Epidemiology, risk factors, and prevention

Epidemiology, risk factors, and prevention

Author's Accepted Manuscript Epidemiology, risk factors, and prevention Radhika Smith MD, David J. Maron MD, MBA, FACS www.elsevier.com/locate/yscrs...

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Author's Accepted Manuscript

Epidemiology, risk factors, and prevention Radhika Smith MD, David J. Maron MD, MBA, FACS


PII: DOI: Reference:

S1043-1489(16)30021-5 http://dx.doi.org/10.1053/j.scrs.2016.04.014 YSCRS566

To appear in:

Seminars in Colon and Rectal Surgery

Cite this article as: Radhika Smith MD, David J. Maron MD, MBA, FACS, Epidemiology, risk factors, and prevention, Seminars in Colon and Rectal Surgery, http://dx.doi.org/10.1053/j.scrs.2016.04.014 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Special Issue: “Current Concepts in Colon Cancer” for Seminars in Colon and Rectal Surgery Epidemiology, Risk Factors, and Prevention

Title Page 1. Authors: Radhika Smith, MD Clinical Fellow Department of Colon and Rectal Surgery Cleveland Clinic Florida Weston, Florida David J. Maron, MD, MBA, FACS Vice Chairman Department of Colon and Rectal Surgery Cleveland Clinic Florida Weston, Florida

2. This original work is from Cleveland Clinic Florida 3. We have no grant support to acknowledge 4. Correspondence David J. Maron, MD, MBA, FACS 2950 Cleveland Clinic Blvd Weston FL 33331 T: (954) 659-5278 F: (954) 659-5252 [email protected]

Abstract Colorectal cancer (CRC) represents a significant burden of disease worldwide. It is the third most commonly diagnosed malignancy with an estimated prevalence of 1.1 million cases. Numerous factors have been linked to the development of CRC.

Non-modifiable factors

associated with risk include age, family history, race, and the presence of inflammatory bowel disease. There are many modifiable factors which also affect risk such as dietary habits, level of physical activity, tobacco abuse, and the use of certain medications such as aspirin, non-steroidal anti-inflammatory drugs and hormone replacement therapy.

Prevention of CRC through the

removal of adenomatous polyp and the rapid diagnosis of early stage CRC remain at the forefront of disease management.

Key words Colon Cancer, Epidemiology, Risk Factors, Prevention, and Screening

Introduction Colon cancer represents a significant burden of disease worldwide. While the treatment modalities of colon cancer differ from that of rectal cancer, the risk factors, pathogenesis and preventative measures for both malignant processes are the same. While the focus of this manuscript is specific to colon cancer, discussion of the epidemiology of one of these processes is often inclusive of the other. Epidemiology Worldwide, colon and rectal cancer (CRC) is the fourth most commonly diagnosed cancer in men and third most common in women. In the United States, CRC is the third most common malignancy in both men and women, and an estimated 49,700 people will die of CRC in 20151. The National Cancer Institute estimates 132,700 new cases will be diagnosed this year with an estimated prevalence of approximately 1.1 million cases1. Approximately 5% of Americans will develop CRC in their lifetime, and it has been estimated that preventable colon cancer deaths has cost the US economy $6.4 billion2. Since 1985, the incidence of CRC in the US has declined by an average of 1.6% per year. This reduction is primarily due to a decrease in the number of distal tumors, which is likely a result of increased rates of screening. Interestingly, the incidence of proximal cancers has remained roughly the same. Age greater than 50 years is the foremost risk factor for CRC. Ninety percent of newly diagnosed cases and 93% of all deaths occur within this age group3,4. The median age of diagnosis is 68 years and the median age of death of is 73 years5.

In a recent population

analysis, the overall incidence of CRC was noted to be on the decline, but there was a paradoxical increase seen in young adults. Using the Surveillance, Epidemiology, and End

Results (SEER) Colorectal Cancer registry, the authors noted an increased incidence of localized, regional, and distant CRCs in patients from 20-49 years of age. By the year 2030, based on current rate of rise, they project an increase in the incidence of colon cancer by 90% for patients 20 to 34 years and by 28% for patients 35 to 496.

Currently, about 15% of colorectal

malignancies are diagnosed in patients between 45-54 years of age2, which suggests there may be a group of patients that are missed in current screening practices. The incidence of colon cancer is about equal between men and women, but rectal cancer seems to have a higher preponderance in males. Men tend to have a significantly higher reported mortality when compared to women, and women tend to have a higher proportion of lesions located in the proximal colon4,7. These findings suggest there may be an effect from sex hormones on the pathogenesis of CRC. In the United States, CRC rates are highest in African Americans and lowest in Asian and Pacific Islanders8. Additionally, Ashkenazi Jewish individuals also appear to be at increased risk9. There is a large body of evidence that suggests race conveys a significant disparity on CRC mortality as well. African American patients have a mortality rate 50% higher than Caucasian Americans and double that of Asian and Pacific Islander patients10. Additionally, African Americans have not experienced the substantial reduction of CRC incidence that has been seen in the Caucasian patient population. In fact, prior to 1980 the incidence of CRC was lower in African American patients11.

