Coverage Policy Manual
Policy #: 2012015
Category: Medicine
Initiated: April 2012
Last Review: April 2018
  Chromoendoscopy as an Adjunct to Colonoscopy

Description:
Chromoendoscopy refers to the application of dyes or stains during endoscopy to enhance tissue differentiation or characterization. When used with colonoscopy, the intent is to increase the sensitivity of the procedure by facilitating the identification of mucosal abnormalities. There are two types of chromoendoscopy; one involves actual spraying of dyes or stains through the working channel of an endoscope. The other type, known as virtual chromoendoscopy, uses a computer algorithm to simulate different colors of light that result from dye or stain spraying.
 
Colonoscopy, a procedure during which colonic and rectal polyps can be identified and removed, is considered the “gold standard” test for colorectal cancer screening and diagnosis of colorectal disease. However, colonoscopy is an imperfect test. A recent systematic review pooled findings from tandem (i.e. back-to-back) colonoscopy studies and found that 22% of polyps were missed on the first colonoscopy (Van Rijn, 2006). Most of the missed polyps, though, were small and, thus, lower-risk of becoming cancerous. The pooled miss rate by polyp size was 2% for polyps 10 mm and larger, 13% for polyps 5-10 mm, and 26% for polyps 1-5 mm.
 
Several adjunct endoscopic techniques, including chromoendoscopy, could potentially enhance the sensitivity of colonoscopy. Chromoendoscopy, also known as chromoscopy and chromocolonoscopy, refers to the application of topical stains or dyes during endoscopy in order to enhance and facilitate the identification of mucosal abnormalities. Chromoendoscopy may be particularly useful for detecting flat or depressed lesions. Standard colonoscopy uses white light to view the colon. In chromoendoscopy, stains are applied resulting in color highlighting of areas of surface morphology of epithelial tissue. The dyes or stains are applied via a spray catheter that is inserted down the working channel of the endoscope. Chromoendoscopy can be used in the whole colon (pan-colonic chromoendoscopy) on an untargeted basis or can be directed to a specific lesion or lesions (targeted chromoendoscopy). Chromoendoscopy differs from endoscopic tattooing in that the former uses transient stains, whereas tattooing involves the use of a long-lasting pigment for future localization of lesions.
 
Stains and dyes used in chromoendoscopy can be placed in the following categories:
  • Absorptive: These stains are preferentially absorbed by certain types of epithelial cells.
  • Contrast: These stains seep through mucosal crevices and highlight surface topography.
  • Reactive: These stains undergo chemical reactions when in contact with specific cellular constituents, which results in a color change.
 
Reactive stains are primarily used to identify gastric abnormalities and are not used with colonoscopy.
Indigo carmine, a contrast stain, is the most commonly used stain with colonoscopy to enhance the detection of colorectal neoplasms. Several absorptive stains are also used with colonoscopy. Methylene blue, which stains the normal absorptive epithelium of the small intestine and colon, has been used to detect colonic neoplasia and to aid in the detection of intraepithelial neoplasia in individuals with chronic ulcerative colitis. In addition, crystal violet (also known as gentian violet), stains cell nuclei and has been applied in the colon to enhance visualization of pit patterns (i.e. superficial mucosal detail).
 
Potential applications of chromoendoscopy as an alternative to standard colonoscopy include:
  • Diagnosis of colorectal neoplasia in symptomatic patients at increased risk of colorectal cancer due to family history of colorectal cancer, personal history of adenomas, etc.
  • Identification of mucosal abnormalities for targeted biopsy as an alternative to multiple random biopsies in patients with inflammatory bowel disease (IBD)
  • Screening the general population for colorectal cancer
 
The equipment used in regular chromoendoscopy is widely available. Several authors of review articles and technology assessments have stated that, although the techniques are simple, procedure, e.g. concentration of dye and amount of dye sprayed, is variable and classification of mucosal staining patterns for identifying specific conditions is not standardized.
 
Virtual chromoendoscopy involves imaging enhancements with endoscopy systems that could potentially be an alternative to dye spraying. One system is the Fujinon Intelligent Color Enhancement (FICE) feature (Fujinon, Inc.). This technology uses post-processing computer algorithms to modify the light reflected from the mucosa from conventional white light to various other wavelengths.
 
Regulatory Status
The Fujinon® endoscope series EPX-4400 and EPX-4400HD (Fujinon, Inc.) have been cleared for marketing by FDA through the 510(k) process. FDA determined that this device was substantially equivalent to existing devices for use in endoscopic observation, diagnosis, treatment, and image recording. The Fujinon EPX-4400 and 4400HD systems include FICE™. This feature is intended to enhance the appearance of images and is used for virtual chromoendoscopy. On February 7, 2011, FDA sent an Urgent Medical Device Corrective Action letter advising users that the FICE feature should no longer be used, because this feature was not reviewed under the premarket notification/510k process.2 In August 2014, the FujiFilm EPX-4440HD Digital Video Processor with FICE and Light Source was cleared by FDA through the 510(k) process. FDA documents state that FICE can be used to supplement white light endoscopy but is not intended to replace histopathologic sampling as a means of diagnosis.
 
The i-scan™ (Pentax), used for virtual chromoendoscopy, was cleared by FDA in April 2013.3 This is a digital image enhancement technology and is part of the Pentax EPK-i5010 Video Processor. The i-scan has several modes that digitally enhance images in real-time during endoscopy. FDA documents state that i-scan is intended as an adjunct following white-light endoscopy and is not intended to replace h
istopathologic analysis.
 
FDA product code: GCT, PEA, FET (endoscopes and accessories).
 
No dye or stain product has been specifically approved by FDA for use in chromoendoscopy.
  
