COMMENTARY

Colorectal Cancer Screening for Persons at Average Risk

William F. Anderson, Kate Z. Guyton, Robert A. Hiatt, Sally W. Vernon, Bernard Levin, Ernest Hawk

Affiliations of authors: W. F. Anderson, E. Hawk (Division of Cancer Prevention/Gastrointestinal and Other Cancer Research Group), R. A. Hiatt (Division of Cancer Control and Population Sciences), National Cancer Institute, Bethesda, MD; K. Z. Guyton, CCS Associates, Mountain View, CA; S. W. Vernon, School of Public Health, University of Texas, Houston; B. Levin, The University of Texas M. D. Anderson Cancer Center, Houston.

Correspondence to: William F. Anderson, M.D., M.P.H., NCI/Division of Cancer Prevention/Gastrointestinal and Other Cancer Research Group, EPN, Room 2144, 6130 Executive Blvd., Bethesda, MD 20892-7317 (e-mail: wanderso{at}mail.nih.gov).

BACKGROUND

In the United States, colorectal carcinoma (CRC) is the fourth most frequently diagnosed and the second most common cause of cancer-specific death for both men and women (1). The lifetime risk of developing CRC is approximately 6% (2), and treatment costs nearly $6 billion annually (3). As for most epithelial cancers, CRC age-specific incidence increases continuously with biologic aging, with the greatest risk occurring in those individuals aged 80 years or older (2) (Fig. 1Go). Of the more than 148 000 estimated new CRC cases in the year 2002 (4), approximately 40% are expected to die within 5 years (2). Death from CRC is especially unfortunate, given that CRC prevention often can be achieved through screening (5).



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Fig. 1. Age-specific colorectal cancer incidence rate (or age-specific colorectal cancer risk) from 1995 through 1999, adjusted to the 2000 U.S. population. The age-specific colorectal cancer risk rises continuously with advancing age. The greatest risk of developing colorectal cancer occurs in men and women who are 80 years old or older at diagnosis. The figure was adapted from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)1 Database.

 
CRC screening affords the opportunity to identify and remove precursor lesions (e.g., preinvasive adenomatous polyps or adenomas) (6). Indeed, direct, longitudinal observation of, and intervention in, the long-term, multi-step process of colorectal carcinogenesis—partially represented by the adenoma-to-carcinoma sequence in Fig. 2Go (7,8)—can be achieved with existing endoscopic technologies (6,9,10). Although efficacy has been demonstrated in this regard, only 44% of U.S. adults aged 50 years or older have recently had any type of CRC screening (11).



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Fig. 2. Model of colorectal carcinogenesis. Model evidence now suggests that colorectal cancer results from the accumulation of diverse structural and functional genomic aberrations, which develop over an extended time interval. Genetic alterations are generally random, but mutations may occur in a preferential order, correlating with histologic progression from the pre-invasive adenoma to carcinoma. Recognizing that the adenoma-to-carcinoma sequence is a long-term, multistep biologic continuum provides the biologic rationale, opportunity, and even responsibility for early colorectal cancer detection. [The figure is reprinted with permission from the International Journal of Clinical Oncology, Springer-Verlag, Tokyo; see (91).]

 
To address these and other concerns, the National Cancer Institute (NCI) convened a workshop in March 2001 to review 1) routine and emerging CRC screening technologies; 2) valid endpoints (or targets) for CRC screening, particularly with regard to comparative evaluations of new and existing technologies; and 3) barriers to screening. This document with commentary from the authors summarizes the NCI workshop proceedings. Appendices A and B provide a complete listing of speakers and attendees.

ROUTINE AND EMERGING CRC SCREENING TECHNOLOGIES FOR PERSONS AT AVERAGE RISK

Approximately 75% of all CRCs occur among persons of "average risk," i.e., those without conditions such as inflammatory bowel disease, familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC), or positive family history of colorectal neoplasia (adenoma or CRC) (12). While there is general consensus concerning the efficacy of CRC screening, slightly differing routine screening strategies are recommended by the American Cancer Society (ACS), the United States Preventive Services Task Force (USPSTF), and the American College of Gastroenterology (ACG) for average-risk individuals beginning at 50 years of age (5,13,14). In 2001, ACS recommended one of the following: annual home-based fecal occult blood test (FOBT), flexible sigmoidoscopy (FS) every 5 years, annual home-based FOBT plus FS every 5 years, double contrast barium enema (DCBE) every 5 years, or colonoscopy every 10 years.

