Incidence and mortality
Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide  and the second leading cause of cancer deaths (irrespective of gender) in the United States. It is estimated that there will be 136,830 new cases diagnosed in the United States in 2014 and 50,310 deaths due to this disease. Between 2006 and 2010, CRC incidence rates in the United States declined by 3.7% per year among adults aged 50 years and older. For the past 20 years, the mortality rate has been declining in both men and women. Between 2006 and 2010, the mortality rate declined by 2.5% per year in men and by 3.0% per year in women. In adults younger than 50 years, CRC incidence rates increased by about 1.8% per year. The overall 5-year survival rate is 65%. 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], 1.16-1.72). 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.
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, though subsite analysis found a statistically significant effect only for rectal 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, though 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.[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 ,1.02-2.07). 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.
Factors associated with a decreased risk of colorectal cancer
A sedentary lifestyle has been associated in some [32,33] but not all  studies with an increased risk of CRC. Numerous observational studies that 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 RR 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.
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 (non-acetylsalicylic 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, 0.58-0.77) 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.[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 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.
Cardiovascular Risks Associated With Celecoxib and Rofecoxib Dose/Drugs
|bid = twice a day; qd = every day; CI = confidence interval; HR = hazard ratio; OR = odds ratio; RR = relative risk.|
|||Rofecoxib <25 mg/qd; rofecoxib >25 mg/qd||OR = 1.47 (0.99-2.17) 3 vs. 58 (1.27-10.17)||Nested case-control study all users|
|||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 sporadic adenoma|
|||Rofecoxib 25 mg/qd||RR (estimated) = 2.66 (95% CI, 1.03-6.86;P = .04)||Chemoprevention sporadic adenoma median study Rx 7.4 months|
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 due to 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.[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.
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 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.
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. In the Women's Health Study (WHS), 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. 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 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, 0.31-0.71]).
A systematic review of 46 observational studies of ASA and CRC in 2007 found a reduction in CRC (odds ratio [OR] for any use 0.80 [0.73-0.87]). 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, 0.64-0.90) 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.
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. 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.
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 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, 0.43-0.94, P = .022). Harms of treatment included upper gastrointestinal hemorrhage and hemorrhagic stroke. 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, 0.69-0.96) and 0.96 in the 325-mg ASA group (95% CI, 0.81-1.13). For advanced neoplasms (adenomas measuring at least 10.0 mm in diameter or with tubulovillous or villous features, severe dysplasia, or invasive cancer), the RRs were 0.59 (95% CI, 0.38-0.92) in the 81-mg ASA group, and 0.83 (95% CI, 0.55-1.23) in the 325-mg ASA group. 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 10-19 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, 0.20-0.63; adjusted mortality HR = 0.24; 95% CI, 0.11-0.52) and also reduced the 20-year risk of rectal cancer (RR = 0.58; 95% CI, 0.36-0.92) 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, 0.61-2.91).
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, 0.45-0.81). 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 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 colorectal (and esophageal) cancer. ORs for maximum aspirin use were 0.55 for colorectal cancer risk (95% CI, 0.41-0.76) and 0.47 for esophageal cancer risk (95% CI, 0.27-0.81) and for any aspirin use were 0.58 for colorectal cancer risk (95% CI, 0.44-0.78) and 0.51 for esophageal cancer (95% CI, 0.31-0.83).
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, 0.47-0.78), liver (RR = 0.52; 95% CI, 0.30-0.93), and bladder (RR = 0.52; 95% CI, 0.28-0.97) were observed among the 100,139 analysis-eligible participants from the CPS 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.
