FDA-2013-N-0816: Joint Meeting of the Gastroenterology-Urology Panel and the Radiological Devices Panel of the Medical Devices Advisory Committee

Transcription

1 September 3, 2013 Margaret Hamburg, M.D. Commissioner Food and Drug Administration 5630 Fishers Lane Rockville, MD FDA-2013-N-0816: Joint Meeting of the Gastroenterology-Urology Panel and the Radiological Devices Panel of the Medical Devices Advisory Committee Dear Dr. Hamburg: On behalf of the American Society for Gastrointestinal Endoscopy (ASGE) and the American College of Gastroenterology (ACG), we appreciate the opportunity to provide comments on the Food and Drug Administration s (FDA) upcoming September 9 meeting to discuss current evidence on the risks and benefits of computed tomography colonography (CTC) for screening of asymptomatic patients for colorectal cancer. Our societies thank the FDA for hosting a meeting on this topic and for facilitating dialogue on evolving research and the gaps in current evidence. Since its founding in 1941, ASGE has been dedicated to advancing patient care and digestive health by promoting excellence in gastrointestinal endoscopy. ASGE, with more than 12,000 members worldwide, promotes the highest standards for endoscopic training and practice, fosters endoscopic research, recognizes distinguished contributions to endoscopy, and is the foremost resource for endoscopic education. The ACG is a physician organization representing gastroenterologists and other gastrointestinal specialists. Founded in 1932, the College currently counts 12,000 physicians among its membership of health care providers of gastroenterology specialty care. Although the vast majority of these physicians are gastroenterologists, the College s membership also includes surgeons, pathologists, hepatologists, and other specialists involved in various aspects of the overall treatment of digestive diseases and conditions. The College has chosen to focus its activities on clinical gastroenterology the issues confronting the gastrointestinal specialist during the treatment of patients. ACG and ASGE have not endorsed CTC as an acceptable alternative for screening compared to colonoscopy for most American patients. As such, we recommend that this panel discuss and review the following evaluation of current evidence when determining whether CT colonography is a safe and effective medical device for colorectal cancer screening in asymptomatic patients. Our comments will 1

2 highlight deficiencies in the efficacy and risks of CTC and risks and will address the following specific areas: Enhancement of CRC screening rates due to the availability of screening CTC Performance characteristics of CTC CTC performance in the elderly Risk of Radiation Extra-colonic findings Emerging areas in colorectal cancer prevention and CTC FDA s process in determining safety and effectiveness In determining whether a medical device is safe and effective, the FDA (and panels) will consider the following factors: The person for whose use the device is represented or intended; The conditions of use for the device, including conditions of use prescribed, recommended, or suggested in the labeling or advertising of the device, and other intended conditions of us; The probable benefit to health from the use of the device weighed against any probable injury or illness from such use; and The reliability of the device. Further, there is a reasonable assurance that a device is safe when it can be determined that the probable benefits to health from use of the device for its intended uses, and conditions of use, outweigh any probable risks. Also, there is a reasonable assurance that a device is effective when it can be determined that in a significant portion of the target population, the use of the device for its intended uses and conditions of use will provide clinically significant results. (21 CFR 860.7) CT colonography devices currently cleared by the FDA for CT colonography Beginning in 2004, the FDA has allowed manufacturers to market CT colonography devices for unrestricted use, including the screening of otherwise healthy asymptomatic patients as a replacement to optical colonoscopy. The FDA cleared these devices under the 510(k) process, a process by which a device can be marketed by claiming substantial equivalence to a device cleared prior to 1976.* *In 2004, FDA cleared the Viatronix V3D Colon device for an intended use of patient screening for detection of colon cancers, See In 2004 FDA cleared the MedicSight COLON CAR device for an intended use of 2D and 3D visualization of polyps and measurement of polyp characteristics such as size and volume. The PEV filter identifies intra-colonic filling defects protruding into the colonic lumen, thereby highlighting potential polyp candidates for further interrogation by the reporting radiologist. In 2004, FDA cleared the Siemens syngo Colonography Software Package with Extended Functionality device for an intended use with a special workflow based on automated segmentation for the visual identification of possible lesions (Polyp Enhanced Viewing). In 2005, FDA cleared the Voxar 3D Product Family device for an intended use of colon Screening (which is intended for the screening of patients for colonic polyps, tumors and other lesions using tomographic Colonography). See: In 2010 FDA cleared the icad VeraLook CTC CAD Software device for an intended use to automatically detect potential polyps in CT Colonography exams. See: 2

