Prevention of Colorectal Neoplasia.
Journal: 2019/November - Clinics in Colon and Rectal Surgery
ISSN: 1531-0043
Abstract:
Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality worldwide. There are well-established screening protocols involving fecal testing, radiographic, and endoscopic evaluations that have led to decreased incidence and mortality of CRC in the United States. In addition to screening for CRC, there is interest in preventing colorectal neoplasia by targeting the signaling pathways that have been identified in the pathway of dysplasia progressing to carcinoma. This review will detail the efficacy of multiple potential preventative strategies including lifestyle changes (physical activity, alcohol use, smoking cessation, and obesity); dietary factors (dietary patterns, calcium, vitamin D, fiber, folate, and antioxidants and micronutrients); and chemopreventive agents (nonsteroidal anti-inflammatory drugs, statins, metformin, bisphosphonates, and postmenopausal hormonal therapy).
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Clin Colon Rectal Surg 29(4): 353-362

Prevention of Colorectal Neoplasia

Lifestyle Modifications

There are several lifestyle modifications with extensive epidemiological evidence that support primary prevention of CRC. As most of these modifiable factors are difficult to effectively randomize, the bulk of the evidence for these factors comes from case–control and cohort studies. In the following sections, we review the effects of exercise, alcohol consumption, smoking cessation, and obesity on CRC prevention.

Exercise

There is a large amount of observational data that suggest that regular physical activity is associated with protection from CRC.12131415 Investigators have hypothesized that interactions between insulin-like growth factor-binding proteins (IGFBP), higher vitamin D levels, higher amounts of water intake, anti-inflammatory action, direct immune action, and/or decreased fecal transit time may account for the preventative effect of exercise.1416 There have been several systematic reviews and meta-analyses based on observational studies that have evaluated the effect of exercise on CRC. In one review of 21 observational studies that included 17,683 patients with colon cancer, a 26% reduction in the rate of colon cancer among patients who exercised was noted (relative risk [RR] = 0.73, 95% confidence interval [CI]: 0.66–0.81).17 Another meta-analysis included 52 studies with a very similar 24% reduction in the rate of colon cancer among patients who exercised (RR = 0.76, 95% CI = 0.72–0.81).16 The exact amount of exercise required to achieve this reduction is unclear, with some studies suggesting walking briskly for 1 to 2 hours per week is enough to result in this reduction while other studies suggest that more exercise is required.161819 With the well-studied benefits of exercise on the risk of CRC, other cancers, cardiovascular disease (CVD), and overall health, patients should be counseled to pursue an exercise regimen, even if this simply consists of a walking program.161720

Alcohol

There is a large amount of observational data that alcohol consumption is related to increased risks of CRC.2122 It is estimated that 3.6% of cancers and 3.5% of all cancer deaths worldwide are attributable to alcohol.23 The exact mechanism of alcohol consumption triggering carcinogenesis is unclear but seems most likely mediated by carcinogenic metabolites such as acetaldehyde, which may directly cause cell injury or gene mutations or indirectly cause decreased glutathione synthesis and free radical formation.2425

Similar to physical activity, there have been several systematic reviews and meta-analyses based on observational trials with a lack of prospective randomized control trials. In one meta-analysis that included 61 studies, a progressive dose–response relationship between alcohol and CRC was found with any drinkers (RR = 1.12, 95% CI = 1.06–1.19); medium drinkers (2–3 drinks/day) (RR = 1.21, 95% CI = 1.13–1.28); and heavy drinkers (≥3 drinks/day) (RR = 1.52, 95% CI = 1.27–1.81).21 There was no relationship observed between light drinkers (≤1 drink/day) and CRC risk (RR = 1.00, 95% CI = 0.95–1.05).21 Another meta-analysis that included five cohort studies in Japan with 2,231,010 person-years studied and 2,802 CRC cases demonstrated a similar progressive dose–response relationship of alcohol intake and CRC risk where 23 to 45.9, 46 to 68.9, 69 to 91.9, and ≥92 g/day were associated with an RR = 1.42 (95% CI = 1.21–1.66), RR = 1.95 (95% CI = 1.53–2.49), RR = 2.15 (95% CI = 1.74–2.64), and RR = 2.96 (95% CI = 2.27–3.86), respectively.26 This study also noted that the alcohol–CRC association was stronger among Japanese than in Western populations.26

When counseling a patient on the role of alcohol on the primary prevention of CRC, one can state that the current literature points to a direct dose–response relationship with long-term alcohol use and CRC that starts at two drinks per day and increases as the number of drinks per day increases.

Smoking Cessation

Smoking is associated with a host of cancers and health risks, and there is strong observational evidence that smoking is associated with adenomatous polyp formation and CRC incidence and mortality.272829 Tobacco and smoking produce a large number of carcinogens that have been shown to directly cause irreversible DNA damage to colorectal mucosa that can initiate the pathway to carcinoma.30

There have been several systematic reviews and meta-analyses based on observational studies investigating the relationship between smoking and CRC risk. One of these studies included 42 observational trials consisting of 15,354 cases and 100,011 controls to examine the effect of smoking on the formation of adenomatous polyps. This study found that in comparison with nonsmokers, current smokers (RR = 2.14, 95% CI = 1.86–2.46); former smokers (RR = 1.47, 95% CI = 1.29–1.67); and ever-smokers (RR = 1.82, 95% CI = 1.65–2.00), all had significantly increased risks of adenomas. Furthermore, there was a relationship wherein ever-smokers had a higher rate of high-risk adenomas.28 Another meta-analysis including 106 observational studies found that ever-smokers had a moderately increased risk of CRC compared with nonsmokers, (RR = 1.18, 95% CI = 1.11–1.25) with a statistically significant dose–response relationship only after 30 years of smoking.27 This same study also reported a higher risk of CRC mortality among ever-smokers compared with nonsmokers (RR = 1.25, 95% CI = 1.14–1.37).27

Thus, while the overall risk of smoking on the rate of CRC is moderate (∼18% higher risk for ever-smokers), patients should be counselled to quit smoking both for their colorectal neoplasia risk in addition to the risks of other cancers and overall health status.

Obesity

The relationship between obesity and CRC has also been assessed in observational studies.313233 The exact mechanism of obesity resulting in CRC is not fully understood but likely involves modulation of endogenous hormones such as insulin, insulin-like growth factors, sex steroids, and adipocyte-derived factors (e.g., leptin and adiponectin).313334

There have been several systematic reviews and meta-analyses based on observational studies to assess the interaction of obesity and CRC. One of these studies evaluated 30 prospective studies and found a 5-unit increase in BMI corresponded to a 30% increased risk of CRC in men (RR = 1.30, 95% CI = 1.25–1.35) and a 12% increased risk of CRC in women (RR = 1.12, 95% CI = 1.07–1.18).33 Another meta-analysis included 13 studies and found that the highest BMI category (not explicitly defined) compared with a reference category was associated with an increased risk of colon cancer (hazard ratio [HR] = 1.16, 95% CI = 1.08–1.24).31 Interestingly, in this analysis, there was no benefit with each 5 kg of weight loss (HR = 0.96, 95% CI = 0.89–1.05) but some mild harm for each 5 kg of weight gain (HR = 1.03, 95% CI = 1.02–1.05).31

The literature does point to an association of obesity and the incidence of CRC. It remains unclear if the association of obesity with colorectal neoplasia is an actual relationship or is confounded by other variables that contribute to CRC risk (e.g., diet, exercise, and alcohol consumption). The literature at this time also suggests that weight loss does not result in improvements in CRC risk.31 It is reasonable to recommend weight loss for overweight and obese patients for their overall health, but it is unclear if this modulates their risk of CRC at this time.

Exercise

There is a large amount of observational data that suggest that regular physical activity is associated with protection from CRC.12131415 Investigators have hypothesized that interactions between insulin-like growth factor-binding proteins (IGFBP), higher vitamin D levels, higher amounts of water intake, anti-inflammatory action, direct immune action, and/or decreased fecal transit time may account for the preventative effect of exercise.1416 There have been several systematic reviews and meta-analyses based on observational studies that have evaluated the effect of exercise on CRC. In one review of 21 observational studies that included 17,683 patients with colon cancer, a 26% reduction in the rate of colon cancer among patients who exercised was noted (relative risk [RR] = 0.73, 95% confidence interval [CI]: 0.66–0.81).17 Another meta-analysis included 52 studies with a very similar 24% reduction in the rate of colon cancer among patients who exercised (RR = 0.76, 95% CI = 0.72–0.81).16 The exact amount of exercise required to achieve this reduction is unclear, with some studies suggesting walking briskly for 1 to 2 hours per week is enough to result in this reduction while other studies suggest that more exercise is required.161819 With the well-studied benefits of exercise on the risk of CRC, other cancers, cardiovascular disease (CVD), and overall health, patients should be counseled to pursue an exercise regimen, even if this simply consists of a walking program.161720

Alcohol

There is a large amount of observational data that alcohol consumption is related to increased risks of CRC.2122 It is estimated that 3.6% of cancers and 3.5% of all cancer deaths worldwide are attributable to alcohol.23 The exact mechanism of alcohol consumption triggering carcinogenesis is unclear but seems most likely mediated by carcinogenic metabolites such as acetaldehyde, which may directly cause cell injury or gene mutations or indirectly cause decreased glutathione synthesis and free radical formation.2425

Similar to physical activity, there have been several systematic reviews and meta-analyses based on observational trials with a lack of prospective randomized control trials. In one meta-analysis that included 61 studies, a progressive dose–response relationship between alcohol and CRC was found with any drinkers (RR = 1.12, 95% CI = 1.06–1.19); medium drinkers (2–3 drinks/day) (RR = 1.21, 95% CI = 1.13–1.28); and heavy drinkers (≥3 drinks/day) (RR = 1.52, 95% CI = 1.27–1.81).21 There was no relationship observed between light drinkers (≤1 drink/day) and CRC risk (RR = 1.00, 95% CI = 0.95–1.05).21 Another meta-analysis that included five cohort studies in Japan with 2,231,010 person-years studied and 2,802 CRC cases demonstrated a similar progressive dose–response relationship of alcohol intake and CRC risk where 23 to 45.9, 46 to 68.9, 69 to 91.9, and ≥92 g/day were associated with an RR = 1.42 (95% CI = 1.21–1.66), RR = 1.95 (95% CI = 1.53–2.49), RR = 2.15 (95% CI = 1.74–2.64), and RR = 2.96 (95% CI = 2.27–3.86), respectively.26 This study also noted that the alcohol–CRC association was stronger among Japanese than in Western populations.26

When counseling a patient on the role of alcohol on the primary prevention of CRC, one can state that the current literature points to a direct dose–response relationship with long-term alcohol use and CRC that starts at two drinks per day and increases as the number of drinks per day increases.

