24 Screening for Colorectal Neoplasms

24

Screening for Colorectal Neoplasms

Thomas E. Read and Philip F. Caushaj

353

Cancer of the colon and rectum is the second leading cause of

cancer-related death in the United States. In 1997, it was esti- mated that 131,000 Americans were diagnosed with colorec- tal cancer, and 55,000 died from this disease.

Without undergoing screening or preventive action, approximately 1 in every 17 people in this country will develop colorectal cancer at some point in life. However, evidence is mounting that col- orectal adenocarcinoma can be prevented by detecting and removing adenomatous polyps, and that detecting early-stage cancers reduces mortality from the disease.

Both polyps and early-stage cancers are usually asymptomatic; cancers that have grown large enough to cause symptoms have a much worse prognosis. This contrast highlights the need for screen- ing in asymptomatic persons.

Most people will be of average risk and require screening for colorectal cancer and polyps beginning at age 50.

However, a substantial number of people are at increased risk because of an inherited predisposition to the disease and need screening or treatment as early as puberty. By virtue of their practice, colon and rectal surgeons, gastroenterologists, and medical oncologists have contact with many patients with col- orectal carcinoma as well as at-risk family members. These specialists have the opportunity to guide the evaluation of at- risk persons and be advocates for appropriate screening exam- inations.

The explosion of genetic research in the last 15 years has enabled us to better understand inherited forms of colorectal cancer, and has helped to define high-risk populations that need endoscopic or genetic screening for these diseases early in life. The adenomatous polyposis coli gene is thought to function as a gatekeeper of colorectal neoplasia. Germline and somatic truncating mutations of the adenomatous polypo- sis coli gene are thought to initiate colorectal tumor formation in familial adenomatous polyposis (FAP) and sporadic col- orectal carcinogenesis, respectively. Genetic testing for FAP can help guide surveillance and treatment of patients at risk for the disease. Hereditary nonpolyposis colorectal cancer

(HNPCC) is thought to be the result of DNA mismatch repair deficiency, and genetic testing for HNPCC may ultimately prove to have clinical value for patients in HNPCC families.

The effectiveness of screening for colorectal cancer has been a subject of controversy. In 1995, the United States Preventive Task Force reversed earlier position statements and endorsed screening of asymptomatic average-risk persons, using fecal occult blood testing and sigmoidoscopy.

In 1996, the federal Agency for Health Care Policy and Research (AHCPR) convened a collaborative group of experts representing the American College of Gastroenterology, American Gastroenterological Association, American Society of Colon and Rectal Surgeons, American Society for Gastrointestinal Endoscopy, and Society of American Gastrointestinal Endoscopic Surgeons to critically evaluate the available evidence on colorectal cancer screening and to develop appropriate clinical practice guidelines.

The panel studied 3500 peer-reviewed publications to assess the performance, effectiveness, acceptability to patients, cost- effectiveness, and outcome of different screening examina- tions. The AHCPR guidelines

were, in essence, endorsed by the American Cancer Society

and are virtually identical to the Practice Parameters for the Detection of Colorectal Neoplasms published by the Standards Committee of the American Society of Colon and Rectal Surgeons.

They provide the framework for this review.

Classification of Risk and Screening Recommendations

The cornerstone in determining a patient’s risk for developing

colorectal cancer is the family history. Failure to properly

investigate a patient’s family history of colorectal neoplasia

can lead to inappropriate and inadequate treatment of both the

patient and at-risk family members.

Average Risk

As can be seen in Table 24-1, the majority of patients who develop colorectal cancer have no identifiable risk factors.

Persons considered to be at average risk for colorectal cancer do not fit any of the higher risk categories. Specifically, aver- age-risk persons have no symptoms associated with colorectal cancer, no personal history of colorectal cancer or adenoma- tous polyps, no family history of colorectal neoplasia, no inflammatory bowel disease, and no unexplained anemia.

Screening recommendations (Table 24-2): The AHCPR panel recommended that average-risk persons should undergo one of the following screening regimens, beginning at age 50:

1. Fecal occult blood testing annually 2. Flexible sigmoidoscopy every 5 years

3. Fecal occult blood testing annually and flexible sigmoi- doscopy every 5 years

4. Air contrast barium enema every 5–10 years 5. Colonoscopy every 10 years

Although the panel stated that all of the screening strategies are acceptable options,

each strategy has unique strengths and weaknesses. The fecal occult blood test (FOBT) is a gua- iac-based test for peroxidase activity that is nonspecific and will fail to detect many small cancers and precancerous lesions.

Nevertheless, several large randomized controlled trials have shown that annual or biannual testing for fecal

occult blood with complete diagnostic evaluation of the colon (primarily with colonoscopy) for patients with a positive FOBT reduces mortality from colorectal cancer.

The AHCPR panel listed FOBT alone as an option for colorectal cancer screening. However, because of the lack of sensitivity of FOBT, the American Cancer Society recommends combin- ing annual FOBT with flexible sigmoidoscopy every 5 years rather than using FOBT alone as a screening method.

A major drawback to using FOBT as a screening technique is poor compliance. Only 38%–60% of the patients in prospective trials completed all the planned FOBT tests,

and use of FOBT in the general population is estimated to be lower than in the research environment.

