Abdom Imaging 27:235–243 (2002) DOI: 10.1007/s00261-001-0164-y

Abdominal Imaging © Springer-Verlag New York Inc. 2002

Colorectal cancer screening issues: a role for CT colonography? P. M. McMahon,1 G. S. Gazelle2 1 2

Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA Decision Analysis & Technology Assessment Group, Zero Emerson Place, Suite 2H, Boston, MA 02114, USA

Abstract Colorectal cancer is the third most common cancer in the United States and will cause 56,700 deaths in 2001, despite the availability of screening tests capable of detecting the disease at earlier stages and reducing mortality. This article reviews the natural history of colorectal cancer, common risk factors and prevention strategies, and the strengths, limitations, and cost effectiveness of available screening tests. Although reminders to undergo colorectal cancer screening have become commonplace in the popular media, compliance with screening guidelines remains poor. Although still an unproven technology for widespread screening, computed tomographic (CT) colonography has several attractive characteristics for a screening test. For example, CT scanners are widely available, in contrast to limited numbers of gastroenterologists and radiologists’ declining skill and interest in barium enema examinations. Also, patients may be less reluctant to undergo CT colonography than screening colonoscopy. Development of virtual bowel cleansing could further increase compliance and thereby reduce mortality from colorectal cancer. Other articles in this Feature Section discuss technical details of CT colonography and its methodologic challenges. Key words: Colorectal neoplasms—Screening—Computed tomographic colonography.

Colorectal cancer (CRC) is the second leading cause of cancer death for men and women [1], an unfortunate and avoidable outcome because most cases of CRC are preventable. Long-dwelling precancerous polyps can be detected during screening and excised [2, 3]. Large, controlled trials have demonstrated that screening asymptomatic people detects cancers at earlier stages [4 – 6], which have high survival rates [1] and low medCorrespondence to: G. S. Gazelle

ical costs [7, 8]. Further, screening populations have decreased incidences of CRC, presumably by removal of precancerous polyps [9]. Due to increasing public awareness of the proven benefits of CRC screening, U.S. participation has increased slightly but is still below 50% [10]. Available screening tests for CRC vary in their sensitivities and specificities, risks, costs, and cost effectiveness, and no particular screening strategy has emerged as the undisputed optimal choice. This article presents an overview of the available tests and discusses the potential role of computed tomographic (CT) colonography in CRC screening.

Incidence and risk factors In 2001, the American Cancer Society has estimated that there will be 135,400 new cases of colorectal cancer and 56,700 deaths from the disease [11]. Between 1973 and 1996, the overall incidence and mortality declined (by 9.1% and 22.6%, respectively) [1]. The higher rates among African Americans have only recently (between 1992 and 1996) begun to decline [1]. Although ageadjusted incidence rates for CRC are higher in men than in women (51.1 vs. 36.2 per 100,000), both sexes have a nearly equal lifetime risk of CRC diagnosis (5.64% for men vs. 5.55% for women) and are equally likely to die of the disease (2.45% lifetime risk) [1]. CRC risk increases with age; the incidence is more than 10 times as high in 60 – 64 year olds as in 40 – 44 year olds [1]. A family or personal history of cancer or polyps, a personal history of inflammatory bowel disease, or membership in a family with a hereditary colorectal cancer syndrome (described below) increase the risk of CRC [11–15]. Additional risk factors are physical inactivity, obesity, high fat intake [16], high levels of red meat consumption [17], and alcohol consumption [18]. Based on prospective data from more than 750,000 adults (part of the Cancer Prevention Study II), Chao et al. [19]

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associated long-term cigarette smoking with an increased risk of CRC death and estimated that smoking caused 12% of U.S. CRC deaths in 1997. Other recent studies have supported the role of cigarettes in increasing CRC risk [20 –22].

Prevention In addition to screening, which allows for removal of precancerous polyps, several other possible methods for prevention of CRC exist. There is a growing body of evidence from animal, epidemiologic, and clinical studies that use of aspirin and nonsteroidal anti-inflammatory drugs (including cyclooxygenase-2 inhibitors) confers protective effects [23–25] through a tumor suppressor pathway [26]. Earlier studies suggested that a diet high in fruits and vegetables or fiber was protective (e.g., [16]), but that conclusion has not been supported by two recent prospective trials [27, 28]. Although high consumption may not be protective, very low (⬍1.5 servings per day) consumption of fruits and vegetables did significantly increase the risk of CRC in a large Swedish trial [29]. There is also evidence that calcium is protective against CRC [30, 31], and a recent review [32] has described evidence of protective effects of folate supplements and estrogen replacement therapy.

