Colonoscopy vs CT colonography to screen for colorectal neoplasia in average-risk patients

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Point/Counterpoint Surg Endosc (2005) 19: 448–456 DOI: 10.1007/s00464-004-8265-7 Springer Science+Business Media, Inc. 2005

Colonoscopy vs CT colonography to screen for colorectal neoplasia in average-risk patients J. M. Hardacre,1 J. L. Ponsky,2 M. E. Baker3 1 2 3

Department of General Surgery, The Cleveland Clinic Foundation, Cleveland, OH, USA University Hospitals of Cleveland, Department of Surgery, 11100 Euclid Avenue, Cleveland, OH 44106-5047, USA Department of Radiology, Hb/6 The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA

Online publication: 27 January 2005

Key words: Colonoscopy — CT colonography — Colorectal cancer

POINT J. M. Hardacre, J. L. Ponsky Colorectal cancer is second only to lung cancer as a cause of cancer-related death in the United States and accounts for 60,000 deaths per year [11]. Benign adenomatous polyps are believed to be the precursors of most colorectal cancers. The detection and removal of such polyps have been shown to reduce the incidence and mortality of colorectal cancer [15, 16, 28]. Therefore, evidence-based guidelines have been formulated for the screening of adults at average risk for colorectal cancer [25]. However, despite the introduction of these guidelines, 50% of the average-risk population in the United States has not been screened by any method [1]. Colonoscopy is the optimal screening test in averagerisk patients. Current recommendations call for its performance every 10 years, starting at age 50 [25]. Colonoscopy enables the detection and removal of polyps during the same procedure. With this method, polyps as small as 1 mm, can be visualized; nevertheless, 10–20% of polyps and up to 5% of cancers may be missed on colonoscopy [8, 9, 23, 28]. Furthermore, colonoscopy requires bowel preparation and conscious sedation, and it carries a number of risks, including a perforation rate as high as 0.14–0.26% [20]. Despite these drawbacks, it is a very accurate test and is the best tool available to screen for colorectal cancer. In 1994, Vinning et al. described CT colonography (CTC) as a method for colorectal evaluation [26]. Soon

thereafter, CTC was studied as a means of investigating various pathological colorectal conditions. Although it still required a bowel preparation, CTC was hailed as a promising investigative tool because it did not require conscious sedation and was noninvasive. To date, CTC has been studied most extensively in patients at higher-than-average risk for colorectal cancer, but recently it has also been evaluated as a screening tool in average-risk patients [3–7, 10, 12–14, 18, 19, 24, 29]. Studies of CTC have shown that it has an overall sensitivity of 21–81% for colorectal polyp detection (Table 1). However, when the data are stratiﬁed according to polyp size, the sensitivity varies greatly. For polyps 6–9 mm, the sensitivity varies from 23% to 85%. For polyps ‡10 mm, the sensitivity of CTC is between 52% and 100%, with a median of 90%. We do not consider such variation in sensitivity to be acceptable in a screening test for colorectal neoplasia. Perhaps the most controversial studies listed in Table 1 are the ones by Pickhardt et al. and Cotton et al. [3, 19]. Both are prospective, multiinstitutional studies that used ‘‘segmental unblinding’’ the reference standard. With segmental unblinding, the colonoscopists were unaware of the CTC results during their initial evaluation; after the initial evaluation, the results of the CTC were revealed and the colon was reinspected to assess diﬀerences. As shown in Table 1, in the Pickhardt study, the sensitivity for polyps ‡6 mm was 89% while for polyps ‡10 mm it was 94%. However, in the Cotton study, the sensitivity for polyps 6–9 mm was only 23% while that for polyps ‡10 mm was 52%. What accounts for these disparities? Technical considerations may have played some role. The Pickhardt study looked only at adenomatous polyps. Further, it used more advanced, three-dimensional software to provide a virtual ‘‘ﬂythrough’’ evaluation of the colon. Finally, it used two types of oral contrast, as opposed to none in the Cotton study, to provide solid-stool tagging and luminal ﬂuid opaciﬁcation. Although these details may account for

449 Table 1. Prospective blinded studies comparing colonoscopy to CT colonography to screen for colorectal neoplasia Per-polyp (%) sensitivity Study

