Pickhardt, Perry J.
The clinical utility of computed tomography colonography (CTC) as a screening tool for colorectal polyps and cancer was established a decade ago . However, although CTC has been validated as a well tolerated and effective diagnostic and screening examination, it remains underutilized due to a number of logistical, political and fiscal obstacles. This delay in implementation of CTC is particularly true within the United States, where early progress has since stagnated compared with the steady gains seen in a number of other countries. The aim of this review is to provide an update on the recent and emerging data addressing the clinical utility of CTC.
The clinical indications for performing CTC can be broadly divided into ‘screening’ and ‘diagnostic’ categories. Since the time of my last CTC update for this journal , a host of studies and publications have provided further validation for both clinical scenarios. The preponderance of important new data surrounds the use of CTC for diagnostic indications, reflecting the most common patterns of CTC utilization throughout the world, where screening of asymptomatic adults by either optical colonoscopy or CTC is seldom performed save for a few select practices. Among the specific diagnostic indications evaluated that are worthy of discussion include symptomatic patients in whom the primary clinical concern is colorectal cancer and postoperative surveillance following colorectal cancer resection. New data regarding the performance of CTC among medicare-aged patients will also be discussed, as will the use of CTC in the general screening population, other performance indicators, patient acceptance, and some additional technical advances.
DIAGNOSTIC COMPUTED TOMOGRAPHY COLONOGRAPHY
Perhaps the most significant CTC trial to be completed in recent years is the so-called SIGGAR trial, which was a UK multicenter randomized comparison of CTC versus standard investigation with colonoscopy or barium enema in the diagnostic setting . Effectively, the study was composed of two separate randomized controlled trials: CTC (n = 1280) versus double-contrast barium enema (n = 2541) and CTC (533) versus colonoscopy (n = 1057). The primary inclusion criterion was symptoms or signs considered suggestive of colorectal cancer by the referring physician (e.g., change in bowel habit, rectal bleeding, abdominal pain, or anemia). The primary diagnostic end points were colorectal cancer and polyps measuring 1 cm or larger. The final, peer-reviewed, trial results have not yet been published but the main findings have been presented in abstract form at scientific meetings. In summary, CTC detected significantly more cancers and large polyps than barium enema, whereas there was no significant difference in detection between CTC and colonoscopy (although there was less ‘clinical uncertainty’ following CTC, according to the study authors). Given the trial design and preliminary reports, these findings are expected to provide high-level evidence that CTC may be comparable to colonoscopy for initial evaluation of patients with suspected colorectal cancer.
CTC is an attractive test for surveillance after colorectal cancer resection, given its ability to noninvasively combine colonic and extracolonic evaluation. Although smaller patients series had suggested that CTC might be useful in this clinical setting, Kim et al. published a more definitive retrospective study of 742 consecutive patients who underwent CTC with IV contrast following curative-intent colorectal cancer surgery, including 548 with colonoscopic correlation. In this series, all six metachronous cancers were identified at CTC, as well as over 80% of all advanced neoplasms. The negative predictive value for nondiminutive adenomas was 100%. In addition, extracolonic evaluation uncovered metastatic recurrence in an additional 11 patients beyond what was detectable by colonoscopy. The study conclusion was that contrast-enhanced CTC is an accurate and practical surveillance tool following colorectal cancer surgery, allowing for simultaneous evaluation of both the colon and extracolonic organs. To validate these retrospective results and to assess the economic benefit, we are currently involved in an ongoing prospective NCI-sponsored multicenter trial (in collaboration with the Mayo Clinic and Fox Chase Cancer Center) evaluating the use of combined contrast-enhanced computed tomography (CT)/CTC against the standard combination of CT and colonoscopy.
