KEY POINTS
Colorectal cancer is a disease in which malignant (cancer) cells form in the tissues of the colon or the rectum.
Cancer that begins in the colon is called colon cancer, and cancer that begins in the rectum is called rectal cancer. Cancer that affects either of these organs may also be called colorectal cancer.
The colon is part of the body’s digestive system. The digestive system removes and processes nutrients(vitamins, minerals, carbohydrates, fats, proteins, and water) from foods and helps pass waste material out of the body. The digestive system is made up of the mouth, throat, esophagus, stomach, and the small and large intestines. The colon (large bowel) is the first part of the large intestine and is about 5 feet long. Together, the rectum and anal canal make up the last part of the large intestine and are 6 to 8 inches long. The anal canal ends at the anus (the opening of the large intestine to the outside of the body).
Colorectal cancer is one of the leading causes of death from cancer in NZ.
The number of new colorectal cancer cases and the number of deaths from colorectal cancer are both decreasing each year, but it is still one of the leading causes of death from cancer in NZ.
Incidence and mortality
Colorectal cancer (CRC) is the third most common malignant neoplasm worldwide [1] and the second leading cause of cancer deaths in men and women combined in the United States.[2] It is estimated that there will be 135,430 new cases diagnosed in the United States in 2017 and 50,260 deaths due to this disease.[2] Between 2004 and 2013, CRC incidence rates in the United States declined by 3% per year among adults aged 50 years and older.[2] In adults younger than 50 years, CRC incidence rates increased by about 2% per year.[2] For the past 20 years, the mortality rate has been declining in both men and women. Between 2005 and 2014, the mortality rate declined by 2.5% per year.[2] Incidence and mortality rates are higher in African Americans compared with other races.[3,4]
The overall 5-year survival rate is 65%. About 4.4% of Americans are expected to develop CRC within their lifetimes.[2,5] The risk of CRC begins to increase after the age of 40 years and rises sharply at ages 50 to 55 years; the risk doubles with each succeeding decade, and continues to rise exponentially. Despite advances in surgical techniques and adjuvant therapy, there has been only a modest improvement in survival for patients who present with advanced neoplasms.[6,7] Hence, effective primary and secondary preventive approaches must be developed to reduce the morbidity and mortality from CRC.
Estimated new cases and deaths from colon cancer in NZ in 2015:
- New cases: XXXX (colon cancer only).
- Deaths: XXXX (colon and rectal cancers combined).
Gastrointestinal stromal tumors can occur in the colon. (Refer to the NCI PDQ summary on Gastrointestinal Stromal Tumors Treatment for more information.)
Finding and treating colorectal cancer early may prevent death from colorectal cancer. Screening tests may be used to help find colorectal cancer. Prevention of bowel cancer is the best defence.
Who Is at Risk?
For the great majority of people, the major factor that increases a person’s risk for colorectal cancer (CRC) is increasing age. Risk increases dramatically after age 50 years; 90% of all CRCs are diagnosed after this age. Incidence and mortality rates are higher in African Americans compared with other races.[1] The history of CRC in a first-degree relative, especially if before the age of 55 years, roughly doubles the risk. A personal history of CRC, high-risk adenomas, or ovarian cancer also increases the risk.[2] Other risk factors are weaker than age and family history. People with an inflammatory bowel disease, such as ulcerative colitis or Crohn disease, have a much higher risk of CRC starting about 8 years after disease onset and are recommended to have frequent colonoscopic surveillance.[3] A small percentage (<5%) of CRCs occur in people with a genetic predisposition, including familial adenomatous polyposis and hereditary nonpolyposis coli.
Etiology and pathogenesis of colorectal cancer
Genetics,[8,9] experimental,[10,11] and epidemiologic [12–14] studies suggest that CRC results from complex interactions between inherited susceptibility and environmental factors. The exact nature and contribution of these factors to CRC incidence and mortality is the subject of ongoing research.
What is prevention?