Patient population

Overall

Hara et al. (1997) [7]a Fenlon et al. (1999) [4] Yee et al. (2001) [29]a Spinzi et al. (2001) [24]b Laghi et al. (2002) [13] Gluecker et al. (2002) [6] Johnson et al. (2003) [12]c Munikrishnan et al. (2003) [18] Ginnerup Pedersen et al. (2003) [5] Iannaccone (2003) [10] Pickhardt et al. (2003) [19]d Macari et al. 2004) [14] Cotton et al. (2004) [3]

›Risk ›Risk ›Risk ›Risk ›Risk ›Risk ›Risk ›Risk ›Risk ›Risk Average risk Average risk ›Risk

NR 71 70 58 58 22 58 76 81 70 NR 21 16

£ 5 mm <45 55 59 56 24 4 NS 53 NS 51 89 12 8

6–9 mm

‡10 mm

66 82 80

75 91 90 62 93 82 63 100 89 100 94 100 52

85 33 54 83 71 83 94 53 23

NR, not reported; NS, not studied a Size categories are <5 mm, 5–9 mm, ‡10 mm b Size categories are <10 mm, ‡10 mm c Size categories are 5–9 mm, ‡10 mm d Size categories are ‡6 mm, ‡8 mm, ‡10 mm; only adenomatous polyps were studied

some of the diﬀerences, it is more likely that they are ultimately the reﬂection of what can be achieved with CTC in some specialized situations vs what is more likely in everyday practice [21]. It is likely that CTC will be further reﬁned such that it has a sensitivity comparable to that of colonoscopy and that it will become available in standard clinical practice. In that event, which test should be used to screen average-risk patients? Proponents of CTC argue for it based on its noninvasive nature, its potential to detect clinically important extracolonic pathology, and the possibility that it may be done with a less-aggressive bowel preparation. Perhaps most important, it is argued that the noninvasive nature of CTC will encourage more people to be screened for colorectal cancer. As proponents of colonoscopy, we argue that with colonoscopy only one test needs to be done for patients in whom polyps are found. Biopsy or removal of the polyps can be done in the same setting. Furthermore, if CTC is to be used and people with polyps are to be spared a second bowel preparation for polyp biopsy or removal, signiﬁcant hurdles in scheduling among radiologists and endoscopists would have to be overcome. One of the key questions at the heart of the debate is, ÔWhat polyp size warrants biopsy or removal?Õ Many practitioners recommend the removal of all polyps, regardless of size, even though this policy leads to the excision of many polyps that are hyperplastic and have no malignant potential. Virtually everyone agrees that polyps ‡10 mm should be submitted to biopsy or removed, but some investigators question the excision of all polyps <10 mm [2]. We agree with the camp that advocates the removal of all polyps, even those £ 5 mm. We base our argument on the fact that it is easier and safer to remove small polyps than large ones. Moreover, multiple procedures are sometimes needed to eliminate large polyps. We are also concerned about the neoplastic potential of even small colorectal polyps. Up to 61% of polyps £ 5

mm are neoplastic and up to 0.1% are carcinomas [27]. Furthermore, 5% of polyps <10 mm have high-grade dysplasia and 1.3% are malignant [6]. Finally, when screening colonoscopy is performed in average-risk patients over age 50, the incidence of advanced adenomas is only 6-9%, but the incidence of polyps <10 mm is as high as 30-50% [2, 4]. Thus, if polyp size had been used in the Pickhard study [17] as a criterion for colonoscopy after CTC, then a 10-mm cutoﬀ would mean that 7.5% of patients needed colonoscopy, a cutoﬀ of 8 mm would mean that 13.5% of patients needed colonoscopy, and a cutoﬀ of 6 mm would mean that 29.7% of patients needed colonoscopy after CTC. That is to say, depending on polyp size, many patients would be getting two tests instead of one. Given the available data, colonoscopy should continue to be the test of choice to screen patients at average risk for colorectal cancer. However, CTC is currently appropriate for patients with obstructing colorectal cancer, patients with an incomplete colonoscopy, and patients who are not candidates for colonoscopy [22]. In the future, CTC technology and applicability may be such that its sensitivity rivals that of colonoscopy; however, even then we would recommend colonoscopy for screening, given its dual diagnostic and therapeutic capabilities.