In 2000, the ACG recommended colonoscopy every 10 years as the preferred screening strategy for persons at average risk, whereas FS every 5 years plus annual FOBT was a reasonable alternative. DCBE every 5 years could be substituted for FS, if it is performed by a radiologist known to conduct high-quality examinations. In 1997, the USPSTF recommended FS (periodicity unspecified) or annual FOBT; new USPSTF recommendations are anticipated within the year.

Stool-Based Screening Tests

Fecal occult blood test (FOBT). The home-based FOBT is the most intensively and definitively studied routine CRC screening test. Nearly 350 000 individuals have participated in four FOBT randomized clinical trials—one in Minnesota (1517) and three in Europe (1826). Meta-analysis of these studies concluded that annual home-based FOBT reduced CRC incidence by approximately 20% and decreased CRC mortality by 16% (27). Acknowledged limitations of one-time FOBT include low sensitivity for adenomas (10%), low sensitivity for CRC (40%–85%), and relatively low specificity for adenomas and CRC combined (90%–98%) (28).

Sensitivity measures the probability of detecting either an adenoma or CRC, whereas specificity estimates the rate of false-positive tests (29). Although FOBT does not have direct toxic consequences, risk is associated with false-positive results, which may provoke unnecessary diagnostic endoscopic examinations with the potential to do harm. In contrast to one-time screening, the Minnesota trial estimated 90% sensitivity for a program of annual FOBT, i.e., programmatic FOBT (17,30). Additional improvements in stool-based tests could not only decrease the risk associated with screening but also decrease the number of people who need to be screened to reduce CRC incidence and mortality, which for FOBT is currently estimated to be 1400 persons to prevent one CRC death in 5 years (31).

Fecal multi-targeted DNA-based assay panel (MTAP) test. MTAP is a promising stool-based test that is currently in development (32,33). One example of MTAP targets 19 DNA alterations associated with colorectal neoplasia: 15 mutational hot spots on K-ras, APC, p53, and Bat-26 gene mutations, and highly-amplifiable longer template DNA (32). In a small feasibility analysis that used archived stool samples, MTAP exhibited higher sensitivity and specificity than standard FOBT for CRC and advanced adenomas (32). Sensitivity was 91% for cancer and 82% for adenomas greater than or equal to 1.0 cm with a specificity of 93% (32). As a follow-up to these findings, NCI has recently funded a randomized clinical trial to assess the performance characteristics of MTAP versus FOBT versus colonoscopy (34). Results from this study as well as others currently in progress will confirm or refute the promise of DNA-based stool assays, but definitive results are not expected for at least 3–5 years.

Endoscopic Screening Strategies

Flexible sigmoidoscopy (FS). FS uses a 60-cm flexible endoscope to directly visualize the distal (or left) colorectum, which includes the rectum, the sigmoid colon, and the descending colon to approximately the splenic flexure. Case–control studies (3538) demonstrated 45%–79% reductions in CRC mortality with FS followed by colonoscopic polypectomy. The single prospective controlled study (39) of screening FS randomly drew 400 men and women aged 50–59 years from the population-based registry of Telemark, Norway. The subjects were offered FS and, if polyps were found, a full colonoscopy with polypectomy and follow-up colonoscopies in 1985 and 1989. A control group was drawn from the same registry. Compared with the control group, the subjects who were not offered initial FS endoscopic screening followed by colonoscopy for positive results demonstrated an 80% reduction in CRC incidence (relative risk = 0.2, 95% confidence interval = 0.03 to 0.95; P = .02) (39).

However, cost estimates for FS screening, followed by colonoscopy as warranted, for the general public are substantial. Annual costs to screen the U.S. population at average CRC risk with FS could exceed $20 billion by the year 2010 (40). Nonetheless, economies of scale may permit effective FS delivery at high-volume centers, as recently demonstrated by Kaiser Permanente (41).