There is no specific CPT coding for chromoendoscopy.  The additional work of the chromoendoscopy would probably be reported with the unlisted CPT code 44799, unlisted procedure, intestine.  

Policy/
Coverage:
Chromoendoscopy as an adjunct to diagnostic or surveillance colonoscopy does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, chromoendoscopy as an adjunct to diagnostic or surveillance colonoscopy is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 

Rationale:
This policy was created with searches of the online MEDLINE database and Clinicaltrials.gov databases. Following is a summary of the key literature.
 
No controlled studies were identified that evaluated the impact of chromoendoscopy on subsequent development of colorectal cancer or on mortality from colorectal cancer. The review focused instead on outcomes related to polyp detection, particularly higher-risk polyps such as those that are at least 5 mm in size.
 
What is the evidence that chromoendoscopy results in higher detection rates of clinically important adenomas/neoplastic lesions compared to standard colonoscopy?
 
Individuals at increased risk of colorectal cancer. Individuals may be at higher risk due to family or personal history, or symptoms suggestive of colorectal disease (excluding patients with known inflammatory bowel disease). Heightened surveillance is the most common approach to high-risk patients. Prophylactic colectomy is sometimes considered for patients who are at extremely high-risk.
 
A 2010 Cochrane review identified randomized controlled trials (RCTs) comparing chromoendoscopy and conventional colonoscopy for the detection of colorectal lesions in individuals at increased risk of colorectal neoplasia due to family history, previous polyp detection or previous colorectal cancer resection (Brown, 2010). The review excluded studies of individuals with inflammatory bowel disease or a known polyposis syndrome. Five RCTs with a total of 1,059 participants met inclusion criteria; only one of the 5 studies had any sites in the United States. Three of the studies used some type of ‘back to back’ design in which each participant underwent the equivalent of 2 colonoscopies.
 
A meta-analysis pooling results of the 5 studies found that a significantly higher number of polyps (all types) were detected with chromoendoscopy than with non-chromoendoscopy interventions; pooled mean difference=0.80, 95% confidence interval (CI): 0.60 to 1.00, p<0.0001. In addition a meta-analysis found that the mean number of neoplastic lesions detected was significantly higher with chromoendoscopy than non-chromoendoscopy. The pooled mean difference=0.39, 95% CI: 0.27 to 0.50, p<0.0001. Tests for heterogeneity were statistically significant in both of the above analyses. According to the study authors, potential reasons for clinical heterogeneity may have been differences in study design and differences in experience level of the endoscopists.
 
In a pooled analysis of per-patient data from the 5 studies, 234/524 (45%) patients in the chromoendoscopy group and 176/535 (33%) patients in the non-chromoendoscopy group had at least one neoplastic lesion detected. The difference between groups was statistically significant; odds ratio (OR): 1.67, 95% CI: 1.29 to 2.15, p<0.0001. A pooled analysis of 4 studies found that 47/497 (9%) in the chromoendoscopy group and 20/512 (4%) in the non-chromoendoscopy group were found to have 3 or more neoplastic lesions (pooled OR: 2.55, 95% CI: 1.49 to 4.36, p=0.006). The Cochrane review concluded, “there appears to be strong evidence that chromoscopy enhances the detection of neoplasia in the colon and rectum. Patients with neoplastic polyps, particularly those with multiple polyps, are at increased risk of developing colorectal cancer. Such lesions, which presumably would be missed with conventional colonoscopy, could contribute to the interval cancer numbers on any surveillance programme.” A limitation of the Cochrane review was that they did not report differences between groups in the number of large lesions.
 
Representative trials included in the Cochrane review and published more recently are described as follows. Hurlstone and colleagues from the United Kingdom (U.K.) published a study in 2004 that randomized individuals to pan-colonic chromoendoscopy using indigo carmine dye (n=128) or conventional colonoscopy (n=132) (Hurlstone, 2004). The study included individuals at increased risk of colorectal cancer due to factors including history of polyps or colorectal signs or symptoms. Patients with known inflammatory bowel disease, colorectal cancer, or familial adenomatous polyposis were excluded. A total of 83 (65%) patients in the chromoendoscopy group and 55 (42%) patients in the standard colonoscopy group had at least one lesion identified; the difference between groups was statistically significant, p<0.01. In addition, significantly more lesions overall, more cases of multiple lesions and more cases of high-grade dysplasia were detected when chromoendoscopy was used. For example, 22 (17%) patients in the chromoendoscopy group and 6 (5%) in the standard colonoscopy group were found to have high-grade dysplasia or beyond, p=0.006.
 
Le Rhun and colleagues in France published findings of a study with 203 patients who had a history of familial or personal colonic neoplasia or alarm symptoms (e.g. change in bowel habit, abdominal pain) after the age of 60 years (Le Rhun, 2006). Patients were randomized to undergo standard colonoscopy (n=100) or high-resolution colonoscopy with chromoendoscopy (n=103). In the chromoendoscopy group, each segment of the colon was examined before and after spraying indigo carmine dye. The primary endpoint, number of adenomas per patient, did not differ significantly between groups. Means were 0.5 [standard deviation (SD): 0.9) in the standard colonoscopy group and 0.6 (SD: 1.0) in the chromoendoscopy group. The number of flat adenomas per patient that were at least 5 mm also did not differ significantly between groups; there were a mean of 0.04 (SD: 0.20) in the standard colonoscopy group and 0.10 (SD: 0.39) in the chromoendoscopy group, p=0.17.
 