COUNTERPOINT M. E. Baker Colorectal carcinoma is the fourth most commonly diagnosed cancer (estimated at nearly 147,000 new cases in 2004) and the second most common cause of cancer deaths in the United States (nearly 57,000 estimated in 2004) [45]. Almost all colorectal carcinomas start as an adenomatous polyp, which over a period of 7–10 years may grow into a malignancy. If these polyps were re-

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moved prior to malignant degeneration, this cancer would be virtually eliminated from the population. Therefore, although this is a common disease with a signiﬁcant impact, it is preventable in almost all cases.

Current strategies for screening for colorectal polyps The Agency for Health Care Research and Quality and multiple medical societies have recommended that all asymptomatic adults over the age of 50 undergo a screening test for colorectal carcinoma [30, 38, 54, 62, 72, 73, 75]. Screening modalities include fecal occult blood tests without or with sigmoidoscopy, the doublecontrast barium enema, and standard colonoscopy. Guaiac-based fecal occult blood testing using a rigid protocol and dietary restriction, whereby three consecutive stool samples with two cards per stool are collected annually, can modestly reduce the mortality of colorectal cancer [62]. This is a very simple, oﬃce-based test, but polyps and even cancers can be missed [62]. Sigmoidoscopy alone also reduces the risk of developing colorectal cancer [62]. The advantage of a sigmoidoscopy is that it can be performed after a cleansing enema rather than requiring the patient to undergo a full colon preparation. But sigmoidoscopy examines only the left colon, akin to a unilateral mammogram; thus, adenomatous polyps and cancers will be missed proximal to the upper limit of the endoscopy. Combing fecal occult blood tests with sigmoidoscopy reduces the risk of colorectal carcinoma more than either test alone. One analysis has shown that it is the most cost-eﬀective of all strategies [38]. Nevertheless, signiﬁcant polyps and cancers may be missed. Any screening test is better than no screening at all. However, test these tests do not examine the entire colon for polyps. The air-contrast barium enema (ACBE) is a complete colon examination; as such, it has the potential to detect signiﬁcant polyps. It requires a bowel preparation, similar to a standard colonoscopy. Because there are still many ﬂuoroscopic rooms in radiology departments in the United States, properly performed ACBE that are then interpreted by well-trained, highly skilled radiologists could increase the number of patients screened for polyps. However, data from the recent National Polyp Study [76] showed that in a surveillance population the ACBE is insensitive for the detection even 1-cm polyps. No prospective data exist on the performance of the ACBE in a screening population. Although there are many problems with this modality from a radiology perspective, and despite the fact that the ACBE remains a recommended screening tool, many gastroenterologists, internists, and surgeons do not believe that it is an adequate means of screening for polyps. At the Cleveland Clinic, an ACBE is rarely requested as a screening exam for colorectal polyp detection. It is usually reserved for elderly or inﬁrm patients who are not candidates for standard colonoscopy or for patients who have had an incomplete colonoscopy. Further, since the advent of endoscopy, fewer and fewer ACBE have been performed in radiology

