Performance improvements of imaging-based screening tests

Best Practice & Research Clinical Gastroenterology 24 (2010) 493–507

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Best Practice & Research Clinical Gastroenterology

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Performance improvements of imaging-based screening tests Cesare Hassan, MD a, *, Perry J. Pickhardt, MD b, c, Douglas K. Rex, MD d a

‘Nuovo Regina Margherita’ Hospital, Via Morosini 30, 00153 Rome, Italy Department of Radiology, University of Wisconsin School of Medicine & Public Health, E3/311 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792-3252, USA c Department of Radiology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA d Division of Gastroenterology/Hepatology, Indiana University Medical Center, Indianapolis, IN, USA b

Keywords: Colorectal cancer screening Colonoscopy CT colonography MR colonography Colon capsule endoscopy

Endoscopic and radiologic tests appear to be more accurate than stool-tests in detecting advanced neoplasia because of direct visualisation of colorectal mucosa. Further technological advances are expected to improve the performance and acceptability of these tests. Several attempts at increasing the adenoma detection rate of colonoscopy have been tested, and in vivo histologic differentiation between neoplastic and hyperplastic polyps may lead to substantial saving in economic and medical resources. Low-volume and non-cathartic bowel preparations may improve CT colonography acceptability, whilst computer-aided detection and low-dose protocols may result in a higher accuracy and safety of this procedure. Despite the lack of ionising radiation, significant drawbacks will likely to limit the role of MR colonography in screening programs. Colon capsule endoscopy appears to be a safe and technically feasible procedure. The suboptimal accuracy of the first generation seems to be substantially improved by the second generation of this device. Ó 2010 Elsevier Ltd. All rights reserved.

Abbreviations: OC, colonoscopy; CTC, CT colonography; MRC, MR colonography; CCE, colon capsule endoscopy; CRC, colorectal cancer. * Corresponding author. E-mail addresses: [email protected] (C. Hassan), [email protected] (P.J. Pickhardt), [email protected] (D.K. Rex). 1521-6918/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpg.2010.04.003

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Colorectal cancer (CRC) screening tests may be broadly divided in two categories according to their mechanisms, namely those tests able to directly visualise the colorectal mucosa (imaging tests), such as endoscopy or radiologic studies, and those tests that exploit an association between blood in the stool and the presence of neoplasia, such as guaiac-based or immunochemical faecal tests. Although the fecal occult blood test (FOBT) has been shown to have a reasonable sensitivity for invasive cancer that has already developed, its accuracy for adenomas, including advanced adenomas, is low. On the other hand, imaging tests are potentially able to detect the vast majority of both colorectal cancers and potentially premalignant advanced adenomas, so that a high CRC prevention rate may be expected [1,2]. The evidence that imaging tests are more sensitive than stool-based tests in detecting colorectal neoplasia does not necessarily mean that these tests represent the optimal approach for CRC screening. Unlike diagnostic medicine for symptomatic or diseased patients, population screening potentially involves many millions of people such that some compromises and trade-offs among feasibility, acceptability, accuracy, reproducibility and costs are needed. At the present time, optical colonoscopy represents the only test that allows for direct visualisation of colorectal mucosa to be widely implemented as an opportunistic screening test across many Western nations. It has been estimated that nearly half of the American population underwent a lower endoscopic examination within the last 5 years, and this has been related with a substantial reduction in CRC incidence in the United States [3]. However, colonoscopy does not necessarily represent an ideal CRC screening test. For instance, population acceptance appears to be suboptimal, with colonoscopy being generally perceived as an invasive test. Although colonoscopy still represents one of the most accurate tests for detecting colorectal neoplasia, its sensitivity is nonetheless hampered by a finite rate of false-negative results and incomplete colonoscopy, resulting in potentially unprevented interval cancers [4]. Flexible sigmoidoscopy represents a less invasive endoscopic approach for CRC screening, and it has been associated with reduced incidence and mortality from colorectal cancer in controlled studies [5]. Similarly to colonoscopy, a wide variation in adenoma detection rates has been observed at sigmoidoscopy screening [6], suggesting a suboptimal sensitivity, at least in some settings. Newer endoscopic and radiologic procedures have the advantages of being more patient-friendly and less invasive for CRC screening, still permitting direct visualisation of the colorectal mucosa. CT colonography (CTC), for instance, does not require sedation or pain control and may reduce or avoid the necessity of a full cathartic preparation. MR colonography (MRC) exploits the recent advances in MR technology, and it potentially represents an even safer option than CTC because of the lack of ionising radiation. Colon capsule endoscopy (CCE) is the first ingestible endoscope that, at least in theory, may be delivered at home. Similar to conventional colonoscopy, however, some of these new tests may be hampered by suboptimal diagnostic accuracy or technical issues that may limit their acceptability in a screening setting. Further technologic advances both in the endoscopy and radiology fields are expected to improve the performance and acceptability of imaging tests in the coming years. The aim of this review is to analyse the current status and future potential for these screening tools. Colonoscopy (OC) OC sensitivity in detecting colorectal neoplasia is crucial in preventing CRC incidence and mortality. An imperfect OC sensitivity has been claimed as a possible cause of interval cancers occurring within a short time from the index OC. Suboptimal OC accuracy for polyps of any size has been shown by both tandem OC studies and head-to-head OC-CTC comparisons [4,7]. In a systematic review of 6 tandem colonoscopy studies, OC miss rate for
10 mm, 6–9 mm, and 5 mm polyps was 2.1%,13%, and 26%, respectively [4]. In a screening CTC study, most clinically significant lesions missed on OC appeared to be located behind a fold or near the anal verge [7]. Suboptimal OC sensitivity may be due to technical limitations of the colonoscope, preventing an adequate visualisation of the whole colorectal mucosa, or to the difficultness to differentiate between normal and flat neoplastic mucosa with white-light endoscopy. OC specificity for neoplasia is also important. Indolent hyperplastic polyps are very frequent in the general population, resulting into high costs of polypectomy and histological examination. It has been estimated that, in a screening setting, over 30% of all the polypectomies are performed for diminutive non-neoplastic lesions [8].

