Colorectal cancer screening

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GASTROENTEROLOGY 0095-4543/01 $15.00 + .OO

COLORECTAL CANCER SCREENING

Marie L. Borum, MD, MPH

EPIDEMIOLOGY

Colorectal cancer causes significant morbidity and mortality in the United States. It is the fourth most common form of cancer and has the second highest mortality rate in this nation. This malignancy will account for approximately 135,000 new cancer cases and nearly 56,000 cancer deaths in 2001.” The average lifetime risk of developing colorectal cancer is approximately 6Y0.8 The incidence of colorectal cancer is almost equal in men and women. This malignancy occurs in all ethnic groups, with African- Americans having the highest prevalence and mortality ratesz0 The estimated 5-year survival is 91% in individuals with localized disease, 60% in individuals with regional spread, and 6% in individuals with distant metastases.40

ADENOMA-CARCINOMA SEQUENCE

More than 95% of colorectal cancers develop from adenomatous polyps. Adenomatous polyps are categorized as tubular, villous, or tubulovillous. Tubular adenomas, the most common type of adenomas, have a low likelihood of undergoing malignant transformation (< 3% of the time). Villous adenomas, accounting for close to 5% of all adenomas, have a malignant potential of 15% to 25%. Tubulovillous adenomas, accounting for approximately 10% to 25% of all adenomas, have elements of both tubular and villous adenomas and an intermediate risk of undergoing malignant transformation.’

From the Division of Gastroenterology, Department of Medicine, The George Washington University Medical Center, Washington, DC

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PRIMARY CARE: CLINICS IN OFFICE PRACTICE

VOLUME 28 NUMBER 3 SEPTEMBER 2001 661

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Malignant transformation of an adenoma is also related to the size of the polyp. Polyps which are less than 1 cm have lower than a 1% likelihood of becoming malignant.51 The U.S. National Polyp Study, which evaluated the effect of polypectomy on the incidence of colorectal cancer, suggested that most small, simple tubular adenomas remain small and clinically be- nign. In contrast, polyps which are larger than 1 cm or contain significant villous tissue or high-grade dys lasia are more likely to develop into cancer, if not detected and resected. 9 7

RISK FACTORS

The incidence of colorectal cancer increases substantially at approximately 50 years of age. The predominant risk factor in most individuals who develop colorectal cancer in the United States is age over 50 years. There are, however, groups of individuals in whom other risk factors have been identified. These include individuals with a personal history of successfully resected colorectal cancer or adenomas, a family history of colon cancer or adenomas, inherited colorectal cancer syndromes (i.e., familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer (HNPCC)), and longstanding ulcerative colitis or, perhaps, Crohn’s ~ o l i t i s . ~ ~ , ~ ~ It has also been suggested that diets high in fat or low in fiber may increase colorectal cancer risk.%

Personal History of Colorectal Cancer

More than 95% of colorectal cancers in the United States arise from adenomatous polyps. Patients who have had a previously resected colorectal cancer have an increased risk for the development of subsequent adenomas or cancers. Approximately 80% of cancer recurrences occur within 2 years and 90% within 4 years of resection. Individuals with previously resected colorectal cancer therefore require close post-operative surveillance.

Personal History of Colonic Adenomas

All individuals with a history of adenomas are at risk for development of additional adenomas. Individuals with previous adenomas can be categorized into different risk groups, however, depending upon the histologic type and number of adenomas that were resected. Data suggests that three or more adenomas may be the primary determinant of subsequent adenoma development. Patients with only one or two tubular adenomas are at lowest risk for recurrent adenomas. Patients with large sessile adenomas tend to have recurrences at the polypectomy site.

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Family History

Individuals with a family history of colorectal cancer are at increased risk for development of the same malignancy. This risk is based upon whether the colorectal cancer was a sporadic cancer or a component of an inherited colorectal cancer syndrome.