Smoking Cessation

Smoking is associated with a host of cancers and health risks, and there is strong observational evidence that smoking is associated with adenomatous polyp formation and CRC incidence and mortality.272829 Tobacco and smoking produce a large number of carcinogens that have been shown to directly cause irreversible DNA damage to colorectal mucosa that can initiate the pathway to carcinoma.30

There have been several systematic reviews and meta-analyses based on observational studies investigating the relationship between smoking and CRC risk. One of these studies included 42 observational trials consisting of 15,354 cases and 100,011 controls to examine the effect of smoking on the formation of adenomatous polyps. This study found that in comparison with nonsmokers, current smokers (RR = 2.14, 95% CI = 1.86–2.46); former smokers (RR = 1.47, 95% CI = 1.29–1.67); and ever-smokers (RR = 1.82, 95% CI = 1.65–2.00), all had significantly increased risks of adenomas. Furthermore, there was a relationship wherein ever-smokers had a higher rate of high-risk adenomas.28 Another meta-analysis including 106 observational studies found that ever-smokers had a moderately increased risk of CRC compared with nonsmokers, (RR = 1.18, 95% CI = 1.11–1.25) with a statistically significant dose–response relationship only after 30 years of smoking.27 This same study also reported a higher risk of CRC mortality among ever-smokers compared with nonsmokers (RR = 1.25, 95% CI = 1.14–1.37).27

Thus, while the overall risk of smoking on the rate of CRC is moderate (∼18% higher risk for ever-smokers), patients should be counselled to quit smoking both for their colorectal neoplasia risk in addition to the risks of other cancers and overall health status.

Obesity

The relationship between obesity and CRC has also been assessed in observational studies.313233 The exact mechanism of obesity resulting in CRC is not fully understood but likely involves modulation of endogenous hormones such as insulin, insulin-like growth factors, sex steroids, and adipocyte-derived factors (e.g., leptin and adiponectin).313334

There have been several systematic reviews and meta-analyses based on observational studies to assess the interaction of obesity and CRC. One of these studies evaluated 30 prospective studies and found a 5-unit increase in BMI corresponded to a 30% increased risk of CRC in men (RR = 1.30, 95% CI = 1.25–1.35) and a 12% increased risk of CRC in women (RR = 1.12, 95% CI = 1.07–1.18).33 Another meta-analysis included 13 studies and found that the highest BMI category (not explicitly defined) compared with a reference category was associated with an increased risk of colon cancer (hazard ratio [HR] = 1.16, 95% CI = 1.08–1.24).31 Interestingly, in this analysis, there was no benefit with each 5 kg of weight loss (HR = 0.96, 95% CI = 0.89–1.05) but some mild harm for each 5 kg of weight gain (HR = 1.03, 95% CI = 1.02–1.05).31

The literature does point to an association of obesity and the incidence of CRC. It remains unclear if the association of obesity with colorectal neoplasia is an actual relationship or is confounded by other variables that contribute to CRC risk (e.g., diet, exercise, and alcohol consumption). The literature at this time also suggests that weight loss does not result in improvements in CRC risk.31 It is reasonable to recommend weight loss for overweight and obese patients for their overall health, but it is unclear if this modulates their risk of CRC at this time.

Dietary Modification and Nutritional Supplements

Epidemiological studies of various geographic dietary patterns' impact on the incidence of CRC have led to several studies to target chemopreventive agents for CRC. Attempts are now being made to better define individual compounds within diets that reduce the risk for CRC to try and identify targeted agents for further study.

Fruits and Vegetables

Increasing intake of fruit and vegetables has been studied in a variety of case–control and cross-sectional studies with some controversy about efficacy.3536373839 The mechanism of this prevention is thought to be multifactorial with effects from micronutrients, dietary fiber, and phytochemicals all interacting to modify colonic inflammation and CRC gene mutations.40

There have been a large number of case–control series and some prospective cohort studies to evaluate the effect of fruits and vegetables on CRC risk. In an analysis of 14 cohort studies that included 756,217 men and women followed up for a period of 6 to 20 years, there was no significant difference between the pooled RRs of CRC for the highest- versus lowest-quintile consumption of fruits (RR = 0.91, 95% CI = 0.82–1.01), vegetables (RR = 0.94, 95% CI = 0.86–1.02), and fruits and vegetables combined (RR = 0.90, 95% CI = 0.77–1.05).35 In the Nurses' Health Study and Health Professional Study including 743,645 total person-years, a difference in fruit and vegetable consumption of one additional serving per day was associated with no change in the rate of CRC (RR = 1.02, 95% CI = 0.98–1.05).37 Another study that included 19 prospective studies demonstrated an 8% risk reduction for fruit and vegetable use comparing the highest- to the lowest-quintile (RR = 0.92, 95% CI = 0.86–0.99) which was statistically significant.41 This relationship was not statistically significant for any of the other quintiles of fruit and vegetable intake, which essentially meant that after consuming 100 g of fruit or vegetable per day (the equivalent of a daily apple), there is no further expected reduction in CRC risk.4142

In contrast to simply increasing fruit and vegetable intake, vegetarian dietary patterns and pescovegetarian patterns did demonstrate significant reductions in CRC rates in a trial including 96,354 men and women with a mean follow-up of 7.3 years.43 In this trial, vegetarians had a 22% lower chance of having CRC as compared with nonvegetarians (RR = 0.78, 95% CI = 0.64–0.95), and pescovegetarians had a 43% lower chance of CRC (RR = 0.57, 95% CI = 0.40–0.82).43

Based on these analyses, increasing fruit and vegetable intake may help with other chronic diseases but do not appear to significantly reduce the risk of CRC. An entirely vegetarian or pescovegetarian dietary pattern does appear to mitigate CRC risk.

Red Meats

Diets high in red meat are associated with increased rates of CRC in several large prospective cohort analyses.444546474849 The mechanism felt to drive this interaction is multifactorial with components of direct mutagenic effect of heterocyclic amines after meat is cooked at high temperature and formation of carcinogenic N-nitroso compounds in the gastrointestinal tract.49

In a meta-analysis of 21 prospective studies, there was a 22% increased rate of CRC for the highest versus lowest intake of red and processed meats (RR = 1.22, 95% CI = 1.11–1.34), and a 14% increased rate of cancer for each 100 g/day increase in red and processed meats (RR = 1.14, 95% CI = 1.04–1.24).49 This study then performed a nonlinear dose–response meta-analysis which demonstrated significant increases in the rate of CRC which was first noticed in patient populations eating as low as 20 g of meat daily.49 This effect plateaued around 140 g/day.49 There is some data that this effect is modulated by genetic characteristics of individuals.50

When reviewing the current literature, the results of these trials point to a mildly increased risk of CRC with red meat consumption. This also corresponds with previously described evidence that vegetarian and pescovegetarian diets reduce the risk of CRC. It is important to note that red meats do have beneficial properties including repletion of vitamin B12 and iron, so counseling patients to limit their red meat intake needs to take this into account.

Dietary Fat

The role of dietary fat patterns and the risk of CRC were initially investigated in epidemiologic-based studies with promising results, but a subsequent randomized controlled trial demonstrated no reduction in risk.485152 Dietary fat was thought to potentially increase CRC risk via changes in cell membrane structure and subsequent changes in cell signaling and repair mechanisms.5354 A large randomized control trial which included 48,835 postmenopausal women demonstrated no benefits with lowering dietary fat consumption on CRC rates.51 Participants in this study were assigned no dietary modification or intensive behavioral dietary modification counseling designed to support reductions in dietary fat, increased consumption of vegetables and fruit, and increased grain servings which resulted in changes in the intervention arm's dietary patterns.51 However, this decreased dietary fat intake did not change the rate of CRC (RR = 1.08, 95% CI = 0.90–1.29).51 Therefore, counseling patients on a balanced diet while minimizing saturated and trans-unsaturated fats is appropriate for their overall health, but it does not appear to impact rates of CRC.

Calcium

The role calcium plays in chemoprevention of CRC has been extensively studied, including three randomized controlled trials and several meta-analyses.55565758 The mechanism that drives this potential interaction is multifactorial with calcium directly mediating decreased inflammation in response to bacterial flora, calcium-binding secondary bile acids or ionized fatty acids and thus diminishing these substances' carcinogenic properties, and calcium mediating direct reduction of cell proliferation and promotion of cell differentiation perhaps through favorable changes on gene expression in the APC/β-catenin pathway.57

There have been discordant results based on systemic reviews, randomized controlled trials, and prospective cohort studies on the role of calcium in colorectal neoplasia.57 A Cochrane review based on two randomized controlled trials with 1,346 subjects with a recent history of colorectal adenoma followed up for 3 to 4 years demonstrated a 26% decreased rate of development of recurrent adenoma among patients who had calcium supplementation of either 1,200 mg/day for 4 years or 2,000 mg/day for 3 years (OR = 0.74, 95% CI = 0.58–0.95).555859 Meanwhile, a prospective, randomized, double-blind, placebo-controlled trial involving 36,282 postmenopausal women where women received 1,000 mg of elemental calcium daily and 400 IU of vitamin D3 daily or placebo for 7 years found no significant difference in the rate of CRC formation between placebo and treatment arms (HR = 1.08, 95% CI = 0.86–1.34).56 A more recent meta-analysis based on prospective nonrandomized observational studies demonstrated a dose–response relationship wherein each 300 mg/day increase in calcium was associated with an 8% reduction risk of CRC (RR = 0.92, 95% CI = 0.89–0.95) from 15 studies with follow-up of 3.3 to 16 years.57

With the current available evidence, calcium supplementation is associated with approximately a 26% reduction in adenomatous polyp formation among patients who already have polyps.60 The optimal dose is unclear, but a dose around 1,200 to 2,000 mg is reasonable for polyp prevention. It is unclear if this will result in CRC prevention in a general patient population.

Vitamin D

Vitamin D has also been studied as a potential chemopreventive agent with a variety of prospective cohort studies and one well-designed randomized controlled trial.5661626364 Vitamin D is thought to act via calcitriol to regulate the cell cycle and cell division by improving differentiation while decreasing proliferation, invasiveness, angiogenesis, and metastatic potential.6165

A systematic review and meta-analysis was performed of nine prospective studies and compared various plasma levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D with the rate of CRC.61 This study found that the highest- versus lowest-quantile of circulating 25-(OH)D levels experienced a 34% decrease in the rate of CRC (OR = 0.66, 95% CI = 0.54–0.81).61 However, this study also made note that there are seasonal variations in the levels of vitamin D and that patients who exercise and take multivitamins also tended to have higher levels of vitamin D potentially confounding their results.61 Another prospective, randomized, double-blind, placebo-controlled trial involving 36,282 postmenopausal women where women received 1,000 mg of elemental calcium daily and 400 IU of vitamin D3 daily or placebo for 7 years found no significant difference in the rate of CRC development between placebo and treatment arms (HR = 1.08, 95% CI = 0.86–1.34).56 Experts who criticized this study felt that a higher level of vitamin D3 supplementation is required (1,000 IU daily felt to be needed) to see an effect on CRC rates and that longer follow-up was needed to see a change.64

Currently, there is not enough evidence to recommend for or against vitamin D supplementation to reduce the risk of CRC. Future randomized trials should include higher levels of vitamin D supplementation.