3 The intended use of these devices appears unrestricted and, therefore, intended for use in screening asymptomatic patients (either expressly or impliedly). Therefore, for nearly 10 years, the FDA has allowed manufacturers to sell CT colonography devices for unrestricted use, including the screening of asymptomatic patients. Yet other FDA guidance on CT scans for asymptomatic patients appears to be inconsistent with these approvals. Background information ASGE and ACG have endorsed the use of CTC for colorectal cancer screening through our joint participation in the U. S. Multi-Society Task Force (MSTF) on Colorectal Cancer, which published screening guidelines in 2008 in conjunction with the American Cancer Society and the American College of Radiology 1. This 2008 document reflects the traditional approach of the MSTF, which has been to endorse screening tests broadly without preference for a particular test 2,3. Our societies have also endorsed more detailed positions, which recommend colonoscopy as the best first option for screening for most Americans 4,5. The process of recommending one test or set of tests before another, because of better efficacy or superiority in other features, is generally termed sequential testing. A sequential approach to colorectal cancer screening is commonly used in the United States, in which colonoscopy is offered first and another test, often the fecal occult blood test (FOBT) (preferably the fecal immunochemical test or FIT) is offered to persons who refuse colonoscopy. We support this approach because of the increasing evidence of its positive impact on colorectal cancer in the United States 6-8. We also support the well done, evidenced-based evaluation by the Centers for Medicare and Medicaid Services (CMS) in 2009 that led to its decision not to cover CTC for screening 9. This process is considered a model of evidenced-based evaluation by CMS 10. Our societies do not see convincing evidence that CTC will positively affect screening uptake, polypectomy rates or reduce screening costs. Currently, CTC is used commonly in the United States to complete colonic imaging in patients with incomplete colonoscopy, though in many institutions barium enema is still used for this indication. We endorse the use of CTC for incomplete colonoscopy. CTC is seldom used for screening asymptomatic persons in the United States. The role of colonoscopy in U.S. screening Colorectal cancer screening in the United States is dominated by colonoscopy, with some ongoing use of FOBT 11. The use of flexible sigmoidoscopy and barium enema for screening have declined dramatically in the United States 11. The incidence of colorectal cancer has been declining in the United States since 1985, and the rate of decline increased in 2001, coincident with the beginning of Medicare coverage of screening colonoscopy 6-8. Much of the decline in colorectal cancer incidence and mortality is directly attributable to the widespread use of colonoscopy in the United States 6-8, since colonoscopy uniquely provides the opportunity to both recognize and resect precancerous lesions 12, and this process reduces colorectal cancer incidence and mortality New findings published in The New England Journal of Medicine (NEJM) highlight the ability to reduce colorectal cancer deaths through polyp detection and removal 12, underscoring the value of colonoscopy and polypectomy. This study reported a 53 percent reduction in colorectal cancer deaths compared to the risk in the general population following removal of adenomatous polyps during colonoscopy. This reduction was achieved although the polypectomy cohort had a 57% prevalence of advanced adenomas, and therefore had a risk of cancer prior to polypectomy far above the general population. We are concerned about the wide application of any alternative imaging test provided as a first option for screening that does not have features making it distinctly superior to colonoscopy, which is diagnosis-only, and because it may displace patients from colonoscopy and polypectomy. 3