The steps necessary for adequate sample collection, combined with dietary restric- tions to avoid agents that can cause false-positive and false- negative results may also hinder compliance with FOBT.

Proper performance of FOBT involves the sampling of atraumatically obtained stool from three consecutive bowel movements in a patient who has not ingested red meat, aspirin, nonsteroidal inflammatory medications, turnips, mel- ons, salmon, sardines, horseradish, or vitamin C for the 2 days preceding the test and throughout the test period.

The restriction of frequently ingested foods and medications, combined with the natural aversion to stool sampling, makes annual FOBT unappealing to many persons.

FOBT should not be confused with random stool guaiac testing, which is the analysis of stool found on digital rectal examination for blood. The lack of adequate diet and medica- tion restriction before the test, potential for trauma to the anal canal during digital rectal examination, and the inability to reliably obtain stool from the distal rectum make the test unreliable.

To date, random stool guaiac examination has not been demonstrated to have benefit in screening for colorectal cancer.

TABLE24-1. Patients with colorectal cancer

75% Average risk (sporadic)

15%–20% Family history of colorectal cancer

3%–8% HNPCC

1% FAP

1% Ulcerative colitis

TABLE24-2. Screening for colorectal cancer and polyps

Risk category Screening method Age to begin screening

Average risk Choose one of the following: 50 yr

FOBT annually^*

Flexible sigmoidoscopy every 5 yr^*

FOBT annually +flexible sigmoidoscopy every 5 yr Air contrast barium enema every 5–10 yr†

Colonoscopy every 10 yr

Family history Choose one of the following: 40 yr, or 10 yr before diagnosis of the youngest affected

1. Colonoscopy every 10 yr family member, whichever is earliest

2. Air contrast barium enema every 5 yr†

HNPCC Colonoscopy every 1–3 yr 21 yr

Genetic counseling Consider genetic testing

FAP Flexible sigmoidoscopy or colonoscopy every 1–2 yr Puberty

Genetic counseling Consider genetic testing

Ulcerative colitis Colonoscopy with biopsies for dysplasia every 1–2 yr 7–8 yr after the diagnosis of pancolitis; 12–15 yr after the diagnosis of left-sided colitis

*The American Cancer Society recommends the combination of yearly FOBT and flexible sigmoidoscopy as preferable to either examination alone.

†Rigid proctoscopy is recommended as an adjunctive examination to allow adequate visualization of the distal rectum. Furthermore, flexible sigmoidoscopy may be necessary to more completely evaluate a tortuous or spastic sigmoid colon.

In some settings, FOBT test slides are rehydrated, which contributes to the high incidence of false-positive tests and is not recommended by the manufacturer. Hemoccult SENSA, which seems to be as sensitive as the original Hemoccult test, is the guaiac technique currently recommended for use.

In the future, immunochemical techniques or genetic analysis of cellular material in stool may prove to be more effective than current FOBT technology in detecting occult colorectal neoplasms via stool sampling.

The effectiveness of sigmoidoscopy as a screening tool depends on its ability to detect cancers and adenomatous polyps in the distal colon. If adenomatous polyps are found at flexible sigmoidoscopy, colonoscopy should be strongly con- sidered because almost one-third of such patients will have neoplastic lesions in the proximal colon.

The effectiveness of sigmoidoscopy in reducing mortality from colorectal can- cer has never been proven by a randomized, controlled trial, although case-control studies have shown a benefit.

There was only a trend toward limited benefit of one-time screening sigmoidoscopy, followed by colonoscopy for patients found to have polyps, in the Telemark study from Norway.

The Prostate, Lung, Colon and Ovary Trial supported by the National Cancer Institute is evaluating flexible sigmoi- doscopy in a randomized, controlled setting, but mortality data are not expected until 2008.

A multicenter prospective trial examining the potential benefit of one-time screening flexible sigmoidoscopy at age 60 is currently underway in the United Kingdom and Italy.

The AHCPR panel listed flexible sigmoidoscopy alone as an option for colorectal cancer screening, although such a strategy will fail to detect neoplasms in the proximal colon unless adenomatous polyps or cancer are found in the distal colon that prompt colonoscopy. For this reason, The American Cancer Society recommends combining flexible sigmoidoscopy every 5 years with annual FOBT, rather than using flexible sigmoidoscopy alone as a screening method.

Although this combined approach may detect more proximal neoplasms than flexible sigmoidoscopy alone, 15%–25% of patients with negative flexible sigmoidoscopy and negative FOBT will have neoplastic lesions in the proximal colon at colonoscopy, calling the rationale for this approach into question.

The efficacy of barium enema in preventing colorectal can- cer mortality has never been evaluated in a controlled trial, but can be inferred from the fact that detecting polyps and early- stage cancers by other methods reduces the incidence and mortality from colorectal cancer. Air contrast barium enema will detect 50%–80% of polyps <1 cm, 70%–90% of polyps

>1 cm, and 50%–80% of Stage I and II adenocarcinomas.

Single column barium enema is less sensitive and should be combined with flexible sigmoidoscopy if used as a screening tool.

