REVIEW Colorectal Cancer Screening Sidney J. Winawer* David Schottenfeld, Betty J. Flehinger

The question of whether or not to screen for colorectal cancer in this country has been a major controversial issue for more than a decade (1-10). Considering the high incidence of this cancer, which will result in approximately 155 000 new cases in 1990, and considering the high mortality rate, which will result concurrently in approximately 60 900 deaths, the issue is a compelling one (11). Physicians and other health care personnel who treat patients with metastatic and fatal colorectal cancer have been seeking ways to advance early detection and, as a consequence, ensure improved survival, reduced mortality, and a better quality of life. While the concepts and technology are currently available to fulfill these clinical goals, their effectiveness has been debated and not uniformly accepted. The concept of the early detection of colorectal cancer had been dormant until developments beginning in the late 1960s and extending into the early 1970s provided the technical means by which this concept could be implemented clinically. These developments included the introduction of the impregnated guaiac slide test (12,13), colonoscopy, and colonoscopic polypectomy (14). These techniques followed the evolution of surgical oncologic principles (15) and the clearer demonstration of the adenoma as the precursor lesion (16).

Screening and Diagnostic Tests Before the introduction of the impregnated guaiac slide tests, patients were asked to bring stool specimens in containers for testing by unreliable reagents. The slide test permitted a more aesthetic approach to testing that was also shown to be more consistently reproducible in the laboratory. A high proportion (65% to 90%) of cancers detected by the guaiac slide test were reported to be early-stage (ie, Dukes' A and B) cancers (2JJ7,9,12,13,17-21). The guaiac slides, however, are tests for peroxidase activity and not specifically for the pseudoperoxidase activity of hemoglobin. A positive test can be affected by foods containing peroxidase activity or can result from benign gastrointestinal sources of bleeding such as hemorrhoids or diverticulosis. Neoplastic lesions may not always yield a positive test because of subthreshold levels of bleeding, generally exceeding 5 to 10 times the upper limit of "physiologic" blood loss, or an intermittent pattern of bleeding (22). Because Vol. 83, No. 4, February 20, 1991

only a small fraction of the stool is tested, there is also the potential for sampling error. With these potential problems and with concern for inadequate sensitivity for neoplastic lesions, attempts were made to modify the test or introduce entirely new methods for stool blood testing. Rehydration of the slides with water before addition of the reagent increased the sensitivity from 50% to 70% to more than 90% for neoplastic lesions, but at a great loss of specificity that resulted in an increased frequency of false positives from 1% to 2% to 6% to 10% (21-24). A quantitative stool test for blood (Hemoquant) has the same limitation of a decreased specificity in relation to enhanced sensitivity (2526). More recently, immunochemical tests have been reported that may have a greater sensitivity without loss of specificity. These new tests have not yet been subjected to large clinical trials (27). To date, the case-finding efforts in clinical practice and controlled clinical trials have used the standard guaiac slide test. Approximately 10% of colorectal cancers may be detected within reach of 7 to 10 cm from the anus by digital rectal examination, and an additional 25% to 35% of colorectal cancers are potentially within the view of a 25-cm rigid sigmoidoscope (25). However, the rigid sigmoidoscope in clinical practice may be passed beyond 20 cm in only 50% of patients, and the discomfort of the procedure is a deterrent to repeated examinations. The risk of perforation has been reported variously as 1 in 1000 to 1 in 10 000 examinations (29). Thus, the previously used 25cm rigid sigmoidoscope has been replaced almost entirely in recent years with flexible sigmoidoscopes ranging in length from 35 to 60 cm. Compared to rigid sigmoidoscopy, the flexible instrument has been shown consistently to detect approximately a two- to threefold greater number of cancers and

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Background

Received November 13, 1990; accepted December 6, 1990. Supported by Public Health Service grant CA-26852 from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. S. J. Winawer, Gastroenterology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY. D. Schottenfeld, School of Public Health, University of Michigan, Ann Arbor, Mich. B. J. Flehinger, IBM Research Division, Thomas J. Watson Research Center, Yorktown Heights, NY. 'Correspondence to: Sidney J. Winawer, MD, Gastroenterology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021.

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Screening Concepts and Risk In considering the efficient and effective application of screening tests, target strategies should be based on population risk factors, and the goals should be assessed in the context of process and outcome criteria. Tests for early detection of colorectal cancer may be used in two distinctly different settings. The first setting, generally known as "screening," occurs in outreach programs in which members of the community of health practitioners urge the general population to undergo single-site testing specifically to identify those individuals who are likely to have colorectal cancer. In the second setting, called 244

"case-finding" by some investigators, tests for cancer are carried out as part of a comprehensive medical examination sought by the patient. In this situation, the physician is able to use other evidence about the state of the patient's health to evaluate the significance of either a negative or a positive screening test. Case-finding also makes it easier to channel the patient into appropriate diagnostic procedures immediately after the positive test results (2,9). Case-finding and screening share the objective of ensuring early detection and the favorable balance of curative intervention in relation to acceptable risks. An ethical issue may be raised as to whether a higher ratio of benefits to risks should be required for inviting well persons in the population to be screened compared with patients who seek medical care and where screening (case-finding) is part of that evaluation. A number of parameters that relate to the feasibility and effectiveness of screening need to be examined. Feasibility parameters include the rate of positive tests; the sensitivity, specificity, and predictiveness of the tests; and patient compliance. Effectiveness parameters include cancer staging, survival, mortality, and cost-effectiveness. A shift to earlier stage cancers associated with improved survival is critical as an early outcome measure; however, early detection may be achieved without any real increase in survival (lead-time bias), and cancers with a more favorable prognosis may be detected by screening because they are slow-growing (length-biased sampling). Lesions detected as a result of screening may result in unnecessary treatment of cancers that would never have surfaced clinically. It is generally agreed that the ideal method of evaluating the effectiveness of a technique for early detection of cancer is a controlled clinical trial with mortality as the outcome measure. If one group is tested regularly and another, similar group is not tested at all, a comparison between the rates of colorectal cancer deaths in the two groups should establish the value of the screening test The assessment of outcome health status requires systematic, unbiased ascertainment of all individuals participating in the trial (2J^,9). In high-risk countries in North America and Western Europe, risks rise substantially over age 50 (Table 1) (28). Groups at increased risk include patients with ulcerative colitis and mucosal Table 1. Risk factors for colorectal cancer Average risk Age 50 years and older, asymptomatic general population High risk Personal history Sporadic colorectal adenomas Colorectal cancer Inflammatory bowel disease' Breast, ovarian, or endometrial cancer Radiation therapy