departments. Due to its infrequent performance, radiologists who have been properly trained in its execution are losing their skills and radiology residents who are still in training do not have enough experience to gain competence in this area. Standard colonoscopy is considered the gold standard for colon polyp detection. In expert hands, 94% of adenomatous polyps >1 cm, 87% of adenomatous polyps between 6 and 9 mm, and 83–86% of adenomatous polyps <5 mm are detected [63]. Further, once detected, these polyps can be removed immediately. Although there is no scientiﬁc evidence that colonoscopy reduces the risk of colorectal carcinoma, given its high sensitivity, most investigators consider it to be the examination of choice for screening the colon. The National Polyp Study Workgroup has estimated that 76-90% of all colorectal cancer could be prevented by regular colonoscopic surveillance [74]. But there are some tradeoﬀs with this very sensitive examination. A signiﬁcant number of polyps measuring < 5 mm are not adenomatous. These are truly falsepositive exams and biopsies. Further, there are a signiﬁcant number of normal or arguably unnecessary colonoscopies. In a population of 1,994 adults >50 years of age, Imperiale et al. found only 5.6% advanced adenomas [44]. In this series, 842/1,994 (42%) had adenomas, most of which were <5 mm (799/1,994). In adenomas <10 mm, only 0.8% and 0.4% had villous histology and high-grade dysplasia, respectively. In a large Veterans Administration study of 3,121 patients, 46% of patients (1,441/3,121) had no polyps [49]. When the number of nonadenomatous polyps (n = 118) is added to that ﬁgure, we see that fully 50% of the patients examined (1,559/3,121) had no adenomatous polyps. Advanced neoplasia was detected in only 10.5% of patients (deﬁned as an adenoma >10 mm with villous histology, high-grade dysplasia, or invasive carcinoma). In a series comparing CT colonography (CTC) with standard colonoscopy reported by Picjhardt et al., 48 of 1,233 patients (3.8%) had adenomas >10 mm [60]. Although every colonoscopist has encountered a case or two where a <5-mm polyp harbors cancer, it hardly seems reasonable that we attempt to remove all polyps [79]. Instead, how we can best reduce colorectal cancer, while making the best use of our health care resources and avoiding invasive procedures in patients who will never develop colon cancer [39]. There is a major psychosocial barrier to colon cancer screening in general and especially as it relates to colonoscopy. Patients generally do not think of their colon as a source of disease. In 1997, based on questionnaires, it was estimated that only 40% of individuals >50 years of age have had either fecal occult blood test and/ or ﬂexible sigmoidoscopy to screen for polyps [65]. It is not known how many have had screening colonoscopies. The bowel preparation for a colonoscopy is uncomfortable and unpleasant. In the lay community, the legend and lore surrounding this preparation is enough to dissuade many patients from undergoing this ordeal. The very thought of inserting a tube into the rectum and colon makes patients hesitant about the procedure. The procedure also requires sedation. Pa-

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tients must take oﬀ a day of work to undergo the procedure and come with a chaperone to drive them home. Moreover, there is a low but well-deﬁned risk of perforation from colonoscopy. Approximately one patient in 1,000 (0.1%) incurs a perforation, three of 1,000 suﬀer major hemorrhage, and the mortality rate is one to three in 10,000 [75]. In a large review of a 10-year singleinstitution experience of >10,000 colonoscopies, the risk of perforation was 0.19% and the risk of death was 0.019% [31]. When a biopsy is performed or conscious sedation is used, the complication rate is higher. To add insult to injury, many insurance companies will not reimburse for a screening colonoscopy. Medicare does pay for screening studies, but rembursement begins only at the age of 63–65-that is, 12–15 years after the recommended age to start regulat screening. This policy poses major barrier to the screening of individuals who are deemed to be at risk (>50 years of age) but are not yet eligible far medicare. Lastly, to add signiﬁcantly to the psychosocial barriers, when a patient desires screening colonoscopy, the wait time may be signiﬁcant. The US Census Bureau estimates that there are nearly 77 million Americans over the age of 50 [70]. However, according to the AMA, in 2000 there were only 8,456 board-certiﬁed gastroenterologists and 24,434 board-certiﬁed general surgeons in the United States [55]. Thus, the number of colonoscopists qualiﬁed to screen the potential patient population is insuﬃcient. Some members of the endoscopy community have proposed that specialized nurses and physicianÕs assistants be trained to perform colonoscopy [53, 64]. But to date, that has not happened. The problem therefore is what method or methods would be most eﬀective to screen large population for colorectal polyps, given the psychosocial barriers, the limitations of the tests, and the scarcity of trained personnel. Although screening strategies other than colonoscopy do reduce the risk of cancer, they are less eﬀective in detecting precancerous polyps because they do not examine the entire colon. However, colonoscopy is expensive, invasive, and psychosocially unacceptable to many patients, and there are not enough trained endoscopists to screen the eligible population. If an eﬀective and socially acceptable alternative to colonoscopy could be developed, then a larger number of eligible patients could be screened for a preventable disease. In the United States, we need a more comprehensive strategy screen the entire colon in a large population of patients. Given the limitations, of the prevalent modalities, there are no reasonable alternatives unless one considers CTC.