Rigid proctoscopy should be considered as an adjunct examination because the balloon on the enema catheter often prevents adequate imaging of the distal rectum. Another major limitation of barium enema as a screening method is

that patients usually require colonoscopy if lesions are detected.

Colonoscopy is the only screening technique that allows

the detection and removal of premalignant lesions throughout the colon and rectum, and is the final common pathway for any positive screening test. Although its effectiveness depends on the skill and experience of the endoscopist to both reach the cecum and to identify small lesions, it remains the gold standard to evaluate the colonic mucosa.

The ability of colonoscopy to reduce colorectal cancer mortality has been demonstrated indirectly through studies showing that detect- ing and removing polyps reduces the incidence of colorectal cancer and that detecting early cancers lowers the mortality from the disease.

Compliance with screening colonoscopy may be superior to that of other methods because no confir- matory examinations are required, and thus, patients are subjected to a single bowel preparation.

CT colography (virtual colonoscopy) was developed in an

attempt to increase compliance with colorectal cancer screen- ing, based on the impression that persons would be more inclined to have a “scan” than a “scope.” The technique involves thin-section computed tomography (CT) with three- dimensional computer reconstructions to examine the colonic mucosa (Figure 24-1A,B).

Although the technique has the advantages of being noninvasive and not requiring sedation, a vigorous oral laxative preparation is required, because adher- ent stool cannot be differentiated from neoplasia on CT. In addition, a rectal catheter and air insufflation is used to dis- tend the colon. CT colography cannot be assumed to be more appealing to all patients who are reluctant to undergo colonoscopy, because many patients are deterred more by the laxative preparation beforehand than by the endoscopic pro- cedure itself, and find rectal air insufflation in the absence of sedation uncomfortable.

Initial trials demonstrated that CT colography was not as sensitive as colonoscopy in the detec- tion of small polyps,

although with improvements in tech- nology and with greater experience with interpretation, CT colography may ultimately prove to be as reliable as colonoscopy in detecting colorectal neoplasia.

Regardless of its accuracy, CT colography suffers (as does contrast enema) from the disadvantage that biopsies cannot be obtained and positive findings require endoscopic confirmation.

The Office of Technology Assessment of the United States

Congress found that FOBT, flexible sigmoidoscopy, air

contrast barium enema, and colonoscopy are equally cost

effective as screening strategies, with an estimated cost of

less than $20,000 per year of life saved (assuming screen-

ing begins at age 50 and is discontinued at age 85).

Although cost-benefit analyses such as these are exceedingly

complex, this estimate is well within the acceptable range

of cost effectiveness by United States health standards

and compares favorably to screening mammography for

women older than age 50. As of January 1, 1998, Medicare

has reimbursed screening examinations for colorectal cancer

in average-risk persons older than the age of 50.

In 2001,

Medicare authorized reimbursement for screening colonoscopy for average-risk persons. As of January 2004, the Centers for Medicare and Medicaid Services guidelines for reimbursement for colorectal cancer screening are as

follows (excerpted from their Web site, http://www.cms.hhs.

gov/medlearn/refcolcn.asp):

●

FOBT: once every 12 months

●

Flexible sigmoidoscopy: once every 48 months

●

Colonoscopy: once every 24 months if the patient is at high risk for colon cancer; and once every 10 years (but not within 48 months of a screening sigmoidoscopy) if the patient is not at high risk for colon cancer

●

Double contrast barium enema: physician can decide to use instead of a sigmoidoscopy or colonoscopy

At present, the choice of screening strategy for average-risk persons is made with influence from primary care physicians, patients, and third-party payers. Although the AHCPR panel’s recommendation of five different screening strategies may offer flexibility, it may also cause confusion and uncertainty.

Two of the five strategies depend on compliance with yearly FOBT, which has been extremely difficult to achieve even in the setting of controlled trials. Only air contrast barium enema and colonoscopy provide total colonic evaluation, and con- trast enema suffers from the necessity of performing colonoscopy if a lesion is detected. Screening colonoscopy every 10–15 years beginning at age 50 may ultimately prove to be the most cost-effective method of screening average-risk persons for colorectal cancer. Hopefully, future technologic advances will allow for total colonic evaluation with minimal patient discomfort and embarrassment, at reasonable cost. If a simple stool-labeling technique is developed that allows for reliable differentiation of stool from mucosa on CT without the need for cathartic bowel preparation, CT colography may fit these criteria.

Personal History of Adenomatous Polyps or Adenocarcinoma

A personal history of adenomatous polyps or colorectal ade- nocarcinoma places a person at higher than average risk for the development of metachronous neoplasms. Surveillance colonoscopy is thus recommended by virtually all consensus groups.

The interval between colonoscopies has been the subject of some debate, and no blanket recommendation can be given for all patients. A rational surveillance strategy should take into account the patient’s age, comorbid condi- tions, life expectancy, completeness of prior examinations, pattern of neoplastic growth, and histologic features of previously resected neoplasms. For instance, a 60-year-old patient in good health who undergoes colonoscopic poly- pectomy of a single small tubular adenoma should probably undergo surveillance colonoscopy in 3–5 years.

