Chemoprevention
        Nonsteroidal anti-inflammatory drugs
        Postmenopausal female hormone supplements
        Use of statins
Dietary Factors
        Dietary fat and meat intake
        Bile acids
        Dietary fiber, vegetables, and fruit
        Calcium
        Vitamins
Other Factors
        Polyp removal
        Physical activity
        Alcohol consumption
        Cigarette smoking
        Fecal occult blood testing

Chemoprevention

Nonsteroidal anti-inflammatory drugs

The clinical utility of nonsteroidal anti-inflammatory drugs (NSAIDs) 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, first-generation nonselective inhibitors of the two functional isoforms of COX, termed COX-1 and COX-2, but 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.[1]

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.[2-5] Four trials that demonstrated this increased risk are summarized in Table 1.

Celecoxib reduces the incidence of adenomas; however, celecoxib does not have a role in reducing the risk of sporadic colorectal cancer (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.[6]

Several, but not all, epidemiological studies have reported a reduction in colon cancer incidence associated with the use of aspirin. Several cohort studies suggest a preventive effect of aspirin. Among a group of more than 600,000 adults enrolled in an American Cancer Society study, mortality in regular users of aspirin was about 40% lower for cancers of the colon and rectum.[7,8] In a study of more than 11,000 men and women in Sweden with rheumatoid arthritis (and presumably ingesting NSAIDs), colon cancer incidence was 37% lower and rectal cancer was 28% lower than predicted from cancer registry data.[9] In a report from the Health Professionals Follow-up Study of 47,000 males, regular use of aspirin (at least 2 times per week) was associated with a 30% overall reduction in CRC, including a 50% reduction in advanced cases.[10] In a Women's Health Study randomized 2 x 2 factorial trial of 100 mg of aspirin every other day for an average of 10 years, similar rates of breast, colorectal, or other site-specific cancers were observed in both the aspirin and placebo arms.[11] 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 aspirin (≥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 aspirin per week for longer than 10 years had a multivariate RR for cancer of 0.47 [95% CI, 0.31–0.71]). A similar dose-response relationship was observed for nonaspirin NSAIDs. The incidence of reported major gastrointestinal bleeding events also appeared to be dose-related.[12] A population-based retrospective cohort study of nonaspirin NSAID use among individuals aged 65 years and older was also associated with lower risk, particularly with increasing durations of use.[13] In the Physicians’ Health Study, 22,000 men aged 40 to 84 years were randomly assigned to receive placebo or aspirin (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.[14] In a subsequent analysis of more than 12 years, both randomized and observational analyses indicated that there was no association between the use of aspirin and the incidence of CRC. The low dose of aspirin and the short treatment period may account for the null findings.[15]

In a randomized study of 635 patients with prior CRC (T1–T2 N0 M0) who had undergone curative resection, aspirin 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 aspirin 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.[16] 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 aspirin group (95% CI, 0.69–0.96) and 0.96 in the 325-mg aspirin 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 aspirin group, and 0.83 (95% CI, 0.55–1.23) in the 325-mg aspirin group.[17] Harms of treatment were similar in the two groups and included upper gastrointestinal bleeding and hemorrhagic stroke.

Several studies conducted in a rigorous manner have demonstrated the effectiveness of sulindac in reducing the size and number of adenomas in familial polyposis.[18,19] 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.[20]

The NSAID piroxicam, at a dose of 20 mg/day, reduced mean rectal prostaglandin concentration by 50% in individuals with a history of adenomas.[21] Several studies assessing the effect of aspirin or other nonsteroidals on polyp recurrence following polypectomy are in progress.[22] 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.[23]

Table 2. Ongoing Phase II/III and Phase III Chemoprevention Trials in Colorectal Neoplasia

Several epidemiologic studies have suggested a decreased risk of colon cancer among users of postmenopausal female hormone supplements.[25-28] For rectal cancer, most studies have observed no association or a slightly elevated risk.[29-31]