Fiber

Dietary fiber is another agent studied as a possible means to decrease CRC incidence. Burkitt noted in the early 1970s that CRC was rare in rural Africa compared with industrial countries, which he proposed was due to dietary fiber.7 Proposed mechanisms for a protective effect include increasing stool bulk, decreasing colonic transit time (thus decreasing contact time with carcinogens), binding bile acids and carcinogens, decreasing colonic pH, and increasing the production of short chain fatty acids.66

There have been many prospective studies and even several randomized or quasi-randomized controlled trials to investigate the use of fiber to decrease colorectal adenomas and carcinomas.58676869 A Cochrane review including five randomized or quasi-randomized studies of patients with a history of adenoma who were randomized to high fiber interventions versus control found no significant differences in the detection of at least one adenoma (RR = 1.04, 95% CI = 0.95–1.13) or more than one adenoma (RR = 0.94, 95% CI = 0.77–1.15) 2 to 4 years after intervention.67 Another prospective study that utilized the Nurse's Health Study and the Health Professionals Follow-up Study that included 1.8 million person-years found no protective effect of fiber on the rate of CRC when adjusting for confounding variables (RR = 0.99, 95% CI = 0.95–1.04).70 Thus, based on current prospective evidence, fiber does not appear to have an impact on colorectal adenoma or carcinoma formation.

Folate

Folate and folic acid received a great deal of attention when several epidemiologic studies found a relationship between their use and decreased CRC rates.71 The mechanism of action of folate supplementation reducing risk of CRC stems from deficiencies in folate resulting in differences in DNA methylation and inappropriate activation of proto-oncogenes and therefore resulting in potential malignant transformation.72

Similar to fiber, initial promising epidemiologic and retrospective studies of the efficacy of folate have not been substantiated by prospective trials. In a well-performed meta-analysis of six randomized trials comparing folic acid versus placebo, there was no difference in the rate of colorectal adenoma among patients who had a personal history of adenoma (RR = 0.93, 95% CI = 0.61–1.41).73 There was also no difference noted in the rate of CRC in a general population in patients who took folic acid versus placebo (RR = 1.13, 95% CI = 0.77–1.64).73 In another well-designed randomized controlled trial, folic acid was associated with higher risks of having three or more adenomas and of non-CRCs.74 This study raised the possibility that folic acid supplementation might paradoxically increase cancer occurrence in select patients.74

In summary, there is good evidence that folic acid and/or folate does not decrease the rate of colorectal adenoma or carcinoma and may paradoxically increase the risk of colorectal adenomas in select patients.

Antioxidants and Micronutrients

Based on epidemiologic data on the role fruits and vegetables play in the development of CRC, there has been a large body of research on individual components in fruits and vegetables that might drive CRC prevention. There are a large number of studied compounds including phytochemicals, various vitamins (A, B6, B12, C, D, E), flavonoids, resveratrol, selenium, garlic, magnesium, ginger, curcumin, and others. A complete discussion of all of these compounds is beyond the scope of this review. In general, while case–control and cohort series have at times been promising for beneficial effects for the bulk of these substances, further investigation with prospective randomized trials has demonstrated a lack of evidence that they prevent colorectal adenoma or carcinomas.42757677 There are ongoing investigations into many of these compounds including in vitro and in vivo modeling that may provide more targeted chemotherapeutics in the future.

Fruits and Vegetables

Increasing intake of fruit and vegetables has been studied in a variety of case–control and cross-sectional studies with some controversy about efficacy.3536373839 The mechanism of this prevention is thought to be multifactorial with effects from micronutrients, dietary fiber, and phytochemicals all interacting to modify colonic inflammation and CRC gene mutations.40

There have been a large number of case–control series and some prospective cohort studies to evaluate the effect of fruits and vegetables on CRC risk. In an analysis of 14 cohort studies that included 756,217 men and women followed up for a period of 6 to 20 years, there was no significant difference between the pooled RRs of CRC for the highest- versus lowest-quintile consumption of fruits (RR = 0.91, 95% CI = 0.82–1.01), vegetables (RR = 0.94, 95% CI = 0.86–1.02), and fruits and vegetables combined (RR = 0.90, 95% CI = 0.77–1.05).35 In the Nurses' Health Study and Health Professional Study including 743,645 total person-years, a difference in fruit and vegetable consumption of one additional serving per day was associated with no change in the rate of CRC (RR = 1.02, 95% CI = 0.98–1.05).37 Another study that included 19 prospective studies demonstrated an 8% risk reduction for fruit and vegetable use comparing the highest- to the lowest-quintile (RR = 0.92, 95% CI = 0.86–0.99) which was statistically significant.41 This relationship was not statistically significant for any of the other quintiles of fruit and vegetable intake, which essentially meant that after consuming 100 g of fruit or vegetable per day (the equivalent of a daily apple), there is no further expected reduction in CRC risk.4142

In contrast to simply increasing fruit and vegetable intake, vegetarian dietary patterns and pescovegetarian patterns did demonstrate significant reductions in CRC rates in a trial including 96,354 men and women with a mean follow-up of 7.3 years.43 In this trial, vegetarians had a 22% lower chance of having CRC as compared with nonvegetarians (RR = 0.78, 95% CI = 0.64–0.95), and pescovegetarians had a 43% lower chance of CRC (RR = 0.57, 95% CI = 0.40–0.82).43

Based on these analyses, increasing fruit and vegetable intake may help with other chronic diseases but do not appear to significantly reduce the risk of CRC. An entirely vegetarian or pescovegetarian dietary pattern does appear to mitigate CRC risk.

Red Meats

Diets high in red meat are associated with increased rates of CRC in several large prospective cohort analyses.444546474849 The mechanism felt to drive this interaction is multifactorial with components of direct mutagenic effect of heterocyclic amines after meat is cooked at high temperature and formation of carcinogenic N-nitroso compounds in the gastrointestinal tract.49

In a meta-analysis of 21 prospective studies, there was a 22% increased rate of CRC for the highest versus lowest intake of red and processed meats (RR = 1.22, 95% CI = 1.11–1.34), and a 14% increased rate of cancer for each 100 g/day increase in red and processed meats (RR = 1.14, 95% CI = 1.04–1.24).49 This study then performed a nonlinear dose–response meta-analysis which demonstrated significant increases in the rate of CRC which was first noticed in patient populations eating as low as 20 g of meat daily.49 This effect plateaued around 140 g/day.49 There is some data that this effect is modulated by genetic characteristics of individuals.50

When reviewing the current literature, the results of these trials point to a mildly increased risk of CRC with red meat consumption. This also corresponds with previously described evidence that vegetarian and pescovegetarian diets reduce the risk of CRC. It is important to note that red meats do have beneficial properties including repletion of vitamin B12 and iron, so counseling patients to limit their red meat intake needs to take this into account.

Dietary Fat

The role of dietary fat patterns and the risk of CRC were initially investigated in epidemiologic-based studies with promising results, but a subsequent randomized controlled trial demonstrated no reduction in risk.485152 Dietary fat was thought to potentially increase CRC risk via changes in cell membrane structure and subsequent changes in cell signaling and repair mechanisms.5354 A large randomized control trial which included 48,835 postmenopausal women demonstrated no benefits with lowering dietary fat consumption on CRC rates.51 Participants in this study were assigned no dietary modification or intensive behavioral dietary modification counseling designed to support reductions in dietary fat, increased consumption of vegetables and fruit, and increased grain servings which resulted in changes in the intervention arm's dietary patterns.51 However, this decreased dietary fat intake did not change the rate of CRC (RR = 1.08, 95% CI = 0.90–1.29).51 Therefore, counseling patients on a balanced diet while minimizing saturated and trans-unsaturated fats is appropriate for their overall health, but it does not appear to impact rates of CRC.

Calcium

The role calcium plays in chemoprevention of CRC has been extensively studied, including three randomized controlled trials and several meta-analyses.55565758 The mechanism that drives this potential interaction is multifactorial with calcium directly mediating decreased inflammation in response to bacterial flora, calcium-binding secondary bile acids or ionized fatty acids and thus diminishing these substances' carcinogenic properties, and calcium mediating direct reduction of cell proliferation and promotion of cell differentiation perhaps through favorable changes on gene expression in the APC/β-catenin pathway.57

There have been discordant results based on systemic reviews, randomized controlled trials, and prospective cohort studies on the role of calcium in colorectal neoplasia.57 A Cochrane review based on two randomized controlled trials with 1,346 subjects with a recent history of colorectal adenoma followed up for 3 to 4 years demonstrated a 26% decreased rate of development of recurrent adenoma among patients who had calcium supplementation of either 1,200 mg/day for 4 years or 2,000 mg/day for 3 years (OR = 0.74, 95% CI = 0.58–0.95).555859 Meanwhile, a prospective, randomized, double-blind, placebo-controlled trial involving 36,282 postmenopausal women where women received 1,000 mg of elemental calcium daily and 400 IU of vitamin D3 daily or placebo for 7 years found no significant difference in the rate of CRC formation between placebo and treatment arms (HR = 1.08, 95% CI = 0.86–1.34).56 A more recent meta-analysis based on prospective nonrandomized observational studies demonstrated a dose–response relationship wherein each 300 mg/day increase in calcium was associated with an 8% reduction risk of CRC (RR = 0.92, 95% CI = 0.89–0.95) from 15 studies with follow-up of 3.3 to 16 years.57

With the current available evidence, calcium supplementation is associated with approximately a 26% reduction in adenomatous polyp formation among patients who already have polyps.60 The optimal dose is unclear, but a dose around 1,200 to 2,000 mg is reasonable for polyp prevention. It is unclear if this will result in CRC prevention in a general patient population.

Vitamin D

Vitamin D has also been studied as a potential chemopreventive agent with a variety of prospective cohort studies and one well-designed randomized controlled trial.5661626364 Vitamin D is thought to act via calcitriol to regulate the cell cycle and cell division by improving differentiation while decreasing proliferation, invasiveness, angiogenesis, and metastatic potential.6165

A systematic review and meta-analysis was performed of nine prospective studies and compared various plasma levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D with the rate of CRC.61 This study found that the highest- versus lowest-quantile of circulating 25-(OH)D levels experienced a 34% decrease in the rate of CRC (OR = 0.66, 95% CI = 0.54–0.81).61 However, this study also made note that there are seasonal variations in the levels of vitamin D and that patients who exercise and take multivitamins also tended to have higher levels of vitamin D potentially confounding their results.61 Another prospective, randomized, double-blind, placebo-controlled trial involving 36,282 postmenopausal women where women received 1,000 mg of elemental calcium daily and 400 IU of vitamin D3 daily or placebo for 7 years found no significant difference in the rate of CRC development between placebo and treatment arms (HR = 1.08, 95% CI = 0.86–1.34).56 Experts who criticized this study felt that a higher level of vitamin D3 supplementation is required (1,000 IU daily felt to be needed) to see an effect on CRC rates and that longer follow-up was needed to see a change.64

Currently, there is not enough evidence to recommend for or against vitamin D supplementation to reduce the risk of CRC. Future randomized trials should include higher levels of vitamin D supplementation.

