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. Incidence and mortality rates are higher in African Americans compared with other races.  The history of CRC in a first-degree relative, especially if before the age of 55 years, roughly doubles the risk. A personal history of CRC, high-risk adenomas, or ovarian cancer also increases the risk.  Other risk factors are weaker than age and family history. People with an inflammatory bowel disease, such as ulcerative colitis or Crohn disease, have a much higher risk of CRC starting about 8 years after disease onset and are recommended to have frequent colonoscopic surveillance.  A small percentage (<5%) of CRCs occur in people with a genetic predisposition, including familial adenomatous polyposis and hereditary nonpolyposis coli.
Note: Separate PDQ summaries on Colorectal Cancer Screening; Colon Cancer Treatment; and Rectal Cancer Treatment are also available.
Based on solid evidence from observational studies, excessive alcohol use is associated with an increased risk of colorectal cancer (CRC).  
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. 
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).  
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).   A similar increase in CRC mortality was found in another large cohort study.  
Based on solid evidence, a family history of CRC in a first-degree relative or a personal history of CRC increases the risk of CRC.     Having a genetic predisposition, including familial adenomatous polyposis and hereditary nonpolyposis coli, also increases risk for CRC. 
Magnitude of Effect: In persons with adenomatous polyposis coli, the risk of CRC by age 40 can be as high as 100%. Persons with hereditary nonpolyposis coli can have a lifetime risk of CRC of about 80%.
Refer to the PDQ summary on Genetics of Colorectal Cancer for more information about family history and hereditary conditions.
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). 
Based on solid evidence, daily aspirin (acetylsalicylic acid [ASA]) reduces CRC incidence and mortality after 10 to 20 years. This is based on three individual participant level data meta-analyses of trials of aspirin used for the primary and secondary prevention of cardiovascular disease.   
Magnitude of Effect: ASA use reduces the long-term risk for developing CRC by 40% about 10 to 19 years after initiation (hazard ratio [HR], 0.60; 95% CI, 0.47–0.76).  Daily doses of 75 to 1,200 mg of ASA reduce the 20-year risk of CRC death by about 33% (HR, 0.67; 95% CI, 0.52–0.86).  
Based on solid evidence, harms of ASA use include excessive bleeding, including gastrointestinal bleeds and hemorrhagic stroke.
Magnitude of Effect: Very low-dose ASA use (i.e., ≤100 mg every day or every other day) results in an estimated 14 (95% CI, 7–23) additional major gastrointestinal bleeding events and 3.2 (95% CI, -0.5 to 0.82) extra hemorrhagic strokes per 1,000 persons over 10 years. These risks increase with advancing age. 
Based on solid evidence, combined hormone therapy (conjugated equine estrogen and progestin) decreases the incidence of invasive CRC. 
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. 
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).
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. 
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.   
Magnitude of Effect: Unknown, probably greater for larger polyps (i.e., >1.0 cm) than smaller ones. 
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.   
There is inadequate evidence that the use of 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 RCT found that celecoxib   and rofecoxib  decreased the incidence of recurrent adenoma, although follow-up was too short to determine whether CRC incidence or mortality 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.
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.  A recent report compared the COX-2 inhibitor celecoxib (200 mg/d) with the nonselective nonsteroidals naproxen (850 mg/d) and ibuprofen (2,000 mg/d) in individuals with severe arthritis (i.e., not using lower doses as for primary prevention). The results showed that serious cardiovascular events were not less common for those taking the nonselective nonsteroidals. However, this study did not assess the comparative safety of lower doses or the safety of the COX-2 inhibitor rofecoxib. 
Magnitude of Effect: The estimated average excess risk of upper gastrointestinal complications in average-risk people attributable to NSAIDs is 4 to 5 per 1,000 people per year.   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.  Serious cardiovascular events are increased by 50% to 60%. 
The evidence is inadequate to determine whether calcium supplementation reduces the risk of CRC.
There is no reliable evidence that a diet started in adulthood that is low in fat and meat and high in fiber, fruits, and vegetables reduces the risk of CRC by a clinically important degree.
Based on fair evidence, conjugated equine estrogens do not affect the incidence of, or survival from, invasive CRC. 
Magnitude of Effect: N/A.
Based on solid evidence, statins do not reduce the incidence or mortality from CRC.
Based on solid evidence, the harms of statins are small.
Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide  and the second leading cause of cancer deaths in men and women combined in the United States.  It is estimated that there will be 135,430 new cases diagnosed in the United States in 2017 and 50,260 deaths due to this disease.  Between 2004 and 2013, CRC incidence rates in the United States declined by 3% per year among adults aged 50 years and older.  In adults younger than 50 years, CRC incidence rates increased by about 2% per year.  For the past 20 years, the mortality rate has been declining in both men and women. Between 2005 and 2014, the mortality rate declined by 2.5% per year.  Incidence and mortality rates are higher in African Americans compared with other races.  