Annual FOBT combined with FS every 5 years. Three lines of indirect evidence support programmatic annual home-based FOBT combined with FS every 3–5 years over either test alone. First, FS and FOBT are complementary. FS visualizes the distal, but not the proximal, colorectum, whereas FOBT may be more sensitive in the proximal than the distal colon (1719). For example, two FOBT randomized clinical trials suggested an increased CRC detection rate in the proximal versus the distal colon (1719). Second, combined tests appear to detect more cancers than either test alone (42). As demonstrated by Lieberman et al. (42), even one-time FOBT plus distal examination of the colorectum detected more colorectal neoplasia than distal endoscopy alone, and a higher proportion of neoplasia should be detected with repeated FOBT over several years (17). Third, combined screening appears to reduce CRC mortality (43). In a prospective cohort analysis (43), the Preventive Medicine Institute–Strang Clinic noted 42% lower cancer mortality for FS plus FOBT versus FS alone, but the study was only of borderline significance (P = .053; one-sided). In addition, two case–control studies (38,44) suggested reduced CRC mortality for FS after controlling for FOBT, as well as reduced CRC mortality for FOBT after controlling for FS.

Colonoscopy. Early detection with either FOBT and/or FS without colonoscopic diagnostic and/or therapeutic follow-up is of no value. Although colonoscopy is the most complete endoscopic procedure, direct evidence to justify routine colonoscopic screening in average-risk individuals is lacking. The FOBT randomized clinical trials provided indirect evidence that follow-up colonoscopic polypectomy for positive results could reduce CRC incidence and mortality (1526). FS case–control studies (3538) demonstrated endoscopic benefit in the distal colon, with the clear implication that visualization of the entire colorectum was better than a partial examination. The National Polyp Study (NPS) (6) showed that surveillance colonoscopic polypectomy after removal of all polyps reduced CRC incidence compared with that in three historical control groups.

Two cohort analyses (45,46) examined colonoscopy in average-risk subjects to determine the prevalence of advanced colorectal neoplasia, defined as adenomas greater than 1.0 cm in diameter, with high-grade dysplasia, villous histology, or invasive CRC. Both studies demonstrated a 6%–10% prevalence of advanced colorectal neoplasia with a 2.5%–4% prevalence of advanced proximal colorectal neoplasia. More than half the advanced proximal disease occurred without distal lesions and presumably would have been missed with FS alone. The addition of one-time FOBT still failed to detect 25% of advanced proximal disease (42). Programmatic FOBT plus FS should be more efficacious than one-time screening (17,30) but, in clinical practice, many persons who begin annual screening fail to undergo more than one test (47). The NCI is currently sponsoring a clinical trial to assess the feasibility of once-in-a-lifetime colonoscopy screening (48,49). Whether a randomized colonoscopy trial will be done was a question that this conference addressed.

Emerging endoscopic technologies. Several emerging imaging technologies have the potential to enhance endoscopic detection of colorectal dysplasia and neoplasia. For example, laser-induced fluorescence spectroscopy can detect dysplastic changes in colorectal mucosa that cannot be visualized by routine endoscopy. In comparative studies (50,51) of adenomatous polyps and adjacent endoscopically normal-appearing mucosa, fluorescence intensity could discriminate dysplastic from normal tissue with sensitivities and specificities in the range of 90%. Alternatively, in situ detection of dysplasia can be achieved with light-scattering spectroscopy, which provides an objective measure of epithelial nuclear enlargement and crowding (52). This closely approximates the criteria used by pathologists to assign histologic diagnoses, with dysplastic nuclei being larger and more crowded. Optical coherent tomography (OCT) is another emerging technology with potential application in CRC screening (53). OCT provides high-resolution images comparable with ultrasound but without the requirement for a liquid medium. Developed in the field of ophthalmology where it was highly successful, OCT has recently been applied to gastrointestinal tissues. Advances in technology and operator usability are required before large-scale validation studies of these emerging technologies can be undertaken.

