Who Is at Risk?

For most people, the major factor that increases a person’s risk for colorectal cancer (CRC) is advancing 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 American individuals compared with other races; however, a meta-analysis found no evidence that African American individuals have higher rates of precancerous lesions. 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 increase 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.

Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide and the third leading cause of cancer deaths in men and women combined in the United States. It is estimated that there will be 152,810 new cases diagnosed in the United States in 2024 and 53,010 deaths due to this disease. Between 2011 and 2019, incidence rates for CRC in the United States declined by about 1% per year overall. However, this declining incidence is confined to individuals aged 65 years and older. Since the mid-1990s, the incidence rate increased by 1% to 2% per year in individuals younger than 55 years and stabilized in individuals aged 55 to 64 years. For the past 20 years, the mortality rate has been declining in both men and women. Over the last decade, the mortality rate declined by 1.8% per year. Incidence and mortality rates are higher in Black individuals than in those of other races; however, a meta-analysis found no evidence that Black individuals have higher rates of precancerous lesions.

The overall 5-year survival rate is 64% for CRC. About 4.12% 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 colorectal cancer (CRC) with the intent of preventing clinical CRC and CRC mortality.

Genetics, experimental, and epidemiologic studies suggest that colorectal cancer (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.

Excessive Alcohol Use

There is evidence of an association of colorectal cancer (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 , 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.

Cigarette Smoking

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 vs. 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.

Obesity

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.

Family/Personal History of Colorectal Cancer and Other Hereditary Conditions

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 (including an attenuated form of polyposis), due to germline mutations in the APC gene, and Lynch syndrome, 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.

Physical Activity

A sedentary lifestyle has been associated with an increased risk of colorectal cancer 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 relative risk (RR) reduction is reportedly 40% to 50%. Large U.S. cohort studies have found statistically significant adjusted RRs of 0.54 (95% confidence interval , 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.

Aspirin

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 colorectal cancer (CRC), but not until at least 10 years after initiation of therapy (pooled relative risk of CRC incidence within 10 years of initiation, 0.99 vs. RR, 0.60 at 10–19 years after initiation). In the Women's Health Study, a randomized 2 × 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 (hazard ratio , 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.

The Cancer Prevention Programme (CAPP2), previously known as the Concerted Action Polyposis Prevention project, investigated chemoprevention of CRC in patients with known Lynch syndrome across 43 international centers. For more information, see the Lynch Syndrome section in Genetics of Colorectal Cancer. Patients were randomly assigned to receive aspirin (600 mg/day), aspirin-placebo, resistant starch (30 g/day), or starch-placebo for up to 4 years. A planned 10-year analysis of CAPP2 data found reduced CRC incidence in patients with Lynch syndrome who took aspirin for at least 2 years when compared with those who took placebo. An intention-to-treat analysis, using Cox proportional hazards regression, showed that aspirin protected against the primary end point of CRC (HR, 0.65; 95% CI, 0.43–0.97; P = .035).

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 CRC 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 CRC 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 HR 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 odds ratios (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. 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.

Hormone Therapy (Estrogen Plus Progestin)

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 end point, 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).

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. 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 (SEER) 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.

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 (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% confidence interval , 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.

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

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 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.

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.

Calcium supplements

A randomized placebo-controlled trial tested the effect of calcium supplementation (3 g calcium carbonate daily ) on the risk of recurrent adenoma. The primary end point 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 , 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.

Dietary Factors

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. 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. 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, the results have been inconsistent. A number of prospective cohort studies have been conducted in the United States and abroad; a systematic review of 13, including the Iowa Women’s Health Study and the Nurses’ Health Study, concluded that there appeared to be a positive association between meat consumption and CRC incidence. However, the authors noted that because only a few studies tried to investigate the independent effect of meat intake on cancer risk, the observed relationship might be attributed entirely to confounding. Similarly, a 2019 systematic review of observational studies, evaluating the association between processed or unprocessed red meat consumption and CRC incidence and mortality, concluded that a reduction of three servings per week resulted in very small to no decreases in those outcomes, although the certainty around these findings was judged low to very low.

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 an 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. This last observation was echoed in a 2019 systematic review of randomized controlled trials of the effect of variable red meat consumption on cancer outcomes. This review relied heavily on the WHI to reach the conclusion that there appears to be little to no effect of red meat intake on CRC incidence, although the certainty around this finding is low because of limitations in available studies.

Explanations for the conflicting results regarding whether dietary fat or meat intake affects the risk of CRC include the following:

• Validity of dietary questionnaires used.
• Differences in the average age of the population studied.
• Variations in methods of meat preparation (in some instances, mutagenic and carcinogenic heterocyclic amines could have been released at high temperatures).
• Variability in the consumption of other foods such as vegetables.
• Possible unadjusted bias from differential screening uptake between meat intake groups.

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.

Estrogen-Only Therapy

The estrogen-only intervention component of the Women’s Health Initiative was conducted among women who had a hysterectomy, with colorectal cancer (CRC) incidence included as a secondary trial end point. 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 (hazard ratio , 1.12; 95% confidence interval , 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).

Statins

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