In 2008, Stoffel and colleagues published findings of a study with 5 sites in the United States, Canada and Israel (Stoffel, 2008). Eligibility criteria included a personal history of colorectal cancer or at least 3 colorectal adenomas. The study involved back-to-back colonoscopies, the first of which was a standard colonoscopy with removal of all visualized polyps. Patients were then randomized to a second standard colonoscopy with intensive inspection (n=23) or chromoendoscopy (n=27). During the first colonoscopy, 17 of 50 (34%) patients had adenomas identified, 11 of 23 (48%) in the intensive inspection group and 6 (27%) in the chromoendoscopy group (p value not reported). During the second colonoscopy, additional adenomas were found in 4 of 23 (17%) in the intensive inspection group and 12 of 27 (44%) in the chromoendoscopy group (p value not reported). The mean size of adenomas found on the second examination was 3.2 mm in the intensive inspection group and 2.7 mm in the chromoendoscopy group. This compared to a mean size of 3.6 mm in the intensive inspection group and 4.7 mm in the chromoendoscopy group during the first examination. In a multivariate analysis, use of chromoendoscopy was significantly associated with an increased likelihood of finding at least one additional adenoma on the second examination (p=0.04).
 
In 2011, Pohl and colleagues in Germany published a large RCT comparing pan-colonic chromoendoscopy with indigo carmine dye to standard colonoscopy (Pohl, 2011). The study included both patients presenting for primary colorectal cancer screening (51%) or diagnostic colonoscopy (49%). Patients with known inflammatory bowel disease, overt bleeding, polyposis syndromes, or a history of surgical resection were excluded. A total of 1,024 patients were randomized, and 16 dropped out, leaving 496 patients in the chromoendoscopy group and 512 patients in the standard colonoscopy group. The mean extubation time was 11.6 minutes in the chromoendoscopy group and 10.1 minutes in the standard colonoscopy group; the difference between groups was statistically significant, p<0.001. The primary study outcome, the proportion of patients with adenomas, differed significantly between groups (p=0.002). A total of 223 patients (46.2%) in the chromoendoscopy group and 186 (36.3%) in the standard colonoscopy group had at least one adenoma identified.
 
The Pohl trial also reported differences in lesion detection rate by size of lesion. There were 151 (30.4%) patients in the chromoendoscopy group and 119 (23.2%) patients in the standard colonoscopy group found to have at least one adenoma that was 5 mm or larger in size; the difference between groups was statistically significant, p=0.012. A total of 64 (12.9%) patients in the chromoendoscopy group and 48 (9.4%) patients in the standard colonoscopy group were found to have at least one adenoma that was 10 mm or larger, p=0.092. The difference between groups in the detection of adenomas 10 mm or larger did not differ significantly between groups; the study may have been underpowered for this analysis.
 
Average-risk patients undergoing screening colonoscopy. There are fewer trials evaluating chromoendoscopy for colorectal cancer screening of average-risk individuals. Some trials include mixed populations of patients undergoing screening and diagnostic colonoscopy but do not report results separately for each group. For example, in the Pohl et al. study, described above, approximately half of the study participants were undergoing screening colonoscopy, but results were not reported separately for this group (Pohl, 2011).
 
One large randomized trial was identified; it was conducted at 4 centers in the U.S. and included 660 individuals (Kahi, 2010). Eligible individuals were at average risk of colorectal cancer, aged 50 years and older, and were undergoing screening colonoscopy for the first time. Participants were randomized to undergo chromoendoscopy with indigo carmine dye (n=321) or standard colonoscopy (n=339). The primary outcomes were differences between groups in the proportion of patients with at least one adenoma and the mean number of adenomas per patient. Neither of these outcomes differed significantly between groups. A total of 178 (56%) of individuals in the chromoendoscopy group and 164 (48%) individuals in the standard colonoscopy group had one or more adenomas, p=0.07. The mean number of adenomas per patient that were 5 mm or smaller differed significantly in the chromoendoscopy group and the standard endoscopy group; mean number of adenomas was 0.8 and 0.7, respectively, p=0.03. However, there was not a statistically significant difference between groups in the number of larger adenomas. The mean number of adenomas per patient that were 10 mm or larger was 0.11 in the chromoendoscopy group and 0.12 in the standard colonoscopy group, p=0.70. A total of 39 (12%) patients in the chromoendoscopy group and 49 (15%) patients in the standard colonoscopy group had 3 or more adenomas; the difference between groups was not statistically significant, p=0.40. The authors stated that the high rate of adenoma detection in both groups may have been due to the use of high-definition colonoscopy. They concluded that “findings do not support the use of high-definition chromocolonoscopy for CRC (colorectal cancer) screening in average-risk patients.”
 
Patients with inflammatory bowel disease. In 2010, Subramanian and colleagues published a meta-analysis of studies evaluating the diagnostic yield of chromoendoscopy for detecting dysplasia in patients with inflammatory bowel disease (IBD) (Subramanian, 2011). To be included in the meta-analysis, studies needed to be prospective, evaluate surveillance colonoscopy in patients with IBD, and compare chromoendoscopy to white light colonoscopy. Six published studies with a total of 1,277 patients met the inclusion criteria. Only one of the studies was included in the United States; 3 used indigo carmine dye, and 3 used methylene blue dye. Data from 4 studies with 1,120 patients on duration of the procedure were pooled. In the pooled analysis, procedures using chromoendoscopy took a mean of 11 minutes longer than white light endoscopy (95% CI: 10 minutes 15 seconds to 11 minutes 43 seconds). The authors stated that chromoendoscopy procedures lasted significantly longer than white light endoscopy but did not report the exact p value for this analysis.
 