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Technological improvements in the OC field mainly aim to increase detection of neoplastic lesions and to perform an in vivo histological diagnosis of colorectal polyps. Although most of these technological improvements are also applicable on flexible sigmoidoscopy, at least in theory, they have not been specifically tested with this procedure. For this reason, we limited our analysis to OC.

Increasing detection Exposing hidden mucosa The angle of view of most commercial colonoscopies is only 140 , requiring time consuming manipulation of the colonoscope tip to maximise mucosal exposure. Wide angle (
170 ) colonoscopies has been compared to standard angle in 3 randomised trials [9–11]. The only benefit observed is that some operators can withdraw faster without decreasing adenoma detection, whilst no gain in adenoma detection has been reported. A transparent plastic cap on the tip of the colonoscope may flatten haustral folds exposing the mucosa on the proximal side of the folds. Cap-fitted OC has been tested in 10 randomised trials, mainly performed in Asian countries [12]. The technique appeared to be technically feasible without significant complications. Despite 4 trials reported an increased polyp detection rate, only 2 studies showed a higher adenoma detection rate (mainly diminutive adenomas), with one study actually showing a decreased adenoma detection rate. Both of the series showing an increased adenoma detection rate seem to be flawed because the gains in the control arms was only 4% and 5% [13,14], as compared to a mean 20% expected gain from previous tandem OC studies. Thus, current evidence does not indicate any consistent improvement in adenoma detection by cap-fitted OC. The Third-Eye Retroscope (Avantis Medical Systems, Sunnyvale CA) is a catheter based imaging system that is passed through the colonoscope working channel and provides a retrograde image of the colon during colonoscope withdrawal. It was shown to dramatically improve detection of artificial polyps embedded on the proximal sides of folds in a model. In an uncontrolled multicentre prospective study, including 249 subjects with 136 adenomas, the device produced an 11% gain in adenoma detection as judged by adenomas that were detected only by the Third-Eye and not by the colonoscope [15]. A multi-center randomised tandem study is in progress at the time of this writing. Highlighting flat lesions Flat and depressed colorectal lesions may account for up to 40% of all the adenomas. Depressed lesions are more likely to contain high-grade dysplasia or invasive cancer as compared to protruding lesions, but are much less common than flat lesions without depression. Widespread application of dye to the lumen of the colon (pan-colonic chromoendoscopy) increases the detection of small flat adenomas [16], but is widely considered too time consuming to be used for routine colonoscopy. Selective application of dye to already-identified suspicious area may be useful in assessing lesion borders, evaluating flat lesions for depression, and predicting histology when combined with optical magnification, but not in increasing neoplastic detection. Electronic highlighting of flat lesions has been attempted with narrow band imaging (NBI) and post imaging processing methods including Fujinon Intelligent Colour Enhancement (FICE) and I-Scan from Pentax. There are too few data with I-Scan to make an assessment. A single randomised trial with FICE was negative [17]. NBI is based on the application of narrow bandwidth filters to standard white-light endoscopy that enables a clear definition of the contrast between the epithelial surface and the adjacent vascular net. There have been 6 randomised trials of NBI [18–23]. There was no difference in adenoma detection rate using NBI compared to white-light OC in any of these studies. According to one study, NBI may have a beneficial learning effect in poor adenoma detectors [18]. High-definition (HD) imaging may provide sufficient improvement in resolution with white-light endoscopy to improve detection of flat lesions. It has recently been used in studies achieving the highest adenoma detection rates ever reported, (
50% in average-risk screening patients) [23]. However, the only randomized trial of HD did not show an increase in the detection rate of adenomas or hyperplastic polyps [24].