The WHS, the largest randomized trial of aspirin to date (N = 39,876), found no reduction in the incidence of colon or other cancers during the 10-year active intervention. However, among women who voluntarily participated in extended follow-up (N = 33,682; 16,913 from the intervention group and 16,769 from the placebo group), there was a significant reduction in CRC incidence (HR = 0.58; 95% CI, 0.42-0.8, P < .001) with a median follow-up of 8 years. Calculated from the beginning of the intervention period through the extended follow-up (median, 18 years) an overall reduction in CRC incidence was observed for the WHS (HR = 0.80; 95% CI, 0.67-0.97; P = .021; P = .012 intervention period versus extended follow-up). During the intervention phase, women were randomly assigned to receive either an annual supply of aspirin (100 mg) or placebo, taken every other day. During the extended follow-up, the intervention was discontinued. Protocol compliance and medical incidences were tracked via identical annual questionnaires throughout the 18-year period. Medical record reviews by a panel of experts blinded to random assignment confirmed the endpoints reported. Whereas previously reported meta-analyses of randomized trials of daily aspirin use demonstrated a reduction in colon cancer incidence with extended follow-up, these findings from the WHS demonstrate a similar effect from aspirin taken every other day.
Postmenopausal female hormone supplements
Several observational studies have suggested a decreased risk of colon cancer among users of postmenopausal female hormone supplements.[67,68,69,70] For rectal cancer, most studies have observed no association or a slightly elevated risk.[71,72,73]
The Women's Health Initiative (WHI) trial examined, as a secondary endpoint, the effect of combined estrogen and 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).
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).
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.
A 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 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. 
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 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 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.[80,81,82] 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.[83,84]
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. In laboratory studies, a high-fat intake increases the incidence of induced colon tumors in experimental animals.[87,88] Several case-control studies have explored the association of colon cancer risk with meat or fat consumption as well as protein and energy intake.[10,89] 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.[96,97] 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).[99,100]
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:
- 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 HCAs could have been released at high temperatures).
- Variability in the consumption of other foods such as vegetables.
In addition, some epidemiological studies have reported lower incidence rates of colon cancer in populations with high intakes of both fat and fiber, compared with populations with high levels of fat but low levels of fiber consumption. Although far from clear-cut, the available evidence suggests CRC risk is possibly associated with some interaction of dietary fat, protein, and caloric intake.
Six case-control studies and two cohort studies have explored potential dietary risk factors for colorectal adenomas.[20,106] 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.
A central effect of bile acids in the etiology and pathogenesis of CRC has been claimed. An increased bile acid concentration in the intestinal tract accompanies a high-fat diet because bile acids are released from the gallbladder after fat ingestion. The concentration of bile acids in the colon is heavily influenced by the amount and type of fat in the diet. The potential mechanism of action of bile salts in colorectal carcinogenesis is unknown, although it has been suggested that it is mediated by diacylglycerol. The conversion of dietary phospholipids to diacylglycerol by intestinal bacteria is enhanced by a high-fat diet. It is proposed that diacylglycerol enters the cell directly, stimulating protein kinase C, which is involved in intracellular signal transduction. There is no high-quality evidence from either observational studies or RCTs to substantiate this claim.
Dietary fiber, vegetables, and fruit
The evidence on whether dietary fiber exerts a protective role in reducing the incidence of CRC is mixed. Most animal and epidemiologic studies show a protective effect of dietary fiber on colon carcinogenesis. The term fiber is used to describe a complex mixture of compounds, including insoluble fiber (typified by wheat bran and cellulose) and soluble fiber (usually dried beans). Ingestion of fiber could modify carcinogenesis in the large bowel by a number of potential mechanisms.[112,113,114] These mechanisms include binding to bile acids, increasing fecal water and possibly diluting carcinogens, and decreasing transit time (not an obvious factor). Fiber may act as a substrate for bacterial fermentation with a resultant increase in bacterial mass and the production of short-chain fatty acids, typified by butyrate. Butyrate has been shown to have anticarcinogenic effects in vitro and is regarded as an important fuel for the colonic epithelium.[115,116] A meta-analysis of 13 case-control studies from nine countries concluded that intake of fiber-rich foods is inversely related to cancers of both the colon and rectum. The analysis did not include fiber supplements. The inverse association with fiber was observed in 12 of the 13 studies and was similar in magnitude for left-sided and right-sided colon and rectal cancers, in men and women, and in different age groups. It has been suggested that the inverse association with fiber may be reflective of some other closely associated dietary constituents, such as the anticarcinogens found in vegetables, fruits, legumes, nuts, and grains.[10,117] These substances include phenolic compounds, sulfur-containing compounds, and flavones.[118,119] In a prospective cohort study of a low-risk population, an inverse association was found with legume intake and the risk of CRC (RR for >2 times/week vs. 1 time/week = 0.53 [95% CI, 0.33-0.86; P for trend = .03]).
