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], 1.16–1.72) 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, 1.11–1.25)[4].

Study Design: One-hundred six observational studies.

Internal Validity: Fair.

Consistency: Good.

External Validity: Good.


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, 1.02–2.07)[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, 0.72–0.81)[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

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.

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.


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, 0.47–0.85). 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, 0.45–0.81), 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 (5–9 years).

Consistency: Consistent.

External Validity: Fair, most data from British men; fewer data from women.

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.

Hormone therapy (estrogen plus progestin)

Based on solid evidence, combined hormone therapy (conjugated equine estrogen and progestin) decreases the incidence of invasive CRC[21].

Based on fair evidence, combination conjugated equine estrogen and progestin has little or no benefit in reducing mortality from CRC. Data from the Women’s Health Initiative (WHI), a randomized, placebo-controlled trial evaluating estrogen plus progestin, with a mean intervention of 5.6 years and a follow-up of 11.6 years showed that women taking combined hormone therapy had a statistically significant higher stage of cancer (regional and distant) at diagnosis but not a statistically significant number of deaths from CRC compared with women taking the placebo[21].

Magnitude of Effect: There were fewer CRCs in the combined hormone therapy group than in the placebo group (0.12% vs. 0.16%; HR = 0.72; 95% CI, 0.56–0.94). A meta-analysis of cohort studies observed a RR of 0.86 (95% CI, 0.76–0.97) for incidence of CRC associated with combined hormone therapy.

There were 37 CRC deaths in the combined hormone therapy arm compared with 27 deaths in the placebo arm (0.04% vs. 0.03%; HR 1.29; 95% CI, 0.78–2.11).

Study Design: Randomized controlled trial and cohort studies

Internal Validity: Good.

Consistency: Good for effect on incidence; N/A for effect on mortality; results were based on one trial.

External Validity: Good.

Estrogen-only therapy

Based on fair evidence, conjugated equine estrogens do not affect the incidence of, or survival from, invasive CRC[22].

Magnitude of Effect: N/A.

Study Design: One randomized controlled trial.

Internal Validity: Good.

Consistency: N/A.

External Validity: Good.

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

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 polyps—which are much more common—is 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.

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

Calcium supplementation

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.

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, 1.02–1.67)[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.


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.

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.


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