CT colonography (virtual colonoscopy) for primary colorectal screening: challenges facing clinical implementation P. J. Pickhardt Department of Radiology, University of Wisconsin Medical School, E3/311 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792-3252, USA
Computed tomographic colonography (CTC), also referred to as virtual colonoscopy, is a minimally invasive test for the detection of colorectal polyps. Although its initial performance characteristics for evaluating lowprevalence populations were rather disappointing [1, 2], a larger multicenter trial in asymptomatic adults subsequently showed that CTC has the potential to be an effective primary screening tool . Key features in the latter study that help explain this improved performance include the use of the three-dimensional endoluminal display for primary polyp detection, oral contrast for tagging of residual fluid and stool, segmental unblinding of CTC results at optical colonoscopy (OC), and use of only multidetector CT scanners . As we await further validation of this rapidly evolving technique, actual clinical implementation of primary CTC screening should proceed without delay by those who are currently able to achieve an acceptable accuracy. The need for immediate action is self-evident, as far too many people are dying from a disease that could have been prevented by effective routine screening in more than 95% of cases . There are many important challenges that are likely to be encountered as CTC screening transitions from the realm of research to daily clinical practice (Table 1). This update focuses primarily on three speciﬁc issues: (a) development of a logical diagnostic algorithm for CTC screening, (b) identifying the most appropriate group of patients to be screened by CTC, and (c) establishing a mutually beneﬁcial working relationship with gastroenterology. Additional challenges and issues that are also important but are not covered in report include demonstrating the relative cost effectiveness of CTC screen-
ing, reimbursement by third-party payers, dedicated training of radiologists, and establishment of standard practice guidelines and accreditation. In the end, I believe that none of these challenges will prove to be insurmountable.
Developing a diagnostic algorithm for CTC screening Total colonic examination, as the term implies, entails evaluation of the entire colon and rectum for polyps and reﬂects the currently preferred screening standard. Although this term is usually applied in support of OC over sigmoidoscopy, CTC also provides total colonic examination, with perhaps even greater mucosal coverage than OC because of its multidirectional nature. For patients undergoing colorectal screening with CTC, the largest detected lesion(s) on that study should primarily determine the next appropriate step. Therefore, a diagnostic algorithm based on polyp size categories is needed to stratify patients into categories such as immediate OC for polypectomy, short-term CTC surveillance, and routine follow-up . In my opinion, adoption of reasonable polyp size thresholds will be a critical requirement for the ultimate success of CTC screening [5, 6]. Specifically, I believe that noninvasive CTC surveillance of small (<1 cm) colorectal polyps represents a logical and clinically sound strategy. The rationale behind this proposed paradigm shift for colorectal screening is outlined in the paragraphs that follow. There is general agreement that immediate OC for polypectomy is probably warranted for all large polyps (‡10 mm) detected at CTC screening. In the recent experience of me and my colleagues, this situation occurs approximately once for every 20 average-risk adults screened by CTC. It is reassuring to note, however, that very few of these large polyps will actually harbor
malignancy in asymptomatic adults, and, if left in place, only a minority would continue to grow over time . Further, it is estimated that fewer than 10% of polyps 10 mm or larger will eventually develop into cancer at 10 years . Nonetheless, the risks of undergoing polypectomy by OC are likely outweighed by the malignant potential of these larger polyps. For asymptomatic adults with polyps 10 mm or larger detected at CTC screening who absolutely refuse to undergo the recommended OC for polypectomy, continued surveillance with CTC should be strongly encouraged. Such noninvasive followup will identify the subset of polyps that will continue to grow, perhaps ultimately convincing the patient to have such a polyp removed. With regard to small (<1 cm) colorectal polyps, there also appears to be general consensus that diminutive lesions ( £5 mm) are of no practical clinical signiﬁcance [3, 8]. Only a fraction of these diminutive polyps is neoplastic; of these, fewer than 1% are histologically advanced, and essentially none are malignant [3, 8, 9]. As such, patients without any polyps larger than 5 mm at CTC should be considered to have a normal screening study and can therefore undergo routine follow-up. This is a fortunate situation for CTC screening because attempts to detect all diminutive lesions would prove not only very time consuming but also unreliable, and subsequent matching at OC would also be fraught with difficulty. Controversy is very likely to center on the clinical management of small but ‘‘intermediate-size’’ polyps (6– 9 mm) detected at CTC, but it should be recognized that this decision will have a signiﬁcant impact on the overall effectiveness of this approach. To wit, if the threshold