The overall 5-year survival rate is 65%. About 4.4% of Americans are expected to develop CRC within their lifetimes.   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.   Hence, effective primary and secondary preventive approaches must be developed to reduce the morbidity and mortality from CRC.
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.
Genetics,   experimental,   and epidemiologic    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.
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 per day) compared with nondrinkers was 1.41 (95% confidence interval [CI], 1.16–1.72).  Case-control studies suggest a modest-to-strong positive relationship between alcohol consumption and large bowel cancers.   A meta-analysis found that the association did not vary by sex or location within the large bowel. 
Five studies have reported a positive association between alcohol intake and colorectal adenomas.  A case-control study of diet, genetic factors, and the adenoma-carcinoma sequence was conducted in Burgundy.  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. 
A large cohort study found a dose-response relationship between alcohol intake and death from CRC, with a RR of 1.2 (95% CI, 1.0–1.5) for four or more drinks per day compared with nondrinkers. 
Most case-control studies of cigarette exposure and adenomas have found an elevated risk for smokers.  In addition, a significantly increased risk of adenoma recurrence following polypectomy has been associated with smoking in both men and women.  In the Nurses’ Health Study, the minimum induction period for cancer appears to be at least 35 years.  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.  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.  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, although subsite analysis found a statistically significant effect only for rectal cancer, but not colon cancer.  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.  However, a 28-year follow-up of 57,000 Finns showed no association between the development of CRC and baseline smoking status, although there was a 57% to 71% increased risk in persistent smokers.  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. 
A meta-analysis of 106 observational studies found a RR (ever smokers compared with nonsmokers) for CRC incidence of 1.18 (95% CI, 1.11–1.25), with an absolute risk increase of 10.8 cases per 100,000 person-years (95% CI, 7.9–13.6). 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, 1.14–1.37), 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. 
At least three large cohort studies have found an association between obesity and CRC incidence or mortality.    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,1.02–2.07).  In the CPS II,  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 18.5–24.9) of 1.47 (95% CI, 1.30–1.66), with a statistically significant dose-response effect.  The effects were similar in men and women.
Some of the earliest studies of family history of CRC were those of Utah families that reported a higher number of deaths from CRC (3.9%) among the first-degree relatives of patients who had died from CRC than among sex-matched and age-matched controls (1.2%). This difference has since been replicated in numerous studies that have consistently found that first-degree relatives of affected cases are themselves at a twofold to threefold increased risk of CRC. Despite the various study designs (case-control, cohort), sampling frames, sample sizes, methods of data verification, analytic methods, and countries where the studies originated, the magnitude of risk is consistent.      
A systematic review and meta-analysis of familial CRC risk was reported.  Of 24 studies included in the analysis, all but one reported an increased risk of CRC if there was an affected first-degree relative. The RR for CRC in the pooled study was 2.25 (95% CI, 2.00–2.53) if there was an affected first-degree family member. In 8 of 11 studies, if the index cancer arose in the colon, the risk was slightly higher than if it arose in the rectum. The pooled analysis revealed an RR in relatives of colon and rectal cancer patients of 2.42 (95% CI, 2.20–2.65) and 1.89 (95% CI, 1.62–2.21), respectively. The analysis did not reveal a difference in RR for colon cancer based on location of the tumor (right side vs. left side). 
Hereditary CRC has two well-described forms: Familial adenomatous polyposis (FAP) (including an attenuated form of polyposis), due to germline mutations in the APC gene,         and Lynch syndrome (also called hereditary nonpolyposis colorectal cancer), which is caused by germline mutations in DNA mismatch repair genes.     Many other families exhibit aggregation of CRC and/or adenomas, but with no apparent association with an identifiable hereditary syndrome, and are known collectively as familial CRC. 
Refer to the PDQ summary on Genetics of Colorectal Cancer for more information about genetic risk factors for CRC.
A sedentary lifestyle has been associated with an increased risk of CRC in some   but not all  studies. Numerous observational studies have examined the relationship between physical activity and colon cancer risk.  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 RRs of 0.54 (95% CI, 0.33–0.90)  and 0.53 (95% CI, 0.32–0.88)  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, 0.72–0.81), with similar results for men and women. 
Evidence from individual participant-level data meta-analyses of randomized controlled trials (RCTs) and observational studies   investigating the use of aspirin for the prevention of cardiovascular disease indicates that acetylsalicylic acid (ASA) use reduces the incidence of CRC, but not until at least 10 years after initiation of therapy (pooled RR of CRC incidence within 10 years of initiation, 0.99 [95% CI, 0.85–1.15] vs. RR, 0.60 [95% CI, 0.47–0.76] at 10–19 years after initiation).  In the Women's Health Study, a randomized 2 x 2 factorial trial of 100 mg of ASA every other day for an average of 10 years, CRC incidence was reduced by about 20% after 17.5 years (HR, 0.80; 95% CI, 0.67–0.97).  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 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. 