Fiber

Dietary fiber is another agent studied as a possible means to decrease CRC incidence. Burkitt noted in the early 1970s that CRC was rare in rural Africa compared with industrial countries, which he proposed was due to dietary fiber.7 Proposed mechanisms for a protective effect include increasing stool bulk, decreasing colonic transit time (thus decreasing contact time with carcinogens), binding bile acids and carcinogens, decreasing colonic pH, and increasing the production of short chain fatty acids.66

There have been many prospective studies and even several randomized or quasi-randomized controlled trials to investigate the use of fiber to decrease colorectal adenomas and carcinomas.58676869 A Cochrane review including five randomized or quasi-randomized studies of patients with a history of adenoma who were randomized to high fiber interventions versus control found no significant differences in the detection of at least one adenoma (RR = 1.04, 95% CI = 0.95–1.13) or more than one adenoma (RR = 0.94, 95% CI = 0.77–1.15) 2 to 4 years after intervention.67 Another prospective study that utilized the Nurse's Health Study and the Health Professionals Follow-up Study that included 1.8 million person-years found no protective effect of fiber on the rate of CRC when adjusting for confounding variables (RR = 0.99, 95% CI = 0.95–1.04).70 Thus, based on current prospective evidence, fiber does not appear to have an impact on colorectal adenoma or carcinoma formation.

Folate

Folate and folic acid received a great deal of attention when several epidemiologic studies found a relationship between their use and decreased CRC rates.71 The mechanism of action of folate supplementation reducing risk of CRC stems from deficiencies in folate resulting in differences in DNA methylation and inappropriate activation of proto-oncogenes and therefore resulting in potential malignant transformation.72

Similar to fiber, initial promising epidemiologic and retrospective studies of the efficacy of folate have not been substantiated by prospective trials. In a well-performed meta-analysis of six randomized trials comparing folic acid versus placebo, there was no difference in the rate of colorectal adenoma among patients who had a personal history of adenoma (RR = 0.93, 95% CI = 0.61–1.41).73 There was also no difference noted in the rate of CRC in a general population in patients who took folic acid versus placebo (RR = 1.13, 95% CI = 0.77–1.64).73 In another well-designed randomized controlled trial, folic acid was associated with higher risks of having three or more adenomas and of non-CRCs.74 This study raised the possibility that folic acid supplementation might paradoxically increase cancer occurrence in select patients.74

In summary, there is good evidence that folic acid and/or folate does not decrease the rate of colorectal adenoma or carcinoma and may paradoxically increase the risk of colorectal adenomas in select patients.

Antioxidants and Micronutrients

Based on epidemiologic data on the role fruits and vegetables play in the development of CRC, there has been a large body of research on individual components in fruits and vegetables that might drive CRC prevention. There are a large number of studied compounds including phytochemicals, various vitamins (A, B6, B12, C, D, E), flavonoids, resveratrol, selenium, garlic, magnesium, ginger, curcumin, and others. A complete discussion of all of these compounds is beyond the scope of this review. In general, while case–control and cohort series have at times been promising for beneficial effects for the bulk of these substances, further investigation with prospective randomized trials has demonstrated a lack of evidence that they prevent colorectal adenoma or carcinomas.42757677 There are ongoing investigations into many of these compounds including in vitro and in vivo modeling that may provide more targeted chemotherapeutics in the future.

Chemoprevention

Nonsteroidal Anti-inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most studied chemopreventive agents for CRC. There are several proposed mechanisms through which NSAIDs cause decreased rates of CRC. Most of these mechanisms are driven by two interactions: NSAIDs induce apoptosis, and cyclooxygenase and inflammation (both of which NSAIDs inhibit) are involved in colonic tumorigenesis.7879

Aspirin

A recently released draft from the United States Preventive Task Force (USPTF) on aspirin gives a grade B recommendation for low-dose aspirin use in adults aged 50 to 59 years for primary prevention of CVD and CRC who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin for 10 years.80 For patients aged 60 to 69 years, there is a grade C recommendation to individualize the decision as to whether or not to use aspirin.80 For patients younger than 50 years and older than 70 years, the USPTF felt there was not enough information to make a recommendation.80 Aspirin thus represents the first chemopreventive agent for CRC that is preliminarily being recommended for a general population.

The efficacy of aspirin in preventing colorectal adenoma and carcinoma progression has been investigated in several randomized controlled trials and systemic reviews and meta-analyses.78818283848586878889 A meta-analysis that included five randomized controlled trials showed that regular use of aspirin reduced the incidence of colonic adenomas by 18% (RR = 0.82, 95% CI = 0.7–0.95).90 Another meta-analysis that included two large randomized trials with follow-up for more than 20 years demonstrated that the use of aspirin at a dose over 300 mg/day was associated with a 26% reduction in the incidence of CRC after a latency of 10 years (HR = 0.74, 95% CI = 0.56–0.97).84 This study also noted that the use of less than 300 mg/day of aspirin did not cause a reduction in the rate of CRC.84 Another meta-analysis that included four prospective, randomized, placebo-controlled trials with doses of aspirin that ranged from 81 to 325 mg/day noted a 17% reduced risk of adenoma (RR = 0.83, 95% CI = 0.72–0.96) and a 28% reduced risk for any advanced lesion (RR = 0.72, 95% CI = 0.57–0.90).86 This review did not find a difference between higher (>160 mg/day) and lower (<160 mg/day) dose aspirin regimens and the rate of CRC.86

Thus, based on high-quality evidence, aspirin does reduce the risk of colorectal adenoma and carcinoma. However, the lowest possible aspirin dose to result in reduced colorectal neoplasia risk is unclear.

The benefit of aspirin in reducing the rate of colorectal neoplasia has to be balanced with its risks (e.g., intestinal bleeding and hemorrhagic strokes).80 In a systematic review and meta-analysis of low-dose aspirin (50–325 mg/day), the pooled risk of major intestinal bleeding (required transfusion or hospitalization) increased significantly by 59% (odds ratio [OR] = 1.59, 95% CI = 1.32–1.91) and hemorrhagic strokes increased by 33% (OR = 1.33 95% CI = 1.03–1.71).91 Thus, while there are clear benefits, there are also clear harms.

The association of aspirin and the human genome has also been evaluated to see if aspirin use can be targeted to specific populations who are likely to benefit from it the most. A large prospective study found that NSAID use was associated with lower risk of CRC, but this risk varied according to genetic variation at two single nucleotide polymorphisms at chromosomes 12 and 15.92 With these results and ongoing research, the future will likely be targeting aspirin use to populations who are more likely to achieve benefit (both in terms of CVD and CRC) and less likely to experience side effects.

For now, the USPTF draft recommendations seem reasonable in recommending low-dose aspirin use in adults aged 50 to 59 years for primary prevention of CVD and CRC who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin for 10 years, and individualizing recommendations in other populations.80

Cyclooxygenase-2 Inhibitors

Cyclooxagenase-2 inhibitors (COX-2 inhibitors), including rofecoxib and celecoxib, have been intensely studied for CRC prevention given their decreased risk of intestinal bleeding compared with aspirin with potential similar efficacy in colorectal neoplasia prevention. In one randomized controlled trial, 1,435 patients with a history of adenoma were assigned to placebo, 200 mg, or 400 mg of celecoxib twice daily.93 At 3-year follow-up, there was a 33% reduction in adenomas in the lower dose celecoxib group (RR = 0.67, 95% CI = 0.59–0.77) and a 45% reduction in adenomas in the higher dose celecoxib group (RR = 0.55, 95% CI = 0.48–0.64).93 Unfortunately, celecoxib at both dose ranges was associated with a significantly higher risk of cardiovascular events which caused the investigators to conclude that celecoxib could not be routinely recommended for prevention of colorectal adenomas.93 Similarly, a randomized controlled trial with rofecoxib demonstrated decreased colorectal adenoma rates but increased rates of cardiovascular events.94

Subsequent analyses have shown that celecoxib is likely safe in patients with low-risk of CVD (either based on clinical parameters or on low high-sensitivity C-reactive protein levels).9596 However, in light of moderate benefit in colorectal adenoma prevention and serious risk of cardiovascular morbidity, no society has endorsed COX-2 inhibitors for prevention of colorectal neoplasia.

Sulindac

Sulindac, another NSAID, has also been studied in a controlled trial that randomized 375 individuals with a history of adenoma to sulindac and ornithine decarboxylase inhibitor difluoromethylornithine (DFMO) or placebo.97 This study demonstrated a 70% reduction in the rate of adenomas (RR = 0.30, 95% CI = 0.18–0.49) and a nonsignificant increase in adverse events.9798 However, use of this combination has not been widely adopted due to concern of hearing loss and cardiovascular toxicity.42 Further studies on DFMO in combination with other chemopreventive strategies are warranted.99

Statins

Several observational studies demonstrated that statins lowered the risk of CRC.100101102 The mechanism influencing tumorigenesis is not well understood but is thought to result from anti-inflammatory processes, inhibition of cholesterol synthesis (which may help cell signaling for apoptosis), and other possible apoptotic mechanisms.103

Several randomized controlled trials that investigate the efficacy of statins have included the incidence of CRC as secondary endpoints in their analysis. A recent systematic review and meta-analysis of 40 studies including 8 randomized controlled trials, 13 cohort studies, and 19 case–control studies involving more than 8 million subjects demonstrated a nonsignificant reduction in the risk of CRC with statin use within the randomized controlled trials (RR = 0.89, 95% CI = 0.74–1.07) but a marginal, yet statistically significant, effect in the cohort studies (RR = 0.91, 95% CI = 0.83–1.00) and case–control studies (RR = 0.92, 95% CI = 0.87–0.98). Statins do have a significant side-effect profile, including myopathy, hepatotoxicity, and strokes.

With the current level of evidence, statins by themselves may contribute a very modest risk reduction for CRC. In light of significant side effects and cost, statins are not recommended for use solely for CRC prevention.

Metformin

Similar to statins, the role of metformin in CRC has been investigated as a secondary endpoint in several studies.104105106107108109 The mechanisms of this action are still poorly defined but are theorized to act via modulations in glucose, insulin, insulin-like growth factor 1, IGFBP, and leptin eventually resulting in decreased cell growth and proliferation.104

There have been several systematic reviews of the role of metformin on the risk of CRC. In one review with 12 randomized controlled trials and 41 observational studies, metformin had no effect on the rate of CRC in the randomized controlled trials (RR = 1.02, 95% CI = 0.41–2.5) but a slight reduction in observational studies (RR = 0.83, 95% CI = 0.74–0.92).109 In light of the lack of effect in randomized trials and potential toxicity, metformin is not recommended solely for colorectal neoplasia prevention.

Bisphosphonates

The efficacy of bisphosphonate use and cancers has been investigated in several observational studies.110111112 Bisphosphonates are proposed to work through inhibition of protein prenylation that eventually results in promotion of apoptosis and inhibition of angiogenesis and tumor cell adhesion.113 The impact of bisphosphonates on CRC was evaluated in a systematic review and meta-analysis of three case–control and one cohort study which demonstrated a 13% reduction in the rate of CRC (OR = 0.87, 95% CI = 0.78–0.97).110 However, this study has been widely criticized, as it excluded a large, prospective null study using the Nurses' Health Study which showed that there was a nonsignificant 3% adjusted reduction in CRC after 5 years of use (RR = 0.97, 95% CI = 0.60–1.56).112 With a lack of prospective randomized data and inconclusive observational data, the role of bisphosphonate therapy in colorectal neoplasia prevention is unclear.