X-Ray Screening Strategies

DCBE. Although readily available in the United States, DCBE tends to be reserved for those who would be poor candidates for colonoscopy or for those in whom colonoscopy was incomplete. According to Medicare data, nearly 250 000 DCBEs are performed annually in the United States. DCBE examines the entire colon and has a sensitivity of 60%–80% for adenomas that are one or more centimeters in diameter (28). DCBE is relatively safe, with about one test-related death per 50 000 examinations (28). Some of the practical and technical limitations are that radiologists lack adequate training, patients receive some radiation exposure, full colon cleansing is required, and diagnostic or therapeutic biopsies cannot be performed.

Virtual colonoscopy. Integrated three-dimensional computed tomography (CT) or virtual colonoscopy is an emerging imaging technique. Virtual colonoscopy couples computer graphics with helical or spiral CT to generate a continuous image of the entire colon. One of the first uses of virtual colonoscopy was in cases where colonoscopy failed or was incomplete. A significant advantage of virtual colonoscopy is that anesthesia or sedation is not required. Disadvantages are the need for colon preparation, discomfort from infusion of gas during the procedure, and the inability to perform a biopsy of suspicious lesions. Purportedly, virtual colonoscopy can detect polyps that are 7–8 mm in diameter, and it has a sensitivity of 75%–91% for lesions greater than 1.0 cm in diameter (5456), but these preliminary results need to be confirmed in larger studies. Although virtual colonoscopy is an appealing technology, issues such as availability, cost, specificity, and inadequate scanner speed currently limit its application as a routine screening option (57).

VALID ENDPOINTS FOR ASSESSMENT OF COLORECTAL CANCER SCREENING

Endpoints are applied in CRC screening to assess the efficacy of screening strategies and technologies. Although CRC incidence or mortality is the most definitive endpoint in colorectal carcinogenesis, precursor lesions may be useful surrogate endpoint biomarkers (Fig. 2Go) (58,59). In the case of adenomas, this intermediate pathology has already become the focus of routine screening and intervention.

Colorectal Cancer Endpoints

The most basic measures of cancer outcome are cancer-specific incidence and mortality rates. Determining cancer incidence is appropriate for elucidating tumor biology as well as for defining screening performance characteristics—sensitivity, specificity, and positive and negative predictive value. However, the detection of new cancer cases is not by itself evidence that screening will reduce cancer mortality, because early detection can be confounded by lead-time, length-time, and overdiagnosis biases (60). For these reasons, the strongest evidence concerning the efficacy of any screening test comes from well-conceived and well-conducted randomized clinical trials that use cancer-specific mortality as the endpoint (6163). Focusing on cancer-specific mortality also examines one of the least ambiguous events and one that is of the most concern to both health care practitioners and the general public (64).

However, extrapolation of even the best data from randomized clinical trials to the general population may be problematic (60). First, potential harmful effects of cancer screening may not be fully appreciated until the technology is widely disseminated. Consider the infrequent but well-documented risks of colonoscopy with biopsies (65) relative to the probable benefit; because the mortality rate from CRC is approximately 1.2 per 10 000 (2), a reduction in CRC deaths could be offset by colonoscopy-associated deaths (1–3 deaths per 10 000 colonoscopies with biopsies) (28). Second, reduced cancer-specific mortality may be replaced by another cause of mortality, negating the impact of screening on overall mortality. For example, in all of the large-scale FOBT randomized clinical trials, overall mortality in the screened and control groups has been virtually identical (1526). In the Danish and Minnesota FOBT trials, the CRC mortality reduction was precisely offset by increased mortality from atherosclerotic cardiovascular disease (66). Furthermore, in the prospective Telemark FS clinical trial, CRC-specific mortality was reduced, but overall mortality was increased in the endoscopy arm (39). Third, randomized clinical trials with cancer-specific mortality can be, at best, difficult and expensive, requiring large sample sizes and/or years or decades to complete, during which time technologic advances could render the findings obsolete.