Dating back to its earliest incarnations in the 1990s, CTC has consistently demonstrated high sensitivity for detecting colorectal cancer, which was confirmed in a recent meta-analysis and systematic review [5▪▪]. A total of 45 published CTC studies dating back to 1994 entailing over 11 000 patients yielded a cumulative sensitivity of 96.1% (398 of 414 cancers). Interestingly, no cancers were missed by CTC when the bowel preparation included both cathartic and tagging agents. These results compared favorably with optical colonoscopy, in which a sensitivity for cancer of 94.7% was found within the studies wherein unblinding of CTC results was performed. The consistently high sensitivity of CTC for colorectal cancer, even in its formative stages, is primarily due to the fact that these lesions are generally readily detectable on two-dimensional evaluation, and do not require high-end three-dimensional evaluation. The importance of bowel preparation and colonic distention must be emphasized, however, as a separate study showed that colorectal cancer detection falls off considerably on routine CT without preparation or distention .
COMPUTED TOMOGRAPHY COLONOGRAPHY PERFORMANCE IN A MEDICARE-AGED COHORT
When the Center for Medicare & Medicaid Services (CMS) issued its national coverage determination in 2009 that left CTC screening noncovered for medicare beneficiaries, one of the major evidence gaps cited was the specific performance characteristics in a cohort aged 65 years and older. To address this perceived shortcoming, a number of publications followed that specifically focused on this concern [7,8▪,9▪,10▪▪]. Kim et al. reported on results in 577 seniors undergoing initial CTC screening and concluded that CTC was a well tolerated and effective screening modality for the older adult population. Abdominal aortic aneurysms accounted for the majority of important extracolonic findings. Macari et al.[8▪] compared colorectal and extracolonic results in 250 seniors undergoing CTC against nonsenior adults and showed similar results for both polyp detection and for recommendations for additional imaging. Johnson et al.[9▪] reported on CTC screening results from 477 adults age 65 years and older from the ACRIN trial and concluded that the difference between senior-aged participants and those younger than 65 years was not statistically significant for most measures of diagnostic performance. Finally, Cash et al.[10▪▪] published their results in over 1400 senior adults undergoing CTC and concluded that the low rates of referral to colonoscopy, the relatively low prevalence of advanced neoplasia, and the low prevalence of important extracolonic findings make CTC a viable option for medicare-aged patients. These cumulative results should satisfy CMS’ concerns regarding the perceived lack of CTC data in the medicare cohort. Interestingly, President Obama himself underwent colorectal cancer screening with CTC in 2010, despite the fact that this test is not covered for medicare beneficiaries under his current watch.
SCREENING COMPUTED TOMOGRAPHY COLONOGRAPHY
Although medicare does not yet cover CTC for screening purposes as described above, it should be noted that a number of national third-party payors will now cover CTC screening. However, widespread implementation of CTC for population screening will require even broader coverage to achieve the critical mass necessary to sustain a robust screening program. Compared with diagnostic CTC, fewer studies have been published recently that focus on screening as the study indication, although most of the medicare-aged cohort studies described above dealt with asymptomatic screening. Another important study by Stoop et al. is discussed below under the section on patient adherence to screening. A recent study by Kim et al. assessed the incidence of colorectal cancer 5 years out from a negative CTC screening examination. The very low rate of incident cancer compared favorably with similar outcome measures following negative colonoscopy screening. These data are important because it supports the CTC practice of nonreporting of diminutive lesions (5 mm and smaller) . Another article found very low rates of cancer and high-grade dysplasia among small (6–9 mm) and even large (1–2 cm) polyps identified at CTC screening .
OTHER COMPUTED TOMOGRAPHY COLONOGRAPHY PERFORMANCE DATA
Within the artificial setting of a clinical validation trial evaluating CTC, all patients generally undergo subsequent optical colonoscopy to serve as a reference standard, regardless of CTC findings . This framework allows for determination of sensitivity and specificity, which cannot be derived in actual clinical practice in which patients are not referred to colonoscopy unless a significant finding is identified at CTC. Going forward in this clinical setting, positive predictive value (PPV) becomes an important quality measure. Several articles have specifically evaluated the PPV of CTC in clinical practice [14–16]. All of these publications demonstrate a PPV for polyps at least 6 mm that is well above 90% for both by-polyp and by-patient considerations. In general, PPV increases with lesion size and was also higher for sessile and pedunculated lesions compared with a flat morphology. It should be noted that these PPV results are substantially higher than what had been previously reported in the clinical trial setting. A high PPV improves the efficiency and cost-effectiveness of CTC as fewer unnecessary (i.e., nontherapeutic) colonoscopy procedures are performed.