Natural history and pathogenesis It is generally agreed that most, if not all, cancers arise from benign adenomatous polyps [3, 33, 34]. A recent review [32] has outlined the hypothesized pathway from polyp to cancer. The mechanism is by accumulation of genetic mutations in oncogenes and tumor suppressor genes such as APC, p53, and SMAD4 [35–38]. According to recent reviews [39, 40], roughly 60% of CRCs are sporadic, another 10 –30% are familial cases, and the remaining 5–10% arise from hereditary syndromes. A mutation in the APC gene is responsible for the inherited genetic syndrome familial adenomatous polyposis (FAP) [41– 44], which accounts for 1% of new CRC cases [45]. Patients with FAP typically develop hundreds to thousands of adenomas as young adults, although the phenotype often depends on the specific mutation [46]. In approximately 15% of CRC cases [38], a malfunction in a “caretaker gene,” or DNA mismatch-repair gene [47], allows mutations in tumor suppressor genes to accumulate. Included in that 15% is the 5% of CRC cases caused by the high DNA replication error rate underlying the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome [38, 48]. The average dwell time, or time required for a precancerous polyp to progress to a carcinoma, generally is estimated at 10 –20 years [34, 49, 50]. However, tumors

P. M. McMahon, G. S. Gazelle: Colorectal cancer screening issues

with defects in mismatch-repair genes may have dwell times as short as 2 years [38]. Differences in polyp size and morphology have been correlated with different prognoses. For example, villous polyps have been shown to have a higher malignant potential than adenomatous (tubular) polyps [33, 34]. Only 1% of polyps smaller than 1 cm are malignant, versus 46% of polyps larger than 2 cm [33]. However, in a histologic review of excised adenomas, flat lesions of 1 cm diameter or smaller were 10 times more likely to harbor high-grade dysplasia than were similarly sized polypoid lesions [51]. In a recent prospective study of colonoscopy as a screening examination, flat and depressed lesions accounted for over half of the early cancerous lesions detected [52]. Screening examinations may vary in their sensitivities for flat lesions, but we are unaware of any studies that have specifically investigated the consequences of screening programs. Anatomic location The predominant subsites of CRC origin differ by race, sex, and geography, and the incidence of cancers at each anatomic location has changed over time [53]. For example, men have a higher proportion of distal lesions than do women, Asians have a greater proportion of distal lesions than do whites, and whites have a greater proportion of distal lesions than do blacks [54 –56]. Studies have reported an increase over time in proximal (right-sided) as opposed to distal (left-sided) cancers in whites and blacks, although the increase appears to be faster among blacks [55, 57, 58]. Unidentified environmental exposures and increased numbers of cholecystectomies (which alter bile salts in the proximal colon [59]) have been proposed as mechanisms for the observed increase in proximal cancers. Survival and treatment Survival and treatment differ by stage at diagnosis. Surgical resection of localized cancers results in a 5-year survival rate of 89.5%, but the rate decreases to 8.3% once distant metastases are present [1]. Blacks have reduced survival rates compared with whites; greater than half of the excess mortality has been attributed to detection at later stages [60]. Late-stage metastatic disease is often treated with surgery (including several methods for ablation of liver metastases) and adjuvant and palliative chemotherapy and radiotherapy regimens [11, 61]. Options for screening The available tests for CRC screening differ in their effectiveness, limitations, risks of complications, and patient acceptance.