Colorectal Adenoma Endpoints

Data relating the pre-invasive polyp to CRC were first reported in 1928 from St. Mark's Hospital (67). Morson (6871) later defined the complete adenoma-to-carcinoma sequence. In the precolonoscopy era, Stryker et al. (72) demonstrated the natural history of the adenoma to carcinoma relationship in 226 patients with adenomas who chose radiographic surveillance over exploratory laparotomy. Their actuarial analysis revealed that the cumulative risk of developing CRC was approximately 1% per year for polyps greater than 1.0 cm in diameter. Wolff and Shinya (9,10) later established the feasibility of removing adenomatous polyps from the entire colorectum with the fiberoptic colonoscope. Thereafter, the NPS demonstrated the potential impact of adenoma detection and removal for cancer control (6).

Adenoma prevalence is related to increasing age, male sex, family history, and method of detection (73). For asymptomatic average-risk individuals older than 50 years, the colonoscopic prevalence rate of adenomatous polyps ranges from 24% to 47%, which is at least twice the sigmoidoscopic prevalence rate (73). After removal of all adenomas at the baseline colonoscopy, the NPS followed more than 2600 patients with surveillance colonoscopy and/or DCBE at 1 and 3 years or at 3 years only (6,74). Follow-up detection rates were 10% and 1% per year for any recurrent adenomas and advanced adenomas, respectively. On the basis of three historical reference groups, reductions in CRC incidence were 76%–90% after colonoscopic polypectomy (P<.001), providing compelling, albeit indirect, evidence that polypectomy can prevent invasive CRC and reduce cancer-specific mortality (3).

Endoscopists routinely attempt to remove all visible adenomas, but not every adenoma may be at elevated risk for CRC development in the near term. Advanced (i.e., larger and more dysplastic) adenomas may be better targets for screening and intervention because of their greater risk of progression over a short interval. Because 56% of baseline adenomas in the NPS were advanced (defined as greater than or equal to 1.0 cm, high-grade dysplasia, or villous component), the study provides at least indirect evidence of the benefit of advanced adenoma removal (6,75). Similarly, a U.K. retrospective cohort analysis (76) demonstrated increased CRC risk with advanced, but not small, adenomas. Predictors of advanced adenomas included age greater than 60 years, adenoma multiplicity, and positive family history (74,7678).

BARRIERS TO ROUTINE COLORECTAL CANCER SCREENING

Despite dissemination of screening guidelines, supporting clinical evidence, and increased reimbursement for CRC screening in asymptomatic individuals at average risk, data from the National Health Interview Surveys (NHIS) and the Behavioral Risk Factor Surveillance System (BRFSS) indicate that screening rates for CRC are statistically significantly lower than those for cervical or breast cancer (7981). From 1987 through 1998, the prevalence of FOBT screening increased from 18% to 29% in men and from 21% to 26% in women; during this same period, the prevalence of endoscopic screening increased from 8% to 19% in men and from 6% to 10% in women.

Survey data indicate that the reasons for eligible persons not participating in CRC screening are generally similar for FOBT and sigmoidoscopy (47). Practical issues, such as conflicts with work or family, inconvenience, being too busy, being out of town, lack of interest, and cost, are most important. Other reasons mentioned by patients, with approximately equal frequency, included the embarrassment or unpleasantness of the test, their lack of interest about subclinical health problems, and their anxiety about potential test results.

Provider barriers to recommending or performing CRC screening have been less well studied (82). To date, consistent patterns in physicians' reasons for not offering FOBT have not been shown; the most frequently cited reasons include forgetfulness, perceived ineffectiveness of the tests, cost, and inconvenience for patients (82). Commonly cited reasons (ascertained in retrospective or cross-sectional surveys) for not offering sigmoidoscopy were patient discomfort, cost, provider inconvenience, lack of time, lack of training or experience, lack of equipment, and poor patient acceptance. Collectively, these data indicate a need to address both patient and physician barriers to CRC screening, if the currently low rates of compliance are to increase.

RESEARCH CHALLENGES AND OPPORTUNITIES FOR THE NEXT 3–5 YEARS

Key scientific research questions regarding CRC screening discussed in the workshop roundtable are summarized with commentary in the following sections.