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In vivo histologic assessment Accurate in vivo histological assessment may avoid the removal of small distal colon hyperplastic polyps, eliminating costs and risks of polypectomy. Second, small precancerous polyps could be resected and discarded without pathologic assessment. The ‘resect and discard’ approach reduces pathology costs, and post-polypectomy surveillance colonoscopy intervals would be based on endoscopic assessment of histology. New techniques allow the visualisation of surface details, such as pits and microvessels, that are distinctly different in adenomas compared with hyperplastic polyps (Fig. 1). Two recent studies assessed whether assessment of diminutive (5 mm) or small (9 mm) polyps with NBI without optical magnification followed by ‘resect and discard’ strategy would allow an efficient selection of the post-polypectomy interval that would be indicated according to pathology results [25,26]. In a prospective study on 451 consecutively identified polyps, endoscopic predictions of adenoma and hyperplastic histology were made with high confidence in 80% and 83% of cases, respectively [25]. These predictions were correct for 91% and 95% of 5 mm polyps. The second study compared optical

Fig. 1. (a) Narrow band image of a hyperplastic polyp. There is an absence of vessels and the classic ‘black dot’ pattern is evident. (b) Narrow band image of an adenoma. Note the dark brown vessels surrounding white tubular structures of varying shape.

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and histopathological diagnosis in 278 10 mm polyps [26]. NBI-based optical diagnosis accurately classified 94% and 89% of the adenoma and hyperplastic polyps, respectively, resulting into an overall 93% accuracy. NBI accuracy in differentiating between neoplastic and hyperplastic lesions has also been shown to be superior to that of HD white-light OC, and comparable to that of chromoendoscopy, with the advantage of reduced procedure time. Although fewer studies are available, FICE, I-Scan, confocal laser microscopy, and endocytoscopy have been shown to be accurate in performing an in vivo histological diagnosis [12]. NBI, FICE and IScan have the advantage of being push button operated systems and are standard equipment on current generation colonoscopes. Summary Attempts to increase detection by means of exposing more mucosa have been generally disappointing. The only possible exception is represented by the Third-Eye, for which the results of the ongoing tandem study are critical. Technological improvements aiming to highlighten flat lesions have been scarcely effective. The only exception is probably represented by HD, especially when considering that the transition from standard resolution to HD is probably inevitable in any case. In vivo histological assessment has been proven to be highly effective and likely to transform small polyp OC management within a short time. This may be projected in huge savings of economic and medical resources. Push button technologies will have the advantage for routine use in that they are inexpensive, easy to learn, fast to perform and still accurate. Computed tomography colonography (CTC) CTC, also referred to as virtual colonoscopy, is a minimally invasive imaging examination of the colon and rectum, involving both adequate bowel preparation and gaseous distention of the large intestine. The CT-acquired images are then displayed on an advanced visualization workstation with complex image analysis and display software to assess the presence or absence of structural lesions such as polyps and cancer. Despite disappointing results in two early multicentre studies in non-screening populations [27,28], CTC efficacy in the screening setting has since been ascertained in three recent screening trials, overall including 4075 subjects, in which improved CTC techniques have been compared with within-subject colonoscopy [2,29,30]. In these studies, CTC sensitivity for polyps
10 mm polyps has been shown to be 90–94%, which is similar to colonoscopy sensitivity [7]. On the other hand, CTC specificity for excluding large neoplasms (
10 mm) has broadly ranged between 84% and 98%. CTC accuracy for 6–9 mm lesions also appears to be somewhat more variable, with a sensitivity of 78–91% and a specificity of 86–93%. Based on these trials, post-CTC colonoscopy referral rates would be projected as high as 7–18% at the 10mm threshold, and 13–30% at the 6-mm threshold. However, in actual clinical practice, positivity rates at the 10-mm and 6-mm polyp size thresholds between CTC and colonoscopy have been similar. For example, a recent study comparing CTC and colonoscopy screening in two separate cohorts of 3120 and 3163 asymptomatic subjects, respectively, showed very similar positivity rates at both 10-mm (5.3% and 4.2%, respectively) and 6-mm thresholds (12.9% and 13.4%, respectively) [31]. The reason for lower rates of positive CTC examinations compared with the prior trials is perhaps best explained by the marked improvement in positive predictive value, which is now well over 90% [32]. In addition, similar rates of advanced neoplasia were found within each screening cohort in this study, with 3.2% in the CTC group (123 total advanced lesions) and 3.4% in the colonoscopy group (121 total advanced lesions). Several technological improvements have been applied in recent years, aimed at improving CTC acceptability, accuracy, and safety. Some of these are briefly discussed below. Bowel preparation In the CTC screening trials, a colonoscopy-like cathartic bowel preparation with either sodium phosphate, polyethylene glycol, or magnesium citrate has been adopted, in part because of the necessity of same-day colonoscopy [2,29,30]. To improve the safety of bowel preparation, the use of