4 Since CMS performed its rigorous analysis of CTC in 2009 and elected not to cover CTC for screening, considerable evidence has emerged to support the efficacy of colonoscopy in prevention of colorectal cancer. Specifically, case-control 13,14,16,17 and cohort 15 studies have established that colonoscopy prevents incident cancer and colorectal cancer mortality. Very recent large-scale population-based studies performed in the United States 14 and Germany 13 have established that colonoscopy prevents incident cancer and colorectal cancer mortality. Unlike early studies from Canada where colonoscopy (performed largely by surgeons) failed to protect against right-sided cancer 16,17, studies in the United States and Germany (where colonoscopy is performed largely by gastroenterologists) have shown substantial protection against both right- and left-sided cancer 13,14. Although no randomized controlled trials of colonoscopy for screening have been completed, the best available evidence confirms that colonoscopy has a protective effect against colorectal cancer (40-60% in the proximal colon and > 80% in the distal colon) that is substantial and consistent with non-canadian studies and considerably exceeds that of FOBT 18,19 and flexible sigmoidoscopy 20,21. In light of this evidence, any changes in policy that might affect utilization of colonoscopy and polypectomy must be evaluated very carefully. At this time, there is no evidence of a protective effect of CTC against colorectal cancer. Will the availability of screening CTC enhance colorectal cancer screening rates? There is a commonly held sentiment that offering more colorectal cancer screening tests will result in more patients undergoing some form of colorectal cancer screening. In a frequently cited study in support of this contention, screening rates were increased in patients offered a choice of colonoscopy or FOBT compared to patients offered only colonoscopy or only FOBT 22. However, a sequential offer of colonoscopy first, followed by an offer on the same day of FOBT to colonoscopy refusers, was not tested. A sequential offer of multiple tests, with the second test offered on a later date, was as effective in whites in achieving overall rates of completion of a screening test 22. A recent study compared a sequential approach of offering flexible sigmoidoscopy first, followed by an offer of FIT to sigmoidoscopy refusers versus offering multiple options from the outset. The study found that the sequential approach maximized the overall screening rate and the percentage of those undergoing the most effective test (sigmoidoscopy) 23. Three randomized controlled, population-based studies found that multiple test options had no impact on screening rates One of these studies specifically compared screening uptakes when patients were offered colonoscopy and CTC versus a choice of colonoscopy or CTC, and found no differences in rates of patients actually undergoing a screening test between the three arms of the study 26. A recent study from the Netherlands was the first randomized controlled trial to compare CTC and colonoscopy for uptake and performance 27. In this study, CTC was performed using a laxative-free protocol. The rate of uptake was higher for CTC at 34% vs. 22% for colonoscopy, indicating that laxative-free CTC was more appealing to Dutch patients than colonoscopy. However, there was no offer of multiple tests made and sequential testing was not examined. The higher acceptance of CTC in the Netherlands (where uptake of screening colonoscopy is extremely low) cannot be extrapolated to the United States where the penetration of colonoscopy is already above 50%. The key result of the study relevant to the United States is that colonoscopy detected 30% more advanced lesions per participating patient compared to CTC 27. Thus, colonoscopy was a more effective screening test than CTC. Had these results been available to Dutch patients prior to the study, it certainly would have influenced their choice of tests. We are certain these results would influence test choice in the United States, where efficacy is of primary importance to patients. Further, this study provided the most detailed evaluation of patients pre-procedure and post-procedure perceptions of CTC and colonoscopy. Even for laxative-free CTC, 4

5 patients actual experienced burden was significantly worse than their pre-procedure expectations whereas, for colonoscopy, the post-procedure perceptions were significantly better than the pre-procedure expectations 28. Taken together, these findings indicate that the availability of CTC is unlikely to increase overall colorectal cancer screening rates in the United States. We are concerned that offering screening CTC will divert patients from colonoscopy and, thereby, from polypectomy. A recent study from a Wisconsin center, where very high quality CTC is available, screening colonoscopy resulted in a 2.5 fold increase in the rate of patients with 6-9 mm lesions undergoing polypectomy compared to CTC 29. Given the results of multicenter studies, which consistently show their performance characteristics of CTC well below that of specialty centers, this diversion of patients from polypectomy will be even greater if screening CTC enters routine clinical practice. In sum, the above studies demonstrate that offering multiple options does not increase screening rates, whereas a sequential approach maximizes screening rates and utilization of the most effective test. We, therefore, contend that CTC is best used for screening only in patients who decline colonoscopy, and that FIT is also