Sporadic Colorectal Cancer

An individual with one first-degree relative with colorectal cancer has a two- to three-fold increased risk for colorectal cancer development. An individual with two first-degree relatives with colorectal cancer or a single first-degree relative diagnosed with colorectal cancer prior to age 50 has a three- to six-fold increase in colorectal cancer development. Two second- degree relatives with colorectal cancer increase an individual’s risk for colorectal cancer development by one- to two-f~ld .~~, 38

Inherited Colorectal Cancer Syndromes

Familial Adenomatous Polyposis

Familial Adenomatous Polyposis (FAP) accounts for approximately 1% of all of the colorectal cancers in the US. It is an autosomally dominant disorder resulting from a germline mutation in the adenomatous polyposis coli (APC) gene on chromosome 5. Individuals develop adenomas in their teenage years, with 95% developing colorectal cancer by age 50 years if a colectomy has not been performed. The presence of more than 100 adenomas is the defining feature of this disorder.”

A variant syndrome, attenuated adenomatous polyposis coli (AAPC), is characterized by fewer polypsz that are located predominantly in the proximal colon. It generally presents at an older age and is associated with mutations near the 5‘ and 3‘ end of the APC gene.24

Gardner’s Syndrome

Gardner ’s syndrome is an autosomally dominant disorder that may develop adenomas of the large and small bowel in association with desmoid tumors of the mesentery and abdominal wall, lipomas, osteomas, and fibro- mas. It has a high risk of cancer formation and is probably a variant of FAP.

Turcot’s Syndrome

Turcot’s syndrome is a disorder that is characterized by colon polyps in association with brain tumors. It may be a variant of FAP or Hereditary Non-polyposis Colorectal Cancer (HNPCC). It has been speculated that if the brain tumors are cerebellar medulloblastomas the condition is likely a

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variant of FAP. If the brain tumors are indolent glioblastoma multiforme, then the condition may be a variant of HNPCC.

Muir- Torre Syndrome

Muir-Torre syndrome is a variant of FAP that is characterized by carcinomas of the colon, duodenum, larynx and sebaceous tumors, and kera- toacanthomata of the face.

Hereditary Non-polyposis Colorectal Cancer (HNPCC)

Hereditary Non-polyposis Colorectal Cancer (HNPCC), or Lynch syndrome, accounts for 2% to 8% of colorectal cancers in the United States. This disorder is autosomally dominant and results from a germline mutation in one of several genes associated with DNA mismatch repair. Two genes, hMLHl and hMSH2, account for the majority of cases. This family of genes is responsible for the repair of mismatched bases that may occur during DNA replication. Tumors in HNPCC demonstrate a phenotype called microsatellite (MIS) instability or replication error. Individuals who inherit this gene defect have a 95% chance of developing a colon cancer or other tumors (i.e., genitourinary system, uterine and ovarian tumors, upper intestinal cancers, lymphoma). The most commonly used criteria for diagnosis is the modified Amsterdam criteria.6

Amsterdam Criteria

- Three or more relatives with CRC (certain cancers can be substituted

- CRC involving more than two generations - more than one relative CRC diagnosed prior to age 50

for CRC); one must be a first-degree relative of the other two

Inflammatory Bowel Disease

Ulcerative colitis is recognized as a risk for colorectal cancer development. The incidence increases with the extent of bowel involvement and the duration of the disease. Approximately 5% of individuals with ulcerative colitis for over 20 years and 12% after 25 years will develop colorectal carcinoma.8 The risk for the development of colorectal cancer in individuals with longstanding Crohn's colitis may also be increased. In individuals with inflammatory bowel disease, the mucosa undergoes dysplasia and proceeds through a series of mutations that can result in colon cancer.

Diet

High dietary fat may increase the risk of colorectal cancer development. The mechanism for cancer-promoting activity of fat has not been well elucidated.