Postmenopausal Hormone Replacement Therapy

Postmenopausal hormone replacement therapy (HRT) was found to reduce the risk of CRC in several epidemiological studies.114115116 There are several proposed mechanisms including a reduction in methylation of a DNA mismatch repair gene and a potential induction of apoptosis via estrogen receptors.117 In a large randomized control trial with 16,608 postmenopausal women between 50 and 79 years of age that compared estrogen plus medroxyprogesterone versus placebo, a 44% reduction in the overall number of CRCs was found in the treatment arm (RR = 0.56, 95% CI = 0.38–0.81).116 However, patients in the HRT group who developed CRC had a higher rate of positive lymph nodes, a higher stage, and a nonsignificant higher number of CRC deaths.118 Thus, any potential gains with lower rates of CRC diagnoses were mitigated by the more advanced stage at diagnosis among patients taking HRT. The reason for this association is not entirely clear. HRT is also associated with an increased risk of breast cancer, venous thromboembolism, coronary artery disease, stroke, and cholecystitis.115 Owing to these findings, postmenopausal HRT is not recommended for the prevention of CRC.

Nonsteroidal Anti-inflammatory Drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most studied chemopreventive agents for CRC. There are several proposed mechanisms through which NSAIDs cause decreased rates of CRC. Most of these mechanisms are driven by two interactions: NSAIDs induce apoptosis, and cyclooxygenase and inflammation (both of which NSAIDs inhibit) are involved in colonic tumorigenesis.7879

Aspirin

A recently released draft from the United States Preventive Task Force (USPTF) on aspirin gives a grade B recommendation for low-dose aspirin use in adults aged 50 to 59 years for primary prevention of CVD and CRC who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin for 10 years.80 For patients aged 60 to 69 years, there is a grade C recommendation to individualize the decision as to whether or not to use aspirin.80 For patients younger than 50 years and older than 70 years, the USPTF felt there was not enough information to make a recommendation.80 Aspirin thus represents the first chemopreventive agent for CRC that is preliminarily being recommended for a general population.

The efficacy of aspirin in preventing colorectal adenoma and carcinoma progression has been investigated in several randomized controlled trials and systemic reviews and meta-analyses.78818283848586878889 A meta-analysis that included five randomized controlled trials showed that regular use of aspirin reduced the incidence of colonic adenomas by 18% (RR = 0.82, 95% CI = 0.7–0.95).90 Another meta-analysis that included two large randomized trials with follow-up for more than 20 years demonstrated that the use of aspirin at a dose over 300 mg/day was associated with a 26% reduction in the incidence of CRC after a latency of 10 years (HR = 0.74, 95% CI = 0.56–0.97).84 This study also noted that the use of less than 300 mg/day of aspirin did not cause a reduction in the rate of CRC.84 Another meta-analysis that included four prospective, randomized, placebo-controlled trials with doses of aspirin that ranged from 81 to 325 mg/day noted a 17% reduced risk of adenoma (RR = 0.83, 95% CI = 0.72–0.96) and a 28% reduced risk for any advanced lesion (RR = 0.72, 95% CI = 0.57–0.90).86 This review did not find a difference between higher (>160 mg/day) and lower (<160 mg/day) dose aspirin regimens and the rate of CRC.86

Thus, based on high-quality evidence, aspirin does reduce the risk of colorectal adenoma and carcinoma. However, the lowest possible aspirin dose to result in reduced colorectal neoplasia risk is unclear.

The benefit of aspirin in reducing the rate of colorectal neoplasia has to be balanced with its risks (e.g., intestinal bleeding and hemorrhagic strokes).80 In a systematic review and meta-analysis of low-dose aspirin (50–325 mg/day), the pooled risk of major intestinal bleeding (required transfusion or hospitalization) increased significantly by 59% (odds ratio [OR] = 1.59, 95% CI = 1.32–1.91) and hemorrhagic strokes increased by 33% (OR = 1.33 95% CI = 1.03–1.71).91 Thus, while there are clear benefits, there are also clear harms.

The association of aspirin and the human genome has also been evaluated to see if aspirin use can be targeted to specific populations who are likely to benefit from it the most. A large prospective study found that NSAID use was associated with lower risk of CRC, but this risk varied according to genetic variation at two single nucleotide polymorphisms at chromosomes 12 and 15.92 With these results and ongoing research, the future will likely be targeting aspirin use to populations who are more likely to achieve benefit (both in terms of CVD and CRC) and less likely to experience side effects.

For now, the USPTF draft recommendations seem reasonable in recommending low-dose aspirin use in adults aged 50 to 59 years for primary prevention of CVD and CRC who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin for 10 years, and individualizing recommendations in other populations.80

Cyclooxygenase-2 Inhibitors

Cyclooxagenase-2 inhibitors (COX-2 inhibitors), including rofecoxib and celecoxib, have been intensely studied for CRC prevention given their decreased risk of intestinal bleeding compared with aspirin with potential similar efficacy in colorectal neoplasia prevention. In one randomized controlled trial, 1,435 patients with a history of adenoma were assigned to placebo, 200 mg, or 400 mg of celecoxib twice daily.93 At 3-year follow-up, there was a 33% reduction in adenomas in the lower dose celecoxib group (RR = 0.67, 95% CI = 0.59–0.77) and a 45% reduction in adenomas in the higher dose celecoxib group (RR = 0.55, 95% CI = 0.48–0.64).93 Unfortunately, celecoxib at both dose ranges was associated with a significantly higher risk of cardiovascular events which caused the investigators to conclude that celecoxib could not be routinely recommended for prevention of colorectal adenomas.93 Similarly, a randomized controlled trial with rofecoxib demonstrated decreased colorectal adenoma rates but increased rates of cardiovascular events.94

Subsequent analyses have shown that celecoxib is likely safe in patients with low-risk of CVD (either based on clinical parameters or on low high-sensitivity C-reactive protein levels).9596 However, in light of moderate benefit in colorectal adenoma prevention and serious risk of cardiovascular morbidity, no society has endorsed COX-2 inhibitors for prevention of colorectal neoplasia.

Sulindac

Sulindac, another NSAID, has also been studied in a controlled trial that randomized 375 individuals with a history of adenoma to sulindac and ornithine decarboxylase inhibitor difluoromethylornithine (DFMO) or placebo.97 This study demonstrated a 70% reduction in the rate of adenomas (RR = 0.30, 95% CI = 0.18–0.49) and a nonsignificant increase in adverse events.9798 However, use of this combination has not been widely adopted due to concern of hearing loss and cardiovascular toxicity.42 Further studies on DFMO in combination with other chemopreventive strategies are warranted.99

Statins

Several observational studies demonstrated that statins lowered the risk of CRC.100101102 The mechanism influencing tumorigenesis is not well understood but is thought to result from anti-inflammatory processes, inhibition of cholesterol synthesis (which may help cell signaling for apoptosis), and other possible apoptotic mechanisms.103

Several randomized controlled trials that investigate the efficacy of statins have included the incidence of CRC as secondary endpoints in their analysis. A recent systematic review and meta-analysis of 40 studies including 8 randomized controlled trials, 13 cohort studies, and 19 case–control studies involving more than 8 million subjects demonstrated a nonsignificant reduction in the risk of CRC with statin use within the randomized controlled trials (RR = 0.89, 95% CI = 0.74–1.07) but a marginal, yet statistically significant, effect in the cohort studies (RR = 0.91, 95% CI = 0.83–1.00) and case–control studies (RR = 0.92, 95% CI = 0.87–0.98). Statins do have a significant side-effect profile, including myopathy, hepatotoxicity, and strokes.

With the current level of evidence, statins by themselves may contribute a very modest risk reduction for CRC. In light of significant side effects and cost, statins are not recommended for use solely for CRC prevention.

Metformin

Similar to statins, the role of metformin in CRC has been investigated as a secondary endpoint in several studies.104105106107108109 The mechanisms of this action are still poorly defined but are theorized to act via modulations in glucose, insulin, insulin-like growth factor 1, IGFBP, and leptin eventually resulting in decreased cell growth and proliferation.104

There have been several systematic reviews of the role of metformin on the risk of CRC. In one review with 12 randomized controlled trials and 41 observational studies, metformin had no effect on the rate of CRC in the randomized controlled trials (RR = 1.02, 95% CI = 0.41–2.5) but a slight reduction in observational studies (RR = 0.83, 95% CI = 0.74–0.92).109 In light of the lack of effect in randomized trials and potential toxicity, metformin is not recommended solely for colorectal neoplasia prevention.

Bisphosphonates

The efficacy of bisphosphonate use and cancers has been investigated in several observational studies.110111112 Bisphosphonates are proposed to work through inhibition of protein prenylation that eventually results in promotion of apoptosis and inhibition of angiogenesis and tumor cell adhesion.113 The impact of bisphosphonates on CRC was evaluated in a systematic review and meta-analysis of three case–control and one cohort study which demonstrated a 13% reduction in the rate of CRC (OR = 0.87, 95% CI = 0.78–0.97).110 However, this study has been widely criticized, as it excluded a large, prospective null study using the Nurses' Health Study which showed that there was a nonsignificant 3% adjusted reduction in CRC after 5 years of use (RR = 0.97, 95% CI = 0.60–1.56).112 With a lack of prospective randomized data and inconclusive observational data, the role of bisphosphonate therapy in colorectal neoplasia prevention is unclear.

Postmenopausal Hormone Replacement Therapy

Postmenopausal hormone replacement therapy (HRT) was found to reduce the risk of CRC in several epidemiological studies.114115116 There are several proposed mechanisms including a reduction in methylation of a DNA mismatch repair gene and a potential induction of apoptosis via estrogen receptors.117 In a large randomized control trial with 16,608 postmenopausal women between 50 and 79 years of age that compared estrogen plus medroxyprogesterone versus placebo, a 44% reduction in the overall number of CRCs was found in the treatment arm (RR = 0.56, 95% CI = 0.38–0.81).116 However, patients in the HRT group who developed CRC had a higher rate of positive lymph nodes, a higher stage, and a nonsignificant higher number of CRC deaths.118 Thus, any potential gains with lower rates of CRC diagnoses were mitigated by the more advanced stage at diagnosis among patients taking HRT. The reason for this association is not entirely clear. HRT is also associated with an increased risk of breast cancer, venous thromboembolism, coronary artery disease, stroke, and cholecystitis.115 Owing to these findings, postmenopausal HRT is not recommended for the prevention of CRC.