a suitable alternative for colonoscopy refusers. Performance characteristics of CTC Since the 2009 evaluation of CTC by CMS, several trials describing performance characteristics of CTC have been reported. The most publicized and important of these is the American College of Radiology Imaging Network (ACRIN) Trial, also known as the National CT Colonography Trial 30. This multicenter U.S. trial enrolled more than 2,500 patients who, after full bowel preparation, underwent CTC followed by same-day optical colonoscopy with segmental unblinding. Participating physicians were evaluated prior to the initiation of the study. Only the top 75% performing physicians were allowed to participate. While CTC enthusiasts point to the 90% per patient sensitivity for detection of patients with polyps 10 mm in size, several results for CTC performance in the ACRIN trial are suboptimal. First, the sensitivity of CTC for patients with polyps in the 6-9 mm range was suboptimal. Many CTC studies use detection of patients with polyps 6 mm as a primary endpoint. All studies of capsule colonoscopy, an alternative diagnosis-only colorectal imaging strategy, use detection of patients with polyps 6 mm as their primary endpoint. The American College of Gastroenterology recommends that all patients with polyps 6 mm be referred for colonoscopy and polypectomy 31. This approach is commonly used in clinical practice. In the National CT Colonography Trial, sensitivity decreased rapidly in the 6-9 mm polyp size range. The data for sensitivity of polyps in this size range were expressed as detection of polyps 5mm, 6 mm, 7mm, etc., so that polyps of all larger sizes, including polyps 10 mm are included in the sensitivity descriptions. No report is actually given for sensitivity for polyps in the 6-9 mm size group alone. Despite that unusual presentation of the data, the sensitivity for polyps 5mm was only 65%, for polyps 6 mm was 78 %, for polyps 7 mm was 84%. Since these sensitivities include polyps 10 mm, the sensitivity for polyps 6-9 mm was clearly very low. Second, the specificity for patients with polyps 10 mm was only 86%. This means that one of seven patients undergoing screening CTC had a lesion 10 mm detected that could not be confirmed by colonoscopy even after unblinding. In the subset of patients age 65 and older the specificity was only 83% (see below), meaning that one in every six Medicare age patients had a lesion identified by CTC that was a false positive. The consequences of this very high false positive rate would be devastating in clinical practice where clinicians must confirm or refute a CTC report of a specific lesion. Colonoscopies performed for positive CTC, accordingly take 61% longer than other colonoscopies 32, because of the need to repeatedly examine the colon in search of a lesion which is often not present. In fact, in the National CT Colonography study, the positive predictive value for lesions 10 mm was a remarkably low at 23%. In clinical practice, many of these patients who have 5

6 false positive CTCs will have repeat CTCs or even repeat colonoscopies because of patient (or provider) confusion and worry regarding discordant test results. This overall rate of false positive tests is approximately threefold greater with CTC than with FIT 33. Furthermore, the reporting of false positive CTC lesions leads to excess cost and worry that often lead to further studies to exclude the presence of a true lesion. Again, these results in the National CT Colonography Trial (despite selecting the top 75% of radiologists to participate) are substantially lower than the results achieved by Pickhardt et al of > 90% sensitivity and specificity for patients with polyps 10 mm in size 34. No study has matched Pickhardt s results and, particularly, they have not been matched in any large multicenter study. In a second multicenter study reported in 2012 by Zalis et al using laxative-free CTC 35, CTC again did not meet the threshold for introduction into clinical practice. For adenomas 10 mm, 8 mm, and 6 mm, the per patient sensitivities of CTC were 0.91, 0.70, and 0.59, respectively, indicating a precipitous drop-off in sensitivity for adenomas 6-9 mm in size. The sensitivity and specificity of colonoscopy were numerically superior at every size of lesion, and both sensitivity and specificity were significantly better for 6-9 mm lesions. The per patient sensitivity for polyps 6 mm of any histology was only A third important trial published recently is the Dutch randomized controlled trial comparing CTC with colonoscopy 27. CTC was performed with a laxative-free protocol. Again, colonoscopy outperformed CTC, detecting advanced neoplasia in 8.7% vs. 6.1% of participating subjects (p=0.02). Thus, 30% of patients with advanced lesions were missed by CTC. Clearly patients would have been better served by a sequential approach to screening in which they were first offered colonoscopy and then CTC only if they declined colonoscopy. Because of these results, and the poor perception of CTC by trial participants, the