A patient in good health who is found to have adenomas that are multi- ple, large, or dysplastic on initial screening colonoscopy should be considered for colonoscopy at an earlier interval, such as 6–12 months. However, a 90-year-old patient with severe comorbidities and limited life expectancy would not

large tumor of the splenic flexure who could not undergo colonoscopy. The circumferential cancer can be seen occupying the lumen of the colon. B This image is of the transverse colon proximal to the cancer.

benefit as much from early surveillance, because removal of premalignant lesions will probably not alter lifespan or quality of life.

Patients who undergo curative resection of colorectal ade- nocarcinoma should undergo regular surveillance colono- scopy to detect new metachronous primary neoplasms. The recommendation of the Standards Task Committee of the American Society of Colon and Rectal Surgeons is for initial postresection colonoscopy at 1 year, followed by colonoscopy every 3–5 years thereafter, depending on the pathology found at the preceding colonoscopic examination.

Obviously, all the considerations made for the selection of postpolypectomy surveillance intervals, as noted above, apply in this situation as well. The purpose of the colonoscopy is not specifically to look for tumor recurrence at the anastomotic suture line, because suture line recurrence in the absence of unresectable extraluminal disease is extremely uncommon,

but rather to search for new primary neoplasms.

Family History of Colorectal Cancer or Adenomatous Polyps

A family history of colorectal cancer or adenomatous polyps increases the risk of developing colorectal cancer. In general, closer familial relationships to affected relatives, younger age of onset, and larger numbers of affected relatives increase the risk.

A careful family history should always be obtained to exclude one of the better-defined inherited colorectal can- cer syndromes, such as HNPCC or FAP.

As a greater understanding of the molecular genetics of colorectal cancer is gained, many patients with familial col- orectal cancer may eventually be categorized as having dis- tinct inherited syndromes. Recently, a germline mutation of the adenomatous polyposis coli gene (I1307K variant) was identified in persons of Ashkenazi Jewish descent that predis- poses to the development of colorectal adenomas and carci- noma.

The mutation causes hypermutability of the adenomatous polyposis coli gene and is thought to contribute to carcinogenesis independent of mismatch repair defi- ciency.

In the future, genetic testing for this mutation in at- risk persons may have clinical utility.

Screening recommendations: The AHCPR panel recom-

mended that patients with first-degree relatives with colorec- tal cancer or adenomatous polyps begin screening for colorectal neoplasia at age 40, or 10 years before the age at diagnosis of the affected relative, whichever is earliest.

Those patients whose first-degree relatives developed col- orectal cancer before age 50 may be at higher risk, and com- plete colonic evaluation with colonoscopy should be strongly considered.

Patients with a second-degree relative with colorectal cancer, or relative with adenomatous polyps diagnosed over age 60, may be screened as an average- risk person.

As of January 1, 1998, Medicare will reimburse for screening colonoscopy for high-risk patients when

performed at least 2 years after the last screening colonoscopy or barium enema.

Hereditary Nonpolyposis Colorectal Cancer

HNPCC is an inherited disorder that predisposes patients to the development of colorectal cancer, with up to 75% of patients developing the disease by age 65.

HNPCC is inherited in an autosomal dominant manner, and is thought to be the result of germline mutations in mismatch repair genes (genes that code for proteins responsible for correcting errors during DNA replication). Patients with HNPCC typically develop cancer between age 40 to 50 and most tumors occur proximal to the splenic flexure. “Nonpolyposis” refers to the distinction between HNPCC and FAP (in which patients have hundreds of polyps), but is somewhat misleading because patients with HNPCC develop adenomatous polyps. The pro- gression from adenoma to carcinoma seems to be accelerated in HNPCC patients as compared with patients with sporadic cancers, and there is a tendency to develop multiple colorec- tal cancers in HNPCC.

Patients with HNPCC are also at high risk for cancers of other organs, especially the ovary and uterus.

The ability to conclusively identify gene carriers is not yet fully developed, thus the penetrance of colorectal cancer in gene carriers can only be estimated (about 90%). In addition, some patients in HNPCC families who do not have identifi- able germline mismatch repair gene mutations will develop colorectal cancer.

For these reasons, the diagnosis of HNPCC in a family remains clinical. The Amsterdam crite- ria (colorectal cancer in three or more family members; two generations affected; one affected person a first-degree rela- tive of another; and one cancer diagnosed before age 50) are the strictest criteria and have the highest concordance with known mismatch repair gene mutations.

These criteria were originally developed for research purposes, to standardize the definition of HNPCC. However, they fail to identify patients who may be affected with HNPCC but do not fit the strict criteria because of unknown or abbreviated family his- tories, as well as patients with a personal or family history of extracolonic malignancies associated with HNPCC. A recent National Cancer Institute working group acknowledged the shortcomings of the Amsterdam criteria as clinical guidelines and published recommendations to expand the clinical suspicion of HNPCC to a broader range of patients.

The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer has also proposed similar criteria.

Microsatellite instability has been reported in 85%–90% of

HNPCC colorectal cancers.

Detection of this phenotype has

been proposed as a screening method to trigger germline

mutational analysis in kindreds with uncertain family histo-

ries.

However, microsatellite instability is also found in

approximately 15% of sporadic cancers, and has not been

universally found to be predictive of familial cancer.