P. M. McMahon, G. S. Gazelle: Colorectal cancer screening issues

Genetic tests may be appropriate for patients suspected of having an inherited syndrome; these tests recently have been reviewed extensively elsewhere [39] (see also www.genetests.org). The simplest, least expensive test, the digital rectal examination, is recommended in conjunction with other screening tests [11]. The fecal occult blood test (FOBT) is noninvasive and inexpensive. Most expert panels have recommended annual or biennial screens with FOBT, typically in conjunction with other examinations that directly visualize the colon. Large, controlled studies have found that annual or biennial screening regimens can reduce CRC mortality by 15–33% [4 – 6, 62]. Annual FOBT screening recently was shown to reduce the cumulative incidence of CRC in the screened population to 80% of that in the control group [9]. All varieties of FOBT detect cancer indirectly, through the presence of blood in the stool. Adenocarcinomas bleed more often, but intermittently, than normal mucosa; thus, even with multiple days of testing, false negatives are common [63, 64]. Further, small (⬍2 cm) adenomas typically do not bleed at all [63]. The sensitivity of FOBT for adenomas has been estimated at only 7–15% [64, 65]. The sensitivity for cancer of the most common FOBT variety, Hemoccult (guaiac based), has been estimated at 46% in its nonrehydrated form. Adding water to the test card (rehydration) increases the sensitivity to 92% [66] but at the expense of specificity and positive predictive value [62, 64]. Screening trials have reported positive predictive values (probability of cancer, given a positive test) of the nonrehydrated Hemoccult at only 3.7–5.6% [62, 67]. The prevalence of CRC in a screening (average-risk) population is low, and false positives can occur after eating peroxidase-containing foods or red meat or be due to other common causes of gastrointestinal bleeding (reviewed by Ahlquist [64]). Specificity estimates for cancer average 96%, but most cancers and nearly 90% of polyps are undetected by FOBT [65]. Newer varieties of FOBT include the HemoQuant (guaiac based), which has a sensitivity similar to that of Hemoccult [65], and others with improved test characteristics, such as HemeSelect (immunochemical) and HemoccultSENSA (guaiac based) [67–70]. Other available screening tests visualize all or part of the colon and can prevent cancer formation (by allowing removal of asymptomatic polyps) and detect early-stage cancers. By taking advantage of the long dwell time of polyps, these tests can be performed less frequently than FOBT, which anticipates cancer by an average of 2 years [67, 71]. Screening guidelines often include sigmoidoscopy at 3- to 5-year intervals, with or without annual FOBT examinations. Sixty-centimeter flexible sigmoidoscopes (FSs) are more common [54] than 20-cm rigid sigmoidoscopes. Some investiagators have asserted that half of all polyps or adenomas are located within reach of the FS

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[50, 72, 73], but only an estimated 80% of FS examinations can view the entire sigmoid colon [74]. Clinical experience suggests that the actual proportion of cancers visible by FS is closer to one-third than to one-half [75] and may decrease over time as the incidence of cancers shifts to the proximal colon. Despite an increased probability of proximal lesions in patients with distal lesions, two recent studies have concluded that offering colonoscopy only to those with positive distal findings would detect only about half of all advanced proximal neoplasms in a screening population [76, 77]. Case control studies have shown that one or more screening sigmoidoscopies in the previous decade reduced patients’ risk of fatal CRC to 21–30% of control subjects’ risk [49, 78]. A trial of once-only FS as a stand-alone screening strategy is underway in the United Kingdom [79]. The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial sponsored by the National Cancer Institute will investigate the effect of FS (at entry and at 5 years) on CRC mortality [80]. Although recruitment for that trial is scheduled to end in 2001, follow-up data will not be available until 2015. Double-contrast barium enema (DCBE), or air-contrast barium enema, refers to X-ray examination of the colon after a barium enema and insertion of air. Most procedures (90 –98%) allow visualization of the entire colon [81– 84]. To our knowledge, DCBE has not been studied in any prospective randomized screening trials; most data on its test characteristics are derived from studies comparing DCBE with colonoscopy. Sensitivity has been estimated at 85% for cancers [85] and 81–100% for polyps larger than 1 cm [84, 86], but sensitivity has been estimated at only 50 – 80% for polyps of 5–9 mm [86]. False positives often are due to adherent stool or air bubbles; specificity for cancers and large polyps has been estimated at 90 –99% [82, 84, 87]. DCBE carries a low (approximately one in 25,000 procedures) risk of bowel perforation [88] and a lower radiation dose (approximately 300–500 mrad) than those accumulated during recommended mammography screenings [89]. Colonoscopy is often recommended as a screening test because it allows simultaneous removal of cancers and premalignant lesions and visualizes the entire colon in most (80 –98%) cases [73, 84, 90, 91]. Colonoscopy recently has been shown to reduce overall and CRCspecific mortalities and the risk of CRC when used for screening HNPCC patients at a frequency of every 3 years [92]. Two recent trials of colonoscopy as a screening examination [76, 77] have not yet reported mortality or follow-up data. Despite its common use as the gold standard examination in trials of other screening tests [85, 93, 94], colonoscopy has a roughly 20% miss rate for adenomas ([95] and references therein) and can fail to detect even large lesions [96 –100]. However, the sensitivity of colonoscopy for cancer [99] or polyps larger than 1 cm