for immediate polypectomy were lowered from 10 mm to 6 mm, the number of OC examinations generated would increase sharply to 30% . Further, because the specificity of CTC for smaller lesions decreases considerably, many of these additional OC studies would actually be triggered by false-positive diagnoses at CTC. Even if a rare 6- to 9-mm malignant polyp is encountered at CTC, it would presumably surpass the 10-mm threshold on follow-up long before extensive invasion or metastatic disease transpires. Fueling this potential controversy over the management of 6- to 9-mm lesions is the relative dearth of information about the natural history of colorectal polyps. There is, however, some very encouraging news that is often overlooked: the existing data on polyp growth rates, although limited, clearly support the validity of noninvasive surveillance of small subcentimeter polyps. Several longitudinal OC studies have been published that followed unresected subcentimeter polyps over time, all of which have demonstrated the indolent nature of these small colorectal polyps. Hofstad et al. reported on the largest and most meaningful of these studies, which followed unresected polyps up to 9 mm with serial OC
P. J. Pickhardt: CTC for primary colorectal screening
examinations over a 3-year period [10, 11]. After the first year of surveillance, only one (0.5%) of 189 subcentimeter polyps crossed the 10-mm threshold . At 3 years, most polyps remained stable or regressed in size, but, more importantly, 5- to 9-mm polyps showed an overall tendency for regression . The researchers concluded that follow-up of unresected colorectal polyps up to 9 mm is safe. It behooves radiologists interested in CTC screening to familiarize themselves with this study because its conclusion closely parallels what I am advocating for noninvasive CTC surveillance. In an earlier study, this same group showed that diminutive tubular adenomas rarely develop to advanced lesions in the short term . In a smaller series, Bersentes et al. found no significant change in the size of subcentimeter polyps at 2-year follow-up, with only a minority of lesions growing larger than 1 mm in diameter . Establishing the appropriate timing for follow-up intervals for patients with small or no polyps detected at CTC represents the other major requirement for a diagnostic screening algorithm. Because standards for time intervals have not been set, we will likely opt for more conservative parameters during the early implementation phase. For example, the routine follow-up interval after a normal CTC study (i.e., no polyps <5 mm detected) could be set at 5 years to coincide with the accepted intervals for sigmoidoscopy and barium enema. As more experience is gained, this interval likely would expand toward the 10-year level that is currently accepted for OC. Although a 3-year follow-up of unresected intermediate-size polyps (6–9 mm) has proved safe, initial CTC surveillance intervals might be set more conservatively at 1 year for 8- to 9-mm lesions and at 2 years for 6- to 7-mm lesions (for example). As discussed below, for patients with adenomatous polyps removed at OC, subsequent follow-up with CTC may be of limited value. There are additional factors that could ﬁne tune adjustments to the CTC screening algorithm. For example, immediate OC or follow-up at a shorter interval might be considered if three or more intermediate-size polyps (6–9 mm) are detected at CTC, somewhat analogous to OC guidelines . Another potential inclusion would be to stratify CTC findings according to diagnostic confidence of the interpreting radiologist. We have found that increased reader confidence for an individual lesion detected at CTC correlates with a significantly increased likelihood that (a) a matched polyp will be found at OC and (b) this matched polyp will be neoplastic . This additional information could help guide radiologists, patients, and referring physicians to the next appropriate step. For example, in our experience, if an 8to 9-mm lesion detected on CTC is assigned low confidence, the chance that a corresponding adenoma would be found at OC was less than 10% compared with a 60% likelihood for high-confidence lesions of a similar size.
P. J. Pickhardt: CTC for primary colorectal screening
Fig. 1. Three-dimensional endoluminal view from CTC shows a smooth, well-defined, pedunculated, 9-mm polyp adjacent to a colonic fold. With this appearance, the likelihood of finding a corresponding polyp at optical colonoscopy approaches 100%.
Not surprisingly, polyp size and morphology affect the likelihood that a lesion detected at CTC is a true polyp at OC; for pedunculated polyps 8 mm or larger that are assigned high confidence, a match was found at CTC in more than 90% of cases (Fig. 1). Although I anticipate much initial debate over how to properly manage this 6- to 9-mm ‘‘gray zone’’ at CTC screening, we should not lose focus on the more important issue at hand. That is, regardless of how we agree to handle subcentimeter polyps detected at CTC screening, the emphasis should be placed on detecting the larger (‡10 mm) polyps, particularly in patients who otherwise may not have been screened at all. In my opinion, concentrating efforts more on the detection and removal of the less common but more dangerous larger polyps in the majority of the screening population would represent a far more efficient, cost-effective, and efficacious strategy than the current practice of ‘‘universal’’ polypectomy in the small minority.