Computed tomographic colonography as an alternative screening examination Computed tomographic colonography, also known as ‘‘virtual colonoscopy,’’ was ﬁrst described as a potential screening method in 1994 [70]. This method built on the potential capabilities of spiral CT technology and advances in computer hardware and software as initially

developed for use in the defense and movie industries. Over the past 10 years, there have been signiﬁcant advances in CT technology, as well as with virtual reality workstations. Currently, multislice CT can create images <1 mm in thickness and scan the entire abdomen and pelvis in < 15 s, an easy breath hold for almost all patients. Thereafter, a three-dimensional (3-D) view can be produced in seconds. As a result of these technological advances, workﬂow, cost, accuracy/eﬃcacy and acceptability have all improved [36, 45, 49]. For CTC to be eﬀective, many requirements must be met. First, as with standard colonoscopy, the patient must undergo a bowel preparation. Although some investigators are working on prepless or low-impact preparations in conjunction with barium stool tagging, currently there are no data to support such an approach. Thus, the standard phospha-soda or colonic lavage preparation is essential. A modern spiral CT scanners must be used. Modern spiral CT scanners are so-called multi-slice scanners-that is, they are capable of creating multiple slices per rotation [60]. The minimum number of slices is four, but eight to is preferable because the more slices created per gantry rotation, the shorter the breath hold for the patient. When the patient is placed on the scanner, a small rectal tube is inserted and the colon is insuﬄated with room air or carbon dioxide (CO2). There is now an automatic CO2 insuﬄator that maintains a constant pressure and therefore distension in the colon. The entire CT scan time should not exceed 10–15 min. Once the scans are completed, the images are sent to a workstation capable of both two-dimensional (2-D) viewing and 3-D endoluminal rendering for proper interpretation. To avoid double preparations, we and others are forming alliances with endoscopists so that a same-day colonoscopy can be performed when an abnormality is detected on the CT. Over the years, the sensitivity and speciﬁcity of CTC have improved. Much of the early and even current investigation has been done in a mixed, rather then classic, screening population. The sensitivity of the exam for polyps >1 cm ranges from 75% to 100% per polyp, while the sensitivity per patient ranges from 78% to 100%. A recent meta-analysis of 14 studies found that pooled per-patient sensitivity for polyps >10 mm was 88% (95% CI, 84%–93%) and the sensitivity for polyps 6-9 mm was 84% (95% CI, 80%–89%) [65]. The pooled per-polyp sensitivity for polyps >10 mm was 0.81 (95% CI 76%–85%) for polyps 6-9 mm it was 0.62 (95% CI, 58%–67%). The controversial studies by Pickardt et al. [59] and Cotton et al. [35] were not included in this metaanalysis. The investigation conducted by Pickhardt et al. involved three US military institutions with ﬁve radiologists and 15 colonoscopists. They evaluated > 1,200 asymptomatic patients over the age of 50 years who were at average risk-essentially a screening population [59]. They used routine stool and ﬂuid tagging and a computer hardware/software combination that automatically subtracted the high-density barium-labeled stool and contrast-enhanced ﬂuid. They also used the endoluminal ﬂy through mode as the primary means of interpretation. The results of this study were very sur-