When findings from all 6 studies were pooled, the incremental yield (IY) of chromoendoscopy over white light endoscopy for the detection of any grade of dysplasia on a per patient basis was 7% (95% CI: 3.2% to 11.3%). The number needed to treat (NNT) with chromoendoscopy to detect one extra patient with dysplasia was 14. The authors did not report separately the difference in detection of high-grade dysplasia. A pooled analysis of 4 studies (total n=1,118) found a 27% (95% CI: 11-42%) increase in detection of flat dysplastic lesions with chromoendoscopy compared to white light colonoscopy. In another pooled analysis of data from all 6 studies, there was a 44% (95% CI: 29-59%) increase in detection of dysplasia using targeted biopsies with chromoendoscopy compared to targeted biopsies with white light colonoscopy. The authors also calculated the miss rates (lesions found only on random biopsies) with chromoendoscopy and white light endoscopy. Significantly fewer dysplastic lesions were detected by random biopsy when chromoendoscopy was used compared to white light endoscopy. The pooled reduction in dysplastic lesions detected by random biopsy alone with chromoendoscopy versus white light colonoscopy was -40% (95% CI: - 53% to -27%). The authors concluded that chromoendoscopy is superior to white light colonoscopy for patients with colonic IBD. They note, however, that the impact of this increased rate of detection on patient outcomes is not clear. The meta-analysis does not address the miss rate of larger lesions.
 
Representative trials including patients with IBD are described below.
 
In 2007, Kiesslich and colleagues in Germany published a study of 161 patients who had ulcerative colitis in clinical remission (Kiesslich, 2007). Eight patients were excluded due to insufficient bowel preparation, leaving 80 patients randomized to conventional colonoscopy and 73 patients randomized to colonoscopy with chromoendoscopy of the entire colon using methylene blue stain. In the standard colonoscopy group, 4 biopsy specimens were taken every 10 cm, and in the chromoendoscopy group, endomicroscopy was performed every 10-15 cm, and biopsy specimens were taken only if there were mucosal irregularities. The study included blinded evaluation of specimens. Intraepithelial neoplasias were identified in 11 of 80 (14%) patients in the chromoendoscopy group and 4 of 73 (5%) patients in the standard colonoscopy group; the difference between groups was not statistically significant (p=0.097). When analyzed as total number of lesions, there was a statistically significant difference between groups (p=0.005). Nineteen intraepithelial neoplasias were identified in the chromoendoscopy group, and 4 intraepithelial lesions were identified in the standard colonoscopy group. Most of the lesions were low grade. High-grade lesions were identified in 7 (8.8%) patients in the chromoendoscopy group and 1 (1.4%) in the standard group; statistical significance was not reported for this analysis. The number patients with flat intraepithelial neoplasias was significantly higher in the chromoendoscopy group (n=16) than in the standard colonoscopy group (n=2), p=0.004. The number of larger lesions in each group was not reported.
 
In 2008, Marion and colleagues evaluated 115 patients with extensive ulcerative colitis or Crohn’s colitis involving at least one-third of the colon (Marion, 2008). Thirteen patients had insufficient bowel preparation and data on 102 patients were analyzed. Patients underwent a single examination with 2 passes of the colonoscope. During the first pass, 4 random biopsies were taken every 10 cm for a total of at least 32 biopsies. In addition, any visible lesions were either biopsied or removed. During the second pass, methylene blue dye was segmentally applied throughout the colon. A targeted biopsy approach was used in which any additional visible lesions were biopsied. The study included blinded evaluation of specimens. In the first pass of the colonoscope using random biopsy, 3 of 102 (3%) patients were found to have dysplasia. In 1 of the 3 patients, an additional dysplastic lesion was found using chromoendsoscopy during the second pass of the colonoscope. No carcinomas were identified by any method. A total of 3,264 random biopsies were taken using standard colonoscopic analysis; 3 of these (0.09%) showed low-grade dysplasia and 16 (0.4%) were indefinite. In addition, before dye spraying, 50 biopsies or resections were performed of visible lesions; 12 (24%) showed low-grade dysplasia, 1 (2%) showed high-grade dysplasia, and 2 (4%) were indefinite. After dye spraying, 82 biopsies were taken. Of these, 21 (26%) showed low-grade dysplasia, 1 (1%) showed high-grade dysplasia, and 13 (16%) were indefinite.
 
What is the evidence that virtual chromoendoscopy results in increased detection of clinically important polyps compared to standard colonoscopy or standard chromoendoscopy?
 
Three randomized controlled trials were identified; two compared virtual chromoendoscopy using FICE to standard white light colonoscopy, and the third compared virtual chromoendoscopy to indigo carmine chromoendoscopy during colonoscopy. The trials, which were all conducted outside of the United States, are summarized briefly below.
 
In 2010, Cha and colleagues in South Korea evaluated patients who were at increased risk of colorectal cancer due to personal history of polyps or gastrointestinal symptoms (Cha, 2010). A total of 135 patients underwent colonoscopy, and 7 were excluded due to poor bowel preparation or diagnosis of colon cancer or intestinal disease. Thus, 128 patients were randomized to white light colonoscopy (n=65) or virtual chromoendoscopy with Fujinon Intelligent Color Enhancement (FICE) (n=63). The overall percentage of adenomas, and the overall number of polyps did not differ significantly between groups. A total of 31 (49.2%) in the FICE group and 23 (35.4%) in the white light group were found to have one or more adenomas (p=0.12). The mean number of adenomas identified per patient was also similar between groups: 1.39 in the FICE group and 1.96 in the white light group, p=0.46. The number of adenomas less than 5 mm in size (the primary study outcome) differed significantly between groups. A total of 28 (44.4%) of patients in the FICE group and 14 (21.5%) in the white light group (p=0.006) were found to have adenomas between 0 and 5 mm. All adenomas identified were low-grade and no complications were reported in either group.
 