Primary prevention involves the use of medications or other interventions before the clinical appearance of CRC with the intent of preventing clinical CRC and CRC mortality.
Cancer prevention is action taken to lower the chance of getting cancer. By preventing cancer, the number of new cases of cancer in a group or population is lowered. Hopefully, this will lower the number of deaths caused by cancer.
To prevent new cancers from starting, researchers look at risk factors and protective factors. Anything that increases your chance of developing cancer is called a cancer risk factor; anything that decreases your chance of developing cancer is called a cancer protective factor.
Some risk factors for cancer can be avoided, but many cannot. For example, both smoking and inheriting certain genes are risk factors for some types of cancer, but only smoking can be avoided. Regular exercise and a healthy diet may be protective factors for some types of cancer. Avoiding risk factors and increasing protective factors may lower your risk, but it does not mean that you will not get cancer.
Different ways to prevent cancer are being studied, including:
- Changing lifestyle or eating habits.
- Avoiding things known to cause cancer.
- Taking medicines to treat a precancerous condition or to keep cancer from starting.
Colorectal Cancer Prevention
KEY POINTS
- Avoiding risk factors and increasing protective factors may help prevent cancer.
- The following risk factors increase the risk of colorectal cancer:
- Age
- Family history of colorectal cancer
- Personal history
- Inherited risk
- Alcohol
- Cigarette smoking
- Obesity
- The following protective factors decrease the risk of colorectal cancer:
- Physical activity
- Aspirin
- Combination hormone replacement therapy
- Polyp removal
- It is not clear if the following affect the risk of colorectal cancer:
- Nonsteroidal anti-inflammatory drugs (NSAIDs) other than aspirin
- Calcium
- Diet
- The following factors do not affect the risk of colorectal cancer:
- Hormone replacement therapy with estrogen only
- Statins
- Cancer prevention clinical trials are used to study ways to prevent cancer.
- New ways to prevent colorectal cancer are being studied in clinical trials.
Avoiding risk factors and increasing protective factors may help prevent cancer.
Avoiding cancer risk factors may help prevent certain cancers. Risk factors include smoking, being overweight, and not getting enough exercise. Increasing protective factors such as quitting smoking and exercising may also help prevent some cancers. Talk to your doctor or other health care professional about how you might lower your risk of cancer.
Factors With Adequate Evidence of Increased Risk of Colorectal Cancer:
The following risk factors increase the risk of colorectal cancer:
Age
The risk of colorectal cancer increases after age 50. Most cases of colorectal cancer are diagnosed after age 50.
Family/personal history of colorectal cancer and other hereditary conditions
Based on solid evidence, a family history of CRC in a first-degree relative or a personal history of CRC increases the risk of CRC.[9–12] Having a genetic predisposition, including familial adenomatous polyposis and hereditary nonpolyposis coli, also increases risk for CRC.[13] Having a parent, brother, sister, or child with colorectal cancer doubles a person’s risk of colorectal cancer.
Magnitude of Effect: In persons with adenomatous polyposis coli, the risk of CRC by age 40 can be as high as 100%. Persons with hereditary nonpolyposis coli can have a lifetime risk of CRC of about 80%.
- Study Design: Case-control and cohort studies.
- Internal Validity: Good.
- Consistency: Good.
- External Validity: Good.
Refer to the PDQ summary on Genetics of Colorectal Cancer for more information about family history and hereditary conditions.
Personal history
Having a personal history of the following conditions increases the risk of colorectal cancer:
- Previous colorectal cancer.
- High-risk adenomas (colorectal polyps that are 1 centimeter or larger in size or that have cells that look abnormal under a microscope).
- Ovarian cancer.
- Inflammatory bowel disease (such as ulcerative colitis or Crohn disease).
Inherited risk
The risk of colorectal cancer is increased when certain gene changes linked to familial adenomatous polyposis(FAP) or hereditary nonpolyposis colon cancer (HNPCC or Lynch Syndrome) are inherited.