In a randomized study of 635 patients with prior CRC (T1–T2 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, 0.46–0.91) after a median duration of treatment of 31 months. The likelihood of detection of a new colonic lesion was lower in the ASA group than in the placebo group (HR for the detection of a new polyp, 0.54; 95% CI, 0.43–0.94, P = .022).  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/day ASA group (95% CI, 0.69–0.96) and 0.96 in the 325 mg/day ASA group (95% CI, 0.81–1.13). For advanced neoplasms (adenomas ≥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/day ASA group, and 0.83 (95% CI, 0.55–1.23) in the 325 mg/day ASA group, respectively. 
ASA has also been evaluated for its potential effects on colorectal cancer mortality. A 2010 individual patient level data meta-analysis analyzed long-term (median follow-up, 18.3 years) data from four RCTs of primary and secondary cardiovascular disease prevention; it found that allocation to use of 75 to 1,200 mg of daily ASA for at least one year reduced the cumulative risk of colon cancer death compared with controls (HR, 0.67; 95% CI, 0.52–0.86). Aspirin reduced colorectal cancer mortality beginning 10 to 20 years after randomization, but not before.  A 2011 individual participant level data meta-analysis examined data from six RCTs of primary or secondary cardiovascular disease prevention. In trials with allocation to ASA after at least 5 years of in-trial follow-up, the hazard ratio for CRC mortality was 0.41 (95% CI, 0.71–1.00). There was no statistically significant effect during the first five years after randomization. 
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 the 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 ORs 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 CRC. Odds ratios (ORs) for maximum aspirin use were 0.55 for CRC risk (95% CI, 0.41–0.76) and for any aspirin use were 0.58 for CRC risk (95% CI, 0.44–0.78). 
The Women's Health Study, the largest randomized trial of aspirin to date (N = 39,876), found no reduction in CRC mortality rates with the use of every other day low-dose aspirin during the first 10 years of follow-up. The study did not report on longer-term risk for CRC mortality. 
Aspirin has several important potential harms associated with its use that should be a part of any consideration of its use as a disease prevention strategy. Regular low-dose aspirin use increases the risks for major gastrointestinal bleeding and intracranial bleeding events, including hemorrhagic strokes. A systematic review of studies of aspirin use for primary cardiovascular disease prevention found that use of 100 mg or more of aspirin daily or every other day increased a person’s risk for a major gastrointestinal bleed by 58% (OR, 1.58, 95% CI, 1.29–1.95) or an intracranial hemorrhage by 30% (OR, 1.30; 95% CI, 1.00–1.68). These risks may be greater among older individuals, men, and those individuals with comorbid risk factors that promote a risk of bleeding. 
Several observational studies have suggested a decreased risk of colon cancer among users of postmenopausal female hormone supplements.     For rectal cancer, most studies have observed no association or a slightly elevated risk.   
The Women’s Health Initiative (WHI) trial examined, as a secondary endpoint, the effect of combined estrogen-plus-progestin therapy and estrogen-only therapy on CRC incidence and mortality. Among women in the combined estrogen-plus-progestin group of the WHI, an extended follow-up (mean, 11.6 years) confirmed that fewer CRC were diagnosed in the combined hormone therapy group than in the placebo group (HR, 0.72; 95% CI, 0.56–0.94); the CRCs in women in the combined group were more likely to have lymph node involvement than the CRCs in women in the placebo group (50.5% vs. 28.6%; P < .001) and were classified at higher stages (regional and distant) (68.8% vs. 51.4%; P = .003). The number of CRC deaths in the combined group was higher than in the placebo group (37 vs. 27 deaths), but the difference was not statistically significant (HR, 1.29; 95% CI, 0.78–2.11). 
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.  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 NPS 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.
An additional long-term follow-up study (median follow-up, 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 National Cancer Institute's Surveillance, Epidemiology and End Results Program. Further, details are not clear regarding factors 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 well described. 
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. 
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, cancer was detected, and patients were 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 year—a very low risk of CRC compared with average risk. The cause of reduced risk—whether due to detection and removal of large polyps or small ones, or selection of individuals at lower risk—is yet unclear.  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.  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.    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. 
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.  
One large cohort study (301,240 people with 3,894 CRC cases) found an association between daily or weekly nonaspirin (non-ASA) nonsteroidal anti-inflammatory drug (NSAID) use and reduced 10-year incidence of proximal and distal colon cancer, but not rectal cancer, with an HR of 0.67 (95% CI, 0.58–0.77) 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. 