MOLECULAR GENETICS

The majority of individuals (approximately 80%) who develop colorectal cancer have not been previous identified as individuals who are at increased risk for the development of colorectal cancer. These individuals develop cancer through a series of genetic errors that result in the development of adenomatous polyps. These polyps subsequently undergo mutations that can result in malignant transformation. This process may take 5 to 15 years to occur.16 It has been hypothesized that certain oncogene and tumor-suppressor gene alterations are the factors that support development of the malignancy. In approximately 80% of individuals, the earliest somatic mutation may involve the adenomatous polyposis coli (APC) gene on chromosome 5 (similar to FAP). In later stages of the process, K-ras mutations, p53 mutations or losses, and DCC (deleted in colon cancer) gene loss may occur. The initiating event may involve a mismatch repair gene. When gene mutation or absence occurs, colonic cells may become more susceptible to other genetic alterations that can result in colorectal cancer development.4,s, 5o

PREVENTION

Cancer prevention may be categorized as primary or secondary. Pri- mary prevention concerns the ability to identify genetic, biologic, and environmental factors that may result in tumor development. Although there are several areas of intense study, there is not firm data available that has been established for primary colorectal cancer prevention; however, epidemiologic data suggests environmental and lifestyle factors may impact upon colorectal cancer development.

The goal of secondary prevention is to identify existing preneoplastic lesions that can be treated. Screening asymptomatic individuals for any disease, including colorectal cancer, is worthwhile if the disease is a ma- jor health problem, effective therapy is available and the screening tools are acceptable and cost effective. A number of screening tests have been developed for colorectal cancer prevention. The absence of definitive in- formation about the best screening strategy has resulted in varying recommendations for colorectal cancer surveillance.

Primary Prevention

Environmental Factors

Epidemiologic studies have revealed markedly different colorectal cancer rates in different areas of the world. This suggests that environmental factors have a potential role in colorectal cancer development. The United States has among the highest rates of colorectal cancer incidence and mortality. The diet in the US and other countries with high colorectal

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cancer rates is high in total fat, red meat and relatively low in fruits, vegetables, and fiber. Individuals who have emigrated from low-risk geographic areas to high risk geographic areas often assume diets similar to their new area of residence resulting in increased incidence of colorectal cancer.* While cancer development is dependent upon genetic alterations, the interaction between the environment and genetics have the potential to influence cancer development. Primary prevention techniques including lifestyle modifications and chemoprevention are therefore being actively investigated.

Lifestyle

Epidemiologic data suggests that excess caloric intake and low levels of physical activity leading to obesity may be associated with an increase risk of colorectal cancer. The mechanism by which excess calories leads to colorectal carcinogenesis has not been elucidated. It is known, however, that physical exercise decreases colonic transit time, which may result in decreased exposure of colonic epithelial cells to luminal carcinogens.* Other factors which may be associated with colorectal cancer development include tobacco use and excess alcohol consumption? Individuals can be en- couraged to maintain normal body weight and regular exercise to achieve overall health benefits, including a potential decrease in colorectal cancer risk. Tobacco and excess alcohol use should be avoided.

Dietary Prevention

It has been suggested that dietary fiber may provide protection against colorectal cancer. High fiber diets may inhibit carcinogenesis by diluting the intestinal content of potentially carcinogenic substances, decreasing the contact between carcinogenic substances and colonic epithelial cells, and a reduction in intestinal transit time. The fiber containing fruits and vegetables may also contain micronutrients, vitamins, and minerals that inhibit or impede carcinogensis reverse premalignant changes or promote growth of normal epithelial It has, therefore, been suggested that diets high in fiber and low in fat content may be beneficial.

Chemoprevention

Chemoprevention can be defined as the use of a specific chemical compound to prevent, inhibit, or reverse carcinogenesis.''f4 Animal studies have suggested that a number of vitamins, minerals, and medications may be helpful in protection against colorectal cancer. Agents that have been and continue to be studied include antioxidant vitamins (A, E, and C), folic acid, vitamin D, calcium, selenium, aspirin, nonsteroidal anti-inflammatory drugs, ursodeoxycholic acid, and hormonal replacement in postmenopausal women. Results, however, have been inconcl~sive.~, 19, 22 Specific recommendations for dietary supplements to protect against colorectal cancer development therefore, have not been made. There are, however,


ongoing human chemoprevention trials that may provide important in- formation regarding primary prevention against colorectal cancer.