Netherlands decided not to use CTC for screening. Finally, the United Kingdom has completed a multicenter randomized trial comparing the performance of CTC to colonoscopy on symptomatic patients. In this study, CTC had comparable performance to colonoscopy for detection of cancer and large lesions, but the referral rate of CTC patients for a colonoscopy was very high at 30%, and the referral rate of colonoscopy patients for CTC because of incomplete colonoscopy was much higher than would be expected in most U.S. centers at 8.2% 36. Using FDA s definition of device effectiveness, it is clear from the results of these recent multicenter trials that CTC remains a less effective screening test than colonoscopy. Although better results are seen with full bowel preparation prior to CTC, both full bowel preparation CTC and laxative-free CTC perform poorly for lesions in the 6-9 mm range. The long-term consequences of this poor sensitivity will be a continued need for repeat procedures at five-year or shorter intervals even with negative CTC, whereas negative colonoscopy has now been shown to have a protective effect lasting 20 years or longer 37. In the United States, where superior efficacy has driven the tremendous growth in colonoscopy, these results on CTC sensitivity will not be well received by clinicians and patients. ASGE and ACG consider efficacy in clinical trials to be the principle reason for patients to be offered CTC only if they decline colonoscopy. Perception of CTC as a no risk and easy procedure Contrary to the perception created by some reports and articles, we caution that CTC does not represent a painless or risk-free procedure, nor does it eliminate the need for bowel cleansing which many patients report as a barrier to screening. Many reports refer to CTC as non-invasive which is inaccurate as CTC, as typically performed in the United States involves the same bowel preparation as traditional colonoscopy. In addition, it involves rectal tube insertions/insufflations, radiation exposure, and sometimes the use of intravenous medication. The risk of perforation associated with screening CTC is typically not recognized but the two largest (total 28,937 patients) multicenter clinical reports on CTC 6

7 suggest this is not a dismissible risk and ranges from 1/1700 to 1/ ,39. It should be noted that this is comparable to many screening colonoscopy trial reported perforation rates. CTC in the elderly In 2009, CMS indicated a need for data on CTC performance in the elderly. Since that time, several studies have been performed to address this need directly. Although one of these studies found adequate results in the elderly, it comes from centers that have consistently reported results that cannot be achieved in large multicenter studies 40. A second study that reported equal yields in the elderly and younger patients 41 can be dismissed because it did not report sensitivity. Furthermore, the equal yields of lesions among older and younger patients reported in this study suggests poor test sensitivity occurred in the elderly, as increasing age is consistently a powerful predictor of an increased prevalence of polyps. The study most relevant to CTC performance in the elderly is the National CT Colonography Trial 30,42. In this study, there was no significant difference in performance between younger and older patients but there were impressive numerical differences that suggested worse performance by CTC in the elderly. For example, the overall per patient sensitivity for adenomas 10 mm was 0.9 but in the elderly it was This numerically lower sensitivity occurred despite a prevalence of advanced disease that was twice as high as the younger patients in the trial. For this size lesion, the specificity overall in the study was only 86%, but in the elderly it was unacceptably low at 83%. The low sensitivity is concerning given strong evidence that advanced lesions convert to cancer faster in the elderly than in young persons 43, and the low specificity is concerning in that one of every six patients undergoing CTC screening in the older population will need a colonoscopy for a lesion that is not present. These colonoscopies are not only unnecessary, but will take longer to complete 32 and often are followed by additional studies to prove that the original CTC was a false positive. Recent FDA Guidance Concerning Radiation Exposure and Radiation Risk of CTC The FDA has published guidance on screening examinations using medical imaging as well as the cumulative effects of ionizing radiation in these various imaging procedures. The FDA's website recognizes that CT uses the highest x-ray dose of any diagnostic imaging device, and that the use of CT "may be associated with an increase in the possibility of fatal cancer of approximately 1 chance in 2000." (See: Also, the FDA noted that CT screenings can be beneficial if a person has signs or symptoms of some particular disease or condition but such use in this population differs from the use of CT screening for people with no signs or symptoms. (See: EmittingProducts/RadiationEmittingProductsandProcedures/MedicalImaging/MedicalX- Rays/ucm htm) The FDA announced in March 2010 that it will study the effects of radiation from CT scans after its expert gastroenterologist and expert radiologist on the research panel concluded that the potential detrimental effects of ionizing radiation outweigh the potential benefits of virtual colonoscopy for those asymptomatic patients receiving colorectal cancer screenings. (See: ACG agreed with these concerns in its comments to the public hearing entitled Device Improvements to Reduce Unnecessary Radiation Exposure from Medical Imaging, held March 30-31, (See: 7

