Endoscopic Screening for Dysplasia in Patients With Longstanding Ulcerative Colitis: Classical Chromo-endoscopy Versus NBI , FICE and EPK-i.
The risk for colon cancer in patients with longstanding ulcerative colitis exceeding the
rectum is increased and therefore patients should be enrolled in a surveillance program
eight years after the diagnosis. Surveillance endoscopies are advised 8 to 10 years after
the diagnosis of ulcerative colitis. The first decade every 3 years, the second decade every
2 years and thereafter every year Until today, most official international guidelines for
endoscopic screening in patients with ulcerative colitis advise to take 4 random biopsies
every 10 centimeters (with a minimum of 32) and of each suspected visible lesion using
standard white light endoscopy.
These guidelines are merely based on consensus during expert opinion meetings rather than
However, some studies have shown that the sensitivity for the detection of dysplasia during
colonoscopy in patients with ulcerative colitis can significantly be enhanced by using
chromo-endoscopy. These studies used methylene blue or indigo carmine as a contrast agent
with or without high magnification endoscopy. Chromo-endoscopy guided targeted biopsies
significantly reduced the number of biopsies for each procedure and detected more neoplastic
lesions. It was therefore concluded that colonoscopy with chromo-endoscopy guided biopsies
is more efficient and cost saving. Chromo-endoscopy with targeted biopsies is an alternative
to white light endoscopy with random biopsies every 10cm. The European Crohn and Colitis
association now suggests that the use of methylene blue or indigo carmine chromoendoscopy is
an alternative to random biopsies for appropriately trained endoscopists and is superior to
random biopsies in the detection rate of neoplastic lesions In this study we want to compare
chromoendoscopy with targeted biopsies as the gold standard with new new endoscopic image
techniques called virtual chromoendoscopy.
From 2005 new endoscopic imaging modalities have been commercialized and are now generally
available to gastroenterologists. They all claim a theoretical advantage in comparison to
standard white light high resolution video endoscopy. These new techniques are called
virtual chromoendoscopy (VC). There are three different systems developed by the three major
competitors of endoscopic equipment: Olympus, Pentax and Fujinon.
Narrow-Band Imaging (NBI) is developed by Olympus inc. and selectively uses certain
wavelengths of the visible light leading to a shift in the excitation spectrum towards blue
light. The intensity of the blue bandwidth is also enhanced. This leads to a more
superficial penetration of the emitted light into the mucosa of the intestine and
enhancement of more superficial structures (e.g. irregularities, small flat lesions or
polyps) and small superficial mucosal vessels (indicative of neoplasia).
The first studies using NBI in Barrett's esophagus demonstrated that the additional value of
NBI in the detection of neoplastic lesions is comparable to chromo-endoscopy (Kara et al.,
2005). However NBI is time saving and easier to perform than chromo-endoscopy because there
is no need to additionally spray dye onto the mucosa.
In a standard population screening study, NBI has shown to aid in the detection and
characterization of polyps in the colon. In particular the presence of a brownish meshed
capillary network has a high diagnostic value in the prediction of the neoplastic nature of
In a very recent tandem study in which white light endoscopy was compared with NBI in 48
patients with longstanding UC there was no additional benefit of NBI. In the 25 patients who
were first endoscoped with white light 8 dysplastic lesions were found. After NBI imaging
another 7 lesions were found. In the 23 patients which were first imaged with NBI 7 lesions
were found and an additional 8 after white light endoscopy (Van den Broek FJ et al 2011.
The Fujinon Intelligent Chromo-Endoscopy (FICE) system uses a similar theoretical principal
as NBI but this is achieved via the use of post hoc computer algorithms, applying different
filters to the stored endoscopic images and enabling a theoretically endless number of
combinations of filters that can be used. Currently 10 different spectrum filters can be
used. There are predefined settings for visualization of the colonic mucosa. There are no
previous data comparing white light endoscopy and FICE in the detection of dysplasia in
longstanding ulcerative colitis.