Another 2010 study, also from South Korea, was by Chung and colleagues (Chung, 2010). This study included 359 asymptomatic patients receiving screening colonoscopies. They received back-to-back examinations with white light colonoscopy or FICE in random order (n=181 received white light first, and n=178 received FICE first). In the initial colonoscopy, a total of 60 (33.7%) of patients in the FICE group and 55 (30.4%) in the white light group were found to have at least one adenoma; the difference between groups was not statistically significant, p=0.74. The primary study endpoint was the adenoma miss rate, defined as an adenoma identified only during the second withdrawal. The adenoma miss rate was 6.6% in the FICE group and 8.3% in the white light group; the difference in miss rates was not statistically significant, p=0.59. All of the missed adenomas were low-grade and non-pedunculated. All but one (which was 6 mm) were 5 mm or less in size. The authors noted that the study included experts in colonoscopy with a high detection rate of adenomas using white light, which might partially explain the lack of significant difference in miss rates.
 
A 2009 industry-supported multicenter RCT by Pohl and colleagues in Germany compared FICE and targeted standard chromoendoscopy using indigo carmine stain (Pohl, 2009). The study included 871 individuals presenting for screening (57%) or diagnostic (43%) colonoscopy. All patients were examined using high resolution zoom endoscopes. Patients in the standard chromoendoscopy group underwent withdrawal using white light colonoscopy. Indigo carmine was applied using a spray catheter through the working channel of the colonoscope for further assessment of any lesions that were identified. In the FICE group withdrawal was performed using FICE at the preset for examining colorectal mucosa. Data were available for analysis on a total of 764 patients (398 in the FICE group and 396 in the standard chromoendoscopy group); 107 patients were excluded for poor bowel preparation, incomplete colonoscopy, or incomplete documentation. A total of 131 (35.6%) patients in the FICE group and 140 (35.4%) patients in the standard chromoendoscopy group were found to have at least one adenoma; the difference between groups was not statistically significant, p=1.0. The number of small adenomas (here defined as no more than 10 mm) did not differ significantly between groups, p=0.41. The proportion of large adenomas >10mm identified in the 2 groups was not reported. The proportion of patients with carcinoma was small in both groups and did not differ significantly; 12 (3.3%) in the FICE group and 12 (3.0%) in the standard chromoendoscopy group, p=0.85.
 
Ongoing Clinical Trials
Chromoendoscopy and Water Method for Screening Colonoscopy trial (NCT01383265): This study is evaluating individuals between the ages of 50 and 75 years who are undergoing screening colonoscopy (NCT01383265). The trial is comparing screening with a warm water infusion (the water method) instead of air sufflation plus chromoendoscopy using 0.008 indigo carmine solution to a control intervention using the water method alone. The primary outcome is the adenoma detection rate. The expected study completion date is April 2012.
 
Summary
Chromoendoscopy is a technique that is intended to increase the sensitivity of colonoscopy by improving the polyp detection rate. Multiple randomized controlled trials and back-to-back colonoscopy studies have evaluated chromoendoscopy in patients at increased risk of colorectal cancer. A Cochrane review of trials comparing chromoendoscopy to standard colonoscopy in high-risk patients (but excluding those with inflammatory bowel disease) found a significantly higher rate of adenoma detection and rate of 3 or more adenomas with chromoendoscopy compared to standard colonoscopy. The evidence for detecting larger polyps, either defined as greater than 5 mm or greater than 10 mm, is less robust. While one study reported a significantly higher detection rate for polyps greater than 5 mm, no studies reported increased detection for polyps greater than 10 mm. Among patients with inflammatory bowel disease, a meta-analysis of clinical trials focusing on patients with inflammatory bowel disease found a statistically significantly higher yield of chromoendoscopy over white light colonoscopy for detecting dysplasia. This evidence establishes that chromoendoscopy improves the polyp detection rate, but it is unclear whether the additional polyps detected are clinically important, and therefore whether the improved polyp detection rate will translate to improved health outcomes. In addition, there are concerns about the comparison group in some of these trials. It is uncertain whether the control groups received optimal colonoscopy, therefore the improved detection rate by chromoendoscopy may be a function of suboptimal standard colonoscopy.
 
There is insufficient evidence on chromoendoscopy in an average-risk screening population. One large randomized controlled trial on chromoendoscopy with screening colonoscopies did not find that high-definition chromoendoscopy identified more clinically meaningful lesions than high-definition white light colonoscopy. In addition, about half of the participants in a recent trial from Germany were average-risk individuals seeking screening colonoscopy, but results of the trial were not stratified by indication for colonoscopy. As a result of these limitations in the evidence for both high-risk and average-risk individuals, as well as a lack of consistent support from clinical reviewers, chromoendoscopy is considered investigational as an adjunct colonoscopy for both of these populations.
 
There is also insufficient evidence that virtual chromoendoscopy improves the detection of clinically significant adenomas or improves health outcomes compared to standard colonoscopy or standard chromoendoscopy. In addition, virtual chromoendoscopy devices have been recalled by the FDA because they did not undergo the proper approval process. Thus, virtual chromoendoscopy is considered investigational.
 
Practice Guidelines and Position Statements
American Gastroenterological Association (AGA): In 2010, a position statement on diagnosis and management of colorectal neoplasia in patients with inflammatory bowel disease (IBD) was published. The AGA recommended that, in patients with IBD, surveillance colonoscopy should include extensive biopsies of all anatomic sections. Chromoendoscopy or another image enhancing technique was recommended for physicians with experience using the technique. The guideline stated that the sensitivity for detecting dysplasia by chromoendoscopy is higher than for white light endoscopy and therefore is an acceptable technique for experienced endoscopists. The guideline noted that training issues and the time required for surveillance examinations need to be examined carefully. It also noted that the natural history of chromoendoscopically detected dysplasia is unknown (Farraye, 2010).
 