Alcohol; Excessive alcohol use
Based on solid evidence from observational studies, excessive alcohol use is associated with an increased risk of colorectal cancer (CRC).[1,2]
Magnitude of Effect: A pooled analysis of eight cohort studies estimated an adjusted relative risk (RR) of 1.41 (95% confidence interval [CI], 1.16–1.72) for consumption exceeding 45 g/day.[1]
- Study Design: Cohort studies.
- Internal Validity: Fair.
- Consistency: Fair.
- External Validity: Fair.
Drinking 3 or more alcoholic beverages per day increases the risk of colorectal cancer. Drinking alcohol is also linked to the risk of forming large colorectal adenomas (benign tumors).
Cigarette smoking
Based on solid evidence, cigarette smoking is associated with increased incidence and mortality from CRC.
Magnitude of Effect: A pooled analysis of 106 observational studies estimated an adjusted RR (current smokers vs. never smokers) for developing CRC of 1.18 (95% CI, 1.11–1.25).[3,4]
- Study Design: 106 observational studies.
- Internal Validity: Fair.
- Consistency: Good.
- External Validity: Good.
Smoking cigarettes is also linked to an increased risk of forming colorectal adenomas. Cigarette smokers who have had surgery to remove colorectal adenomas are at an increased risk for the adenomas to recur (come back).
Obesity
Based on solid evidence, obesity is linked to an increased risk of colorectal cancer and death from CRC.
Magnitude of Effect: In one large cohort study, the adjusted RR for developing colon cancer for women with a body mass index of more than 29 was 1.45 (95% CI, 1.02–2.07).[5,6] A similar increase in CRC mortality was found in another large cohort study.[7,8]
- Study Design: Large cohort studies.
- Internal Validity: Fair.
- Consistency: Good.
- External Validity: Good.
Risk Factor Summary:
- Family history of colorectal cancer in a first-degree relative.[2]
- Personal history of colorectal adenomas, colorectal cancer, or ovarian cancer.[3–5]
- Hereditary conditions, including familial adenomatous polyposis (FAP) and Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]).[6]
- Personal history of long-standing chronic ulcerative colitis or Crohn colitis.[7]
- Excessive alcohol use.[8]
- Cigarette smoking.[9]
- Race/ethnicity: African American.[10,11]
- Obesity.[12]
Factors With Adequate Evidence for a Decreased Risk of Colorectal Cancer:
The following protective factors decrease the risk of colorectal cancer:
Physical activity
Based on solid evidence, a lifestyle that includes regular physical activity is associated with a decreased incidence of CRC.
Magnitude of Effect: A meta-analysis of 52 observational studies found a statistically significant 24% reduction in CRC incidence (RR, 0.76; 95% CI, 0.72–0.81).[14]
- Study Design: Cohort studies and meta-analysis.
- Internal Validity: Fair.
- Consistency: Good.
- External Validity: Good.
Aspirin
Benefits
Based on solid evidence, studies have shown that taking aspirin lowers the risk of colorectal cancer and the risk of death from colorectal cancer. The decrease in risk begins 10 to 20 years after patients start taking aspirin. Daily aspirin (acetylsalicylic acid [ASA]) reduces CRC incidence and mortality after 10 to 20 years, based on three individual participant level data meta-analyses of trials of aspirin used for the primary and secondary prevention of cardiovascular disease.[15–17]
Magnitude of Effect: ASA use reduces the long-term risk for developing CRC by 40% about 10 to 19 years after initiation (hazard ratio [HR], 0.60; 95% CI, 0.47–0.76).[18] Daily doses of 75 to 1,200 mg of ASA reduce the 20-year risk of CRC death by about 33% (HR, 0.67; 95% CI, 0.52–0.86).[16,17]
- Study Design: Individual patient level data meta-analyses of randomized controlled trials (RCTs) of ASA for primary and secondary cardiovascular prevention.
- Internal Validity: Fair, some data from registries and death certificates, some loss to follow-up; variations in ASA dose and timing; adherence to ASA unknown after end of trials (5–9 years); trials designed to answer a different primary hypothesis (cardiovascular disease prevention).