Secondary Prevention

The prolonged time necessary for the development of colonic neoplasia allows for time to detect and eliminate adenomatous and neoplastic lesions before they are advanced.57 Incorporating effective colorectal cancer screening tests has the potential to reduce mortality. Various models have been employed to examine colorectal screening strategies that are sensitive, specific, and cost effe~tive.'~, 30 The available screening tests include fecal occult blood tests (FOBTs), flexible sigmoidoscopy, and colonoscopy and barium enema.

Fecal Occult Blood Tests

Colorectal adenomas and cancer may bleed intermittently. Detection of blood in the stool can lead to an evaluation that identifies and removes preneoplastic lesions. Fecal occult blood testing (FOBT) is a widely used surveillance technique. These qualitative chromogen tests rely on oxidative conversion of a colorless compound to a colored one in the presence of the pseudoperoxidase activity of hemoglobin. The tests have been standard- ized with the use of guaiac-impregnated paper and developing solutions. They have been widely studied and are readily available, convenient, and inexpensive.

A number of studies have examined the potential benefit of fecal occult blood testing for detection of colorectal neoplasms. The majority of studies report that a large percentage of detected lesions are adenomas or early malignartcie~.~~ There have been, however, five long-term prospective, controlled trials that have evaluated the use of FOBT for detection of colonic lesions. Two of these trials were preformed in the US.53 Mandel et a1 reported the results of a prospective trial of asymptomatic individuals between 50 and 80 years who were screened with annual rehydrated hemoccult tests followed by a colonoscopy in those who had a positive result.32 There was a reduction in colorectal cancer mortality rate by 33%. In the Minnesota Trial, Mandel et aP2 reported that few cancers were missed by annual FOBT screening followed by colonoscopy. The sensitivity for cancer detection was reported to be 92%.'O Other controlled trials also reported a significant reduction in colorectal cancer m0rtality.2~. 54

The effectiveness of fecal occult blood tests depends upon the amount of blood loss, degree of fecal hydration (increases sensitivity), amount of hemoglobin degradation (decreased sensitivity owing to storage or action of fecal flora), and the absence of interfering substances that may either enhance or inhibit oxidation of the developing solution. It is reported that approximately 2 mL of blood in the stool is necessary to produce a positive result. Sampling of multiple stool specimens improves sensitivity. Location of a colonic lesion may also affect detection of blood in the stool.

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Proximal colon lesions are reported to produce fewer false negative tests because of the presumed greater blood loss that occurs with these lesions. Sensitivity rates in the multiple FOBT investigations ranged from 26% to 92% with reported specificity of 90% to 99%. The differences in the sensitivity and specificity rates were related to differences in study designs.', 32, 48, 54

False positive results can occur when foods are consumed which contain nonhuman hemoglobin or peroxidase containing fruits and vegetables (i.e., broccoli, turnips, cauliflower, radishes, cantaloupes). Gastric irritants (i.e., salicylates, NSAIDs) producing upper gastrointestinal bleeding and nonneoplastic conditions (i.e., hemorrhoids, rectal fissures) can result in a false positive test. False negative tests can occur when testing is performed during a time in which the colorectal adenoma or neoplasia is not

Ascorbic acid and other antioxidants may also interfere with test reagents, resulting in a false negative te~t .2~ Extended delay prior to testing the stool sample may also result in a false negative test.33

Rehydration of stored slides has been reported to improve sensitivity, but this procedure results in a decrease in specificity52 and is no longer recommended for screening in average risk population. Although the value of a positive test performed in conjunction with a digital rectal examination has been debated, a recent study suggests that there is not an increase in false positive tests when fecal occult blood testing is performed in this manner.15

Efforts are ongoing to improve FOBT screening with the development of hemoglobin immuoassays with improved sensitivity and specificity.

Flexible Sigmoidoscopy

The 60 cm sigmoidoscope, used by an experienced examiner, can quickly and accurately evaluate the distal colon. Cohort and case-control studies have reported a 60% to 85% reduction in mortality from distal cancer.'8, 34, 43 Selby et a143 reported that screening proctosigmoidoscopy in a large health maintenance organization reduced mortality from large bowel cancer by approximately 60Y0.4~ Newcomb et aP5 also reported a significant reduction in mortality from cancers within the reach of the sigrnoido~cope.~~ There are no controlled trials that have systematically evaluated this procedure for colorectal cancer screening.