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magnesium citrate has been recently shown to be as efficacious as sodium phosphate in achieving an adequate level of preparation in a cohort of 115 patients at high risk of phosphate nephrotoxicity compared with a sodium phosphate preparation in similarly sized cohort [33]. Cathartic bowel preparation is often regarded as one of the most unpleasant aspects of CRC screening using imaging tests. The lower volume of the magnesium citrate and sodium phosphate preps tend to have an intrinsic advantage over the high-volume PEG prep. In addition, the possibility of labelling solid and liquid faecal material at CTC by adding oral contrast agents (the so-called ‘faecal tagging’ technique) [34] has led to the best performance results in clinical CTC studies [2,29,30]. This also opens the possibility for non-cathartic approaches to CTC, which could potentially improve overall adherence rates. However, there are significant trade-offs to this approach that must be considered [35]. Although sometimes referred to as ‘prep-less’ CTC, this term is a misnomer as these non-cathartic preparations can be quite elaborate and onerous on the patient. Furthermore, the lack of catharsis precludes the opportunity for same-day polypectomy, forcing the patient to undergo a second bowel preparation on a separate day for subsequent invasive colonoscopy. In addition, the reduced accuracy with non-cathartic CTC will presumably lead to unnecessary endoscopy in some cases. Nonetheless, non-cathartic CTC has been shown to be feasible [36], and is clearly worth pursuing as a secondary option to further improve adherence rates. However, the centres that are currently performing CTC screening in the largest volumes continue to utilise a cathartic bowel preparation with oral contrast tagging in a ‘one-stop shop’ manner that has been strongly endorsed by the AGA as the preferred approach. That being said, it may be possible that some patients undergoing bowel preparation without the use of cathartics but with the use of ionic iodinated oral contrast (diatrizoate) may actually be adequately prepared for same-day endoscopy (Fig. 2). The simple explanation for this would be that diatrizoate essentially has a cathartic effect. Computer-aided detection (CAD) Despite the very high CTC sensitivity for large colorectal lesions, significant variability in reader performance could limit the reproducibility of the procedure. Although identifiable technical factors

Fig. 2. Non-cathartic bowel preparation for CT colonography. Supine 2D transverse image from CTC obtained after non-cathartic bowel preparation with water-soluble ionic iodinated oral contrast (diatrizoate) shows excellent results without any identifiable solid residue. Note the uniform tagging of the residual luminal fluid and the extensive sigmoid diverticulosis.