8 The past five years have seen a large increase in lay press coverage of the potential cancer risk of medical radiation, as well as reports of gross errors in delivering diagnostic radiation that have resulted in excessive radiation patient exposure 44. There is continued debate about how medical radiation risk should be modeled, with one school endorsing no risk with total doses below 100 msieverts or single doses below 50 msieverts 44, and others endorsing the linear, no-threshold model in which even low doses of radiation confer some cancer risk 43. At the present time, the actual truth about the relationship of medical radiation dosing and cancer risk remains unknown. Utilizing the linear no-threshold model, there have been estimates that show a single abdominal-pelvic CT scan at age 50 would produce a 0.14% lifetime risk of cancer 45. Such a level of cancer risk, if real, would make CTC by far the highest risk colorectal cancer screening test. Another report estimated that 29,000 deaths would eventually result from the CT scans performed in 2007 in the U.S. alone 46. In the context of this uncertainty, there are European countries that have made the use of medical radiation in asymptomatic persons illegal except for performance of mammography. Recent studies have established protocols for low-dose CTC that lower the total radiation exposure onehalf to one-third the dose of a standard radiation dose during CTC. Although these doses likely reduce risk, they are not negligible. Further, it is unclear how low-dose CTC protocols would be enforced in clinical practice if Medicare coverage of screening CTC is approved. Finally, in our clinical experience, radiologists rarely offer information to symptomatic or asymptomatic patients about the potential risks of diagnostic medical radiation. This convention is unfortunate, as informed consent is an expectation of nearly every other medical procedure. Establishment of an informed consent process for delivery of medical radiation seems particularly appropriate, when diagnostic x-rays are used in asymptomatic persons, who may incur a cancer risk two or more decades later. ACG and ASGE urge the FDA to further consider the implications of repeated radiation emissions from CTC and other radiologic scans during routine screening procedures in asymptomatic patients. Medical research suggests that the harmful effects of radiation during routine screening procedures should be avoided and that the threshold risk for increased radiation related cancer is increased after one abdominal CT scan 47,48. As Johnson et al discussed, the FDA lists radiation derived from radiological sources as a known carcinogen, yet the U.S. Federal Government has not established guidelines for acceptable indications and radiation doses for CT scans. Extra-colonic findings Most recent studies have found that the use of strict criteria for evaluation of extra-colonic findings (ECF) on CTC can limit the percentage of patients undergoing further evaluation for ECF to about 10% 27. The prevalence of ECFs clearly increases with age, hence higher rates of evaluation could be expected in the elderly. Two exceptions among the recent results have reported 24% and 50% of patients requiring additional evaluation of ECF 49,50. Clearly, strict criteria for evaluation are essential to maintaining costeffectiveness. Although CTC may be beneficial to some patients who are diagnosed with early stage extra-colonic cancers or large abdominal aortic aneurysm, body scanning for asymptomatic cancers is not an endorsed practice in the United States, and abdominal aortic aneurysms can be screened with less expensive methods such as ultrasound that do not require radiation. Whether the balance between the detection of clinically important and clinically insignificant ECFs constitutes a net benefit remains uncertain. 8