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polyps and is better tolerated (29 JO). Although the longer 60cm sigmoidoscope has the potential for reaching the splenic flexure and detecting 50% to 60% of colorectal cancers, in most patients the average depth of insertion is usually between 40 and 50 cm into the upper • sigmoid or distal descending colon. Theoretically, the longer the scope, the greater the yield in a screening setting of asymptomatic average-risk people; however, there has been no significant difference in yield between 35- and 60-cm scopes, although less time and training and lower risk were associated with the shorter scopes (31J2). With either instrument, the entire rectum and sigmoid colon can be examined completely and easily with relatively high patient compliance. The digital rectal examination is usually performed before sigmoidoscopy. Introduction of the fecal occult blood test and flexible sigmoidoscopy for screening would have been of little potential value without development of the colonoscope, which was introduced into the United States around 1970. The first instruments were cumbersome, with only two-way deflecting tips. Initially, on the average, colonoscopy required several hours, with fluoroscopic control during insertion. Over the subsequent 3 years, more flexible instruments with 360° deflection were introduced; today there are video electronic endoscopes that transmit the image with brightness and clear resolution by computer chips to a TV monitor. Average colonoscopy now requires only 15 to 20 minutes, and complete examination to the cecum is possible in 75% to more than 90% of patients, depending on the experience of the endoscopist (33 J4). For the first time, an accurate assessment could be made of colonic pathology. Biopsies and brush cytology could be done and, after introduction of colonoscopic polypectomy into clinical practice in the United States in about 1973, polyps could be removed throughout the colon with safety (14). Colonoscopic polypectomy thus increased the attractiveness of screening, which could now encompass detection of early cancers and premalignant polyps. One could consider not only a reduction in cancer mortality but also a reduction in its incidence from the interruption of the adenoma-adenocarcinoma sequence (16). Colonoscopy was considered to be a useful diagnostic test that could be applied to patients who had a positive occult blood test or to average-risk people in whom a polyp was found on sigmoidoscopic screen. However, colonoscopy was also rapidly applied as a primary screening technique in people at increased risk, such as those with ulcerative colitis, personal history of colorectal polyps or cancer, or family history of colorectal cancer (13).

Family history Familial adenomatous polyposis Gardner's syndrome Turcot's syndrome Okifield's syndrome Juvenile polyposis Hereditary non-polyposis colorectal cancer syndromes (HNPCQ Flat adenoma syndrome Sporadic colorectal cancer Sporadic colorectal adenoma

Journal of the National Cancer Institute

dysplasia or with Crohn's granulomatous colitis; individuals with a personal or family history of adenomatous polyps or colon cancer or a personal history of breast, endometrial, or ovarian cancer, and individuals with a personal history of radiation therapy for urinary bladder cancer (2,28).

Screening Trials in Average-Risk Individuals

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Several studies and programs that were initiated around the world to evaluate screening using stool occult blood testing suggested that this method may have potential value for colorectal cancer (35-38). A large study that is in progress in Germany encourages screening of asymptomatic women and men in doctors' offices on a periodic basis (39). There are also five controlled trials studying the possible usefulness of the stool blood test in screening for colorectal cancer (Table 2) (17-21). One trial was initiated in 1975 by the Memorial Sloan-Kettering Cancer Center (MSKCC; New York, NY) in collaboration with the Preventive Medicine Institute-Strang Clinic (New York, NY) to evaluate the stool occult blood test for detecting colorectal cancer in conjunction with rigid sigmoidoscopy in the setting of a comprehensive preventive medical examination (17). Patients over age 40 who presented at the clinic were assigned to either the study or control group based on date of enrollment. All 21 756 participants underwent a comprehensive examination, which included a general physical examination, a health history questionnaire, and sigmoidoscopy with a 25-cm rigid scope. Patients assigned to the study group were also offered stool blood testing, while control patients were not. Incorporation of the stool blood test was feasible, with approximately 75% of patients being willing to prepare their slides at the time of their enrollment. The overall rate of positive tests was 1.7% with nonhydrated slides and was strongly age dependent. The rate of positivity was higher for patients who had not had peri-

odic sigmoidoscopic examinations in previous years. The overall predictive value of a positive test for adenomas and cancer was 30%; this measure of screening test efficiency was correlated with the prevalence of disease and thus increased with increasing patient age. The majority of patients with a positive stool blood test underwent diagnostic procedures within the year after screening. The barium enema missed 25% of the neoplastic lesions diagnosed by coionoscopy. The sensitivity of the stool blood test for cancer was estimated at 70% and specificity at 98%. A distinct stage difference between study and control groups (P

Colorectal cancer screening.

REVIEW Colorectal Cancer Screening Sidney J. Winawer* David Schottenfeld, Betty J. Flehinger The question of whether or not to screen for colorectal...
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