Flat lesions, especially those in the right colon have received considerable attention in recent years, as the serrated polyp pathway to cancer has been elucidated. As with optical colonoscopy, superficially elevated lesions are less conspicuous at CTC compared with classic sessile and pedunculated polyps, but are nonetheless detectable with appropriate technique . For a given linear size, however, flat lesions are significantly less aggressive histologically than nonflat lesions , which is somewhat reassuring. At CTC (and colonoscopy), small hyperplastic polyps tend to be flatter than adenomatous polyps , which seems to be accentuated by increased luminal distention. One useful feature at CTC that likely improves detection of flat lesions is the tendency for oral contrast to adhere to their surface. As noted above, the PPV for flat lesions detected at CTC is considerably lower [14,15], which likely reflects a combination of over-calling (i.e., CTC false positives) and lesions missed at optical colonoscopy (i.e., colonoscopic false negatives). Carpet lesions, also referred to as ‘laterally spreading tumors’, are large (≥ 3 cm) flat lesions that are most often found in the cecum and rectum. With reasonable technique, these are readily detectable at CTC. At histology, they often have a villous component, with or without high-grade dysplasia, but are less often malignant compared with nonflat colorectal masses.
PATIENT ACCEPTANCE AND ADHERENCE
The ultimate success of any new colorectal screening test will depend in large part on the willingness of individuals to submit to it. Put another way, even the most accurate tool will fail if patient acceptance and adherence are poor. Although some limited data on patient acceptance with CTC exists from the earlier clinical trials, experience in the actual clinical setting was generally lacking until recently. In addition, little was known about the potential or actual impact CTC might have on overall screening adherence. A number of key publications have recently addressed these important areas.
A survey of 250 consecutive individuals undergoing CTC screening published by Moawad et al. found that over one-third would have foregone colorectal cancer screening if CTC had not been an available option. Furthermore, of the 57 patients in this cohort who had experienced both CTC and colonoscopy, an overwhelming 95% preferred CTC. A subsequent larger multicenter study by Pooler et al.[20▪▪] which surveyed over 1400 adults who underwent CTC screening also found a very high satisfaction rate. Over 90% rated their screening experience with CTC as ‘excellent’ or ‘good’, and over 90% indicated that they would choose CTC again for their next screening. Among individuals who had experienced both CTC and colonoscopy, CTC was favored by a nearly 6 : 1 ratio. Importantly, 30% indicated they might not have undergone screening if CTC were not an option, suggesting a positive impact on overall adherence rates for colorectal cancer screening.
As mentioned, increasing adherence rates to colorectal cancer screening is a critical goal for success. Two additional recent studies have shed new light on the potential impact CTC can have on screening participation. A Dutch randomized controlled trial by Stoop et al.[21▪▪] evaluated participation in screening and found an impressive 55% increase with CTC over colonoscopy. If these results are reflective of a general screening population, the clinical and economic benefits of CTC screening would be substantial. Furthermore, if both CTC and colonoscopy were offered as screening options, the additive value would increase adherence even more. Cash et al.[22▪▪] recently reported on the impact of CTC screening on participation rates within US military treatment facilities. At the National Naval Medical Center, which has a dedicated CTC screening program, compliance rates for colorectal cancer screening increased by more than 15% in 2009 and 2010 because of CTC alone. At our own medical center, the overall volume of optical colonoscopy has significantly increased since the introduction of a parallel CTC screening program, allaying any fears of a ‘turf battle’.