1) One of the most appropriate target lesions for CRC screening and prevention is the adenoma.

Several lines of evidence support the adenomatous polyp as the target of choice for CRC screening and prevention. A primary consideration is that colorectal carcinogenesis is most curable in the adenoma phase, whereas the CRC risk conferred by pre-adenomas (including aberrant crypt foci [ACF]) is less certain. Given the protracted timeline for CRC development, it is not clear that targeting pre-adenomas in average-risk individuals would impact CRC burden. The limited morbidity and mortality associated with endoscopy arises largely from polypectomy and could potentially be reduced by targeting only advanced, rather than all, adenomas for removal. The NPS provided at least indirect evidence of the benefit of removing advanced adenomas, because 56% of the baseline adenomas were advanced (75). However, the neoplastic evolution from adenoma to advanced adenoma has not been fully established and will be difficult to establish in the future, because current standards of care require histologic assessment and removal of all suspicious polypoid lesions. Risk of malignancy increases with high-grade dysplasia, villous histology, and size of the advanced adenoma, although further definition of these criteria is warranted. The growth rate of advanced adenomas, which might inform the appropriate screening interval, is also not defined. The best available data come from the landmark NPS (74) and the study of Stryker et al. (72). However, the NPS dealt with surveillance rather than screening intervals, and Stryker et al. did not include histologic assessments. Current technologies, as well as novel molecular and imaging modalities, could be used to further characterize adenomas, advanced adenomas, and other precancerous lesions—and to define the longitudinal risk conferred by these various lesions. Continued support of such efforts is justified.

2) At present, there is no preferred CRC screening strategy.

Despite well-established consensus that CRC screening reduces CRC burden, there is lack of agreement on the preferred screening strategy, because most available technologies have never been directly compared. An ideal screening tool would be noninvasive, efficacious, available, safe, high quality, affordable, and acceptable. Stool-based tests are the only truly noninvasive screening strategies. FOBT potentially examines the entire colorectum, requires no cathartic preparation, has affordable single unit cost, and can be done in the privacy of the home. Annual programmatic home FOBT may have 90% sensitivity for CRC (17,30), but it is much less sensitive for adenomas (83), and many persons who begin annual FOBT fail to undergo more than one test, limiting its actual sensitivity for cancer as well (47). Molecular enhancements (e.g., MTAP), although still in development (3234), have the potential to improve the performance characteristics of stool-based screening examinations, and continued investment in this promising area is warranted.

Invasive endoscopic screening options include FS, combined annual FOBT plus FS, and colonoscopy. FS to the splenic flexure can potentially identify most, if not all, advanced proximal adenomas (45,46). One-time FOBT plus FS still misses 25% of advanced proximal colorectal neoplasia without distal lesions (42). Programmatic FOBT plus FS is a logical alternative to single FOBT plus FS, but this would be best assessed in a randomized clinical trial. Once-in-a-lifetime colonoscopy could be more efficient and could be cost-effective compared with programmatic FOBT and/or FS, although the appropriate age at which it should be performed and many other questions remain to be defined. Results from the NCI-sponsored feasibility study (48,49) of once-in-a-lifetime colonoscopy are eagerly awaited. Although as yet unproven, noninvasive imaging by CT colography would be an attractive screening test, particularly if colon preparation was not required. A preparation-free approach has the potential to enhance compliance and thus expand the screened population, which could have a significant impact on public health. Additional studies of this approach would be useful. Virtual colonoscopy, chromoendoscopy, and other enhancements to FS or colonoscopy might improve diagnostic yield but, again, relative performance characteristics between current and emerging screening options would best be tested in a comparative randomized clinical trial.

3) A definitive randomized clinical trial of colonoscopy screening with a mortality endpoint is highly desirable but may not be feasible.