At present, the “true” definition of HNPCC remains uncer- tain. Neither refined clinical criteria nor germline mutational analysis has provided a model of the syndrome that is predic- tive of phenotype in all cases. Clinically, the absence of microsatellite instability or mismatch repair gene mutation does not negate a family history that suggests an autosomal dominant predisposition to developing colorectal cancer. At- risk family members still require aggressive screening.

Screening recommendations: Expert panels convened by

the AHCPR

and the Cancer Genetics Studies Consortium

recommend that persons who are members of a family that fits clinical criteria for HNPCC undergo colonoscopy at age 20–25, and repeat colonoscopy every 1–3 years. The short time interval between colonoscopies results from the acceler- ated adenoma to carcinoma progression thought to occur in HNPCC. Patients and their family members should be referred for genetic counseling. Germline testing for mis- match repair gene mutations can be considered,

but because the predictive value of such testing is only 30%–50%,

colonoscopy should be performed regardless.

Familial Adenomatous Polyposis

FAP is caused by a defect in the adenomatous polyposis coli gene, which is inherited in an autosomal dominant manner.

Patients with FAP develop hundreds of adenomatous polyps as early as puberty, and will ultimately develop colorectal cancer, usually by age 40.

Patients with FAP are also prone to develop a variety of extracolonic tumors, notably duodenal adenomas and carcinomas, and desmoid tumors.

FAP mutations do occur spontaneously, accounting for patients who are diagnosed with the disease without a family history of FAP.

Attenuated FAP is a rare variant of the dis- ease, with polyps and cancers developing later in life.

The most frequently used genetic test for FAP is an assay for a truncated protein product of the mutated adenomatous polyposis coli gene. Because only about 80% of families with FAP will have a mutation that produces a truncated protein, the predictive value of testing at-risk family members is great- est if the proband (affected relative) has a positive test.

Screening recommendations: Patients with a family history

of FAP should undergo flexible sigmoidoscopy or colonoscopy at puberty.

Lower endoscopy should be repeated every 1–2 years. Genetic testing should be consid- ered, especially in large pedigrees where genotyping might be more cost effective than repeated endoscopy.

If the proband has a positive truncated protein assay, at-risk relatives who test negative may be screened as average-risk persons.

Because of the socioeconomic, medicolegal, and emotional issues surrounding genetic testing, it cannot be emphasized enough that genetic testing for FAP should be done after genetic counseling and informed consent.

Trained genetic counselors can guide patients through the testing process and help interpret results. Giardiello et al.

found that 32% of physicians ordering genetic tests for FAP misinterpreted the

results of the test, and that less than 20% of patients tested had received pretest genetic counseling or written informed con- sent. These numbers are sobering when one considers that FAP has 100% mortality if left untreated. Patients should also undergo screening upper endoscopy for duodenal adeno- mas.

Inflammatory Bowel Disease

Patients with ulcerative colitis have an increased risk of developing colorectal cancer. This risk begins approximately 7–8 years after diagnosis in patients with pancolitis, and 12–15 years after diagnosis in patients with limited left-sided colitis.

There may be an increased risk of colorectal cancer in patients with Crohn’s colitis, although this is less well defined.

Screening recommendations: It is common practice for

patients with ulcerative colitis to undergo screening colonoscopy with multiple random biopsies looking for dys- plasia every 1–2 years, beginning 7–8 years after diagnosis in patients with pancolitis and 12–15 years after diagnosis in patients with left-sided colitis.

However, evidence that surveillance reduces mortality, or is better than timing a colectomy according to extent and duration of disease, is weak.

Future Directions

It is troubling that so much energy and expense is devoted to the cure of advanced or recurrent colorectal cancer in the United States, while so little is devoted to screening for polyps and early-stage cancers. It is estimated that only 10%–30% of adults older than the age of 50 in this country undergo any regular screening for colorectal neoplasia.

In a report issued in 2002, the United States General Accounting Office found that colorectal cancer screening is the least utilized preventive health benefit available to Medicare beneficiaries (General Accounting Office, Medicare–Beneficiary Use of Clinical Preventive Services, Report No. GAO-22-422; April 2002). As is the case in the general population, only 25% of Medicare beneficiaries are screened each year with FOBT, compared with much higher rates for other regular cancer screening tests such as mam- mography (75%) or Pap smear testing (66%). Until recently, screening for colorectal cancer has not received much public- ity in the United Sates, despite colorectal cancer being the second leading cause of cancer-related death in this country, and despite having a well-defined, identifiable, and treatable precursor lesion (the adenomatous polyp). Both health care professionals and the public need to become more aware of the potential benefits of colorectal cancer screening.

As the genetics of inherited colorectal cancer syndromes

become better understood, it will be possible to conclusively

identify high-risk populations. It is of paramount importance

that screening efforts be directed toward these populations.

Genetic counselors are invaluable resources, both to counsel family members and to help direct genetic testing.

References

1. Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics, 1997.

CA Cancer J Clin 1997;47:5–27.

2. Newcomb P, Norfleet R, Storer B, Surawicz T, Marcus P.

Screening sigmoidoscopy and colorectal cancer mortality. J Natl Cancer Inst 1992;84:1572–1575.

3. Kronborg O, Fenger C, Olsen J, Jorgensen OD, Sondergaard O.

Randomised study of screening for colorectal cancer with faecal- occult-blood test. Lancet 1996;348:1467–1471.