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account for most CTC performance differences (e.g., 2D versus 3D polyp detection, use of oral contrast tagging, different CTC software platforms, etc), reader experience and training have also been shown to affect CTC accuracy, rendering it a somewhat operator-dependent technique. In an effort to reduce variability in CTC performance, computer-aided detection (CAD) algorithms have been developed. CAD provides a second opportunity for lesion detection (Fig. 3). CAD has been shown to be effective in situations where radiologists must detect small lesions that occur infrequently, such as in screening mammography. This may also be the case for CTC, when considering that an estimated 10,000–15,000 images must be scrutinised for each large adenoma identified in the screening setting. Stand-alone CAD performance (i.e. automated CAD reading without human interaction) has been recently evaluated in two large screening cohorts [37–39]. The first study analysed the DoD screening cohort, with a testing dataset of 792 asymptomatic subjects [37]. CAD sensitivity for adenomas
8 mm and
10 mm polyps were 76% and 86%, respectively, which was not statistically different from those of blinded colonoscopy. CAD false-negatives were usually localised at the air-fluid boundary, which can be a difficult location for CAD to analyse. The number of false-positive marks per patient at the same thresholds was 6.7 and 2.1 per patient, respectively. The majority of large false-positives were caused by the ileo-caecal valve, and only 0.9% of CAD false-positive marks coincided with that of the radiologist. This suggests that most CAD false-positive marks would be rejected by the radiologist, perhaps without a significant impact on specificity. The second stand-alone CAD trial evaluated a separate screening cohort of 3077 consecutive asymptomatic adults [38]. Per-patient CAD sensitivity was 94% and 97% at the 6-mm and 10-mm thresholds, respectively. Per-polyp CAD sensitivity for all polyps, regardless of histology, was 90% and 96% at the 6-mm and 10-mm size thresholds, respectively. CAD sensitivity for advanced neoplasia and cancer was 97% and 100%, respectively. The mean and median false-positive rates were 9.4 and 6 per patient, respectively. Among the 373 patients with a positive CTC, CAD detected an additional 15 polyps
6 mm, including 4 large polyps, that were missed by the

Fig. 3. Computer-aided detection (CAD) for CT colonography. Screen capture of a diagnostic interface for CTC interpretation shows CAD marks on the colon map, 2D images, and 3D display. The list of all CAD marks is also displayed for the user.

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prospective expert primary 3D read but found at subsequent colonoscopy. These excellent stand-alone results are encouraging but do not guarantee effective interaction between the computer program and the human reader. Beyond stand-alone CAD evaluation, reader performance studies attempt to assess the complex interactions between CAD and the human interpreter, typically employing CAD in a second-read mode after the initial human interpretation. Some of these reader performance studies have shown that CAD may improve sensitivities at the expense of specificity [40–42] and may also hold more positive impact for inexperienced readers. As expected, overall reading time increases when CAD is employed in the standard second-read paradigm, but typically adds just a few minutes to the interpretation. Radiation dose A major issue that has surrounded CTC implementation in a screening setting is the theoretic risk of cancer induced by low levels of ionising radiation. Currently, the median estimated effective dose from a CTC evaluation is in the 5–6 mSv range (i.e., 2–3 mSv per series) [43]. This effective dose is much lower than a typical diagnostic CT scan due to the intrinsic nature of the interface between the air-filled colonic lumen and its soft tissue wall, which allows for significant dose reduction without loss of accuracy. Part of the debate over radiation exposure in CTC screening centres relies upon whether or not a relevant health risk exists at these low levels. The official position of the Health Physics Society is that at such low doses, any potential risk is too small to be reliably quantified and may be nonexistent [44]. Even noted proponents of the controversial linear, no-threshold model of radiation risk have concluded that the benefit–risk ratio of CTC screening is large [45]. Furthermore, the radiation exposure associated with CTC is comparable or less than the levels received during a typical barium enema examination, suggesting that CTC is now being held to a higher standard [46]. To put these exposure levels in perspective, the dose from CTC is on par with the background dose from cosmic radiation received over a 1-year period. In addition, the dose is applied to an adult population typically older than 50 years of age (and not an adolescent group in which risk of a future induced cancer is more of a concern), and the majority of the chest is not imaged (which increases the theoretic risk of bronchogenic cancers). Consequently, the documented real benefits from screening for colorectal cancer greatly outweigh the very small theoretic risk related to radiation, especially when compared to the known risks of colonoscopy [47]. Debate over the presence or absence of actual risk related to low-level radiation aside, it nonetheless behooves us to keep the dose as low as possible without significantly impacting upon study quality. Recent and upcoming advances in MDCT technology will allow for even greater reductions in effective dose. For example, tube current modulation techniques have already resulted in significantly lower doses by applying mA only as needed and not at a static level (Fig. 4) [48]. Even more substantial dose reductions are possible with new approaches to CT image reconstruction. The first generation of novel reconstruction algorithms beyond the standard filtered backprojection technique includes adaptive statistical iterative reconstruction (ASIR), which can provide dose reductions in the 40–50% range [49]. The potential for even greater dose reduction, in the range of an order of magnitude, may be possible with model based iterative reconstruction (MBIR) and other emerging algorithms, which could render the discussion of theoretical risks a moot point. Summary CTC has demonstrated high sensitivity for the detection of relevant colorectal neoplasia in the screening setting, which could lead to substantial increases in compliance if issues related to CTC availability, coverage, and inclusion in national screening programs are resolved. The feasibility of noncathartic CTC as a potential secondary option has the potential to further increase screening compliance. CAD may play a role in ensuring reproducibility of high diagnostic performance. CTC has a very attractive risk profile, and is clearly a safer test than invasive colonoscopy as a primary screening tool. The possibility for further reductions in radiation dose are expected to address the lingering theoretic concerns of carcinogenesis related to low levels of ionising radiation.