9 In Madison, WI, where CTC quality is excellent and insurance coverage has been available, CTC procedural volumes were noted to level off and remain steady over several years, which was attributed in part to the discontent of referring physicians over the nuisance of ECF evaluations and patient anxiety over incidental ECFs 51. Emerging areas in colorectal cancer prevention and CTC Serrated lesions It is now recognized that up to 30% of colorectal cancers do not arise through conventional adenomas but rather through a serrated polyp pathway characterized by proximal colon location, hypermethylation and mutations in the BRAF oncogene 52. The predominant precancerous lesion in this pathway is the sessile serrated polyp (SSP). SSP is synonymous with sessile serrated adenoma but is commonly now called SSP because most of the lesions are not dysplastic. Hypermethylated cancers arising through this pathway are over-represented among cancers that develop after colonoscopy, and difficulty in detecting SSPs may be a major contributor to why colonoscopy is less effective in proximal colon cancer protection compared to distal cancer protection. SSPs have proven a challenge for endoscopists to detect because of their subtle appearance and an invariable sessile or flat morphology 52. Based on the endoscopic appearances of these lesions, there is widespread expectation in the GI community that these lesions will be very difficult to detect by CTC. Unfortunately, there are few data specifically evaluating the sensitivity of CTC for these lesions. Pickhardt et al reported that the sensitivity of CTC was lower for hyperplastic and nonadenomatous polyps 53. However it is now recognized that many lesions called hyperplastic by pathologists even a few years ago are now recognized as SSPs by pathologists. In the recent study of laxative-free CTC by Zalis et al, overall sensitivity was reported for all polyps, but for lesions over 1 cm in size only the sensitivity for adenomas was reported. The significance of this is uncertain, but given that the per-patient sensitivity for polyps of any histology 6 mm was only 0.47, and that the perpatient sensitivity for patients with adenomas 6 mm was 0.59, it is highly likely that CTC had very poor sensitivity for SSPs in this study 35. Specific study of CTC and its sensitivity for this group of polyps is needed to understand whether CTC can identify SSPs, and thereby prevent the development of hypermethylated cancers. Flat adenomas and cancers The CTC detection of flat lesions (including cancers) has been extremely variable and not well studied, in particular outside experienced centers of excellence. High miss rates for flat polyps and cancer have been evident 54 and the sensitivity and optimal techniques of CTC for the detection of flat lesions have not yet been established. The recommendation of CTC screening intervals for five years was modeled after the interval recommendation for screening barium enema and is widely endorsed by radiologists. Since the sensitivity of CTC for large polyps is often said to be comparable to colonoscopy, the endorsement of CTC at 5-year rather than 10-year intervals clearly reflects the uncertainty associated with poor detection of lesions < 1 cm in size. Given variable detection of flat polyps by CTC, 1 and poor detection of serrated lesions, even 5-year intervals for CTC may not provide adequate protection in high risk patients. 9

10 Summary Despite the enthusiasm for CTC screening within a portion of the radiologic community, multiple problems preclude the introduction of CTC as a routinely used screening test for colorectal cancer. These problems include: the diagnosis-only nature of CTC, the high cost of CTC compared to other diagnosis-only tests, the lack of evidence that CTC availability will have a significant impact on overall adherence, the potential of CTC to displace patients from colonoscopy screening and associated polypectomy, the low sensitivity of CTC compared to colonoscopy for polyps < 10 mm in size, the poor specificity of CTC in the single most important recent trial of CTC (the National CT Colonography Trial) as well as other recent trials, the unknown and likely poor sensitivity of CTC for detection of proximal colon serrated lesions, the potential for radiation induced cancer in asymptomatic patients, and the cost and inconvenience and worry associated with incidental extra-colonic findings. Since 2009, an evidence base supporting the powerful impact of colonoscopy on colorectal cancer has emerged. No evidence of this type is available for CTC. As the FDA concludes, it remains unclear whether CTC provides net benefits for asymptomatic patients. Given the problems and questions associated with CTC as a screening test outlined in these comments, we do not see sufficient evidence for CMS to alter its 2009 decision not to cover CTC for screening. CTC should only be offered as a screening test to patients who fail to complete colonoscopy, or decline colonoscopy. Patients who decline colonoscopy are also well served by FIT screening. Thank you for the opportunity to offer these comments. If we may provide any additional information, please contact Lakitia Mayo, Director of Health Policy and Quality, ASGE at or lmayo@asge.org, or Brad Conway, Vice President of Public Policy, ACG, at , or bconway@acg.gi.org. Sincerely, Kenneth K. Wang, MD, FASGE President American Society for Gastrointestinal Endoscopy Ronald Vender, MD, FACG President American College of Gastroenterology 10

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