Conclusion

There is a large body of literature devoted to finding agents and lifestyle changes that decrease the risk of colorectal neoplasia. In general, a healthy lifestyle (exercising, minimal alcohol consumption, smoking cessation, healthy diet, low red meat intake) is associated with decreased CRC (and likely decreased polyp formation or progression of polyps to cancer) along with improvements in other arenas of health. Multiple chemopreventive agents have been studied with variable results as detailed in Table 1. Based on current evidence, it is reasonable to recommend calcium supplementation to prevent adenoma formation in patients with a personal history of adenoma, although it is unclear if this will decrease their risk of CRC. A recent draft by the USPTF also recommends aspirin for CRC prevention in a specific patient population. As we further our understanding of the complex interplay between the human genome, the fecal microbiome, and additional therapeutics, more individualized recommendations about specific agents and combinations of agents to prevent colorectal neoplasia will be made to maximize benefit while minimizing side effects. All patients should be encouraged to continue appropriate screening in addition to any chosen lifestyle, dietary, and/or chemopreventive agent(s).

Table 1

Different interventions with risk reductions for colorectal neoplasia
InterventionRisk reduction for CRC (RR with 95% CI)Recommendation
Exercise0.76 (0.72–0.81)16Perform regular physical activity for overall health and colorectal neoplasia prevention
Alcohol use: heavy drinking vs. none1.52 (1.27–1.81)21Limit regular alcohol intake to ≤1 drink/day for overall health and colorectal neoplasia prevention
Smoking1.18 (1.11–1.25)27Council on smoking cessation for overall health and colorectal neoplasia prevention
Weight loss (per 5 kg lost)0.96 (0.89–1.05)31Weight loss likely does not change CRC risk. Reasonable to council on weight loss for overall health
Fruit and vegetable intake (one additional serving a day)1.02 (0.98–1.05)37Increasing fruit and vegetable intake likely does not change CRC risk. Reasonable to council on weight loss for overall health
Vegetarian diet0.78 (0.64–0.95)43Vegetarian diet and pescovegetarian diet appear to decrease CRC risk
Red meats1.22 (1.11–1.34)49Reduction of red meats is associated with moderate reduction in colorectal neoplasia. Need supplementation of iron and vitamin B12
Dietary fats1.08 (0.90–1.29)51Reduction in dietary fats does not change CRC risk. Reasonable to council for overall health
CalciumAdenoma: 0.74 (0.58–0.95)55
Carcinoma: 1.08 (0.86–1.34)56
Recommend in patients with personal history of polyps (1,200–2,000 mg/day). Unclear if prevents carcinoma
Vitamin D1.08 (0.86–1.34)56Vitamin D supplementation does not modulate risks of CRC
Fiber0.99 (0.95–1.04)70Fiber supplementation does not modulate risks of CRC
Folic acid1.13 (0.77–1.64)73Folic acid supplementation does not modulate risks of CRC
AspirinAdenoma: 0.83 (0.72–0.96)86
Carcinoma: 0.74 (0.56–0.97)84
Recommend low-dose aspirin use in adults aged 50–59 years for primary prevention of CVD and CRC who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin for 10 years. Otherwise individualize recommendations80
COX-2 inhibitorAdenoma: 0.67 (0.59–0.77)93Good data on efficacy for colorectal adenoma prevention, but carries increased risks of cardiovascular morbidity. Not recommended at this time for routine use
Statins0.89 (0.74–1.07)100Marginal if any efficacy with considerable side effects. Not recommended solely for CRC prevention
Metformin1.02 (0.41–2.5)109Likely not efficacious for CRC prevention. Not recommended solely for CRC prevention
Bisphosphonates0.97 (0.60–1.56)112Conflicting studies on efficacy for colorectal neoplasia prevention. No prospective randomized data. Not recommended solely for CRC prevention
Postmenopausal hormone therapy0.56 (0.38–0.81)116Reduction in overall incidence of CRC but no difference in CRC mortality. Also associated with significant adverse events. Not recommended for CRC prevention

Abbreviations: CRC, colorectal cancer; CVD, cardiovascular disease.

Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
Address for correspondence Alyssa Fajardo, MD Department of Surgery/Colorectal Surgery, Indiana University School of Medicine, 545 Barnhill Dr., Emerson Hall 535, Indianapolis, IN 46202, ude.iupui@tiawa

Abstract

Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality worldwide. There are well-established screening protocols involving fecal testing, radiographic, and endoscopic evaluations that have led to decreased incidence and mortality of CRC in the United States. In addition to screening for CRC, there is interest in preventing colorectal neoplasia by targeting the signaling pathways that have been identified in the pathway of dysplasia progressing to carcinoma. This review will detail the efficacy of multiple potential preventative strategies including lifestyle changes (physical activity, alcohol use, smoking cessation, and obesity); dietary factors (dietary patterns, calcium, vitamin D, fiber, folate, and antioxidants and micronutrients); and chemopreventive agents (nonsteroidal anti-inflammatory drugs, statins, metformin, bisphosphonates, and postmenopausal hormonal therapy).

Keywords: chemoprevention, primary prevention, colorectal cancer, adenoma
Abstract

Colorectal cancer (CRC) is the third most common cancer and cause of cancer mortality among men and women in the United States with an incidence of 50/100,000 and mortality rate of 16.3/100,000.1 This translates to a 5% lifetime risk of CRC in the United States.12 Both the incidence and mortality of CRC in the United States have been gradually declining over the last decade, which is attributed to improved screening.12 Screening is associated with a 15 to 33% decrease in mortality following a diagnosis of CRC, and colonoscopy with polypectomy is associated with CRC prevention.345 While the improvements in incidence and mortality are encouraging given the high prevalence of CRC, there are still significant strides to be made in primary prevention.

Early epidemiologic studies that analyzed trends in CRC across nationalities and time provided initial evidence of the influence of environmental factors on the incidence of CRC.678 These early studies have driven research focusing on prevention of colorectal neoplasia with lifestyle modifications (e.g., exercise and dietary modification) and pharmacologic or natural agents collectively known as chemoprevention.9 CRCs are thought to arise from cumulative histologic and molecular changes that eventually result in abnormal regulation of cellular function, cell growth, differentiation, adhesion, and migration.10 The eventual endpoint of these changes is the transformation of colonic epithelial cells to adenomatous polyps and then into invasive carcinomas.1011 With the well-studied sequential stepwise transformation of colorectal neoplasms as discussed in more detail earlier in this issue, there are multiple targets for chemopreventive agents to stop this progression. It may be assumed that prevention of cancer may also be, at least in part, due to decreasing colorectal polyp formation.

The ideal primary preventative agent must target a step in carcinogenesis, have efficacy, be cost-effective, have easy administration, and have a favorable side effect profile. In this article, we will review a wide host of primary preventative strategies to prevent colorectal adenoma and carcinoma formation.