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Fig. 4. Low-dose CT colonography with tube current modulation. Supine (a) and prone (b) images from CTC show the differences in noise level and image quality at 38 mA using tube current modulation (a) and a static level of 150 mA (b). Both series are diagnostic for colorectal evaluation, although extracolonic evaluation becomes somewhat compromised at lower doses.

Magnetic resonance colonography (MRC) Analogous to CTC, MRC uses cross-sectional imaging to allow for 2D and 3D assessment of the colonic lumen. As witnessed by the markedly lower number of published studies on MRC compared with CTC, CTC appears to be better suited for colorectal screening, in part reflecting the ease, speed, and reproducibility of performing CT, as well as the increased spatial resolution, decreased cost, and wider availability of CT [50]. In contrast, bowel imaging using MR in the setting of inflammatory bowel disease is witnessing significant growth. Colonography-specific imaging is more straightforward with CTC compared with MRC, as the latter often involves the use of hydrocolon and intravenous contrast techniques. Until recently, the gadolinium-based intravenous contrast agents applied with MR examinations were believed to have a more favourable safety profile than the iodinated CT intravenous contrast agents. This balance has been upset, however, with the discovery of nephrogenic systemic fibrosis and its relationship to gadolinium-based MR contrast [51]. With regards to colonography, the CT-based version is largely performed without intravenous contrast, which further improves the safety

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profile of CTC. The one advantage MRC does has over CTC is to the lack of ionising radiation, therefore avoiding the theoretical risks described above. Similar to CTC, MRC generally involves bowel preparation and colonic distention. From an imaging standpoint, there are two main approaches to MRC: bright-lumen and dark-lumen techniques. With the bright-lumen technique, the colon is filled via 1500–2000 ml water-based enema, spiked with paramagnetic contrast. To minimise false-positive results, acquisitions in both supine and prone positions are required. Dark-lumen MRC most often employs a simple tap water enema in conjunction with the intravenous contrast administration, although room or carbon dioxide are sometimes used to distend the colon. Avoidance of the hydrocolon technique would likely increase acceptability and uptake of MRC by more centres, due to the lack of messy spillage potential. However, there have been lingering issues related to the soft tissue–gas interface that have prevented its widespread implementation [52]. Unlike CTC, there have been no large multi-centre screening trials evaluating MRC. The largest screening study to date was a single-centre study involving 315 subjects [53]. At the 10-mm size threshold, the per-patient specificity in this study was 100%, but per-patient sensitivity was only 70%. Most other published studies have involved smaller symptomatic or high-rish risk cohorts. A recent meta-analysis identified 13 studies with a total of 1285 patients in which MRC accuracy for colorectal lesions was verified by within-subject colonoscopy [54]. Per-patient summary estimates of sensitivity and specificity values for
10 mm polyps were 88% and 99%, respectively. Pooling of the MRC performance for polyps <10 mm was prevented by the high degree of heterogeneity, but polyp detection has generally dropped considerably for sub-centimetre polyps. Technological advances with MRC have been mainly focused on bowel preparation, insufflation technique, and certain MR imaging advances (e.g., parallel imaging). Similar to CTC, MRC raises the possibility of non-cathartic or minimal bowel preparations through the use of faecal tagging. Feasibility has been demonstrated in a number of published studies [54,55]. However, the same challenges for non-cathartic evaluation that apply to CTC (see above) also apply to MRC. In addition, 3D endoluminal evaluation, which is so critical for polyp detection with CTC is less robust with current MRC capabilities. The liquid enema required for most MRC protocols represents a substantial challenge and an enormous barrier for widespread implementation. For this reason, a number of investigators have evaluated gaseous distention of the colon for MRC [52]. Although initial feasibility was demonstrated, one study using air insufflation showed a very poor 13% sensitivity for polyp detection in 156 patients undergoing MRC [56]. The major underlying technical issue involves the difficulty MR imaging has in handling airsoft tissue interfaces. One novel approach that has been applied to avoid both liquid enema and gaseous distention involves the use of fluid distention via oral ingestion of polyethylene glycol (PEG) [57]. Summary Despite encouraging performance in smaller cohorts, no large multi-center trial has been conducted to evaluate MRC for colorectal cancer screening. More importantly, there are a number of fundamental drawbacks that will likely limit the role of MRC for screening, including technical limitations, study complexity, interpretation times, cost, and availability. In addition, the solitary advantage that MRC currently holds over CTC – namely, the lack of ionising radiation, will likely become a moot issue with the emerging CT techniques for dose reduction. Colon capsule endoscopy (CCE) The PillCam COLON capsule (CCE) represents a non-invasive, safe and painless endoscopic test of the colon, and it may also claim to be the only per os administered CRC screening test. CCE is an ingestible capsule equipped with an endoscope that has two imagers, enabling it to acquire video images from both ends. The device measures 31 by 11 mm and acquires images at a rate of 4 frames per second. The preprogrammed ‘sleep’ mode allows recording of images from the oesophagus and the stomach for 3 min before the capsule switches to sleep mode for 1 h 45 min in order to conserve battery life (total operating time: 10 h). During this period, the capsule is likely to transit most of the small bowel and reach approximately the level of the terminal ileum. The system includes a sensor