Risk Factors

Using a logistic regression model and adjusting for age and family history, Platz et al. suggested that modification of six risk factors can decrease the occurrence of CRC by 70%12. These risk factors include obesity, physical inactivity, alcohol consumption, early adulthood cigarette smoking, red meat consumption, and low intake of folic acid. Numerous other factors such as family history, inflammatory bowel disease, medications, and the hormonal milieu have all been associated to varying degrees with the development of CRC. The reported incidence of CRC in some Western countries is up to ten times higher than that of many far eastern and developing nations13. In addition, the rapid rise in rates of malignancy among migrants from low-risk to high-risk areas also indicates that there are significant environmental influences in the pathophysiology of CRC14,15.

Dietary Factors A 1981 landmark report in the Journal of the National Cancer Institute estimated that 35% of US cancer deaths were attributable to dietary influence13. Given the complexity and variability of diets, it is very difficult to directly define the implications of these factors. Many of these presumed risks are based on observational studies, and any prospective or controlled studies are difficult to reliably interpret. Despite these limitations, many factors have been causally associated with the development of or protection against CRC.

Dietary Fat It is known that countries with high dietary fat consumption have a higher incidence of CRC than populations who consume less16. Dietary fat has been shown to have a carcinogenic effect in animal models17,18 and numerous case control studies have shown an association with the development of CRC in subjects with high dietary fat intake19-23. There are very few studies, however, evaluate dietary fat as a risk factor and also control for total energy intake.


authors have theorized instead that the risk conferred may be from the total caloric intake rather than the total amount of fat consumed24. Willett, et al. demonstrated a two-fold increase in the rate of CRC in individuals who were the highest consumers of animal fat when compared to those who consumed the least24. Few other studies, however, have shown similar results. In a prospective clinical trial, over 48,000 females were randomized to a high-fiber, low-fat diet or control (no dietary modification). No difference was seen in the incidence of CRC between the groups at a followup of more than eight years, although the authors comment that target diet modification was only met by two-thirds of the subjects. Overall, the evidence to suggest an association between increased dietary fat and increased risk of CRC is weak. Red Meat Consumption The increase in dietary animal fat by red meat is another hypothesis of carcinogenesis in CRC. Thought to be more of an influence, however, is the increase in fecal concentration of endogenous nitrosamines25 and tryptophan metabolites found in red meat26 and the carcinogens that result from the cooking of meat27. Two meta-analyses demonstrate this association28,29. Their results indicate that a daily increase of 100g of meat is associated with a 12-17% increased risk of CRC and an increase of 25g of processed meat is associated with a 49% increased risk29.

One study proposed that if the average red meat intake is reduced to 70g per week in regions with high intake, the risk of developing CRC would decrease by 7–24%28. As those individuals who consume increased amounts of red meat also tend to consume a diet lower in fiber and live a more sedentary lifestyle, it is difficult to determine whether meat intake is as important as these other factors. Alcohol Through direct toxic effects and through the reduction of folate bioavailability, increased alcohol consumption has been linked to an increase in CRC. It has been suggested that people who consume an average of two to four alcoholic beverages per day have a 23% higher risk of CRC than those who consume less than one drink per day30. Tobacco Abuse Because of the slow progression to cancer seen with consistent and prolonged tobacco abuse, it has been difficult to study its effects on CRC development. In November 2009, the International Agency for Research on Cancer definitively reported that tobacco smoking can cause CRC31.

A meta-analysis of 106 observational studies demonstrated that smoking was

associated with an absolute risk increase of 10.8 cases and 6 deaths per 100,000 person-years. For both incidence and mortality, the association was stronger for cancer of the rectum when compared to cancer of the colon. Inflammatory Bowel Disease Ulcerative Colitis In 1925, Crohn and Rosenberg first reported the complication of malignancy after long standing ulcerative colitis (UC)32. Malignancy accounts for 17% of all deaths in patients with UC33, but the degree of increased risk is inconsistently reported. Some studies quote a risk as

