one or two small (<1 cm) tubular adenomas; such persons were not referred either for colonoscopy workup, or for colonoscopic surveillance. In a follow-up of 10 years, the left-sided CRC incidence in the low-risk group (about 95% of attendees were low risk) was 0.02% to 0.04% per yeara very low risk of CRC compared with average risk. The cause of reduced riskwhether due to detection and removal of large polyps or small ones, or selection of individuals at lower riskis yet unclear. 76 The natural history of large polyps is not well known, but some evidence suggests that such lesions become clinical CRC at a rate of approximately 1% per year. 77 As a result of the strong data about the impact of endoscopy on the left colon, evidence from multiple studies has raised questions about the ability of endoscopy to reduce CRC mortality in the right colon. 78 79 80 Thus, it is unclear what the overall impact of endoscopy (e.g., colonoscopy screening) is, and whether there may be a large difference in impact on the left side of the colon compared with the right side. 78

Other studies suggest that the polyps with the greatest potential to progress to CRC are larger polyps (i.e., >1.0 cm), which include most of those with villous or high-grade histologic features. Retrospective cohort studies also show the harms associated with polypectomy, including bleeding. 81 82

Diet modification

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. 83 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.