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P. M. McMahon, G. S. Gazelle: Colorectal cancer screening issues

Table 1. American Cancer Society Guidelines for surveillance and screening for colorectal polyps and cancer in individuals with high or increased risk Risk category High IBD, chronic ulcerative colitis, Crohn’s disease

FAP

HNPCC

Increased People with a single small (⬍1 cm) adenomatous polyp People with a single large (ⱖ1 cm) or multiple adenomatous polyps of any size or with high-grade dysplasia Personal history of CRC (resection with curative intent) CRC in first-degree relative ⬍60 years or ⱖ2 firstdegree relative of any age

Recommended strategy

Beginning

Colonoscopy with biopsy for dysplasia q 1–2 years

8 years after start of pancolitis; 12–15 years after start of leftsided colitis Puberty

Total colectomy indicated if genetic test positive; refer to center with experience in FAP management Colonoscopy q 2 years until age 40, then q 1 year, if genetic test positive or if patient not tested Colonoscopy 3–6 years after polyp removal; if normal, as per average risk recommendations Colonoscopy within 3 years after polyp removal; if normal, repeat in 3 years; if normal, as per average risk recommendations Colonoscopy within 1 year after resection; if normal, repeat in 3 years; if still normal, colonoscopy q 5 years Colonoscopy q 5–10 years

Age 21 years

Initial polyp detection Initial polyp detection

Within 1 year of CRC resection Age 40 or 10 years before youngest case of CRC

CRC, colorectal cancer; FAP, familial adenomatous polyposis; HNPCC, hereditary nonpolyposis colorectal cancer; IBD, inflammatory bowel disease; q, every Source: CA Cancer J Clin 2001;51(1):38 –75

[101] has been estimated at 95%. The sensitivity for smaller polyps is accordingly lower: 85% for polyps averaging 0.8 cm [100] and 75% for polyps smaller than 1 cm [85]. The most invasive of the screening options, colonoscopy carries a risk of perforation estimated at one in 1000 procedures and a death rate of one to three in 10,000 procedures [90, 91, 102, 103]. This rate may be unacceptably high for a screening examination, given that the death rate from CRC in individuals 50–54 years old is only 1.8 per 10,000 [104]. Further, these complication rates may be underestimates because they are based on performance by expert endoscopists, who are in short supply in the United States [105]; procedures performed by less well-trained practitioners may carry higher risks. Additional risks include rare complications from sedation or bowel preparation [106] and the possibility of disease transmission from inadequate sterilization of equipment [107]. In the future, the list of recommended screening options may include CT or magnetic resonance colonography (also called virtual colonoscopy), a promising but unproven technology. Although the risk of perforation is essentially eliminated for the screening examination, bowel cleansing and air insufflation are still required, and any polyps or lesions detected still necessitate conventional colonoscopy. However, virtual bowel cleansing (recently outlined by Johnson and Dachman [108]), which presumably would make the examination much more acceptable to patients, might be an important factor in increasing compliance rates.

Greater detail on the technologic developments and challenges in CT colonography is provided elsewhere in this Feature Section, and preliminary evidence of the performance characteristics of CT colonography has been reviewed elsewhere [108 –110]. We focus on studies most relevant to screening average-risk populations. A recent study [111] of asymptomatic (screening) and symptomatic populations examined by conventional colonoscopy and CT colonography reported CT colonography sensitivities of 90 –94% for large (⬎1 cm) polyps and adenomas but sensitivities below 70% for smaller (⬍5 mm) lesions; test performance was not significantly different between the two patient populations. False positives (primarily in areas of poor bowel preparation or distention) resulted in a specificity of 72% for polyps [111]. Another study in a screening population [112] reported less enthusiastic results: CT colonography detected only one of four lesions 2 cm and larger (but the investigators noted that all the missed lesions were flat). For adenomas of 1–1.9 mm, the sensitivity of CT colonography increased to 60% [112].