Recent noteworthy advances in CTC technique include new data on noncathartic bowel preparations [15,21▪▪,23▪▪] and computer-aided detection (CAD) [24,25]. Potential benefits of noncathartic or laxative-free CTC include improved patient acceptance and adherence, but these must be weighed against the potential disadvantages, which include the inability for same-day polypectomy and reduced accuracy. The aforementioned randomized controlled trial by Stoops et al.[21▪▪] employed a noncathartic preparation, which may explain the somewhat lower per-patient yield for advanced neoplasia. A recent noncathartic CTC trial by Zalis et al.[23▪▪] in 605 adults showed a reasonable per-patient sensitivity for large adenomas (91%) but a reduced specificity (85%). Sensitivity for small adenomas (6–9 mm) dropped off considerably but patient experience with CTC was improved over colonoscopy. At present, noncathartic CTC appears to represent a reasonable screening alternative for individuals unwilling to undergo a cathartic preparation (for either CTC or colonoscopy). The studies by Mang et al. and Lawrence et al. evaluated the stand-alone performance of CAD for polyp detection at CTC. Both studies demonstrated good CAD performance, with sensitivities of 90% or more, associated with an acceptable false-positive rate, indicating the maturation of CAD as a supplementary diagnostic tool.
Recent advances and more extensive clinical experience with CTC provide further support for its utility in practice. CTC has now matured as a diagnostic tool and is poised to make a positive impact on patient care as both a useful diagnostic and screening test. CTC should not be viewed as a potential replacement for colonoscopy, but rather as an additional effective option that could significantly increase overall screening rates, as well as provide for colorectal evaluation in cases unfit for colonoscopy.
Conflicts of interest
P.J.P. has served as a consultant for Viatronix, Bracco, iCAD, and Check-Cap; and is co-founder of VirtuoCTC.
Grant support: NIH 1R01CA144835, 1R01CA155347.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 101–102).
1. Pickhardt PJ, Choi JR, Hwang I, et al. Computed tomographic virtual colonoscopy to screen for colorectal neoplasia in asymptomatic adults. New Engl J Med 2003; 349:2191–2200.
2. Pickhardt PJ. Noninvasive radiologic imaging of the large intestine: a valuable complement to optical colonoscopy. Curr Opin Gastroenterol 2010; 26:61–68.
3. Halligan S, Lilford RJ, Wardle J, et al.
Design of a multicentre randomized trial to evaluate CT colonography versus colonoscopy or barium enema for diagnosis of colonic cancer in older symptomatic patients: The SIGGAR study. Trials 2007; 8.
4. Kim HJ, Park SH, Pickhardt PJ, et al. CT colonography for combined colonic and extracolonic surveillance after curative resection of colorectal cancer. Radiology 2010; 257:697–704.
5▪▪. Pickhardt PJ, Hassan C, Halligan S, Marmo R. Colorectal cancer: CT colonography and colonoscopy for detection – systematic review and meta-analysis. Radiology 2011; 259:393–405.
This is a systematic review and meta-analysis that shows the sensitivity of CTC for colorectal cancer is as good or better than optical colonoscopy.
6. Ozel B, Pickhardt PJ, Kim DH, et al. Accuracy of routine nontargeted CT without colonography technique for the detection of large colorectal polyps and cancer. Dis Colon Rectum 2010; 53:911–918.
7. Kim DH, Pickhardt PJ, Hanson ME, Hinshaw JL. CT colonography: performance and program outcome measures in an older screening population. Radiology 2010; 254:493–500.
8▪. Macari M, Nevsky G, Bonavita J, et al. CT colonography in senior versus nonsenior patients: extracolonic findings, recommendations for additional imaging, and polyp prevalence. Radiology 2011; 259:767–774.
This provides evidence for CTC performance in a medicare-aged cohort.
9▪. Johnson CD, Herman BA, Chen M-H, et al. The national CT colonography trial: assessment of accuracy in participants 65 years of age and older. Radiology 2012; 263:401–408.