4. Winawer SJ, Flehinger BJ, Schottenfeld D, Miller DG.

Screening for colorectal cancer with fecal occult blood testing and sigmoidoscopy. J Natl Cancer Inst 1993;85:1311–1318.

5. Winawer SJ, Zauber AG, Ho MN, et al. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 1993;329:1977–1981.

6. Muller AD, Sonnenberg A. Protection by endoscopy against death from colorectal cancer. A case-control study among veter- ans. Arch Intern Med 1995;155:1741–1748.

7. Winawer SJ, Fletcher RH, Miller L, et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 1997;112:594–642.

8. Frame PS, Berg AO, Woolf S. U.S. Preventive Services Task Force: highlights of the 1996 report. Am Fam Physician 1997;

55:567–576, 581–582.

9. Levin B, Bond JH. Colorectal cancer screening: recommenda- tions of the U.S. Preventive Services Task Force. American Gastroenterological Association. Gastroenterology 1996;111:

1381–1384.

10. Laken SJ, Petersen GM, Gruber SB, et al. Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Nat Genet 1997;17:79–83.

11. Byers T, Levin B, Rothenberger D, Dodd GD, Smith RA.

American Cancer Society guidelines for screening and surveil- lance for early detection of colorectal polyps and cancer: update 1997. American Cancer Society Detection and Treatment Advisory Group on Colorectal Cancer. CA Cancer J Clin 1997;47:154–160.

12. Simmang CL, Senatore P, Lowry A, et al. Practice parameters for detection of colorectal neoplasms. The Standards Committee, The American Society of Colon and Rectal Surgeons. Dis Colon Rectum 1999;42:1123–1129.

13. Rockey DC, Koch J, Cello JP, Sanders LL, McQuaid K. Relative frequency of upper gastrointestinal and colonic lesions in patients with positive fecal occult-blood tests. N Engl J Med 1998;339:153–159.

14. Hardcastle JD, Chamberlain JO, Robinson MH, et al.

Randomised controlled trial of faecal-occult-blood screening for colorectal cancer. Lancet 1996;348:1472–1477.

15. Mandel JS, Bond JH, Church TR, et al. Reducing mortality from colorectal cancer by screening for fecal occult blood. Minnesota Colon Cancer Control Study. N Engl J Med 1993;328:1365–1371.

16. Anderson LM, May DS. Has the use of cervical, breast, and col- orectal cancer screening increased in the United States? Am J Public Health 1995;85:840–842.

17. Ransohoff DF, Lang CA. Screening for colorectal cancer with the fecal occult blood test: a background paper. American College of Physicians. Ann Intern Med 1997;126:811–822.

18. Nakama H, Fattah AS, Zhang B, Kamijo N. Digital rectal exam- ination sampling of stool is less predictive of significant colorec- tal pathology than stool passed spontaneously. Eur J Gastroenterol Hepatol 2000;12:1235–1238.

19. Colorectal Cancer Screening: Clinical Practice Guidlines in Oncology. JNCCN 2003;1:72–93.

20. Traverso G, Shuber A, Levin B, et al. Detection of APC muta- tions in fecal DNA from patients with colorectal tumors. N Engl J Med 2002;346:311–320.

21. Limburg PJ, Devens ME, Harrington JJ, Diehl NN, Mahoney DW, Ahlquist DA. Prospective evaluation of fecal calprotectin as a screening biomarker for colorectal neoplasia. Am J Gastroenterol 2003;98:2299–2305.

22. Read TE, Read JD, Butterly LF. Importance of adenomas 5 mm or less in diameter that are detected by sigmoidoscopy. N Engl J Med 1997;336:8–12.

23. Selby J, Friedman G, Quesenberry C, Weiss N. A case-control study of screening sigmoidoscopy and mortality from colorectal cancer. N Engl J Med 1992;326:653–657.

24. Thiis-Evensen E, Hoff GS, Sauar J, Langmark F, Majak BM, Vatn MH. Population-based surveillance by colonoscopy: effect on the incidence of colorectal cancer. Telemark Polyp Study I.

Scand J Gastroenterol 1999;34:414–420.

25. Thiis-Evensen E, Hoff GS, Sauar J, Majak BM, Vatn MH. The effect of attending a flexible sigmoidoscopic screening program on the prevalence of colorectal adenomas at 13-year follow-up.

Am J Gastroenterol 2001;96:1901–1907.

26. Atkin WS, Edwards R, Wardle J, et al. Design of a multicentre randomised trial to evaluate flexible sigmoidoscopy in colorectal cancer screening. J Med Screen 2001;8:137–144.

27. Lieberman D, Smith F. Screening for colon malignancy with colonoscopy. Am J Gastroenterol 1991;86:946–951.

28. Achkar E, Carey W. Small polyps found during fiberoptic sig- moidoscopy in asymptomatic patients. Ann Intern Med 1988;

109:880–883.

29. Brady PG, Straker RJ, McClave SA, Nord HJ, Pinkas M, Robinson BE. Are hyperplastic rectosigmoid polyps associated with an increased risk of proximal colonic neoplasms?

Gastrointest Endosc 1993;39:481–485.