Defining the appropriate patient population for CTC screening The early feasibility studies for CTC were necessarily carried out in polyp-rich cohorts. The ideal population for primary CTC screening in my opinion, however, consists of asymptomatic, average-risk adults . One reason for this is simply that these patients are least likely to require subsequent OC, whereas symptomatic patients or those with a high a priori risk should perhaps proceed
straight to OC because of its therapeutic capability. This risk stratification approach would minimize the number of patients requiring CTC and OC examinations. In effect, given the current shortage of gastroenterologists, OC should be viewed as a limited resource and, as such, is better utilized as a therapeutic procedure for removing significant (i.e., large) polyps, rather than being tied up performing negative diagnostic examinations. It could be argued that the known risks of perforation and clinically signiﬁcant bleeding associated with OC polypectomy, occurring in about 0.2% and 1% to 2% of cases, respectively , outweigh the minimal cancer risk posed by subcentimeter polyps, at least in the short term. Seemingly small risks of a test are amplified when applied to large numbers in an otherwise healthy screening population. In particular, perforation at OC may be particularly devastating (physically and emotionally) when it occurs in a perfectly healthy 50-year-old adult—primum non nocere. Therefore, reserving OC for removal of the more important, large colorectal polyps found by CTC in asymptomatic adults helps to preserve a valuable resource and makes sense from a risk-benefit point of view. Another issue that needs to be addressed is whether CTC or OC is the more appropriate test for surveillance after polypectomy. Evidence from experience at the Mayo Clinic suggests that CTC surveillance in these patients might be less sensitive for detecting additional polyps at follow-up . In a published study of 703 patients, 75% of whom were undergoing surveillance after polypectomy, the sensitivity for large adenomas (‡10 mm) was only 35% to 36% for two of the three experienced reviewers. However, because CTC performance was not specifically reported for the group after polypectomy, the effect related to differences in CTC technique and interpretation cannot be separated. Regardless, these findings suggest that CTC may not be as well suited to a surveillance population, where the more readily detected polyps have already been removed.
Cooperation with gastroenterology for colorectal screening It is important that we as radiologists continue to work closely with our gastroenterology colleagues as our approach to colorectal screening evolves. I ﬁrmly believe that CTC screening, if properly implemented, will result in a ‘‘win-win-win’’ for patients, radiologists, and gastroenterologists alike . For the intended screening population (and society as a whole), the potential added benefit of CTC screening is obvious because any increase in effective colorectal screening should lead to a net reduction in cancer incidence and mortality rate. For radiologists, there is now a viable opportunity to make a substantive and fulfilling contribution to screening for colorectal cancer.
For gastroenterologists, CTC screening should be viewed not as a threat but rather as a means to improve their practices. It is not the intention to have CTC replace diagnostic OC as a primary screening tool, but rather to provide another effective complement for screening. As such, CTC could be initially targeted to average-risk adults who are reluctant to undergo OC for primary screening . The net effect of this approach should be an increased frequency of (truly) therapeutic OC, relatively less time spent on negative (nontherapeutic) examinations, and quite possibly an overall increase in the total number of OC examinations performed. I assume that the gastroenterologist’s level of gratification that results from endoscopic removal of a 2.5-cm tubulovillous adenoma would exceed that of a negative OC study (not to mention the difference in remuneration). As active participants in a comprehensive colorectal screening service, it would behoove radiologists and gastroenterologists to strive for a ‘‘one-stop shop’’ experience for their patients. Patients undergoing primary CTC screening at our institution are allowed to choose one of three options in the event a large polyp is detected: same-day therapeutic OC, next-day OC, or OC scheduled in the near future. The ﬁrst two options avoid the need for complete re-preparation of the colon, which is highly valued by many patients but requires a signiﬁcant commitment from the radiologist to rapidly interpret the CTC study. A commitment from the gastroenterologist is also required to provide this same-day or next-day service. This cooperative arrangement functions as a two-way street because same-day CTC add-ons due to incomplete OC are also anticipated.
Conclusion Despite the multiple challenges facing the widespread clinical implementation of CTC screening, these hurdles are greatly overshadowed by the immediate need for increased participation in effective screening. CTC represents a very promising means for addressing this critical public health concern, assuming we can shift our focus away from the detection and removal of small, clinically unimportant polyps in the minority and concentrate more on the larger, potentially dangerous polyps in the majority. Although this update has focused primarily on the issues surrounding the development of a diagnostic screening algorithm, identiﬁcation of an
P. J. Pickhardt: CTC for primary colorectal screening
appropriate target population, and establishment of an effective relationship with gastroenterology, other challenges loom that are of equal importance. For example, I am currently involved in projects or activities related to cost effectiveness, reimbursement, radiologist training, and extracolonic ﬁndings. Stay tuned for (hopefully) positive developments in these areas and more in the near future, at least some of which could profoundly affect the future of CTC for primary colorectal screening.
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