The appropriate frequency of sigmoidoscopy screening has not been established. Various studies recommended different performance intervals.34, 39, 43 Based upon various recommendations, current guidelines suggested repeating screening examinations every five years.8 The primary disadvantage of the flexible sigmoidoscopy is that it is unable to detect lesions that are beyond the reach of the instrument. Currently, approximately 40% of all colorectal cancers arise proximal to the splenic flexure and approximately 75% of these individuals do not have a neoplasm distal to the splenic flexure. The flexible sigmoidoscopic examination, therefore, will be normal in approximately 30% of patients with colorectal ~ancer.~'


Colonoscopy

Colonoscopy has been increasingly advocated as a colorectal screening strategy. It has been evaluated in several cross-sectional screening studies in average risk individuals. The examination is estimated to have to a 95% sensitivity rate.31 It requires sedation, however, has higher risks related to the procedure and anesthetic administration, requires performance in an endoscopy suite, and is more expensive than other screening proce- dures. In the past, many insurers have not reimbursed for this procedure as a screening modality in average risk persons because of the higher initial costs, however, an increasing number of insurers are covering colonoscopic examinations at less frequent intervals than used for other screening techniques.

Several studies reported that the anatomic distribution of polyps support the use of colonoscopy for ~creening . '~ ,~~,~ ' A c ase-control study that compared individuals who had colonoscopy and polyp removal at least every three years to individuals who refused surgical intervention reported a significantly lower incidence and mortality rate associated with colorectal ~ancer.~' Both cohort and case-control studies indicate that en- doscopic polypectomy reduces the incidence and mortality from colorectal c a n ~ e r . ' ~ , ~ , ~ ~ The U.S. National Polyp Study provides significant supportive evidence that colonoscopic polpectomy provides an effective secondary prevention of colorectal cancer? Colonoscopy may become the procedure of preference because it can evaluate the entire colon, as well as identify and remove premalignant lesions.

Barium Enema

The effectiveness of double contrast barium enema as a routine screening technique has not been directly evaluated.37 Use of this test as a surveillance technique is based on the reported sensitivity of 80% to 95% and specificity of approximately 90% in identifying lesions. In the National Polyp Study, however, barium enema was reported to miss approximately 50% of the adenomas over l ~ m . 5 ~ Limited data on screening populations results in difficulty in determining effective screening intervals using this procedure, however, barium enema is incorporated into screening recommendations as an optional procedure.

Genetic Testing

There have been significant advances in our knowledge regarding genetic alterations and colon carcinogenesis. Specific tests are not yet available for the majority of individuals who are at risk for the development of sporadic colorectal cancer. A preliminary study has reported, however, that ras gene mutations can be identified in the stool of individuals with adenomas and carcinorna~.~~

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In individuals in families affected with FAP, genetic testing for altered product of the APC gene is available. Genetic testing, in the context of a genetic counseling program, can allow for early and accurate identification of family members who are at risk and will require intensive surveillance.% Genetic testing for mutations in the hMSH2 and hMLHl genes may become readily available for family members with HNPCC.26

SCREENING

The optimal strategy for colorectal cancer screening continues to be evaluated. Based upon the available data, practice guidelines have been developed by a number of organizations. The U.S. Preventive Services Task Force, a consortium of medical and surgical digestive disease societies, and the American Cancer Society are among a number of organizations that have developed recommendations for screening. An overview of recommended guidelines is outlined below.

Recommendations for Individuals with Average Risk for Colorectal Cancer

In general, recommended screening for asymptomatic, average risk individuals includes annual FOBT with a flexible sigmoidoscopy every five years, beginning at age 50. Combining fecal occult blood testing and flexible sigmoidoscopy has been reported to reduce colorectal cancer screening mortality by more than 50%.8 A colonoscopy is recommended whenever a screening test is positive. Screening should be individualized and should be discontinued when advanced age or serious comorbidity would not allow for continued benefit from screening. Some organizations support the option of performing a flexible sigmoidoscopy with double contrast barium enema every five years or performing a colonoscopy every ten years." 55

Recommendations for Individuals with Increased Risk for Colorectal Cancer

Family History

An individual with a family history of colorectal cancer may be at increased risk for the development of the malignancy; however, different patterns of inherited risk have been identified. These patterns include individuals who have a relative with a history of familial adenomatous polyposis syndromes (comprising of < 1% of all colorectal cancers), hereditary nonpolyposis colorectal cancer syndromes (comprising approximately 2- 8% of colorectal cancers), or sporadic cancers. Screening recommendations are based upon the potential inheritance pattern.