In the Women’s Health Initiative Trial, 16,608 postmenopausal women aged 50 to 79 years were randomly assigned to a combination of conjugated equine estrogens (0.625 mg/day) plus medroxyprogesterone (2.5 mg/day) or placebo. There were 43 invasive CRCs in the hormone group and 72 in the placebo group (HR = 0.56; 95% CI, 0.38–0.81; P = .003). The invasive CRCs in the hormone group were similar in histologic features and grade to those in the placebo group but with a greater number of positive lymph nodes (mean ± standard deviation 3.24 ± 4.1 vs. 0.8 ± 1.7; P = .002) and were more advanced (regional or metastatic disease; 76.2% vs. 48.5%; P = .004).[32]

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 [33] nor a meta-analysis of four randomized controlled trials [34] found any effect of statin use.

The studies reviewed below include those on adenomas; special note is made if a study applies to adenomas only.

Colon cancer rates are high in populations with high total fat intakes and are lower in those consuming less fat.[35] 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.[36] In laboratory studies, a high-fat intake increases the incidence of induced colon tumors in experimental animals.[37,38] Several case-control studies have explored the association of colon cancer risk with meat or fat consumption as well as protein and energy intake.[39,40] Although positive associations with meat consumption or with fat intake have been found frequently, the results have not always achieved statistical significance.[41] 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.[42] In Norway, an increased risk for processed meat only was found,[43] a finding that was confirmed in the Netherlands.[44] A clearly defined gradient in 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.[45] 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.[46] No increase in risk with meat or fat consumption was seen, however, in two other large prospective studies, the American Cancer Society’s Cancer Prevention Study II and the Iowa Women’s Health Study.[47,48] 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).[49] 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).[50,51]

A randomized controlled dietary modification study was undertaken among 48,835 postmenopausal women aged 50 to 79 years who were also enrolled in the Women's Health Initiative. 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 the 8.1 years of follow-up. There was no evidence of reduction in invasive CRCs between intervention and comparison groups with a HR of 1.08 (95% CI, 0.90–1.29).[52] Likewise, there was no benefit of the low-fat diet on all-cancer mortality, overall mortality, or cardiovascular disease.[53]

Explanations for the conflicting results regarding whether dietary fat or meat intake affects risk of CRC [44] include: (a) validity of dietary questionnaires used; (b) differences in the average age of the population studied; (c) variations in methods of meat preparation (in some instances, mutagenic and carcinogenic HCAs could have been released at high temperatures [54]); and (d) variability in the consumption of other foods such as vegetables.[55] 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.[56] 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.[57,58] 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.[59] In a multicenter randomized controlled trial, 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.[60]

A central effect of bile acids in the etiology and pathogenesis of CRC has been claimed.[61] 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.[62] The potential mechanism of action of bile salts in colorectal carcinogenesis is unknown, although it has been suggested that it is mediated by diacylglycerol.[63] 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.

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.[22] 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.[64-66] 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.[66] Butyrate has been shown to have anticarcinogenic effects in vitro and is regarded as an important fuel for the colonic epithelium.[67,68] 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.[69] 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.[39,69] These substances include phenolic compounds, sulfur-containing compounds, and flavones.[70,71] 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).[49]

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.[72] 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 found no difference in risk of CRC between women in the highest compared with 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).[73]

Many epidemiologic studies have examined the relationship between fruit and vegetable intake and the incidence of colon and/or rectal cancer,[74] 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 Nurses' Health Study and 47,325 men in the Health Professionals Follow-up Study.[75] 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 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.[76]

Six case-control studies and three cohort studies have explored potential dietary risk factors for colorectal adenomas.[57,58,73] 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.[73]

High-fiber cereal supplements during a 3-year period did not result in a decrease in adenoma recurrence in a randomized controlled trial of 1,303 individuals.[77] In a multicenter randomized controlled trial, 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 risk of recurrence of colorectal adenomas.[60]

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.[78] Indirect effects on bile acid metabolism and a direct effect on colonic epithelial cells are also possible.