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array and a data recorder worn by the patient during the procedure. Bowel preparation mainly consists of 4 l of polyethylene glycol solution (PEG) before capsule ingestion and 1 or 2 sodium phosphate boosters, each followed by another litre of water, after capsule ingestion leading to 5–6 l of liquids in 2 days. A recent meta-analysis identified 8 studies with a total of 837 patients, in which CCE accuracy for colorectal lesions was verified by within-subject colonoscopy [58]. CCE was able to visualise all the colon in 86% of the cases, with a good level of preparation in 77% of the patients. CCE sensitivity for polyps of any size and significant findings (
6 mm polyps or >3 polyps) were 71% (95% CI: 66–76%) and 68% (95% CI: 56–79%), respectively. CCE specificity for polyps of any size and significant findings were 75% (95% CI: 66–83%) and 82% (95% CI: 77–85%), respectively. CCE identified 16 of the 21 cancerous lesions detected by colonoscopy (pooled sensitivity ¼ 76%). When cumulatively considering these studies, the first generation of CCE appeared to be a safe and feasible technique to visualise the colon, but characterised by a suboptimal accuracy and a high variability in the technical performances. Several improvements have been put forward in the last years, leading to the creation of a second generation of CCE (CCE-2). Polyp detection The suboptimal accuracy of CCE-1 has been primarily related with the inability to adequately image the mucosa when the capsule was accelerated by the peristalsis, especially in the transverse colon. For this reason, the new CCE-2 has been enabled to automatically increase the frame rate from 4 to 35 images per second when in motion, returning to 4 when stationary to save battery energy (Fig. 5). A second improvement involved the optics. The angle of view from each capsule end has been increased from 156 to 172 for each lens, in order to nearly cover 360 of the colon surface. CCE-2 has been tested in a multicentre Israeli study, enrolling 104 patients [59]. Bowel preparation was adequate in 78% of the patients, and 81% of the capsules were excreted after 8 h, when, due to logistic constrains and according to the study protocol, blinded colonoscopy was performed. CCE-2 sensitivity for
6 mm and
10 mm appeared to be 89% and 88%, with corresponding specificities of 76% and 89%, respectively. Colonoscopy and biopsy detected 11 patients with adenomatous polyps
6 mm, which included 5 patients with adenomatous polyps
10 mm, one of which was cancer. All these patients were detected by CCE-2.

Fig. 5. A 30 mm carcinoma at the right flexure detected by colonoscopy and second generation colon capsule endoscopy (Courtesy of Prof Rami Eliakim).