American Society for Gastrointestinal Endoscopy (ASGE): In 2006 they published a guideline on endoscopy in the diagnosis and treatment of inflammatory bowel disease. Among other recommendations, the guideline recommends colonoscopic surveillance for patients with long-standing ulcerative colitis and extensive Crohn’s disease colitis. The guideline states: “Chromoendoscopy offers the potential for improved sensitivity during colonoscopic surveillance by allowing for targeted biopsies of enhanced mucosal abnormality. While promising, chromoendoscopy has not yet been adopted in routine practice (Leighton, 2006).”
 
American Cancer Society and U.S. Multi-Society Task Force on Colorectal Cancer: In 2006, they published 2 consensus guidelines on surveillance colonoscopy after cancer resection or polypectomy. The post-cancer resection guideline states, “chromoendoscopy (dye-spraying) and magnification endoscopy are not established as essential to screening or surveillance.” Similarly, the post-polypectomy guideline states, “the application of evolving technologies such as chromoendoscopy, magnification endoscopy, narrow-band imaging, and computed tomography colonography are not established for post-polypectomy surveillance at this time (Rex, 2011) (Winawer, 2006).”
 
2013 Update
A literature search was conducted using the MEDLINE database through March 2013. There was no new literature that would prompt a change in the coverage statement.  A 2012 study using a modified back-to-back colonoscopy designed was published in 2012 by Kiriyama et al. in Japan (Kiriyama, 2012).  The study included 102 consecutive patients who received virtual chromoendoscopy using FICE and white-light colonoscopy in random order. Patients were eligible for study inclusion if they had been referred for a colonoscopy following sigmoidoscopy or for postoperative surveillance after anterior resection. Individuals with known inflammatory bowel disease, bleeding and polyposis syndrome were excluded. The right-sided colon was examined. All lesions identified on either examination were removed and specimens were sent for evaluation. Two patients were excluded from the analysis because insertion was not possible, leaving 100 patients in the analysis. A total of 110 lesions were detected. Of these, 65 lesions were detected using FICE and 45 with white-light; the difference in the number of detected lesions did not differ significantly between groups. Most of the detected lesions, 59 (91%) of those found using FICE and 38 (84%) of those detected using white-light colonoscopy were neoplastic. The miss rate was defined as the proportion of total lesions in that group detected on the second examination. Significantly more lesions were missed by FICE as the second procedure (28 of 61 lesions, 46%) than with white-light colonoscopy (12 of 39 lesions, 24%) (p=0.03) as the second procedure. There was not a statistically significant difference between the FICE and white-light examinations in terms of the number of neoplastic lesions that were 5 mm or larger. Twenty-six of 59 (44%) neoplastic lesions detected by FICE and 14 of 38 (37%) of neoplastic lesions detected by white-light colonoscopy were at least 5 mm in size.
 
Ongoing Clinical Trials
Chromoendoscopy and water method for screening colonoscopy trial (NCT01383265): This study is evaluating individuals between the ages of 50 and 75 years who are undergoing screening colonoscopy. The trial is comparing screening with a warm water infusion (the water method) instead of air sufflation plus chromoendoscopy using 0.008 indigo carmine solution to a control intervention using the water method alone. The primary outcome is the adenoma detection rate.
 
Chromoendoscopy for dysplasia detection in chronic inflammatory bowel disease (NCT01505842): This is a randomized trial comparing the rate of dysplasia detection associated with colonoscopy with chromoendoscopy compared to conventional white-light colonoscopy. The chromoendoscopy intervention is using 0.2-0.5% Indigo-Carmine solution. In both groups, 32 random biopsies will be taken, as well as biopsies from suspicious areas. The study aims to enroll 300 individuals with ulcerative colitis or Crohn's colitis.
  
2014 Update
A literature search conducted through February 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Patients with inflammatory bowel disease:
A meta-analysis of studies on the diagnostic accuracy of chromoendoscopy for identifying dysplasia in patients with IBD and using histopathologic diagnosis as the reference standard also included 6 RCTs (Wu, 2012). The primary end points were the sensitivity and specificity of chromoendoscopy compared with histologic diagnosis. Pooled sensitivity of chromoendoscopy was 83.3% (95% CI, 35.9% to 99.6%) and the pooled specificity was 91.3% (95% CI, 43.8% to 100%). The authors of the meta-analyses concluded that chromoendoscopy has high diagnostic accuracy compared with white-light colonoscopy for patients with colonic IBD. However, the impact of this increased rate of detection on patient outcomes is not clear.
 
Average-risk patients undergoing screening colonoscopy:
Two studies using modified back-to-back designs in patients undergoing screening colonoscopy were conducted by Chung et al in South Korea. The larger study, published in 2013, included 1650 average-risk adults, 550 in each of 3 groups (Chung, 2013). During the colonoscopy, the endoscope was fully inserted and each of 3 colonic segments (ascending, transverse, descending) was inspected twice during withdrawal. Participants were randomized to first withdrawal with narrow-band imaging (NBI), virtual chromoendoscopy using FICE or white-light colonoscopy. White light was used in all groups for the second inspection. Ninety-one patients (5.5%) were excluded from analysis due to inadequate bowel preparation. For the primary outcome, the adenoma detection rate, there was not a statistically significant difference among the 3 groups. The percentage of patients with at least 1 adenoma was 24.5% in the NBI group, 23.6% in the FICE group, and 25.3% in the white-light group, p=0.75. Moreover, the mean number of adenomas per patient was 0.35 in the NBI group, 0.36 in the FICE group, and 0.37 in the white-light group, p=0.59. The adenoma miss rate, defined as an adenoma identified only during the second inspection, was 22.9% in the NBI group, 26.0% by FICE, and 20.8% in the white-light-only group. The miss rate in the enhanced screening groups was not significantly higher than in the white-light group, p=0.30. The mean size of the missed adenomas was 3.6 mm, which was smaller than the mean size of adenomas found during the first withdrawal, which was 4.4 mm.
 