Several [79-82] but not all [58,83] epidemiologic studies have observed an inverse relationship between calcium intake and cancer risk. Interpretation of these studies can be quite complex. For example, 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 [84] and some but not all human studies [85-88] 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.[89] 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.[90] 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.[91] The results of other ongoing adenoma recurrence studies are awaited with interest (refer to Table 2). 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).[92] 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.[93]

In a prospective cohort study of 35,215 Iowa women, 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).[94] The Women's Health Study, however, showed no relationship between CRC in women and the use of 600 IU of vitamin E every other day.[95] 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.[96] 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 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 50% lower risk of CRC.[97] In a population-based case-control study, an inverse relationship between vitamin D intake and risk of CRC was found.[98]

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, aspirin use, smoking, body mass, physical activity, and intakes of red meat, alcohol, methionine, and fiber.[99] In a double-blind, placebo-controlled, two-factor, phase III randomized clinical trial (Aspirin/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, body mass index, baseline plasma folate, or aspirin 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).[100]

Ongoing studies of dietary and other interventions in the chemoprevention of colorectal neoplasia are listed in Table 2.

The National Polyp Study showed a reduction of more than 75% in the subsequent incidence of CRC after colonoscopic polypectomy compared with three nonconcurrent, external control groups.[101]

A sedentary lifestyle has been associated in some [102,103] but not all [104] studies with an increased risk of CRC. There are numerous observational studies that have examined the relationship between physical activity and colon cancer risk.[105] 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%. It is not known, however, whether or to what degree the observed association is due to confounding variables such as diet or a genetic predisposition to colon cancer. In a population-based case-control study of CRC among Chinese men and women in Western North America and China, colon and rectal cancer risk was elevated among men employed in sedentary occupations on both continents.[106] Further, the association between CRC risk and saturated fat was stronger among the sedentary than among the active population. Perhaps related to physical activity, body mass was found to be correlated with rectal cancer in men in an Australian study [104] and with CRC in men in Sweden.[107] One study showed that physical activity in men, 2 hours or more per week, was more strongly associated with reduced risk for advanced adenomas (adenomas ≥10.0 mm in diameter, a villous adenoma, or an adenoma with high-grade dysplasia) versus nonadvanced adenomas.[28]

Obesity is associated with a twofold increase in the risk of CRC in premenopausal women.[108]

There is evidence of an association of CRC with alcoholic beverage consumption. In a meta-analysis, this association was weak.[109] In another review, statistically significant elevations of risk were found in males, particularly in regard to beer consumption and rectal cancer. It is hypothesized that alcohol may act to stimulate mucosal cell proliferation, to activate intestinal procarcinogens and possibly provide a source of unabsorbed carcinogens that can reach the distal large bowel.[110] Subsequently published case-control studies suggest a modest-to-strong positive relationship between alcohol consumption and large bowel cancers.[111,112]

Five studies have reported a positive association between alcohol intake and colorectal adenomas.[113] A case-control study of diet, genetic factors, and the adenoma-carcinoma sequence was conducted in Burgundy.[114] 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.[114]

Most case-control studies of cigarette exposure and adenomas have found an elevated risk for smokers.[57] In addition, a significantly increased risk of adenoma recurrence following polypectomy has been associated with smoking in both men and women.[57] In the Nurses’ Health Study, the minimum induction period for cancer appears to be at least 35 years.[115] 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.[116] 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.[117] 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.[118] 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.[119] 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.[120] 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.[121]

The Minnesota randomized trial of fecal occult blood tests investigated reduction in incidence of CRC. Nearly 85% of patients with a positive test underwent diagnostic procedures that included colonoscopy or double-contrast barium enema plus flexible sigmoidoscopy. After 18 years of follow-up, the incidence of CRC was reduced by 20% in the annually screened arm and 17% in the biennially screened arm.[122]

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