Proponents favor a randomized clinical trial of colonoscopy screening; however, data that support colonoscopy as the preferred screening strategy (14), although compelling, are indirect. a) Trial proponents argue that a definitive, large-scale, randomized colonoscopic screening trial with a mortality endpoint would promote evidence-based consensus. Such a study could compare commonly used screening modalities (e.g., colonoscopy versus FOBT or FS or FOBT plus FS). The trial could define the efficacy and benefit-to-harm ratio of colonoscopic screening as well as the importance of proximal (right) versus distal (left) polypectomy. b) The trial could provide solid evidence that would stimulate increased adherence to routine colon cancer screening. c) If initiation of such a trial is postponed, the opportunity to assess the efficacy of colonoscopic screening in a randomized manner could be missed because of the widespread implementation of routine screening colonoscopy. d) The study of natural history and risk factors for CRC could be facilitated by prospective collection of stool, tissue, and blood during the trial.

Opponents provide the following arguments against a randomized trial of colonoscopy screening: a) A randomized clinical trial is not needed because there are already compelling indirect data that colonoscopy is an effective, and possibly even the preferred, screening tool [i.e., evidence accumulated from hundreds of thousands of participants in FOBT (1526), FS (3539,76), and colonoscopy studies (42,45,46)]. b) An efficacious randomized clinical trial would not ensure effectiveness in the general populace; that is a more complex issue related to availability (capacity), safety, quality, compliance, and affordability. With nearly 80 million adults aged 50 years or older (84) and fewer than 8000 practicing gastroenterologists in the United States (85), it seems unlikely that the present infrastructure could implement nationwide colonoscopic screening, even if it were found to be clearly more efficacious. Moreover, population-based colonoscopic screening might have a narrow therapeutic margin. The technical quality of the community-based colonoscopy also would vary with the training and expertise of the endoscopist (86,87). High unit cost could be problematic to some individuals, particularly those without insurance. c) The opportunity to conduct such a large-scale trial already may have passed. Colonoscopy is generally accepted as the "gold standard" for CRC screening. Public acceptance and provider reimbursement for the procedure are well established and, therefore, randomization to a trial that limited subjects to other tests would probably have to consider significant contamination of the control arm. In light of current knowledge, it is also not clear how a negative study would be interpreted or accepted. d) The cost and size of such a trial would be enormous. Although CRC is a major public health problem, it is nonetheless a protracted and somewhat rare event in the general population. The lifetime risk of dying from CRC in the United States is 2.43% (1 in 41) (2). Therefore, relatively few events would occur during the course of a colonoscopy trial with a mortality endpoint, necessitating a very long duration and sample size estimates as high as 100 000 participants, resulting in tens of millions of dollars in costs.

4) Reducing barriers to routine colorectal cancer screening recommendations is a priority.

In 2000, the National Cancer Institute (NCI) Colorectal Cancer Progress Review Group identified, as a priority area, research into short- to medium-term (5- to 10-year) strategies for effective implementation of currently recommended methods of early detection at the population level (88). To date, studies (47,82) evaluating different methods to increase FOBT or sigmoidoscopy adherence have largely focused on patient populations, and most were directed at improving FOBT adherence. Minimal or relatively impersonal contact (e.g., asking individuals to pick up an FOBT) yielded rates of adherence between 10% and 30% (47,82). More personalized strategies, such as mailed interventions with telephone follow-up, increased adherence up to 50%. Few studies (82) have evaluated the effects of interventions directed at providers to increase performance or recommendation of CRC screening. A number of NCI-funded studies (89) that address some of the limitations of prior research are ongoing.

Summary. Despite universal endorsement of CRC screening, less than half the average-risk population over age 50 has undergone a CRC screening examination of any type. Nevertheless, the adenoma-to-carcinoma sequence is a long-term, multistep continuum that provides a compelling biologic rationale, opportunity—and even responsibility (90,91)—for CRC screening and prevention. Therefore, a primary challenge is to investigate and address barriers to the implementation of routine CRC screening guidelines. Additional research efforts should focus on determining the preferred strategy for detecting adenomas. It is not clear that all strategies would have a favorable therapeutic index or could be applied to the general population. A head-to-head comparison of available technologies in a randomized clinical trial with a CRC mortality endpoint would be the most direct approach to this issue. Although evidence from a randomized clinical trial would provide the type of evidence that could favorably affect screening behavior, its feasibility is limited because of the long duration, large sample size, high cost, and low subject and provider acceptance that such a study may encounter. In the absence of such a long-term, large-scale, colonoscopy randomized clinical trial, smaller, less costly trials that estimate new and emerging technologies against reasonable surrogate endpoint biomarkers (i.e., any adenoma and advanced adenomas) should be considered to assess relative efficacies, as well as to answer important biologic questions relating to pre-invasive colorectal neoplasia.