30. Rex DK, Smith JJ, Ulbright TM, Lehman GA. Distal colonic hyperplastic polyps do not predict proximal adenomas in asymp- tomatic average-risk subjects. Gastroenterology 1992;102:

317–319.

31. Mehran A, Jaffe P, Efron J, Vernava A, Liberman A. Screening colonoscopy in the asymptomatic 50- to 59-year-old population.

Surg Endosc 2003;17(12):1974–1977.

32. Steine S, Stordahl A, Lunde OC, Loken K, Laerum E. Double- contrast barium enema versus colonoscopy in the diagnosis of neoplastic disorders: aspects of decision-making in general prac- tice. Fam Pract 1993;10:288–291.

33. Hixson LJ, Fennerty MB, Sampliner RE, McGee D, Garewal H.

Prospective study of the frequency and size distribution of polyps missed by colonoscopy. J Natl Cancer Inst 1990;82:

1769–1772.

34. Hixson LJ, Fennerty MB, Sampliner RE, Garewal HS.

Prospective blinded trial of the colonoscopic miss-rate of large colorectal polyps. Gastrointest Endosc 1991;37:125–127.

35. Fork FT. Double contrast enema and colonoscopy in polyp detection. Gut 1981;22:971–977.

36. Fenlon HM, Nunes DP, Clarke PD, Ferrucci JT. Colorectal neo- plasm detection using virtual colonoscopy: a feasibility study.

Gut 1998;43:806–811.

37. Rex DK. CT and MR colography (virtual colonoscopy): status report. J Clin Gastroenterol 1998;27:199–203.

38. Akerkar GA, Yee J, Hung R, McQuaid K. Patient experience and preferences toward colon cancer screening: a comparison of vir- tual colonoscopy and conventional colonoscopy. Gastrointest Endosc 2001;54:310–315.

39. Fenlon HM, Nunes DP, Schroy PC 3rd, Barish MA, Clarke PD, Ferrucci JT. A comparison of virtual and conventional colonoscopy for the detection of colorectal polyps. N Engl J Med 1999;341:1496–1503.

40. Pickhardt PJ, Choi JR, Hwang I, et al. Computed tomographic virtual colonoscopy to screen for colorectal neoplasia in asymp- tomatic adults. N Engl J Med 2003;349:2191–2200.

41. Wagner JL. Cost-effectiveness of screening for common cancers.

Cancer Metastasis Rev 1997;16:281–294.

42. Wagner J. From the Congressional Office of Technology Assessment. JAMA 1990;264:2732.

43. Bull Am Coll Surg 1998;83:13.

44. Walsh JM, Terdiman JP. Colorectal cancer screening: scientific review. JAMA 2003;289:1288–1296.

45. Winawer SJ, Zauber AG, O’Brien MJ, et al. Randomized com- parison of surveillance intervals after colonoscopic removal of newly diagnosed adenomatous polyps. The National Polyp Study Workgroup. N Engl J Med 1993;328:901–906.

46. Read TE, Mutch MG, Chang BW, et al. Locoregional recurrence and survival after curative resection of adenocarcinoma of the colon. J Am Coll Surg 2002;195:33–40.

47. Winawer SJ, Zauber AG, Gerdes H, et al. Risk of colorectal can- cer in the families of patients with adenomatous polyps. National Polyp Study Workgroup. N Engl J Med 1996;334:82–87.

48. Fuchs CS, Giovannucci EL, Colditz GA, Hunter DJ, Speizer FE, Willett WC. A prospective study of family history and the risk of colorectal cancer. N Engl J Med 1994;331:1669–1674.

49. Frayling IM, Beck NE, Ilyas M, et al. The APC variants I1307K and E1317Q are associated with colorectal tumors, but not always with a family history. Proc Natl Acad Sci USA 1998;95:

10722–10727.

50. Gryfe R, Di NN, Lal G, Gallinger S, Redston M. Inherited col- orectal polyposis and cancer risk of the APC I1307K polymor- phism. Am J Hum Genet 1999;64:378–384.

51. Prior TW, Chadwick RB, Papp AC, et al. The I1307K polymor- phism of the APC gene in colorectal cancer. Gastroenterology 1999;116:58–63.

52. Rozen P, Shomrat R, Strul H, et al. Prevalence of the I1307K APC gene variant in Israeli Jews of differing ethnic origin and risk for colorectal cancer. Gastroenterology 1999;116:54–57.

53. Woodage T, King SM, Wacholder S, et al. The APCI1307K allele and cancer risk in a community-based study of Ashkenazi Jews. Nat Genet 1998;20:62–65.

54. Gryfe R, Di NN, Gallinger S, Redston M. Somatic instability of the APC I1307K allele in colorectal neoplasia. Cancer Res 1998;58:4040–4043.

55. Burke W, Petersen G, Lynch P, et al. Recommendations for fol- low-up care of individuals with an inherited predisposition to

cancer. I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium. JAMA 1997;277:915–919.

56. Lynch HT, Smyrk T. Hereditary nonpolyposis colorectal cancer (Lynch syndrome). An updated review. Cancer 1996;78:

1149–1167.