- Consistency: Generally consistent.
- External Validity: Fair, most data (>75%) from men.
Harms
Based on solid evidence, harms of ASA use include excessive bleeding, including gastrointestinal bleeds and hemorrhagic stroke.
Magnitude of Effect: Very low-dose ASA use (i.e., ≤100 mg every day or every other day) results in an estimated 14 (95% CI, 7–23) additional major gastrointestinal bleeding events and 3.2 (95% CI, -0.5 to 0.82) extra hemorrhagic strokes per 1,000 persons over 10 years. These risks increase with advancing age.[19]
- Study Design: Evidence obtained from RCTs, cohort studies, and meta-analyses comparing ASA with placebo or no treatment for the primary prevention of cardiovascular disease.[19]
- Internal Validity: Fair, data is from clinically and methodologically heterogeneous trials.
- Consistency: Good.
- External Validity: Fair, data on specific subgroups is limited.
The possible harms of aspirin use (100 mg or less) daily or every other day include an increased risk of stroke and bleeding in the stomach and intestines. These risks may be greater among the elderly, men, and those with conditions linked to a higher than normal risk of bleeding.
Combination hormone replacement therapy (estrogen plus progestin)
Studies have shown that combination hormone replacement therapy (HRT) that includes both estrogen and progestin lowers the risk of invasive colorectal cancer in postmenopausal women.
However, in women who take combination HRT and do develop colorectal cancer, the cancer is more likely to be advanced when it is diagnosed and the risk of dying from colorectal cancer is not decreased.
Based on solid evidence, combined hormone therapy (conjugated equine estrogen and progestin) decreases the incidence of invasive CRC.[20]
Based on fair evidence, combination conjugated equine estrogen and progestin has little or no benefit in reducing mortality from CRC. Data from the Women’s Health Initiative (WHI), a randomized, placebo-controlled trial evaluating estrogen plus progestin, with a mean intervention of 5.6 years and a follow-up of 11.6 years showed that women taking combined hormone therapy had a statistically significant higher stage of cancer (regional and distant) at diagnosis but not a statistically significant number of deaths from CRC compared with women taking the placebo.[20]
Magnitude of Effect: There were fewer CRCs in the combined hormone therapy group than in the placebo group (0.12% vs. 0.16%; HR, 0.72; 95% CI, 0.56–0.94). A meta-analysis of cohort studies observed a RR of 0.86 (95% CI, 0.76–0.97) for incidence of CRC associated with combined hormone therapy.
There were 37 CRC deaths in the combined hormone therapy arm compared with 27 deaths in the placebo arm (0.04% vs. 0.03%; HR, 1.29; 95% CI, 0.78–2.11).
- Study Design: RCT and cohort studies.
- Internal Validity: Good.
- Consistency: Good for effect on incidence; not applicable (N/A) for effect on mortality; results were based on one trial.
- External Validity: Good.
Harms
Based on solid evidence, harms of postmenopausal combined estrogen-plus-progestin hormone use include increased risk of breast cancer, coronary heart disease, and thromboembolic events.
The possible harms of combination HRT include an increased risk of having:
- Breast cancer.
- Heart disease.
- Blood clots.
Magnitude of Effect: The WHI showed a 26% increase in invasive breast cancer in the combined hormone group, a 29% increase in coronary heart disease events, a 41% increase in stroke rates, and a twofold higher rate of thromboembolic events.[21]
- Study Design: Evidence from RCTs.
- Internal Validity: Good.
- Consistency: Good.
- External Validity: Fair.