Sporadic Cancers

The age at which surveillance is initiated is dependent upon the age of colorectal cancer diagnosis in affected relatives. Screening should begin earlier than the age at which the youngest affected relative was diagnosed. It has been suggested with individuals with a high family risk (young age of diagnosis of the first degree relative or more than two affected relatives) should undergo colonoscopy every five years beginning at age 40.'

Familial Adenomatous Polyposis Syndrome

Individuals in this group should begin screening between the ages of 10 and 12. Genetic counseling and testing should be conducted. Flexible sigmoidoscopy should be conducted annually or biannually for those who have a positive genetic test. Prophylactic colectomy is indicated when adenomas begin to appear. Periodic upper endoscopy should be performed every one to three years to evaluate for development of duodenal carcinomas.'

Hereditary Nonpolyposis Colorectal Cancer Syndrome (Lynch Syndrome)

of 20 and 25. Colonoscopy should be conducted every one to two years.' Initial screening for colorectal cancer should begin between the ages

Inflammatory Bowel Disease

Individuals with ulcerative colitis have an increased risk for the development of colorectal cancers. Studies suggest that the increase in colorectal cancer prevalence begins after approximately ten years of disease.29 Stud- ies have demonstrated that screening programs in individuals with ulcerative colitis result in a decrease in colorectal cancer m~rtality.~ Suggested screening guidelines include colonoscopic surveillance with serial biopsies beginning approximately ten years following the diagnosis of pancolitis or left-sided colitis. Colonoscopy should be repeated every 2 to 3 years until the individual has had the diagnosis of ulcerative colitis for 20 years. After 20 years of the disease, colonoscopy should be conducted every year.'

The incidence of colorectal cancer in individuals with Crohn's colitis is also increased;& however, the extent of the risk is not as well defined as in ulcerative colitis. It has been assumed that the colorectal cancer risk is related to the extent of colonic involvement and duration of disease. While there are no specific guidelines, it has been suggested that colonoscopic surveillance begin after individuals have had the disease for ten years.7

Individuals with a History of Colonic Adenomas

Screening of individuals who have had adenomatous polyps should be individualized and based upon the histologic type and number of adenomas.

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Individuals who had had one or two small (< 1 cm) tubular adenomas may not be at significantly increased risk for colorectal cancer development and surveillance colonoscopy can be performed every five years.47 Individuals with a history of large or multiple (> 3) adenomatous polyps or adenomatous polyps with villous change or high-grade dysplasia have a 3- to 5-fold increase in colorectal cancer risk and surveillance colono- scopies can be performed every three years.3 If the three year examination is negative, subsequent examinations can be done in five years.58 If multiple adenomas have been removed, repeat colonoscopy can be performed in one to two years. Following a negative colonoscopy, the screening inter- val may be increased. Removal of large, sessile adenomas should result in a follow-up colonoscopy in two to six months to ensure complete excision and no recurrence at the previous adenoma site.

Individuals with a History of Colorectal Cancer

Individuals who have had curative colorectal cancer resection have an increased risk for the development of polyps or colorectal cancer. Repeat colonoscopy can be performed within one year of resection to ensure no evidence of recurrent cancer. Subsequent surveillance can be performed in two to three years to detect metachonous polyps. If the three year follow up is negative, colonoscopic surveillance can be done every five years.'

SUMMARY

Colorectal cancer causes significant morbidity and mortality in the United States. Adherence to currently recommended screening guidelines have the potential to significantly impact colorectal cancer mortality. Screening of the asymptomatic, average-risk population can reduce mortality by more than 50%. Individuals at higher risk require more intense surveillance.

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