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 (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. 
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.     Four trials that demonstrated this increased risk are summarized in the Table 1. In addition, a network meta-analysis of all large scale randomized, controlled trials (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 terms of cardiovascular effects. Naproxen seemed least harmful. 
|Authors||Dose/Trial Drug||Risk||Study Type|
|||Rofecoxib <25 mg/qd; rofecoxib >25 mg/qd||OR, 1.47 (0.99–2.17) vs. 3.58 (1.27–10.17)||Nested case-control study all users|
|||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)|
|||Rofecoxib 25 mg/qd||RR, 1.92 (95% CI, 1.19–3.11; P = .008)||Chemoprevention of sporadic adenoma|
|||Rofecoxib 25 mg/qd||RR (estimated), 2.66 (95% CI, 1.03–6.86; P = .04)||Chemoprevention of sporadic adenoma; median study Rx 7.4 months|
|bid = twice a day; qd = every day; CI = confidence interval; HR = hazard ratio; OR = odds ratio; RR = relative risk; Rx = prescription.|
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. 
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 because of increased risk of cardiovascular events, and because there are other effective ways, such as screening to reduce CRC mortality.  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. 
Several rigorous studies have demonstrated the effectiveness of sulindac in reducing the size and number of adenomas in familial polyposis.   In a randomized, double-blind, placebo-controlled study of 77 patients with FAP, 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. 
The NSAID piroxicam, at a dose of 20 mg/day, reduced mean rectal prostaglandin concentration by 50% in individuals with a history of adenomas.  Several studies assessing the effect of ASA or other nonsteroidals on polyp recurrence following polypectomy are in progress.  In several of these studies, mucosal prostaglandin concentration is being measured.
The potential for use of NSAIDs as a primary prevention measure is being studied. There are, however, several unresolved issues that preclude 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. 
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.  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.  The results of other ongoing adenoma recurrence studies are awaited with interest. 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).  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, although other factors may also be responsible. 
Colon cancer rates are high in populations with high total fat intakes and are lower in those consuming less fat.  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.  In laboratory studies, a high-fat intake increases the incidence of induced colon tumors in experimental animals.   Several case-control studies have explored the association of colon cancer risk with meat or fat consumption as well as protein and energy intake.   Although positive associations with meat consumption or with fat intake have been found frequently, the results have not always achieved statistical significance.  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.  In Norway, an increased risk for processed meat only was found,  a finding that was confirmed in the Netherlands.  A clearly defined gradient in the 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.  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.  In two other large prospective studies, the CPS II and the Iowa Women’s Health Study (IWHS), no increase in the risk of colon cancer was seen with meat or fat consumption.   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).  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).  
A randomized controlled dietary modification study was undertaken among 48,835 postmenopausal women aged 50 to 79 years who were also enrolled in the WHI. 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 did the comparison group during the 8.1 years of follow-up. There was no evidence of reduction in invasive CRCs between the intervention and comparison groups with a HR of 1.08 (95% CI, 0.90–1.29).  Likewise, there was no benefit of the low-fat diet on all-cancer mortality, overall mortality, or cardiovascular disease. 
Explanations for the conflicting results regarding whether dietary fat or meat intake affects the risk of CRC  include:
Six case-control studies and two cohort studies have explored potential dietary risk factors for colorectal adenomas.   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.  In a multicenter RCT, 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. 
Thus, the evidence is inadequate to determine whether reducing dietary fat and meat would reduce CRC incidence.
The estrogen-only intervention component of the WHI was conducted among women who had a hysterectomy, with CRC incidence included as a secondary trial endpoint. CRC incidence was not decreased among women who had taken estrogens; after a median of 7.1 years of follow-up, 58 invasive cancers occurred in the estrogen arm compared with 53 invasive cancers in the placebo arm (HR, 1.12; 95% CI, 0.77–1.63). Tumor stage and grade were similar in the two groups; deaths after CRC were 34% in the hormone group compared with 30% in the placebo group (HR, 1.34; 95% CI, 0.58–3.19). 
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  nor a meta-analysis of four RCTs  found any effect of statin use.
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Added text to state that a recent report compared the COX-2 inhibitor celecoxib with the nonselective nonsteroidals naproxen and ibuprofen in individuals with severe arthritis and showed that serious cardiovascular events were not less common for those taking the nonselective nonsteroidals; however, the study did not assess the comparative safety of lower doses or the safety of the COX-2 inhibitor rofecoxib (cited Nissen et al. reference 33).
Description of the Evidence
Revised text to state that about 4.4% of Americans are expected to develop colorectal cancer within their lifetimes (cited Howlader et al. as reference 5).
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