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prising, with the CT performing as well as the standard colonoscopy. Several aspects of this study should be noted. For one thing, it did not report overall numbers of polyps but adenomatous polyps alone. Most of the other studies comparing CTC with standard colonoscopy have reported overall numbers of polyps. This study used routine stool and ﬂuid tagging with oral barium and iodine preparations. The workstations used for interpretation automatically subtracted the high-density tagged stool and ﬂuid. In addition, the radiologists used the 3-D virtual, endoluminal method of primary interpretation rather than the 2-D view used by most other investigators. In almost all prior published work, stool and ﬂuid tagging was not used. Further, the 3-D method in these early studies was used for problem solving rather than for primary interpretation. It may be that prior authors did not use the 3-D method because it has historically been regarded as too time-consuming and cumbersome. As a result, they grew comfortable and eﬃcient using the 2-D axial views for interpretation. Relatively old data from the Mayo Clinic show that the 3-D endoluminal method of interpretation is not statistically better than the 2-D method and that when both are used together they are complementary [40]. However, we and others prefer to use the 3-D method as the primary method of interpretation for detection (sensitivity) and the 2-D method for characterization (speciﬁcity) [57, 59]. Thus, we detect a polypoid lesion on the 3-D rendering and then determine whether it is a polyp, stool, or even an inverted diverticulum based on the 2-D images. The study by Cotton et al. was conducted in nine centers and included >600 patients who had been referred for a clinically indicated colonoscopy [35]. Thus, they did not study a screening population. Nine radiologists interpreted the CT scans (up to two radiologists per center). All that was required was that they had performed 10 exams prior to the study. In the discussion, it is stated that ‘‘only one of the centers had substantial prior involvement with the technique.’’ But this center ‘‘contributed the most participants (n = 184) and had the best results, with a primary outcome sensitivity of 82%.’’ Up to three endoscopists per center was allowed, but it is not clear how many participated. A variety of CT scanners were used, with one scanner reconstructing at a slice thickness of 5 mm (although this slice thickness is not universally considered to be state of the art, this was the center with the most experience and the best results). It is not clear what hardware/software combinations were used to interpret, but standard 2-D and 3-D processing was available. The radiologists used 2-D techniques as their primary mode of investigation. This study also diﬀers from the one conducted by Pickhardt et al. in that all polyps were reported, rather than just adenomatous polyps. The authors stated that ‘‘there were 29 advanced lesions of >6 mm in diameter (19 adenomas with villous features, 2 with high-grade dysplasia and 8 cancers).’’ There were a total of 119 polyps that measured 6-9 mm and 54 that were >1 cm; thus, there were 173 polyps >6 mm. We do not know

how many tubular adenomas or hyperplastic polyps were identiﬁed among these 173. It maybe that hyperplastic polyps are not identiﬁed as readily on CT because they are more compressible or pliable. The results of this study, however, were very disappointing. Whereas CTC identiﬁed only 39% of polyps >6 mm, conventional colonoscopy identiﬁed 99% (an unusually high sensitivity when compared to other colonoscopy studies). The sensitivity of CTC for polyps >1 cm was a disappointing 55-67%. An additional 13% of polyps were detected when the 3-D endoluminal ﬂythrough was reviewed. One major problem with the Cotton et al. study was the apparent number of inexperienced CT readers. I did not feel comfortable interpreting CTC until I had evaluated 50–75 exams, all with colonoscopic correlation. Thus, the required minimum of 10 examinations for qualiﬁcation to interpret CTC seems very low. Perhaps the major conclusion that can be drawn from this work is that intensive training and certiﬁcation are needed before radiologists attempt to interpret this exam. This study sounds an important cautionary note that calls into question both the current status and future direction of this technique. But most important, it shows that CTC is demanding and diﬃcult and there is clearly a learning curve. There is an undeniable need for the training and certiﬁcation of radiologists in the interpretation of CTC. Congress passed the Mammography Quality Standards Act (MQSA) in 1992, and reauthorized it in 1998 [51]. It mandates the direct written notiﬁcation of all patients of their results in lay terms, the creation of a system to direct self-referred patients to a health care provider, and the auditing of outcome data for each physician and for the entire facility; it also deﬁnes initial and continuing experience requirements for radiologists, technologists, and medical physicists, and regulates equipment and radiation dose [51]. Although I am no advocate of the federal regulation of health care, I have designed our CTC program at the Cleveland Clinic on the model of the MQSA guidelines. An organization such as the American College of Radiology could develop standards for CTC along those lines. Does such a program exist for colonoscopy? We know that in an academic environment, during an ongoing study of double colonoscopy, a 95% sensitivity for 1-cm polyps was achieved [62]. But, we do not know its sensitivity in community practice. Further, to my knowledge, there is no speciﬁc clariﬁcation for endoscopists. One of the potential advantages of CTC is the detection of extracolonic pathologies. Depending on the population scanned and the philosophy of the interpreting radiologist, extracolonic conditions are found in up to 15% of patients [41]. Most investigators would consider these ﬁndings to warrant further workup in 5– 10% of cases. Reported ﬁndings have included a renal cell carcinoma, an abdominal aortic aneurysm >4 cm in diameter, lymphadenopathy, and a pelvic mass. Conversely, some of these abnormalities may ultimately prove to be benign but they will ﬁrst require further workup—usually CT and/or MRI with contrast enhancement—for evaluation. These so-called false-po-

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sitive ﬁndings may increase the cost of medical care. A recent analysis in nearly 700 patients showed that radiologic follow-up costs in these cases averaged $23,380, based on 2002 Medicare reimbursement rates [39]. The average additional costs above the cost of the CTC were $34.33.