APPENDIX A

Speakers:

David Ahlquist, M.D.; Carolyn Alidge, B.S.; Wendy Atkin, Ph.D.; John H. Bond, M.D.; Martin Brown, Ph.D.; Joseph T. Ferrucci, M.D.; Robert Fletcher, M.D., M.Sc.; Seth Glick, M.D.; John Gohagan, Ph.D.; Peter Greenwald, M.D., Dr.P.H.; Stanley R. Hamilton, M.D.; Brian Harvey, M.D., Ph.D.; Ernest Hawk, M.D., M.P.H. (co-chairman); Robert A. Hiatt, M.D., Ph.D.; Carrie Klabunde, Ph.D.; Richard Klausner, M.D.; Bernard Levin, M.D. (co-chairman); Theodore R. Levin, M.D.; Kevin Lewis, B.A.; David Lieberman, M.D.; Marion Nadel, Ph.D.; Larry Norton, M.D.; Michael Pignone, M.D., M.P.H.; David Ransohoff, M.D.; Bjorn J. Rembacken, M.B., Ch.B.; Douglas Rex, M.D.; Francis J. Scholz, M.D.; Robert Smith, M.D.; Jacques Van Dam, M.D., Ph.D.; Sally W. Vernon, Ph.D.; Sidney Winawer, M.D.; Steven H. Woolf, M.D., M.P.H.; Graeme Young, M.D., F.R.A.C.P.

APPENDIX B

Attendees:

William Anderson, M.D., M.P.H.; Rachel Ballard-Barbash, M.D., M.P.H.; Hans Berkel, M.D., Ph.D.; Richard Boxer, M.D.; Durado D. Brooks, M.D., M.P.H.; Jeff Brown; Nelvis Castro; Julie Cheh, M.P.H.; James F. Coan; Denise Collins, R.Ph.; Richard Farrell; L. Peter Fielding, M.D.; Andrew Freedman, Ph.D.; Ralph S. Freedman, M.B.B.C., Ph.D.; Kate Z. Guyton, Ph.D., D.A.B.T.; Don Hardison; Elizabeth Harvey, Ph.D.; Donald Henson, M.D.; Gary Kelloff, M.D.; Amy Kelly; Levy Kopelovich, Ph.D.; Stan Lapidus; Michael Miller, M.P.H.; Kate Murphy; Paul F. Pinsky, Ph.D.; Mike Retsky; Michael Ross, M.D.; Anna Schenck, Ph.D.; Kara Smigel-Croker, M.S., R.D.; Andrew Spiegel; Asad Umar, D.V.M., Ph.D.; Jaye L. Viner, M.D.; David M. Walsworth, M.D.; Sandy White; Jeffrey Wisotzkey, Ph.D.; Barbara J. Woodhouse; Ann Zauber, Ph.D.

NOTES

The Commentary includes the report on different presentations and discussions carried out at a workshop sponsored by the National Cancer Institute, held on March 1–2, 2001.

Bernard Levin is a member of the Scientific Advisory Board of Enterix. He has received research support from Pharmacia and payment for educational activities on its behalf.

We are indebted to David Ransohoff, M.D., University of North Carolina at Chapel Hill, for his review, comments, and suggestions. We also wish to thank the many speakers and attendees who attended the workshop and provided valuable insight and expertise.

1 Editor's note: SEER is a set of geographically defined, population-based, central cancer registries in the United States, operated by local nonprofit organizations under contract to the National Cancer Institute (NCI). Registry data are submitted electronically without personal identifiers to the NCI on a biannual basis, and the NCI makes the data available to the public for scientific research.Back

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Manuscript received January 10, 2002; revised May 28, 2002; accepted June 11, 2002.


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