Screening guidelines Recommended strategies for CRC screening depend on individual risk factors for the development of the disease; those at higher risk require more aggressive screening. However, it is important to note that the majority of CRC occurs in patients with no family history.

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Table 2. US screening guidelines and Medicare reimbursement for average-risk individuals Agency, year issued

Recommended strategy beginning at age 50 years

Comments; source

American Cancer Society, 2001

Option 1 (preferred): FOBT q 1 year ⫹ FS q 5 years Option 2: FS q 5 years Option 3: FOBT q 1 year Option 4: Colonoscopy q 10 years Option 5: DCBE q 5 years FOBT q 1 year and/or FS q ⫻ years

All positive tests should be followed up with colonoscopy; American Cancer Society, CA Cancer J Clin 2001;51(1): 38–75

US Preventive Service Task Force, 1996

American Gastroenterology Association, AHRQ Task Force, 1997

Medicare coverage, 1998

Option 1: FOBT q 1 year; positive test followed by colonoscopy or DCBE ⫾ FS Option 2: FS q 5 years Option 3: FOBT q 1 year ⫹ FS q 5 years Option 4: DCBE q 5–10 years Option 5: Colonoscopy q 10 years FOBT q 1 year ⫹ FS (or DCBE) q 4 years

Insufficient evidence to recommend a periodicity for FS: USPSTF guide to clinical preventive services, 2nd ed, 1996; update currently in progress Colorectal cancer screening: clinical guidelines and rationale, 1997; Gastroenterology 1997;112(2):594–642

Fed Reg 1997;62:59078

DCBE, double-contrast barium enema; FOBT, fetal occult blood test; FS, flexible sigmoidoscope; q, every

High-risk individuals are members of families with hereditary colorectal cancers, such as FAP and HNPCC, and persons with inflammatory bowel disease. These individuals should consider genetic testing, if appropriate [39], and begin aggressive colonoscopy screening decades earlier than those at average risk. Patients with increased risk are those with family or personal histories of CRC or a personal history of polyps. Recommended surveillance and screening protocols are shown in Table 1. Persons not included in any of the categories shown in Table 1 are at average risk for sporadic development of CRC. Table 2 lists current U.S. screening guidelines for average-risk individuals from the American Cancer Society, the U.S. Preventive Service Task Force, the American Gastroenterology Association, and the Agency for Healthcare Research and Quality (formerly the Agency for Health Care Policy and Research). For the most current guidelines for CRC screening, refer to the National Guideline Clearinghouse (www.guideline.gov), a comprehensive database of evidence-based clinical practice guidelines produced by the Agency for Healthcare Research and Quality.

Cost effectiveness Recent reviews are in agreement that screening for CRC in average-risk populations is cost effective [113–115], but published cost-effectiveness analyses have recommended a wide variety of screening strategies, ranging from stand-alone annual FOBT protocols to complex strategies using combinations of tests, to one-time endoscopic examinations (e.g., [116 –126]). These studies are

difficult to compare because they model seemingly endless numbers of different strategies, use different assumptions of underlying disease progression, estimates of test characteristics and costs, and report results in different outcome measures (e.g., dollars per cancer detected, dollars per life saved, and dollars per life-year saved [LYS]). Published studies may also suffer from methodologic flaws, leading researchers to recommend inappropriate strategies. For example, we reanalyzed the results of three often-cited studies [118, 120, 121] following currently accepted standards for performing cost-effectiveness analyses [127]. A concordant strategy involving DCBE (every 3 years, or every 5 years with annual FOBT) emerged as optimal from all three studies, with an incremental cost-effectiveness ratio of less than $56,000/LYS (1999 U.S. dollars) [128]. Recent modeling efforts have come to different conclusions and do little to solve the dilemma of which strategies are most cost effective. Helm et al. [129] projected the results of the three large trials of FOBT screening [4, 5, 62] onto the U.S. population and estimated that FOBT screening could achieve a modest (15%) reduction in CRC mortality, at a cost of $2500/LYS. Screening colonoscopy performed every 10 years was recommended as the “most cost-effective” strategy at $11,382/LYS (compared with annual FOBT) by Sonnenberg et al. [126]. Frazier, et al. [130] compared all strategies currently recommended by expert panels and found that screening colonoscopy was dominated (offered less benefit at a higher cost) by strategies combining FS and FOBT. They concluded that FS every 5 years plus rehydrated annual FOBT was the most effective of the recommended strategies, at $92,900/LYS (compared with the same strategy using nonrehydrated FOBT) [130]. An-