This provides evidence for CTC performance in a medicare-aged cohort.
10▪▪. Cash BD, Riddle MS, Bhattacharya I, et al. CT colonography of a medicare-aged population: outcomes observed in an analysis of more than 1400 patients. AJR Am J Roentgenol 2012; 199:W27–W34.
This provides evidence for CTC performance in a medicare-aged cohort.
11. Kim DH, Pooler BD, Weiss JM, Pickhardt PJ. Five year colorectal cancer outcomes in a large negative CT colonography screening cohort. Eur Radiol 2012; 22:1488–1494.
12. Pickhardt PJ, Kim DH. Performance of CT colonography for detecting small, diminutive, and flat polyps. Gastrointest Endosc Clin N Am 2010; 20:209–226.
13. Pickhardt PJ, Hain KS, Kim DH, Hassan C. Low rates of cancer or high-grade dysplasia in colorectal polyps collected from computed tomography colonography screening. Clin Gastroenterol Hepatol 2010; 8:610–615.
14. Pickhardt PJ, Wise SM, Kim DH. Positive predictive value for polyps detected at screening CT colonography. European Radiology 2010; 20:1651-1656.
15. Zueco Zueco C, Sobrido Sampedro C, Corroto JD, et al.
CT colonography without cathartic preparation: positive predictive value and patient experience in clinical practice. Eur Radiol 2012; 22:1195-1204.
16. Iafrate F, Hassan C, Ciolina M, et al. High positive predictive value of CT colonography in a referral centre. Eur J Radiol 2011; 80:E289–E292.
17. Pickhardt PJ, Kim DH, Robbins JB. Flat (Nonpolypoid) colorectal lesions identified at CT colonography in a US screening population. Acad Radiol 2010; 17:784–790.
18. Summers RM, Liu JM, Yao JH, et al. Automated measurement of colorectal polyp height at CT colonography: hyperplastic polyps are flatter than adenomatous polyps. Am J Roentgenol 2009; 193:1305–1310.
19. Moawad FJ, Maydonovitch CL, Cullen PA, et al. CT colonography may improve colorectal cancer screening compliance. Am J Roentgenol 2010; 195:1118–1123.
20▪▪. Pooler BD, Baumel MJ, Cash BD, et al. Screening CT colonography: multicenter survey of patient experience, preference, and potential impact on adherence. Am J Roentgenol 2012; 198:1361–1366.
This is a multicenter study of patient acceptance for CTC, suggesting a positive impact on adherence.
21▪▪. Stoop EM, de Haan MC, de Wijkerslooth TR, et al. Participation and yield of colonoscopy versus noncathartic CT colonography in population-based screening for colorectal cancer: a randomised controlled trial. Lancet Oncol 2012; 13:55–64.
This is a randomized controlled trial showing increased participation for CTC over optical colonoscopy in the screening setting.
22▪▪. Cash BD, Stamps K, McFarland EG, et al.
Clinical use of CT colonography for colorectal cancer screening in military training facilities and potential impact on HEDIS® measures. J Am Coll Radiol 2012 (in press).
This shows the impact of CTC on colorectal cancer screening adherence within the US military health system.
23▪▪. Zalis ME, Blake MA, Cai W, et al. Diagnostic accuracy of laxative-free computed tomographic colonography for detection of adenomatous polyps in asymptomatic adults a prospective evaluation. Ann Intern Med 2012; 156:692–771.
This is the first large trial to evaluate the performance of noncathartic CTC for screening.
24. Mang T, Bogoni L, Salganicoff M, et al. Computer-aided detection of colorectal polyps in CT colonography with and without fecal tagging a stand-alone evaluation. Invest Radiol 2012; 47:99–108.
25. Lawrence EM, Pickhardt PJ, Kim DH, Robbins JB. Colorectal polyps: stand-alone performance of computer-aided detection in a large asymptomatic screening population. Radiology 2010; 256:791–798.
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