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Portability of CCE All the available studies on CCE have been performed in a hospital setting. CCE-2 has been provided with a new portable wireless data recorder able to automatically identify when the CCE enters into the small bowel. It also owns an user-friendly interface, sending active, customised reminders to the patient, mainly in relation to the different laxative booster intakes after capsule ingestion and end of procedure. Despite no attempt has been made, CCE-2 seems to be quite close to become the first imaging test that may be completely performed at home. Bowel preparation The main issue regarding CCE acceptability in a screening setting is represented by the tolerability and safety of the preparation. An initial attempt to reduce the PEG component from 4 to 3 l has been successful. A split of the PEG dose between the day before and the day of the examination has also been successful [59]. A relevant issue is represented by the potential sodium phosphate nephrotoxicity. However, initial attempts to exclude sodium phosphate by CCE preparation failed, because the lack of the sodium phosphate propulsive force resulted into a low CCE excretion rate. Summary The main shortcomings of CCE appears to be related with technical feasibility, accuracy, and acceptability. It may be anticipated that technical improvements will reduce the risk of battery exhaustion during the procedure, assuring a high rate of complete colorectal examination. CCE-2 accuracy appeared to be substantially improved over the first generation, but further confirmations are critical (an European multi-center trial is ongoing). Bowel preparation remains the most challenging issue to be addressed in the upcoming years. Different regimens or new substances may be expected to be tested in order to improve its acceptability and safety. Potential impact of performance improvements of imaging-based screening tests in a programmatic setting OC represents the ultimate step of any CRC screening program. For this reason, it is currently recommended after a positive FOBT or a positive flexible sigmoidoscopy in nationwide screening programs. Of note, a high rate of neoplasia, especially advanced neoplasia, is expected in these patients [1]. It is likely that the progressive transition from standard instruments to high-definition colonoscopes with NBI technology will allow a wide implementation of the ‘resect and discard’ approach for diminutive lesions, resulting in substantial savings of medical and economic resources. The same may be applicable to current flexible sigmoidoscopy programs. On the other hand, it is still unclear whether the high-definition instruments will increase OC sensitivity in these dedicated settings. The possibility of a primary organised OC screening program is still under debate. However, the convenience of such an approach probably depends more on the availability, acceptability, and safety of this procedure rather than on its intrinsic technological improvements. CTC with limited bowel preparation has been tested as potential triage technique in patients with a positive FOBT, showing reasonable predictive values and a higher acceptability to patients than colonoscopy. However, due to the high prevalence of clinically relevant lesions in FOBT-positive patients, CTC is unlikely to be an efficient triage technique in a first round FOBT population. Similarly to OC, the possibility of a primary CTC organised screening program appears to depend more on the availability of CT machines and appropriately trained radiologists rather than CTC technological improvements. However, the availability of CAD could represent an advantage for CTC as compared to endoscopy, since it may reduce the inter-observer variability in adenoma detection. Substantial dose reductions may be expected with the evolution of CT technology. This could positively affect the risk/benefit ratio of an eventual organised screening program with CTC. At the present time, there are insufficient data to prospect a potential role for MRC or CCE in a programmatic screening setting.

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Research agenda  Is the ‘resect and discard’ policy for diminutive polyps feasible and efficient in a colonoscopy screening setting?  Will the ‘Third-Eye’ reduce the miss rate for advanced neoplasia in the right colon?  Will the very high detection rate of HD colonoscopy result in a higher CRC prevention rate?  Will low-volume or non-cathartic bowel preparations for CT colonography improve population adherence?  Will computer-aided detection as stand-alone or concurrent reader reduce the variability in reader performances in a CT colonography screening program?  To what extent will newer CT colonography protocols reduce the radiation dose?  Will the second generation of colon capsule endoscopy reduce the accuracy variability observed with the first generation?  Will a home-based examination with colon capsule endoscopy be feasible and effective?  Will the colon capsule bowel preparation become more tolerable and effective?

Practice points  Technological improvements aiming to increase neoplasia detection at colonoscopy generally failed  Narrow band imaging, and similar modalities, allows an accurate in vivo histological assessment of diminutive polyps, differentiating between hyperplastic and neoplastic lesions  Low-volume bowel preparation for CT colonography in conjunction with faecal tagging are effective, also permitting a same-day colonoscopy  The advantages of a non-cathartic approach over a low-volume preparation for CT colonography are still unclear  Preliminary results of stand-alone computer-aided detection for CT colonography in a screening setting are comparable to human performances  Technological improvements in CT technology should substantially reduce radiation dose beyond the already low levels achieved with CT colonography  Current technology is inadequate in supporting a CRC screening program with MR colonography  Colon capsule endoscopy is a safe and feasible tool to explore the colon.  Accuracy of the first generation of colon capsule as compared to colonoscopy appeared to be suboptimal  Accuracy of the second generation of colon capsule appeared to be substantially improved, but further trials are critical

Funding source No funding was obtained. Disclosure PJP: Consultant for Medicsight, Viatronix, & Philips; Co-founder of VirtuoCTC. DR: Olympus – research support. Conflict of interest statement None.

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