57. Myrhoj T, Bisgaard ML, Bernstein I, Svendsen LB, Sondergaard JO, Bulow S. Hereditary non-polyposis colorectal cancer: clini- cal features and survival. Results from the Danish HNPCC reg- ister. Scand J Gastroenterol 1997;32:572–576.

58. Rodriguez-Bigas MA, Boland CR, Hamilton SR, et al. A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst 1997;89:1758–1762.

59. Box JC, Rodriguez-Bigas MA, Weber TK, Petrelli NJ. Clinical implications of multiple colorectal carcinomas in hereditary nonpolyposis colorectal carcinoma. Dis Colon Rectum 1999;42:

717–721.

60. Fitzgibbons RJ Jr, Lynch HT, Stanislav GV, et al. Recognition and treatment of patients with hereditary nonpolyposis colon cancer (Lynch syndromes I and II). Ann Surg 1987;206:289–295.

61. Watson P, Lin KM, Rodriguez-Bigas MA, et al. Colorectal car- cinoma survival among hereditary nonpolyposis colorectal carci- noma family members. Cancer 1998;83:259–266.

62. Park JG, Vasen HF, Park KJ, et al. Suspected hereditary non- polyposis colorectal cancer: International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC) criteria and results of genetic diagnosis. Dis Colon Rectum 1999;42:710–715.

63. Samowitz WS, Slattery ML, Kerber RA. Microsatellite instability in human colonic cancer is not a useful clinical indicator of famil- ial colorectal cancer. Gastroenterology 1995;109:1765–1771.

64. Vasen HF, van BM, Buskens E, et al. A cost-effectiveness analy- sis of colorectal screening of hereditary nonpolyposis colorectal carcinoma gene carriers. Cancer 1998;82:1632–1637.

65. Leppert M, Dobbs M, Scambler P, et al. The gene for familial polyposis coli maps to the long arm of chromosome 5. Science 1987;238:1411–1413.

66. Arvanitis ML, Jagelman DG, Fazio VW, Lavery IC, McGannon E. Mortality in patients with familial adenomatous polyposis.

Dis Colon Rectum 1990;33:639–642.

67. Vasen HF, Griffioen G, Offerhaus GJ, et al. The value of screen- ing and central registration of families with familial adenoma- tous polyposis. A study of 82 families in The Netherlands. Dis Colon Rectum 1990;33:227–230.

68. Rustin RB, Jagelman DG, McGannon E, Fazio VW, Lavery IC, Weakley FL. Spontaneous mutation in familial adenomatous polyposis. Dis Colon Rectum 1990;33:52–55.

69. Spirio L, Olschwang S, Groden J, et al. Alleles of the APC gene:

an attenuated form of familial polyposis. Cell 1993;75:951–957.

70. Giardiello FM, Brensinger JD, Petersen GM, et al. The use and interpretation of commercial APC gene testing for familial ade- nomatous polyposis. N Engl J Med 1997;336:823–827.

71. Cromwell DM, Moore RD, Brensinger JD, Petersen GM, Bass EB, Giardiello FM. Cost analysis of alternative approaches to colorectal screening in familial adenomatous polyposis.

Gastroenterology 1998;114:893–901.

72. Marcello PW, Asbun HJ, Veidenheimer MC, et al. Gastroduo- denal polyps in familial adenomatous polyposis. Surg Endosc 1996;10:418–421.

73. Fireman Z, Grossman A, Lilos P, et al. Intestinal cancer in patients with Crohn’s disease. A population study in central Israel. Scand J Gastroenterol 1989;24:346–350.

74. Gollop JH, Phillips SF, Melton LD, Zinsmeister AR. Epide- miologic aspects of Crohn’s disease: a population based study in Olmsted County, Minnesota, 1943–1982. Gut 1988;29:49–56.

75. Kvist N, Jacobsen O, Norgaard P, et al. Malignancy in Crohn’s disease. Scand J Gastroenterol 1986;21:82–86.

76. Gyde SN, Prior P, Macartney JC, Thompson H, Waterhouse JA, Allan RN. Malignancy in Crohn’s disease. Gut 1980;21:

1024–1029.

77. Greenstein AJ, Sachar DB, Smith H, Janowitz HD, Aufses AJ.

Patterns of neoplasia in Crohn’s disease and ulcerative colitis.

Cancer 1980;46:403–407.

78. Weedon DD, Shorter RG, Ilstrup DM, Huizenga KA, Taylor WF.

Crohn’s disease and cancer. N Engl J Med 1973;289:1099–1103.

79. Provenzale D, Kowdley KV, Arora S, Wong JB. Prophylactic colectomy or surveillance for chronic ulcerative colitis? A deci- sion analysis. Gastroenterology 1995;109:1188–1196.

80. Lennard JJ, Melville DM, Morson BC, Ritchie JK, Williams CB.

Precancer and cancer in extensive ulcerative colitis: findings among 401 patients over 22 years. Gut 1990;31:800–806.

81. Screening for colorectal cancer—United States, 1992–1993, and new guidelines. MMWR 1996;45:107–110.

82. Brown ML, Potosky AL, Thompson GB, Kessler LG. The knowledge and use of screening tests for colorectal and prostate cancer: data from the 1987 National Health Interview Survey.

Prev Med 1990;19:562–574.