Criteria for evaluating a screening examination Obuchowski et al. proposed the following 10 criteria for a good screening examination or test [55]: 1. The disease must have serious consequences. 2. The screening population must have a high incidence of a detectable preclinical phase of the disease. 3. The screening test must have high accuracy for identifying the detectable preclinical phase of the disease. 4. The disease must be associated with little pseudodisease. 5. The test must detect disease before a critical point. 6. The test must not cause signiﬁcant morbidity. 7. The test must be aﬀordable and readily available. 8. For the test to be acceptable, treatment must exist when the disease is detected. 9. The treatment must be more eﬀective when it is instituted before the onset of symptoms. 10. The treatment must not be too risky or toxic. These criteria can be applied to colon cancer screening tests, as follows: First: It is obvious that the disease has serious consequences. Second: the incidence of signiﬁcant adenomatous polyps is relatively high-between 5% and 10% in the screening population [43, 48]. (Interestingly, this is a much higher incidence than the rate of breast cancer detected in the screening population by mammography. Yet mammography is widely accepted as a vital screening test in the United States.) Third: The data on colonoscopy strongly suggest that it is highly accurate in detecting signiﬁcant polyps >1 cm. The data for CTC, while not quite as good are certainly acceptable and better than any of the other tests currently available. Fourth: In type I pseudodisease, the disease never progresses and may regress. Adenomatous polyps can and do regress. In type II pseudodisease, the disease progresses slowly; the patient is asymptomatic and dies before the disease becomes clinically evident. The rate of progression from adenoma to carcinoma is estimated to be only 2.5 polyps/1,000/year [55]. The risk of a 2-cm polyp containing malignancy varies from 10% to 50% [74]. The time it takes for an adenomatous polyp to progress to carcinoma is estimated to be take 7–10 years. Autopsy series have shown the incidence of asymptomatic colorectal carcinoma to be 0.5% in the 60th decade, 1% in the 70th decade, and 1.5% in the 80th decade [33]. Thus pseudodisease is a problem in colorectal polyp detection. Nevertheless, most physicians

would still consider screening for polyps to be socially and economically desirable. Fifth: Most gastroenterologists and colorectal surgeons consider a 1-cm polyp to be a critical point because the incidence of cancer is in such cases <1%. We know that most of these polyps can be detected by colonoscpy, but the data for CTC are also acceptable. Sixth: Standard colonoscopy is associated with a known morbidity and mortality [31, 74]. Most perforations occur in the sigmoid colon. Electrocautery injury during biopsy and mechanical injury caused by penetration of the endoscopeÕs tip and shaft are the most common complications. To my knowledge, there is only one reported case of perforation from a CTC [46], and this was in a patient with a distal obstructing rectosigmoid cancer. Although to date far fewer CTC exams than colonoscopies have been performed world wide, it is likely that the risk of perforation from CTC in a screening population will ultimately prove to be even lower than the very minimal risk of perforation from colonoscopy. Seventh: the current Medicare reimbursement for a standard screening colonoscopy is $600–700. In the nonMedicare population, the charges can exceed $2,500. Most third-party carriers will not pay for a screening exam. Thus, a motivated patient between the ages of 50 and 65 must often pay out of pocket for the study. Costs for a CTC vary, but at the Cleveland Clinic, we charge $750. It is likely that the cost will decrease as the number of these procedures increases. Moreover, cost-beneﬁt analyses indicate that any colon cancer screening program is cost-eﬀective [30, 37, 53, 61, 71, 74]. Colonoscopy is available, but there are not enough endoscopists to evaluate all potential patients. Similarly, CTC is potentially readily available, but there are still not enough trained radiologists to make a signiﬁcant impact on the population. Eighth: Treatment exists when a polyp is detected. Ninth: When a polyp is removed before becoming cancerous, the risk of colorectal carcinoma is almost eliminated. Although polyps can bleed, most 1-cm polyps are asymptomatic. Almost all polyps <1 cm are still noncancerous. Thus, the timely removal of polyps <1 cm is eﬃcacious in preventing colon cancer. Tenth: Although there is a known perforation rate associated with polyp removal, it is at an acceptably low rate to justify the performance of a biopsy. In sum, based on the criterial proposed by Obuchowski et al. [56], CTC, like colonoscopy, appears to be a very good screening study for colorectal polyps. However, both examinations are limited by the scarcity of skilled and experienced practitioners.