References

  • 1. Kohler B A, Sherman R L, Howlader Net al.Annual report to the Nation on the Status of Cancer, 1975-2011, featuring incidence of breast cancer subtypes by race/ethnicity, poverty, and state. J Natl Cancer Inst. 2015;107(6):djv048.[Google Scholar]
  • 2. Jemal A, Siegel R, Xu J, Ward ECancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277–300.[PubMed][Google Scholar]
  • 3. Winawer S J, Zauber A G, Ho M Net al.Prevention of colorectal cancer by colonoscopic polypectomy. N Engl J Med. 1993;329(27):1977–1981.[PubMed][Google Scholar]
  • 4. Mandel J S, Bond J H, Church T R. et al.Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med. 1993;328(19):1365–1371.[PubMed]
  • 5. Kronborg O, Fenger C, Olsen J, Jørgensen O D, Søndergaard ORandomised study of screening for colorectal cancer with faecal-occult-blood test. Lancet. 1996;348(9040):1467–1471.[PubMed][Google Scholar]
  • 6. King H, Locke F BCancer mortality among Chinese in the United States. J Natl Cancer Inst. 1980;65(5):1141–1148.[PubMed][Google Scholar]
  • 7. Burkitt D PEpidemiology of cancer of the colon and rectum. Cancer. 1971;28(1):3–13.[PubMed][Google Scholar]
  • 8. Trowell H, Southgate D A, Wolever T M, Leeds A R, Gassull M A, Jenkins D JLetter: Dietary fibre redefined. Lancet. 1976;1(7966):967.[PubMed][Google Scholar]
  • 9. Theisen CChemoprevention: what's in a name? J Natl Cancer Inst. 2001;93(10):743.[PubMed][Google Scholar]
  • 10. Kinzler K W, Vogelstein B. New York, NY: McGraw-Hill; 1998. Colorectal tumors; pp. 565–587. [PubMed]
  • 11. Fearon E R, Vogelstein BA genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759–767.[PubMed][Google Scholar]
  • 12. Kiningham R BPhysical activity and the primary prevention of cancer. Prim Care. 1998;25(2):515–536.[PubMed][Google Scholar]
  • 13. Winawer S J, St John D J, Bond J Het al.Prevention of colorectal cancer: guidelines based on new data. Bull World Health Organ. 1995;73(1):7–10.[Google Scholar]
  • 14. Trojian T H, Mody K, Chain PExercise and colon cancer: primary and secondary prevention. Curr Sports Med Rep. 2007;6(2):120–124.[PubMed][Google Scholar]
  • 15. Kruk J, Aboul-Enein H YPhysical activity in the prevention of cancer. Asian Pac J Cancer Prev. 2006;7(1):11–21.[PubMed][Google Scholar]
  • 16. Wolin K Y, Yan Y, Colditz G A, Lee I MPhysical activity and colon cancer prevention: a meta-analysis. Br J Cancer. 2009;100(4):611–616.[Google Scholar]
  • 17. Boyle T, Keegel T, Bull F, Heyworth J, Fritschi LPhysical activity and risks of proximal and distal colon cancers: a systematic review and meta-analysis. J Natl Cancer Inst. 2012;104(20):1548–1561.[PubMed][Google Scholar]
  • 18. Wolin K Y, Lee I M, Colditz G A, Glynn R J, Fuchs C, Giovannucci ELeisure-time physical activity patterns and risk of colon cancer in women. Int J Cancer. 2007;121(12):2776–2781.[Google Scholar]
  • 19. Chao A, Connell C J, Jacobs E Jet al.Amount, type, and timing of recreational physical activity in relation to colon and rectal cancer in older adults: the Cancer Prevention Study II Nutrition Cohort. Cancer Epidemiol Biomarkers Prev. 2004;13(12):2187–2195.[PubMed][Google Scholar]
  • 20. Oguma Y, Shinoda-Tagawa TPhysical activity decreases cardiovascular disease risk in women: review and meta-analysis. Am J Prev Med. 2004;26(5):407–418.[PubMed][Google Scholar]
  • 21. Fedirko V, Tramacere I, Bagnardi Vet al.Alcohol drinking and colorectal cancer risk: an overall and dose-response meta-analysis of published studies. Ann Oncol. 2011;22(9):1958–1972.[PubMed][Google Scholar]
  • 22. Cho E, Smith-Warner S A, Ritz Jet al.Alcohol intake and colorectal cancer: a pooled analysis of 8 cohort studies. Ann Intern Med. 2004;140(8):603–613.[PubMed][Google Scholar]
  • 23. Boffetta P, Hashibe M, La Vecchia C, Zatonski W, Rehm JThe burden of cancer attributable to alcohol drinking. Int J Cancer. 2006;119(4):884–887.[PubMed][Google Scholar]
  • 24. Ferrari P, Jenab M, Norat Tet al.Lifetime and baseline alcohol intake and risk of colon and rectal cancers in the European prospective investigation into cancer and nutrition (EPIC) Int J Cancer. 2007;121(9):2065–2072.[PubMed][Google Scholar]
  • 25. Seitz H K, Pöschl G, Simanowski U AAlcohol and cancer. Recent Dev Alcohol. 1998;14:67–95.[PubMed][Google Scholar]
  • 26. Mizoue T, Inoue M, Wakai Ket al.Alcohol drinking and colorectal cancer in Japanese: a pooled analysis of results from five cohort studies. Am J Epidemiol. 2008;167(12):1397–1406.[PubMed][Google Scholar]
  • 27. Botteri E, Iodice S, Bagnardi V, Raimondi S, Lowenfels A B, Maisonneuve PSmoking and colorectal cancer: a meta-analysis. JAMA. 2008;300(23):2765–2778.[PubMed][Google Scholar]
  • 28. Botteri E, Iodice S, Raimondi S, Maisonneuve P, Lowenfels A BCigarette smoking and adenomatous polyps: a meta-analysis. Gastroenterology. 2008;134(2):388–395.[PubMed][Google Scholar]
  • 29. Giovannucci EAn updated review of the epidemiological evidence that cigarette smoking increases risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2001;10(7):725–731.[PubMed][Google Scholar]
  • 30. Hecht S STobacco carcinogens, their biomarkers and tobacco-induced cancer. Nat Rev Cancer. 2003;3(10):733–744.[PubMed][Google Scholar]
  • 31. Karahalios A, English D R, Simpson J AWeight change and risk of colorectal cancer: a systematic review and meta-analysis. Am J Epidemiol. 2015;181(11):832–845.[PubMed][Google Scholar]
  • 32. Moghaddam A A, Woodward M, Huxley RObesity and risk of colorectal cancer: a meta-analysis of 31 studies with 70,000 events. Cancer Epidemiol Biomarkers Prev. 2007;16(12):2533–2547.[PubMed][Google Scholar]
  • 33. Larsson S C, Wolk AObesity and colon and rectal cancer risk: a meta-analysis of prospective studies. Am J Clin Nutr. 2007;86(3):556–565.[PubMed][Google Scholar]
  • 34. Qasim A, O'Morain CPrimary prevention of colorectal cancer: are we closer to reality? Eur J Gastroenterol Hepatol. 2010;22(1):9–17.[PubMed][Google Scholar]
  • 35. Koushik A, Hunter D J, Spiegelman Det al.Fruits, vegetables, and colon cancer risk in a pooled analysis of 14 cohort studies. J Natl Cancer Inst. 2007;99(19):1471–1483.[PubMed][Google Scholar]
  • 36. van't Veer P, Jansen M C, Klerk M, Kok F JFruits and vegetables in the prevention of cancer and cardiovascular disease. Public Health Nutr. 2000;3(1):103–107.[PubMed][Google Scholar]
  • 37. Michels K B, Edward Giovannucci, Joshipura K Jet al.Prospective study of fruit and vegetable consumption and incidence of colon and rectal cancers. J Natl Cancer Inst. 2000;92(21):1740–1752.[PubMed][Google Scholar]
  • 38. Lee J E, Chan A TFruit, vegetables, and folate: cultivating the evidence for cancer prevention. Gastroenterology. 2011;141(1):16–20.[Google Scholar]
  • 39. van Duijnhoven F J, Bueno-De-Mesquita H B, Ferrari Pet al.Fruit, vegetables, and colorectal cancer risk: the European Prospective Investigation into Cancer and Nutrition. Am J Clin Nutr. 2009;89(5):1441–1452.[PubMed][Google Scholar]
  • 40. van Breda S G, de Kok T M, van Delft J HMechanisms of colorectal and lung cancer prevention by vegetables: a genomic approach. J Nutr Biochem. 2008;19(3):139–157.[PubMed][Google Scholar]
  • 41. Aune D, Lau R, Chan D Set al.Nonlinear reduction in risk for colorectal cancer by fruit and vegetable intake based on meta-analysis of prospective studies. Gastroenterology. 2011;141(1):106–118.[PubMed][Google Scholar]
  • 42. Crosara Teixeira M, Braghiroli M I, Sabbaga J, Hoff P MPrimary prevention of colorectal cancer: myth or reality? World J Gastroenterol. 2014;20(41):15060–15069.[Google Scholar]
  • 43. Orlich M J, Singh P N, Sabaté Jet al.Vegetarian dietary patterns and the risk of colorectal cancers. JAMA Intern Med. 2015;175(5):767–776.[Google Scholar]
  • 44. Yoon H, Benamouzig R, Little J, François-Collange M, Tomé DSystematic review of epidemiological studies on meat, dairy products and egg consumption and risk of colorectal adenomas. Eur J Cancer Prev. 2000;9(3):151–164.[PubMed][Google Scholar]
  • 45. Chao A, Thun M J, Connell C Jet al.Meat consumption and risk of colorectal cancer. JAMA. 2005;293(2):172–182.[PubMed][Google Scholar]
  • 46. Cross A J, Ferrucci L M, Risch Aet al.A large prospective study of meat consumption and colorectal cancer risk: an investigation of potential mechanisms underlying this association. Cancer Res. 2010;70(6):2406–2414.[Google Scholar]
  • 47. MacLennan R, Macrae F, Bain Cet al.Randomized trial of intake of fat, fiber, and beta carotene to prevent colorectal adenomas. J Natl Cancer Inst. 1995;87(23):1760–1766.[PubMed][Google Scholar]
  • 48. Willett W C, Stampfer M J, Colditz G A, Rosner B A, Speizer F ERelation of meat, fat, and fiber intake to the risk of colon cancer in a prospective study among women. N Engl J Med. 1990;323(24):1664–1672.[PubMed][Google Scholar]
  • 49. Chan D S, Lau R, Aune Det al.Red and processed meat and colorectal cancer incidence: meta-analysis of prospective studies. PLoS ONE. 2011;6(6):e20456.[Google Scholar]
  • 50. Figueiredo J C, Hsu L, Hutter C Met al.Genome-wide diet-gene interaction analyses for risk of colorectal cancer. PLoS Genet. 2014;10(4):e1004228.[Google Scholar]
  • 51. Beresford S A, Johnson K C, Ritenbaugh Cet al.Low-fat dietary pattern and risk of colorectal cancer: the Women's Health Initiative Randomized Controlled Dietary Modification Trial. JAMA. 2006;295(6):643–654.[PubMed][Google Scholar]
  • 52. Prentice R L Sheppard L Dietary fat and cancer: consistency of the epidemiologic data, and disease prevention that may follow from a practical reduction in fat consumption Cancer Causes Control 19901181–97., discussion 99–109 [[PubMed]
  • 53. Weijenberg M P, Lüchtenborg M, de Goeij A Fet al.Dietary fat and risk of colon and rectal cancer with aberrant MLH1 expression, APC or KRAS genes. Cancer Causes Control. 2007;18(8):865–879.[Google Scholar]
  • 54. Kuriki K, Wakai K, Hirose Ket al.Risk of colorectal cancer is linked to erythrocyte compositions of fatty acids as biomarkers for dietary intakes of fish, fat, and fatty acids. Cancer Epidemiol Biomarkers Prev. 2006;15(10):1791–1798.[PubMed][Google Scholar]
  • 55. Weingarten M A, Zalmanovici A, Yaphe JDietary calcium supplementation for preventing colorectal cancer and adenomatous polyps. Cochrane Database Syst Rev. 2008;(1):CD003548.[PubMed][Google Scholar]
  • 56. Wactawski-Wende J, Kotchen J M, Anderson G Let al.Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med. 2006;354(7):684–696.[PubMed][Google Scholar]
  • 57. Keum N, Aune D, Greenwood D C, Ju W, Giovannucci E LCalcium intake and colorectal cancer risk: dose-response meta-analysis of prospective observational studies. Int J Cancer. 2014;135(8):1940–1948.[PubMed][Google Scholar]
  • 58. Bonithon-Kopp C Kronborg O Giacosa A Räth U Faivre J; European Cancer Prevention Organisation Study Group. Calcium and fibre supplementation in prevention of colorectal adenoma recurrence: a randomised intervention trial Lancet 200035692381300–1306. [[PubMed]
  • 59. Baron J A, Beach M, Mandel J Set al.Calcium supplements for the prevention of colorectal adenomas. N Engl J Med. 1999;340(2):101–107.[PubMed][Google Scholar]
  • 60. Bond J H; Practice Parameters Committee of the American College of Gastroenterology. Polyp guideline: diagnosis, treatment, and surveillance for patients with colorectal polyps Am J Gastroenterol 200095113053–3063. [[PubMed]