low as 1.4% at 18 years34 while others as high as 34% after 25 years of disease35. In response to this, a meta-analysis was published which included 116 studies, 41 of which reported on colitis duration. The authors determined the incidence of cancer to be three per 1,000 person-year’s duration. Nineteen studies reported their results stratified into 10-year intervals and authors calculated the probability of 2% cancer incidence after 10 years of colitis, 8% by 20 years, and 18% by 30 years of disease36. In addition to the duration of disease, factors that may affect the development of CRC in ulcerative colitis include the extent and severity of the colitis, the presence of inflammatory psuedopolyps, and a concomitant diagnosis of primary sclerosing cholangitis. In a cohort of over 3,000 patients with UC, the increased risk of CRC was 1.7, 2.8, and 14.8 in patients with ulcerative proctitis, left-sided colitis, and pancolitis, respectively37. Crohn’s Colitis The relationship of malignancy and Crohn's disease (CD) is less clear than with UC. Risk estimates are variable and within the observational data that is available there are conflicting results. A published meta-analysis included 14 papers with 12 reporting CRC risk. The cumulative risk analysis for all patients with CD at any site reported an incidence of CRC after 10 years of 2.9%, 5.6% by 20 years, and 8.3% after 30 years38. Most studies show a significantly higher risk of small intestinal cancer in patients with Crohn’s when compared to the general population. Family History An affected first-degree relative has consistently been associated with an increased risk in the development of CRC. Approximately 20% of those diagnosed with CRC have a close relative who was also diagnosed with the disease, and roughly 5-6% of all patients have a

defined germline mutation39. A meta-analysis of 47 studies concluded that these patients have two to three times the risk of developing CRC when compared to individuals with no family history. The authors quote a lifetime risk of 1.8% for a 50-year old with no family history. In a patient with one affected relative, the risk increases to 3.4%, and to 6.9% if there are two or more affected relatives40. Further, in patients with a relative diagnosed at a young age or with more than one affected relative, the risk increases to 3 to 6 times that of the general population40,41. Family history has also been found to be protective with an increase in overall survival. This is likely due to heighted awareness leading to earlier detection and adherence to screening recommendations42. Endoscopic screening and a thorough history to evaluate for associated familial syndromes are of paramount importance in all patients with a family history of CRC Prevention Detection and Removal of Precursor Lesions CRC is a highly prevalent disease with a long latent period in which the majority of cancers will develop from an established precursor lesion. Current screening practices are effective, simple, and inexpensive.

Numerous studies have demonstrated a reduction of

mortality through early detection and prevention by the initiation of screening practices. It has been estimated that without appropriate screening and preventative measures, approximately one in 17 Americans will develop CRC43. Screening endoscopy enables primary prevention through the detection and removal of adenomatous polyps44 and allows for secondary prevention through the detection of cancers at an earlier stage. At least 95% of colorectal cancers arise from the adenoma to carcinoma sequence45,46, and while the five year survival of localized CRC is approximately 91%, survival rates drop to approximately 70% in patients with advanced disease with the presence of lymph node metastasis and to 13% with distant spread47.

Despite this fact, just over half (58.8%) of adults aged 50-75 received CRC screening based on current guidelines in 201348.

The U.S. Preventative Services Task Force currently

recommends that all adults of average risk begin screening at age 50 years and continue until age 75 years. Screening for those patients age 76-85 is under the discretion of the treated physician, and the group recommends against routine screening in all patients over the age of 8549. Appropriate screening modalities include: 1. Fecal occult blood testing annually 2. Flexible sigmoidoscopy every 5 years 3. Fecal occult blood testing annually and flexible sigmoidoscopy every 5 years 4. Air contrast barium enema every 5 to 10 years 5. Flexible colonoscopy every 10 years Screening of average-risk individuals reduces the incidence and mortality of CRC. Each test for screening confers unique advantages with associated limitations and risks. Availability of resource and patient preferences play an important role in the selection of screening tests that allow for widespread delivery of care and compliance with recommendations.

The most

effective way to reduce the incidence of CRC and improve outcomes remains with early detection of adenomas and cancers by adherence to screening protocols set forth in evidence based guidelines.

The efficacy of various screening modalities and new technology are

discussed in “Advances in Colonoscopy and Screening” elsewhere in this issue.

Chemoprevention Aspirin and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) There are good data to support the associated risk reduction of adenomas and CRC at all stages in patients who take NSAIDs, but the mechanism by which way these medications work to this end is unknown. Numerous observational studies and several controlled trials have demonstrated risk reduction50-55, but the potential for side effects of these medications have outweighed the benefit when considering routine chemoprevention. A systematic meta-analysis was undertaken by the United States Preventative Services Task Force (USPSTF)56 which examined 15 case-control studies, 11 cohort studies, and five randomized controlled trials of aspirin as chemoprophylaxis of CRCs and adenomas and 20 case-control studies, four cohort studies and four randomized controlled trials of non-aspirin NSAIDs.