Other studies have corroborated the effects of dietary fiber. One study used a supplement of 10 g/day of wheat bran, cellulose, and oat bran and found a decreased mutagenic activity of fecal contents in those receiving wheat bran and cellulose supplementation, although no measurable inhibition was observed during oat bran supplementation. Fecal-total and secondary bile acid excretion increased during oat fiber supplementation.
Despite the evidence from case-control studies of a protective effect, results from the large prospective Nurses' Health Study (NHS) found no difference in the risk of CRC between women in the highest quintile group compared with the lowest quintile group with respect to dietary fiber, after adjusting for age, known risk factors, and total energy intake (RR = 0.95; 95% CI, 0.73-1.25).
Many epidemiologic studies have examined the relationship between fruit and vegetable intake and the incidence of colon and/or rectal cancer, with considerable variation in findings. Perhaps the most definitive analysis to date is a prospective study that examined dietary intake data based on food frequency questionnaires from 88,764 women in the NHS and 47,325 men in the Health Professionals Follow-up Study. The study included a total of 1,743,645 person-years of follow-up, 937 cases of colon cancer, and 244 cases of rectal cancer. On the basis of analyses adjusted for numerous covariates, the authors found no association in women or men between overall fruit and vegetable consumption and the risk of colon or rectal cancer. Associations were not observed when the data were examined for subgroups of fruits or vegetables (with the exception of legumes, which were associated with an increased risk of colon cancer in women) or individual fruits or vegetables (with the exception of prunes, which were associated with an increased risk of colon cancer in men). Results did not change when data were examined by vitamin use status, smoking status, or family history of CRC, nor were elevated risks seen when individuals with very low levels of fruit and vegetable consumption were compared with those having the highest levels. For women and men combined, the covariate-adjusted RR of colon cancer associated with one additional serving of fruits and vegetables per day was 1.02 (95% CI, 0.98-1.05); the comparable RR for rectal cancer was 1.02 (95% CI, 0.95-1.09).
In a population-based prospective cohort study of 61,463 women in Sweden, individuals who consumed very low amounts of fruits and vegetables (<1.5 servings of fruit and vegetables/day) had a RR for developing CRC of 1.65 (95% CI, 1.23-2.2; P trend = .001) as compared with those individuals who consumed more than 2.5 servings. There was little evidence, however, of a benefit for higher as compared with moderate consumption (more than vs. fewer than 3.5 servings). Limitations of this study are that dietary intake during the study period was not reassessed over time, and the influence of physical activity could not be accurately determined. In addition, the conclusion about very low amounts of intake of fruits and vegetables is based on a retrospective subdivision of the lowest quartile of consumption, and its strength has not been adjusted for other potential confounding factors.
Six case-control studies and three cohort studies have explored potential dietary risk factors for colorectal adenomas.[20,106,120] Four of the nine found an association of fiber, carbohydrates, and/or vegetables with reduced risk. In one study, cases with moderate or severe dysplasia had a significantly lower intake of cruciferous vegetables than those with mild dysplasia. No significant effect of dietary fiber on colorectal adenoma was found in the large cohort study of U.S. nurses.