Patients with IBD:
One RCT was identified that evaluated virtual chromoendoscopy in patients with IBD. This was a 2013 trial by Neumann et al in Germany in which 83 patients with mild or inactive IBD were randomized to high-definition white-light endoscopy or virtual chromoendoscopy (Neumann, 2013). Seventy-eight (94%) patients completed the study; the other 5 were excluded due to insufficient bowel preparation. During endoscopy, biopsies were taken from the most distal part of mucosal inflammation; random biopsies were taken to determine the extent and severity of inflammation. Histopathologic analysis was done by a pathologist blinded to endoscopic findings. Endoscopic examination findings on the extent of disease agreed with histopathologic findings in 19 of 39 (48.7%) of the white-light group and 36 of 29 (92.3%) of the virtual chromoendoscopy group. The difference between groups was statistically significant, favoring virtual chromoendoscopy. In terms of disease activity, the agreement between endoscopic prediction and disease activity and histopathologic findings was 21 of 39 (53.9%) in the white-light group and 36 of 39 (89.0%) in the virtual chromoendoscopy group, p=0.066. Although agreement was higher in the virtual chromoendoscopy group, there was not a significantly significant difference between groups at the p<0.05 level.
 
Comparison Between Chromoendoscopy and Virtual Chromoendoscopy (NBI, I-scan, FICE) for Detection of Neoplasia in Long Standing Ulcerative Colitis (NCT01882205): This RCT is comparing endoscopic screening with chromoendoscopy using methylene blue 0.1% to virtual chromoendoscopy (FICE and i-Scan) in patients with ulcerative colitis. The primary outcome is the difference in the number of neoplastic lesions detected. The investigators aim to enroll 402 individuals (Sponsored by Universitaire Ziekenhuizen Leuven (Belgium), 2014).
 
2015 Update
A literature search conducted through February 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In 2014, Freire and colleagues reported on 162 patients with a confirmed diagnosis of longstanding (at least 8 years) left-sided or extending ulcerative colitis that was clinically inactive (Freire, 2014). Patients were randomized to undergo conventional colonoscopy or colonoscopy with chromoendoscopy (using methylene blue). Seventeen patients were excluded from the analysis due to poor bowel preparation. A total of 104 lesions were identified in the chromoendoscopy group and 63 were identified in the conventional colonoscopy group. The primary study outcome, number of intraepithelial neoplasias detected, did not differ significantly between groups (7 in the chromoendoscopy group and 6 in the conventional colonoscopy group). All neoplasias were low grade; no high-grade lesions or carcinomas were found. Compared with standard histological evaluation, the sensitivity and specificity of   chromoendoscopy for detecting intraepithelial neoplasia was 85.7% and 97.9%, respectively.
 
A meta-analysis by Omata and colleagues, published in 2014, compared the polyp detection rate with virtual chromoendoscopy (ie, FICE or i-scan) and white light colonoscopy (Omata, 2014). The study included patients of all risk levels and was limited to RCTs. Five trials on FICE/i-scan met eligibility criteria and the analysis did not find a significantly higher detection rate with virtual chromoendoscopy. The pooled relative risk (RR) of the efficacy of virtual chromoendoscopy compared with conventional chromoendoscopy for adenoma/neoplasia detection was 1.09 (95% CI, 0.97 to 1.23 (p>0.05).
 
2016 Update
A literature search conducted using the MEDLINE database through March 2016 did not reveal any new information that would prompt a change in the coverage statement. One retrospective analysis and one applicable position statement was identified.
I
n 2015, Mooiweer et al published a retrospective analysis of data on 937 patients with ulcerative colitis or Crohn disease who were undergoing surveillance with colonoscopy (Mooiweer, 2015). The study compared neoplasia detection with chromoendoscopy (440 procedures in 401 patients) and white-light colonoscopy (1802 procedures in 772 patients). Neoplasia was detected in 48 of 440 colonoscopies performed with chromoendoscopy (11%; 95% CI, 8% to 14%) and 189 of 1802 procedures performed with white-light colonoscopy (10%; 95% CI, 9% to 12%). The between-group difference in the rate of detection was not statistically significant (p=0.80). Chromoendoscopy was not associated with an increased rate of neoplasia detection; however, patients were not randomized to the 2 treatment groups and may not have been comparable.
 
American Society for Gastrointestinal Endoscopy and American Gastroenterological Association
In 2015, the American Society for Gastrointestinal Endoscopy and the American Gastroenterological Association published the SCENIC consensus statement on surveillance and management of dysplasia in patients with IBD (Laine, 2015). The statement was developed by an international multidisciplinary group representing a variety of stakeholders, and incorporated systematic reviews of the literature. Relevant recommendations are as follows:
 
    • “When performing surveillance with white-light colonoscopy, high definition is recommended rather than standard definition. (80% agreement; strong recommendation: low-quality evidence).”
    • “When performing surveillance with standard-definition colonoscopy, chromoendoscopy is recommended rather than white-light colonoscopy (85% agreement; strong recommendation; moderate-quality evidence).”
 