While both reports

showed a risk reduction in adenoma and cancer formation, there was a greater potential for harm, and the USPSTF recommended against the routine use for risk reduction. Patients who do require aspirin or NSAIDs for alternative indications such as cardiovascular health or analgesia may experience the benefits of risk reduction. Hormone Replacement Therapy Estrogen may have a direct protective effect on colonic mucosa and also decreases bile acid secretion which can lead to a reduction in CRC. Many observational studies and welldesigned randomized controlled trials have reported that those women who use postmenopausal replacement hormones have lower rates of CRC than those who do not57-59. A meta-analysis of 18 studies showed postmenopausal women who had taken hormone replacement experienced a 20% risk reduction in the incidence of CRC. The authors also noted a 34% reduction among women who were actively taking hormones at the time of the study60. The Women’s Health

Initiative trial analyzed the overall effect of estrogen plus progestin and included enrollment of over 16,000 postmenopausal women. The authors found that the use of hormone replacement was associated with a deceased incidence of CRC.

Interestingly, the malignancies that

developed in women who took hormone replacement were diagnosed at a more advanced stage and with a greater number of positive lymph nodes despite similar screening frequency. Unfortunately, the trial was terminated prematurely because of the increased rate of breast cancer and therefore hormone replacement is not recommended for chemoprevention61.


findings have been reported with oral contraceptives62. Dietary Changes Fruit and Vegetable Intake Evidence that a diet high in fruits and vegetables will reduce the risk of CRC is highly inconsistent and observed associations are weak. These foods are rich in antioxidants and thought to have a protective impact against cancer formation. A meta-analysis which included 19 prospective studies showed a very modest but statistically significant nonlinear inverse association between fruit and vegetable intake and CRC risk63. Extremely high consumption of fruits and vegetables do not seem to have a protective effect, however extremely low intake of these foods could pose an increased risk64. Fiber The initial observation of low rates of colon cancer in areas of Africa where fiber consumption and stool bulk are high began an inquiry of whether high fiber intake is protective against CRC65. This theory is based around the ability of fiber to reduce the mucosal exposure to ingested carcinogens through increased gastrointestinal transit time and the absorption and dilution of various carcinogens. Further, the byproduct of fiber metabolism generates molecules

such as butyrate which may have protective effects66. The science to support this is mixed, however. A meta-analysis of aggregated data from 37 observational studies and 16 case-control studies found an association between high fiber intake and lower rates of CRC67. Conversely, a randomized controlled trial which attempted to show a reduction in adenomatous polyps after initiation of a low fat, high fiber diet with fiber supplementation did not show any reduction of high risk or advanced adenoma formation at a follow-up of four years68. Calcium Many observational studies have shown an association between calcium, vitamin D, and a reduction in CRC69-72.

This association was not substantiated by a large multi-centered

randomized, double-blind, placebo-controlled trial73.

The authors randomized over 36,000

postmenopausal women to calcium and vitamin D versus placebo and followed them for the development of CRC for an average of 7 years. This intervention was found to have no effect on the incidence of cancer. While the duration of follow up could have been a limiting factor, the authors do not recommend routine supplementation in this demographic to reduce the risk of malignancy.

Furthermore, a Cochran review aggregated the two published randomized

controlled trials and could not find conclusive evidence to recommend the general use of calcium supplementation to prevent CRC74. Folate There has been significant controversy around the role folate plays in CRC pathogenesis. Folate is an essential B vitamin that is involved in nucleotide synthesis and methylation reactions. It has been proposed that an inadequate intake of folate may increase the risk of CRC due to hypomethylation of DNA and by uracil misincorporation in DNA repair75. In 1998, the US and Canadian governments mandated folic acid fortification in all cereal grain to reduce the

incidence of neural tube defects.

Immediately following this intervention, there was a reversal

in the downward trend both countries had experienced in the preceding years of the incidence of CRC. Controlling for other factors, it was hypothesized the additional folate may have been wholly or partly responsible for the observed increase76. That same year, a multi-center doubleblinded, randomized placebo-controlled clinical trial examined the effect of folic acid supplementation on the incidence of polyps and cancer formation77. Participants were randomly assigned to receive 1 mg/day of folic acid or placebo and followed with colonoscopy at three to five years. The authors found that folic acid was associated with higher risks of having three or more adenomas and with the development of non-colorectal cancers. Conversely, an analysis over 100,000 patients enrolled in the Cancer Prevention Study II Nutrition Cohort found total folate intake was significantly associated with lower risk of CRC78. A recently published metaanalysis looked at 27 case controlled and cohort studies and also suggested that higher folate intake can offer a reduction in the risk of CRC79. Physical Activity There is a large body of evidence that consistently supports the role of physical activity in the reduction of CRC. A meta-analysis of 21 studies found that most physically active people have a 27% risk reduction of colon cancer80.

Additionally, it has been demonstrated that

patients with an established diagnosis of CRC who were physically inactive had higher all-cause mortality than their matched active cohort81. The American Cancer Society and the Centers for Disease Control and Prevention recommend engaging in at least 150 minutes of moderateintensity activity or 75 minutes of vigorous-intensity activity each week82. In 2012, only about half of US adults met these physical activity guidelines83.



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