High-fiber cereal supplements during a 3-year period did not result in a decrease in adenoma recurrence in a RCT of 1,303 individuals. In a multicenter RCT, a diet low in fat (20% of total calories) and high in fiber (18 g of dietary fiber/1,000 kcal) and fruits and vegetables (3.5 servings per 1,000 kcal) was not associated with a reduction in the risk of recurrence of colorectal adenomas.
In a prospective cohort study of 35,215 women in the IWHS, an inverse association between the risk of colon cancer and vitamin E intake was found; the RR for the highest compared with the lowest quartile was 0.3 (95% CI, 0.19-0.54). The WHS, however, showed no relationship between CRC in women and the use of 600 IU of vitamin E every other day. In a meta-analysis of 14 randomized trials of supplemental antioxidant vitamins encompassing 170,025 individuals, no evidence of prevention of colorectal adenomas or cancer or other gastrointestinal tumors was found. A systematic review of published observational studies that provide sufficient data to calculate the dose-response relationship of serum 25-hydroxyvitamin D or oral intake of vitamin D with the risk of CRC was conducted. The results suggested that a daily intake of 1,000 IU of vitamin D-half the safe upper limit for intake established by the National Academy of Sciences-and a concentration of serum 25-hydroxyvitamin D of 33 ng/mL were each associated with a 50% lower risk of CRC. In a population-based case-control study, an inverse relationship between vitamin D intake and risk of CRC was found.
A prospective cohort study observed that higher energy-adjusted folate intake in the form of multivitamins containing folic acid was related to a lower risk for colon cancer (RR = 0.69; 95% CI, 0.52-0.93) for intake of more than 400 µg/day compared with intake of 200 µg/day or less after controlling for age, family history of CRC, ASA use, smoking, body mass, physical activity, and intakes of red meat, alcohol, methionine, and fiber. In a double-blind, placebo-controlled, two-factor, phase III RCT (ASA/Folate Polyp Prevention Study) involving 1,021 men and women with a recent history of colorectal adenoma, folic acid (1 mg/day) was associated with higher risks of developing at least one advanced adenoma (11.6% for folic acid [n = 35]); 6.9% for placebo [n = 21]; unadjusted RR = 1.67; 95% CI, 1.00-2.80; P = .05). Folic acid ingestion was associated with higher risks of having three or more adenomas and of non-CRCs. There was no effect modification by sex, age, smoking, alcohol use, BMI, baseline plasma folate, or ASA use. There was no apparent effect on overall adenoma incidence (44.1% for folic acid [n = 221]); 42.4% for placebo [n = 206]; unadjusted use ratio 1.04; 95% CI, 0.9-1.20; P = .58).
It has been hypothesized that orally ingested calcium lowers colon cancer risk by binding bile acids and fatty acids, thereby reducing exposure to toxic intraluminal compounds. Indirect effects on bile acid metabolism and a direct effect on colonic epithelial cells are also possible.
Several [133,134,135,136] but not all [106,137] epidemiologic studies have observed an inverse relationship between calcium intake and cancer risk. Interpretation of these studies can be quite complex. In Utah, an inverse relationship between colon cancer and calcium was observed in a study that compared members of the Church of Jesus Christ of Latter-Day Saints (Mormons) and Seventh Day Adventists with a group from the U.S. population at large. Both study groups have higher calcium intakes, mainly milk and dairy products, than the national average. Unlike the Seventh Day Adventists, however, the Mormon group had a consumption of meats and fat similar to that of the general population.
Experimental studies in rodents  and some but not all human studies [139,140,141,142] have described a decrease in colonic epithelial cell proliferation after the administration of calcium citrate. Human studies using the labeling index are dependent on a complex methodology. 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, though other factors may also be responsible.
Use of statins
Overall, evidence indicates that statin use neither increases nor decreases the incidence or mortality of CRC. Although some case-control studies have shown a reduction in risk, neither a large cohort study  nor a meta-analysis of four RCTs  found any effect of statin use.
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