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other study concluded that FS every 5 years may actually be cost saving [131]. To our knowledge, only one cost-effectiveness analysis of CT colonography has been published; Sonnenberg et al. [125] compared the costs (to a third-party payer) and benefits of no screening, colonoscopy screening, and CT colonography. They reported results for CT colonography and colonoscopy versus no screening, but when incremental cost-effectiveness ratios were calculated according to standard methods [127], CT colonography was excluded by extended dominance (their calculations). Thus the reported value of $11,483/LYS of CT colonography versus no screening is not relevant. Further, incremental cost-effectiveness ratios are designed to compare all relevant alternatives [127], but that study [125] failed to include many feasible strategies (notably FS and DCBE); thus, even the incremental cost-effectiveness ratio for colonoscopy versus no screening ($11,226/LYS) may not be meaningful. Perfect compliance with screening regimens will result in the largest reductions in CRC mortality, but it does not follow that high compliance rates are required for a strategy to be cost effective [132]. For example, lower compliance may make colonoscopy screening more cost effective [126]. Despite the current debate over cost effectiveness, screening by some method should be encouraged.

Future directions and patient participation Groups such as the National Colorectal Cancer Research Alliance (www.nccra.org) and the National Colorectal Cancer Roundtable have been joined by the popular press, television programs, and the Today Show’s Katie Couric to increase public awareness of the benefits of CRC screening [133-137]. The U.S. Congress named March as National Colorectal Cancer Screening Awareness Month, and the Massachusetts Department of Public Health is currently (June 2001) running a campaign with the tagline “Life begins at 50” that urges CRC screening. Medicare added coverage of CRC screening examinations in 1998 [138], and Congress may soon mandate that all private insurance plans follow suit. The Eliminate Colorectal Cancer Act of 2001 (S. 710, H.R. 1520) was introduced by Senator Kennedy and Representative Slaughter (http://thomas.loc.gov/; last accessed June 12, 2001). Compliance with U.S. screening guidelines is poor; only 9.5% of respondents in a 1997 survey reported having had FOBT within the past year and FS during the preceding 5 years [139]. A comprehensive review of 18 studies of interventions designed to increase FOBT compliance [140] concluded that even the most intensive strategies rarely increased adherence to the screening regimen above 50%. Typical reasons offered by patients

P. M. McMahon, G. S. Gazelle: Colorectal cancer screening issues

for nonparticipation in FS and FOBT examinations include lack of current health problems or symptoms, practical reasons, and embarrassment or fear of pain or injury [140]. Physician encouragement may be an important component in increasing participation, but more research is needed on the factors that influence physicians’ recommendations. A recent survey reported that 71% of gastroenterologists recommended FS every 5 years plus annual FOBT to patients, but 77% choose colonoscopy for themselves [141]. The study suffered from a low (24%) response rate, so the results may not be generalizable. Painful screening examinations may lead patients to avoid repeat examinations. Reduced screening participation over time would be an undesirable trend because CRC risk increases with age. Colonoscopy and FS are rated as more painful or uncomfortable than DCBE by patients who have had both tests [142, 143]. Although virtual colonoscopy is noninvasive, one patient group that received conventional and virtual (CT) colonoscopies rated the conventional colonoscopy as less painful, uncomfortable, and embarrassing [144]. This may, however, relate to the use of amnestic medications during conventional colonoscopy. At our institution, 85% of patients who received both conventional and virtual (CT) colonoscopies stated they would prefer to have CT colonography if given the option (M. E. Zalis, M.D., personal communication, July 2001). Despite the availability (and insurance coverage, in many cases) of CRC screening tests, most Americans do not comply with recommended screening guidelines. Whether the noninvasive nature of CT colonography would increase the public’s willingness to be screened for CRC remains to be determined. At present, the important thing to convey to patients is that the choice of test is less critical than choosing to get tested in the first place. A screening test performed as infrequently as every 5 or 10 years can detect precancerous lesions and prevent CRC, a disease with a 5.6% lifetime risk of development [1]. Acknowledgments. This work was supported in part by training grant 5T-15 LM07092 from the National Library of Medicine to P. M. McMahon.

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