Conclusions Where do we stand with CTC today? There are two indications for CTC: an incomplete colonoscopy and a screening examination for patients in whom a standard colonoscopy is centraindicated or not desirable due to comorbid conditions. At the Cleveland Clinic, we cur-

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rently have a well-deﬁned process of same-day add-on CTC when a colonoscopy is incomplete. Thus, a patient needs to undergo only one bowel preparation for the screening. In experienced hands, CTC is also a reasonable screening test for polyp detection in an average-risk patients. However, CTC should be performed only by radiologists with extensive experience. This experience can only be gained through ongoing experience in correlation with colonoscopy in a research environment or after the completion of extensive course work under the instruction of an experienced radiologist. The advantage of CTC is that it has the potential to screen large numbers of patients, and identify those who are still asymptomatic but are nonetheless appropriate candidates for therapeutic colonoscopy. Thus, if CTC were considered to be the ﬁst-line screening tool for colorectal cancer, the relatively limited resources of colonoscopy would be conserved for the truly needy. Where is CTC going? Currently, there are centers studying low-impact bowel preparations for CTC [34, 47, 58, 78]. Patients are placed on a low-residue diet for 1-2 days, during which time they ingest small amounts of barium. If low-residue stool can be eﬀectively and consistently tagged, techniques that cleanse the colon electronically can be used to remove the high-density barium-tagged colonic contents. This approach would obviate the use of cathartics prior to the study. Thus, patients in whom no polyp is detected would not need a cathartic or a colonoscopy, whereas those with polyps would undergo a subsequent bowel preparation and colonoscopy. In addition to these strategies for implementing lowimpact preparation or prepless CTC, work is under way on the use of computer-aided detection (CAD) as a means of assisting the radiologist in the detection of polyps. This technology has been very successful in mammography [32, 42, 56, 67] and is now being applied in lung cancer screening programs [66, 68, 76, 77]. If accurate, CAD could reduce the interpretation time and thus increase the number of patients studied per day. Currently, most radiologists experienced in CTC would not want to interpret more than ﬁve studies per day, due to the demanding, meticulous nature of the process. Given the fact that there are not enough radiologists to interpret the growing number of CT scans performed in the United States, any assistance is sure to be embraced enthusiastically by radiologists. The potential combination of low-impact bowel preparation, stool tagging, and CAD promises to be the most exciting development yet in the rapid evolution of this technique. Currently, in experienced hands, CTC is nearly equivalent to standard colonoscopy in detecting polyps >1 cm and it approaches colonoscopy in detecting polyps ‡7 mm. Even if one accepts that the data reported by Cotton et al. [35] provide an accurate assessment, this test is clearly the next best thing to colonoscopy. However, CTC is still not ready for primetime use in every radiology department by every boardcertiﬁed radiologist. Indeed, I would estimate that CTC will not have a signiﬁcant impact on the potential screening population for at least 3 years. However, because it could signiﬁcantly increase the number of eli-

gible who are actually evaluated, it has the potential to greatly decrease the incidence of colon cancer in the general population. To compensate for the relatively poorer performance of CTC vis-a-vis colonoscopy, the follow-up period could be shortened to 5 years, rather than the 10 years recommended for colonoscopy [50]. Advances in stool tagging, low-impact bowel preparations, electronic colon cleansing, and especially CAD can be expected to improve the technique substantially. However, the most critical step toward its wider dissemination and acceptance as the optimal choice for ﬁrst-line screening of adults at average risk for colorectal cancer is to redouble our eﬀorts to train and certify more radiologists in CTC.

Acknowledgment. I am grateful to C. Daniel Johnson, MD, and David Einstein, MD, for their careful reading and constructive criticism of the manuscript.

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