Polyp removal
Benefits
Most colorectal polyps are adenomas, which may develop into cancer. Removing colorectal polyps that are larger than 1 centimeter (pea-sized) may lower the risk of colorectal cancer. It is not known if removing smaller polyps lowers the risk of colorectal cancer. Based on fair evidence, removal of adenomatous polyps reduces the risk of CRC. Much of this reduction likely comes from removal of large (i.e., >1.0 cm) polyps, while the benefit of removing smaller polyps—which are much more common—is unknown. Some but not all observational evidence indicates that this reduction may be greater for left-sided CRC than for right-sided CRC.[22–24]
Magnitude of Effect: Unknown, probably greater for larger polyps (i.e., >1.0 cm) than smaller ones.[25]
- Study Design: Evidence obtained from cohort studies and one RCT of sigmoidoscopy.[23]
- Internal Validity: Good.
- Consistency: Consistent.
- External Validity: Good.
Harms
Based on solid evidence, the major harms of polyp removal during colonoscopy or sigmoidoscopy include a tear in the wall of the colon and bleeding.
Magnitude of Effect: Seven to nine events per 1,000 procedures.[26–28]
It is not clear if the following affect the risk of colorectal cancer:
Nonsteroidal anti-inflammatory drugs (NSAIDs) other than aspirin
It is not known if the use of nonsteroidal anti-inflammatory drugs or NSAIDs (such as sulindac, celecoxib, naproxen, and ibuprofen) lowers the risk of colorectal cancer.
Studies have shown that taking the nonsteroidal anti-inflammatory drug celecoxib reduces the risk of colorectal adenomas (benign tumors) coming back after they have been removed. It is not clear if this results in a lower risk of colorectal cancer.
Taking sulindac or celecoxib has been shown to reduce the number and size of polyps that form in the colon and rectum of people with familial adenomatous polyposis (FAP). It is not clear if this results in a lower risk of colorectal cancer.
The possible harms of NSAIDs include:
- Kidney problems.
- Bleeding in the stomach, intestines, or brain.
- Heart problems such as heart attack and congestive heart failure.
Calcium
It is not known if taking calcium supplements lowers the risk of colorectal cancer.
Diet
It is not known if a diet low in fat and meat and high in fiber, fruits, and vegetables lowers the risk of colorectal cancer.
Some studies have shown that a diet high in fat, proteins, calories, and meat increases the risk of colorectal cancer, but other studies have not.
The following factors do not affect the risk of colorectal cancer:
Hormone replacement therapy with estrogen only
Hormone replacement therapy with estrogen only does not lower the risk of having invasive colorectal cancer or the risk of dying from colorectal cancer.
Statins
Studies have shown that taking statins (drugs that lower cholesterol) does not increase or decrease the risk of colorectal cancer.
Cancer prevention clinical trials are used to investigate actions that can be taken to prevent cancer.
Cancer prevention clinical trials are used to study ways to lower the risk of developing certain types of cancer. Some cancer prevention trials are conducted with healthy people who have not had cancer but who have an increased risk for cancer. Other prevention trials are conducted with people who have had cancer and are trying to prevent another cancer of the same type or to lower their chance of developing a new type of cancer. Other trials are done with healthy volunteers who are not known to have any risk factors for cancer.
The purpose of some cancer prevention clinical trials is to find out whether actions people take can prevent cancer. These may include exercising more or quitting smoking or taking certain medicines, vitamins, minerals, or food supplements.
New ways to prevent colorectal cancer are being studied in clinical trials.
Clinical trials are taking place in many parts of the country. Information about clinical trials can be found in the Clinical Trials section of the NCI website. Check NCI’s list of cancer clinical trials for colon cancer prevention trials or rectal cancer prevention trials that are now accepting patients.
Follow-up and Survivorship
Limited data and no level 1 evidence are available to guide patients and physicians about surveillance and management of patients after surgical resection and adjuvant therapy. The American Society of Clinical Oncology and the National Comprehensive Cancer Network recommend specific surveillance and follow-up strategies.[31,32]
Following treatment of colon cancer, periodic evaluations may lead to the earlier identification and management of recurrent disease.[33–36] The impact of such monitoring on overall mortality of patients with recurrent colon cancer, however, is limited by the relatively small proportion of patients in whom localized, potentially curable metastases are found. To date, no large-scale randomized trials have documented an OS benefit for standard, postoperative monitoring program.[37–41]
CEA is a serum glycoprotein frequently used in the management of patients with colon cancer. A review of the use of this tumor marker suggests the following:[42]
- A CEA level is not a valuable screening test for colorectal cancer because of the large numbers of false-positive and false-negative reports.