  • 61. Lee J E, Li H, Chan A Tet al.Circulating levels of vitamin D and colon and rectal cancer: the Physicians' Health Study and a meta-analysis of prospective studies. Cancer Prev Res (Phila) 2011;4(5):735–743.[Google Scholar]
  • 62. Weinstein S J, Yu K, Horst R L, Ashby J, Virtamo J, Albanes DSerum 25-hydroxyvitamin D and risks of colon and rectal cancer in Finnish men. Am J Epidemiol. 2011;173(5):499–508.[Google Scholar]
  • 63. Jacobs E T, Alberts D S, Benuzillo J, Hollis B W, Thompson P A, Martínez M ESerum 25(OH)D levels, dietary intake of vitamin D, and colorectal adenoma recurrence. J Steroid Biochem Mol Biol. 2007;103(3–5):752–756.[Google Scholar]
  • 64. Chung M, Lee J, Terasawa T, Lau J, Trikalinos T A. Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2011;155(12):827–838.[PubMed]
  • 65. Ingraham B A, Bragdon B, Nohe AMolecular basis of the potential of vitamin D to prevent cancer. Curr Med Res Opin. 2008;24(1):139–149.[PubMed][Google Scholar]
  • 66. Moore M A, Park C B, Tsuda HSoluble and insoluble fiber influences on cancer development. Crit Rev Oncol Hematol. 1998;27(3):229–242.[PubMed][Google Scholar]
  • 67. Asano T, McLeod R SDietary fibre for the prevention of colorectal adenomas and carcinomas. Cochrane Database Syst Rev. 2002;2(2):CD003430.[PubMed][Google Scholar]
  • 68. Alberts D S, Martínez M E, Roe D J. et al.Lack of effect of a high-fiber cereal supplement on the recurrence of colorectal adenomas. Phoenix Colon Cancer Prevention Physicians' Network. N Engl J Med. 2000;342(16):1156–1162.[PubMed]
  • 69. Fuchs C S, Giovannucci E L, Colditz G Aet al.Dietary fiber and the risk of colorectal cancer and adenoma in women. N Engl J Med. 1999;340(3):169–176.[PubMed][Google Scholar]
  • 70. Michels K B, Fuchs C S, Giovannucci Eet al.Fiber intake and incidence of colorectal cancer among 76,947 women and 47,279 men. Cancer Epidemiol Biomarkers Prev. 2005;14(4):842–849.[PubMed][Google Scholar]
  • 71. Giovannucci E, Stampfer M J, Colditz G Aet al.Folate, methionine, and alcohol intake and risk of colorectal adenoma. J Natl Cancer Inst. 1993;85(11):875–884.[PubMed][Google Scholar]
  • 72. Duthie S JFolic acid deficiency and cancer: mechanisms of DNA instability. Br Med Bull. 1999;55(3):578–592.[PubMed][Google Scholar]
  • 73. Carroll C, Cooper K, Papaioannou Det al.Meta-analysis: folic acid in the chemoprevention of colorectal adenomas and colorectal cancer. Aliment Pharmacol Ther. 2010;31(7):708–718.[PubMed][Google Scholar]
  • 74. Cole B F, Baron J A, Sandler R Set al.Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA. 2007;297(21):2351–2359.[PubMed][Google Scholar]
  • 75. Chan A T, Giovannucci E LPrimary prevention of colorectal cancer. Gastroenterology. 2010;138(6):2029–2.043E13.[Google Scholar]
  • 76. Jänne P A, Mayer R JChemoprevention of colorectal cancer. N Engl J Med. 2000;342(26):1960–1968.[PubMed][Google Scholar]
  • 77. Arber N, Levin BChemoprevention of colorectal neoplasia: the potential for personalized medicine. Gastroenterology. 2008;134(4):1224–1237.[PubMed][Google Scholar]
  • 78. Garcia-Albeniz X, Chan A TAspirin for the prevention of colorectal cancer. Best Pract Res Clin Gastroenterol. 2011;25(4–5):461–472.[Google Scholar]
  • 79. Fajardo A D, Robb B WChemoprevention for colorectal neoplasia. Clin Colon Rectal Surg. 2008;21(4):304–312.[Google Scholar]
  • 80. Draft Recommendation Statement . US Preventive Services Task Force; 2015. Aspirin to Prevent Cardiovascular Disease and Cancer. [PubMed]
  • 81. Sandler R S, Halabi S, Baron J Aet al.A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med. 2003;348(10):883–890.[PubMed][Google Scholar]
  • 82. Rostom A, Dubé C, Lewin G. et al.Nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors for primary prevention of colorectal cancer: a systematic review prepared for the U.S. Preventive Services Task Force. Ann Intern Med. 2007;146(5):376–389.[PubMed]
  • 83. Grau M V, Sandler R S, McKeown-Eyssen Get al.Nonsteroidal anti-inflammatory drug use after 3 years of aspirin use and colorectal adenoma risk: observational follow-up of a randomized study. J Natl Cancer Inst. 2009;101(4):267–276.[Google Scholar]
  • 84. Flossmann E Rothwell P M; British Doctors Aspirin Trial and the UK-TIA Aspirin Trial. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies Lancet 200736995731603–1613. [[PubMed]
  • 85. Cook N R, Lee I M, Gaziano J Met al.Low-dose aspirin in the primary prevention of cancer: the Women's Health Study: a randomized controlled trial. JAMA. 2005;294(1):47–55.[PubMed][Google Scholar]
  • 86. Cole B F, Logan R F, Halabi Set al.Aspirin for the chemoprevention of colorectal adenomas: meta-analysis of the randomized trials. J Natl Cancer Inst. 2009;101(4):256–266.[Google Scholar]
  • 87. Burn J, Gerdes A M, Macrae Fet al.Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet. 2011;378(9809):2081–2087.[Google Scholar]
  • 88. Benamouzig R Uzzan B Deyra J et al.Prevention by daily soluble aspirin of colorectal adenoma recurrence: 4-year results of the APACC randomised trial[Erratum appears in Gut. 2012 Mar;61(3):472]Gut 2012612255–261. [[PubMed]
  • 89. Baron J A, Cole B F, Sandler R Set al.A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med. 2003;348(10):891–899.[PubMed][Google Scholar]
  • 90. Dubé C, Rostom A, Lewin G. et al.The use of aspirin for primary prevention of colorectal cancer: a systematic review prepared for the U.S. Preventive Services Task Force. Ann Intern Med. 2007;146(5):365–375.[PubMed]
  • 91. Whitlock E P, Williams S B, Burda B U, Freightner A, Beil T. AHRQ Publication; 2015. Aspirin Use in Adults: Cancer, All-Cause Mortality, and Harms: A Systematic Evidence Review for the U.S. Preventive Services Task Force; p. 13. [PubMed]
  • 92. Nan H, Hutter C M, Lin Yet al.Association of aspirin and NSAID use with risk of colorectal cancer according to genetic variants. JAMA. 2015;313(11):1133–1142.[Google Scholar]
  • 93. Bertagnolli M M, Eagle C J, Zauber A Get al.Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med. 2006;355(9):873–884.[PubMed][Google Scholar]
  • 94. Kerr D J, Dunn J A, Langman M Jet al.Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer. N Engl J Med. 2007;357(4):360–369.[PubMed][Google Scholar]
  • 95. Chan A T, Sima C S, Zauber A G, Ridker P M, Hawk E T, Bertagnolli M MC-reactive protein and risk of colorectal adenoma according to celecoxib treatment. Cancer Prev Res (Phila) 2011;4(8):1172–1180.[Google Scholar]
  • 96. Solomon S D, Wittes J, Finn P Vet al.Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials: the cross trial safety analysis. Circulation. 2008;117(16):2104–2113.[Google Scholar]
  • 97. Meyskens F L Jr, McLaren C E, Pelot Det al.Difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas: a randomized placebo-controlled, double-blind trial. Cancer Prev Res (Phila) 2008;1(1):32–38.[Google Scholar]
  • 98. Zell J A, Pelot D, Chen W P, McLaren C E, Gerner E W, Meyskens F LRisk of cardiovascular events in a randomized placebo-controlled, double-blind trial of difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas. Cancer Prev Res (Phila) 2009;2(3):209–212.[Google Scholar]
  • 99. Laukaitis C M, Gerner E WDFMO: targeted risk reduction therapy for colorectal neoplasia. Best Pract Res Clin Gastroenterol. 2011;25(4–5):495–506.[Google Scholar]
  • 100. Lytras T, Nikolopoulos G, Bonovas SStatins and the risk of colorectal cancer: an updated systematic review and meta-analysis of 40 studies. World J Gastroenterol. 2014;20(7):1858–1870.[Google Scholar]
  • 101. Bonovas S, Filioussi K, Flordellis C S, Sitaras N MStatins and the risk of colorectal cancer: a meta-analysis of 18 studies involving more than 1.5 million patients. J Clin Oncol. 2007;25(23):3462–3468.[PubMed][Google Scholar]
  • 102. Broughton T, Sington J, Beales I LStatin use is associated with a reduced incidence of colorectal cancer: a colonoscopy-controlled case-control study. BMC Gastroenterol. 2012;12:36.[Google Scholar]
  • 103. Xiao H, Yang C SCombination regimen with statins and NSAIDs: a promising strategy for cancer chemoprevention. Int J Cancer. 2008;123(5):983–990.[PubMed][Google Scholar]
  • 104. Sehdev A, Shih Y C, Vekhter B, Bissonnette M B, Olopade O I, Polite B NMetformin for primary colorectal cancer prevention in patients with diabetes: a case-control study in a US population. Cancer. 2015;121(7):1071–1078.[Google Scholar]
  • 105. Tsilidis K K, Capothanassi D, Allen N E. et al.Metformin does not affect cancer risk: a cohort study in the U.K. Clinical Practice Research Datalink analyzed like an intention-to-treat trial. Diabetes Care. 2014;37(9):2522–2532.[PubMed]
  • 106. Marks A R, Pietrofesa R A, Jensen C D, Zebrowski A, Corley D A, Doubeni C AMetformin use and risk of colorectal adenoma after polypectomy in patients with type 2 diabetes mellitus. Cancer Epidemiol Biomarkers Prev. 2015;24(11):1692–1698.[Google Scholar]
  • 107. Kowall B, Stang A, Rathmann W, Kostev KNo reduced risk of overall, colorectal, lung, breast, and prostate cancer with metformin therapy in diabetic patients: database analyses from Germany and the UK. Pharmacoepidemiol Drug Saf. 2015;24(8):865–874.[PubMed][Google Scholar]
  • 108. Zhang Z J, Zheng Z J, Kan Het al.Reduced risk of colorectal cancer with metformin therapy in patients with type 2 diabetes: a meta-analysis. Diabetes Care. 2011;34(10):2323–2328.[Google Scholar]
  • 109. Franciosi M, Lucisano G, Lapice E, Strippoli G F, Pellegrini F, Nicolucci AMetformin therapy and risk of cancer in patients with type 2 diabetes: systematic review. PLoS ONE. 2013;8(8):e71583.[Google Scholar]
  • 110. Thosani N, Thosani S N, Kumar Set al.Reduced risk of colorectal cancer with use of oral bisphosphonates: a systematic review and meta-analysis. J Clin Oncol. 2013;31(5):623–630.[PubMed][Google Scholar]
  • 111. Singh H, Nugent Z, Demers A, Mahmud S, Bernstein CExposure to bisphosphonates and risk of colorectal cancer: a population-based nested case-control study. Cancer. 2012;118(5):1236–1243.[PubMed][Google Scholar]
  • 112. Khalili H, Huang E S, Ogino S, Fuchs C S, Chan A TA prospective study of bisphosphonate use and risk of colorectal cancer. J Clin Oncol. 2012;30(26):3229–3233.[Google Scholar]
  • 113. Rennert G, Pinchev M, Rennert H S, Gruber S BUse of bisphosphonates and reduced risk of colorectal cancer. J Clin Oncol. 2011;29(9):1146–1150.[Google Scholar]
  • 114. Grodstein F, Martinez M E, Platz E Aet al.Postmenopausal hormone use and risk for colorectal cancer and adenoma. Ann Intern Med. 1998;128(9):705–712.[PubMed][Google Scholar]
  • 115. U.S. Preventive Services Task Force . Postmenopausal hormone replacement therapy for primary prevention of chronic conditions: recommendations and rationale. Ann Intern Med. 2002;137(10):834–839.[PubMed]
  • 116. Chlebowski R T, Wactawski-Wende J, Ritenbaugh Cet al.Estrogen plus progestin and colorectal cancer in postmenopausal women. N Engl J Med. 2004;350(10):991–1004.[PubMed][Google Scholar]
  • 117. Solimando R, Bazzoli F, Ricciardiello LChemoprevention of colorectal cancer: a role for ursodeoxycholic acid, folate and hormone replacement treatment? Best Pract Res Clin Gastroenterol. 2011;25(4–5):555–568.[PubMed][Google Scholar]
  • 118. Simon M S, Chlebowski R T, Wactawski-Wende Jet al.Estrogen plus progestin and colorectal cancer incidence and mortality. J Clin Oncol. 2012;30(32):3983–3990.[Google Scholar]
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