For this recommendation, the evidence cited consisted of 8 trials using standard-definition colonoscopy that compared while-light colonoscopy alone to chromoendoscopy. The proportion of patients with dysplasia detected was 0% to 10% greater in the individual studies and the difference was not statistically significant in any study. However, the authors stated that meta-analyses found a significantly greater proportion of patients with dysplasia were detected when chromoendoscopy was used. The document also stated that chromoendoscopy increased the duration of colonoscopy and that is it not known whether the additional lesions detected with chromoendoscopy are associated with the same increased risk of CRC as those detected by white-light colonoscopy.
 
“When performing surveillance with high-definition colonoscopy, chromoendoscopy is suggested rather than white-light colonoscopy. (84% agreement; conditional recommendation; low-quality evidence).”
 
Panelists did not reach consensus regarding the use of chromoendoscopy in random biopsies of patients with IBD undergoing surveillance.
 
Commentaries in 2 gastroenterology journals questioned whether the SCENIC guidelines would be accepted as standard of care in IBD surveillance (Higgins, 2015; Marion, 2015). Both commentaries noted that the guidelines consider the outcome of detection of dysplasia and not disease progression or survival. Moreover, the authors note the lack of longitudinal data on clinical outcomes in patients with dysplastic lesions detected using chromoendoscopy.
   
2017 Update
A literature search conducted through February 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
A 2010 Cochrane review by Brown and Baraza identified RCTs that compared chromoendoscopy and conventional colonoscopy for the detection of colorectal lesions in individuals at increased risk of colorectal neoplasia due to family history, previous polyp detection, or previous CRC resection (Brown, 2010). Reviewers excluded studies of individuals with IBD or a known polyposis syndrome. Five RCTs (total N=1059 participants) met inclusion criteria; only 1 of the 5 studies had sites in the United States. Three studies used some type of “back-to-back” design in which each participant underwent the equivalent of 2 colonoscopies.
 
Marion and colleagues reported on a prospective cohort of patients with ulcerative colitis or Crohn colitis in 2008, with long-term follow-up published in 2016 (Marion, 2016). In the initial study, data were available on 102 patients. The study involved a single examination with 2 passes of the colonoscope. During the first pass, 4 random biopsies were taken every 10 cm for a total of at least 32 biopsies. At that time, any visible lesions were either biopsied or removed using a targeted biopsy protocol. During the second pass, methylene blue dye was segmentally applied throughout the colon, accompanied by targeted biopsy of any abnormality or lesion identified through spraying. The study included blinded evaluation of specimens. In the first pass of the colonoscope using random biopsy, 3 (3%) of 102 patients were found to have dysplasia. In 1 of the 3 patients, an additional dysplastic lesion was found using chromoendoscopy during the second pass. No carcinomas were identified by either method. A total of 3264 random biopsies were taken using standard colonoscopic analysis; 3 (0.09%) showed low-grade dysplasia, and 16 (0.4%) were indeterminate. In addition, before dye spraying, 50 biopsies or resections of visible lesions were performed; 12 (24%) showed low-grade dysplasia, 1 (2%) showed high-grade dysplasia, and 2 (4%) were indeterminate. After dye spraying, 82 biopsies were taken. Of these, 21 (26%) showed low-grade dysplasia, 1 (1%) showed high-grade dysplasia, and 13 (16%) were indeterminate.
 
In 2016, follow-up data were reported on 68 (67%) of the 102 patients in the cohort (Marion, 2016). Median length of follow-up was 28 months. Surveillance intervals varied from 6 to 12 months, depending on findings from the initial examination. During follow-up, patients underwent a mean of 3.15 endoscopy procedures (range, 1-5) with random biopsies. Follow-up endoscopies appeared to use a protocol similar to the index examination. Using random biopsies, 6 dysplastic lesions were identified in 5 patients. White light- targeted biopsy identified 11 dysplastic lesions in 11 patients and methylene blue dye with targeted biopsy identified 27 dysplastic lesions from 27 patients. Targeted biopsy with chromoendoscopy and targeted biopsy with white-light colonoscopy were each significantly more likely to detect dysplasia than random biopsy. Four patients were referred for colectomy after the index examination and 6 additional patients were referred during follow-up. A positive chromoendoscopy examination was significantly associated with having colectomy sooner (hazard ratio [HR], 12.1; 95% CI, 3.2 to 46.2; p<0.001). The study was not powered to estimate survival rates with white-light versus chromoendoscopy targeted biopsies. No carcinomas were found in any patient during the study and no adverse events were reported.
 
Gasia and colleagues retrospectively analyzed data from a cohort of 454 patients who had IBD for at least 8 years who were undergoing surveillance at a single tertiary care center (Gasia, 2016). The endoscopic approach used was at physician discretion; however, only 1 of 8 endoscopists had training in chromoendoscopy. A total of 126 patients had standard colonoscopy, 182 had high-definition (HD) colonoscopy (124 with random biopsies, 58 with targeted biopsies), 28 had chromoendoscopy (4 with random biopsies, 24 with targeted biopsies), and 118 had virtual chromoendoscopy (64 with random biopsy, 54 with targeted biopsies). Rates of neoplasia detection were significantly higher in the targeted biopsy groups (19.1%; 95% CI, 13.4% to 26.5%) than in the random biopsy groups (8.2%; 95% CI, 5.6% to 11.7%). Rates of neoplasia detection did not differ significantly in the HD colonoscopy, chromoendoscopy, and virtual chromoendoscopy groups that received with targeted biopsy.
 
2018 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2018. No new literature was identified that would prompt a change in the coverage statement.
 
 

CPT/HCPCS:
44799Unlisted procedure, small intestine
G6021Unlisted procedure, intestine

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