- Postoperative CEA testing should be restricted to patients who would be candidates for resection of liver or lung metastases.
- Routine use of CEA levels alone for monitoring response to treatment should not be recommended.
The optimal regimen and frequency of follow-up examinations are not well defined because the impact on patient survival is not clear and the quality of data is poor.[39–41]
Factors Associated with Recurrence
Diet and exercise
No prospective randomized trials have demonstrated an improvement in outcome with a specific diet or exercise regimen; however, cohort studies suggest that diet or exercise regimen may improve outcome. The cohort studies contain multiple opportunities for unintended bias, and caution is needed when using the data from them.
Two prospective observational studies were performed with patients enrolled on the Cancer and Leukemia Group B (CALGB-89803 [NCT00003835] trial), which was an adjuvant chemotherapy trial for patients with stage III colon cancer.[43,44] In this trial, patients in the lowest quintile of the Western dietary pattern compared with those patients in the highest quintile experienced an adjusted hazard ratio (HR) for disease-free survival of 3.25 (95% confidence interval [CI], 2.04–5.19; P < .001) and an OS of 2.32 (95% CI, 1.36–3.96; P < .001). Additionally, findings included that stage III colon cancer patients in the highest quintile of dietary glycemic load experienced an adjusted HR for OS of 1.76 (95% CI, 1.22–2.54; P < .001) compared with those in the lowest quintile. Subsequently, in the Cancer Prevention Study II Nutrition Cohort, among 2,315 participants diagnosed with colorectal cancer, the degree of red and processed meat intake before diagnosis was associated with a higher risk of death (relative risk [RR], 1.29; 95% CI, 1.05–1.59; P = .03), but red meat consumption after diagnosis was not associated with overall mortality.[45][Level of evidence: 3iiA]
A meta-analysis of seven prospective cohort studies evaluating physical activity before and after a diagnosis of colorectal cancer demonstrated that patients who participated in any amount of physical activity before diagnosis had a RR of 0.75 (95% CI, 0.65–0.87; P < .001) for colorectal cancer-specific mortality compared with patients who did not participate in any physical activity.[46] Patients who participated in a high amount of physical activity (vs. a low amount) before diagnosis had a RR of 0.70 (95% CI, 0.56–0.87; P = .002). Patients who participated in any physical activity (compared with no activity) after diagnosis had a RR of 0.74 (95% CI, 0.58–0.95; P = .02) for colorectal cancer-specific mortality. Those who participated in a high amount of physical activity (vs. a low amount) after diagnosis had a RR of 0.65 (95% CI, 0.47–0.92; P = .01).[46][Level of evidence: 3iiB]
Aspirin
A prospective cohort study examined the use of aspirin after a colorectal cancer diagnosis.[47] Regular users of aspirin after a diagnosis of colorectal cancer experienced an HR of colon cancer-specific survival of 0.71 (95% CI, 0.65–0.97) and an OS of 0.79 (95% CI, 0.65–0.97).[47][Level of evidence: 3iiA] One study evaluated 964 patients with rectal or colon cancer from the Nurse’s Health Study and the Health Professional Follow-up Study.[48] Among patients with PI3K-mutant colorectal cancer, regular use of aspirin was associated with an HR for OS of 0.54 (95% CI, 0.31–0.94; P = .01)[48][Level of evidence: 3iiiA]
Factors With Inadequate Evidence of an Association With Colorectal Cancer
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Benefits
There is inadequate evidence that the use of NSAIDs reduces the risk of CRC. In people without genetic predisposition but with a prior history of a colonic adenoma that had been removed, three RCT found that celecoxib [29,30] and rofecoxib [31] decreased the incidence of recurrent adenoma, although follow-up was too short to determine whether CRC incidence or mortality would have been affected.
Based on solid evidence, NSAIDs reduce the risk of adenomas, but the extent to which this translates into a reduction of CRC is uncertain.
- Study Design: No adequate studies with CRC outcome.
- Internal Validity: N/A.
- Consistency: N/A.
- External Validity: N/A.
Harms
Based on solid evidence, harms of NSAID use are relatively common and potentially serious, and include upper gastrointestinal bleeding, chronic kidney disease, and serious cardiovascular events such as myocardial infarction, heart failure, and hemorrhagic stroke.[32] A recent report compared the COX-2 inhibitor celecoxib (200 mg/d) with the nonselective nonsteroidals naproxen (850 mg/d) and ibuprofen (2,000 mg/d) in individuals with severe arthritis (i.e., not using lower doses as for primary prevention). The results showed that serious cardiovascular events were not less common for those taking the nonselective nonsteroidals. However, this study did not assess the comparative safety of lower doses or the safety of the COX-2 inhibitor rofecoxib.[33]
Magnitude of Effect: The estimated average excess risk of upper gastrointestinal complications in average-risk people attributable to NSAIDs is 4 to 5 per 1,000 people per year.[34,35] The excess risk varies with the underlying gastrointestinal risk, however, it likely exceeds ten extra cases per 1,000 people per year in more than 10% of users.[36] Serious cardiovascular events are increased by 50% to 60%.[35]
Calcium supplementation
There is inadequate evidence to determine whether calcium supplementation reduces the risk of CRC. A randomized placebo-controlled trial tested the effect of calcium supplementation (3 g calcium carbonate daily [1,200 mg elemental calcium]) on the risk of recurrent adenoma.[101] The primary endpoint was the proportion of patients (72% of whom were male) in whom at least one adenoma was detected following a first and/or second follow-up endoscopy. A modest decrease in risk was found for both developing at least one recurrent adenoma (adjusted risk ratio [ARR], 0.81; 95% CI, 0.67–0.99) and in the average number of adenomas (ARR, 0.76; 95% CI, 0.60–0.96). The investigators found the effect of calcium was similar across age, sex, and baseline dietary intake categories of calcium, fat, or fiber. The study was limited to individuals with a recent history of colorectal adenomas and could not determine the effect of calcium on risk of the first adenoma, nor was it large enough or of sufficient duration to examine the risk of invasive CRC. After calcium supplementation is stopped, the lower risk may persist up to 5 years.[102] The results of other ongoing adenoma recurrence studies are awaited with interest. It is important to note that the dose of calcium salt administered may be important; the usual daily doses in trials have ranged from 1,250 to 2,000 mg of calcium.
In a randomized, double-blind, placebo-controlled trial involving 36,282 postmenopausal women, the administration of 500 mg of elemental calcium and 200 IU of vitamin D3 twice daily for an average of 7.0 years was not associated with a reduction in invasive CRC (HR, 1.08; 95% CI, 0.86–1.34; P = .051).[103] The relatively short duration of follow-up, considering the latency period of CRC of 10 to 15 years, and suboptimal doses of calcium and vitamin D, may account for the negative effects of this trial, although other factors may also be responsible.[104]
Dietary factors
Dietary fat and meat intake
There is no reliable evidence that a diet started in adulthood that is low in fat and meat and high in fiber, fruits, and vegetables reduces the risk of CRC by a clinically important degree. Colon cancer rates are high in populations with high total fat intakes and are lower in those consuming less fat.[105] On average, fat comprises 40% to 45% of total caloric intake in high-incidence Western countries; in low-risk populations, fat accounts for only 10% of dietary calories.[106] In laboratory studies, a high-fat intake increases the incidence of induced colon tumors in experimental animals.[107,108] Several case-control studies have explored the association of colon cancer risk with meat or fat consumption as well as protein and energy intake.[12,109] Although positive associations with meat consumption or with fat intake have been found frequently, the results have not always achieved statistical significance.[110] A number of prospective cohort studies have been conducted in the United States and abroad. In Japan, an increased risk of colon cancer with increased frequency of meat consumption was observed in the group with infrequent vegetable consumption among a group of 265,000 men and women.[111] In Norway, an increased risk for processed meat only was found,[112] a finding that was confirmed in the Netherlands.[113] A clearly defined gradient in the risk for frequency of meat and poultry consumption was not observed in a population of Seventh Day Adventists that included a large proportion of vegetarians.[114] A prospective study among female nurses showed an increased risk of colon cancer associated with red meat consumption (beef, pork, lamb, and processed meat) and also with the intake of saturated and monounsaturated fat, predominantly derived from animals.[115] In two other large prospective studies, the CPS II and the Iowa Women’s Health Study (IWHS), no increase in the risk of colon cancer was seen with meat or fat consumption.[116,117] In a prospective cohort study of a low-risk population of non-Hispanic white members of the Adventist Health Study, a positive association between meat (both red and white) intake and colon cancer was observed (RR for ≥1 time per week vs. no meat intake, 1.85; 95% CI, 1.19–2.87; P for trend = .01).[118] It has been hypothesized that the heterocyclic amines (HCAs) formed when meat and fish are cooked at high temperatures may contribute to the increased risk of CRCs associated with meat consumption that has been observed in epidemiologic studies. A population-based case-control study in Sweden, however, found no evidence of increased risk associated with total HCA intake; for colon cancer the RR was 0.6 (95% CI, 0.4–1.0), and for rectal cancer it was 0.7 (95% CI, 0.4–1.1).[119,120]
A randomized controlled dietary modification study was undertaken among 48,835 postmenopausal women aged 50 to 79 years who were also enrolled in the WHI. The intervention promoted a goal of reducing total fat intake by 20%, while increasing daily intake of vegetables, fruits, and grains. The intervention group accomplished a reduction of fat intake of approximately 10% more than did the comparison group during the 8.1 years of follow-up. There was no evidence of reduction in invasive CRCs between the intervention and comparison groups with a HR of 1.08 (95% CI, 0.90–1.29).[121] Likewise, there was no benefit of the low-fat diet on all-cancer mortality, overall mortality, or cardiovascular disease.[122]
Explanations for the conflicting results regarding whether dietary fat or meat intake affects the risk of CRC [113] include:
- Validity of dietary questionnaires used.
- Differences in the average age of the population studied.
- Variations in methods of meat preparation (in some instances, mutagenic and carcinogenic HCAs could have been released at high temperatures).[123]
- Variability in the consumption of other foods such as vegetables.[124]
Six case-control studies and two cohort studies have explored potential dietary risk factors for colorectal adenomas.[22,125] Three of the eight studies found that higher fat consumption was associated with increased risk. High fat intake has been found to increase the risk of adenoma recurrence following polypectomy.[126] In a multicenter RCT, a diet low in fat (20% of total calories) and high in fiber, fruits, and vegetables did not reduce the risk of recurrence of colorectal adenomas.[127]
Thus, the evidence is inadequate to determine whether reducing dietary fat and meat would reduce CRC incidence.
Factors and Interventions With Adequate Evidence of No Association With Colorectal Cancer
Estrogen-only therapy
Benefits
Based on fair evidence, conjugated equine estrogens do not affect the incidence of, or survival from, invasive CRC.[37]
Magnitude of Effect: N/A.
- Study Design: Evidence from RCTs.
- Internal Validity: Good.
- Consistency: Good.
- External Validity: Fair.
Statins
Benefits
Based on solid evidence, statins do not reduce the incidence or mortality from CRC.
Harms
Based on solid evidence, the harms of statins are small.
Related Summaries
US NCI PDQ summaries containing information related to colon cancer include the following:
- Colorectal Cancer Prevention
- Colorectal Cancer Screening
- Genetics of Colorectal Cancer
- Unusual Cancers of Childhood Treatment (childhood cancer of the colon)