Finally, Pentax released a new high definition endoscopy system in 2007, the I-scan system,
which also allows post hoc modification of the images. On the one hand, surface enhancement
enables to better highlight mucosal changes. Spectral modification allows to apply different
modes in analogy with to FICE system. For instance the p-mode for pattern recognition helps
to accentuate epithelial features. The TE-mode helps to assess the vasculature of the
gastrointestinal mucosa. Recently new filters were developed such as the colon mode,
specifically designed for the colon. In one study VC with I-scan TE-mode was compared to CE
and standard white light endoscopy in 69 patients. In both the VC and CE mode 11 dysplastic
lesions were found (Hoffman et al 2010). Data about the improvement of detection of
dysplasia are lacking until now.
Adjustment of the light spectrum is usually combined with a better and higher image
resolution of the new generation endoscopes. Fujinon and Pentax use a so called super-CCD to
increase the pixel resolution of the scope to 1.300.000 and 1.400.000 respectively and
combined it with a DVI output signal. Olympus opted for an improved video resolution by
incorporating high definition television (HDTV) in the latest processors.
These new imaging techniques have a theoretical advantage which is extendedly used for sales
purposes but has however so far not been proven in ulcerative colitis patients. We want to
test their clinical use in the screening for neoplastic lesions in patients with long
standing ulcerative colitis. The scientific and clinical relevance of this study is clear.
If NBI and/or FICE and/or I-scan have a better detection rate than chromo-endoscopy, the
latter can be replaced by virtual chromo-endoscopy. Even if the detection by NBI and/or FICE
and/or I-scan is not statistically different from standard chromo-endoscopy, they still can
replace the latter because it is technically easier to use. If however these techniques have
a lower adenoma detection rate than classical chromo-endoscopy we will be able to show that
there is no place for these techniques in the detection of UC related neoplasia, despite the
Because the multicenter character of the study, and the availability of only one system in
most hospitals, we will test the differences between all three modalities and classical
The endoscopic procedure as such is not much different from a standard endoscopic procedure
that patient should be advised to undergo according to good clinical practice. The bowel
preparation is similar as in a normal colonoscopy, and can be performed either at home or in
the endoscopy department. The endoscopes used in the study include the H180Q series of
Olympus, the 5000 series of Fujinon and the HD series of Pentax. They are not different in
terms of design or size compared to standard colonoscopies and are all commercially
Patients will be randomized between one of the following techniques:
1. Chromo-endoscopy with methylene blue 0,1% (groups A-C-E) An Olympus spray catheter is
used through the biopsy channel of the endoscope to apply the dye, a saline solution
with methylene blue in a concentration of 0.1%. This technique was already validated in
previous studies. Besides the extra time needed for dying the entire colon mucosa, no
other manipulations are needed for this technique. Moreover, the time needed to dye can
be recovered because only chromo-endoscopy guided biopsies will be taken instead of
random biopsies throughout the colon, which normally also requires a considerable
amount of time. Previous studies using chromo-endoscopy versus conventional screening
colonoscopy did not show a significant difference in total procedure time. The
endoscopes used do not differ from the ones used in the other randomization arms and
include either an Olympus H180Q colonoscope, Fujinon EC 590 ZW/M colonoscope or a
Pentax 3890i colonoscope. All three endoscopes are CE approved and are commercially
2. Narrow band imaging with HDTV (Group B) This technique involves an Olympus H180Q
colonoscope that is CE approved and commercially available. The procedure involves a
normal white light endoscopy during progression of the scope. Once the caecum is
reached the entire procedure will be performed in NBI modus. This has no influence or
side effects for the patients because NBI modus is switched on by pushing a button on
3. Fujinon Intelligent Color Enhancement (FICE) with super CCD chip (Group D) This
technique involves a Fujinon EC 590ZW/M colonoscope that is CE approved and
commercially available. The procedure involves a normal white light endoscopy during
progression of the scope. Once the caecum is reached the entire procedure will be
performed in FICE modus n° 4. This has no influence or side effects for the patients
because FICE modus is switched on by pushing a button on the scope.
4. I-scan with High Definition colonoscope (group F) This technique involves a PENTAX
EC3890Fi colonoscope that is CE approved and commercially available. The procedure
involves a normal white light endoscopy during progression of the scope. Once the
caecum is reached the entire procedure will be performed in the TE- modus (Tissue
enhancement mode) with surface enhancement on medium (range low-medium-high). This has
no influence or side effects for the patients because the c- modus is switched on by
pushing a button on the scope.
Only targeted biopsies of visible mucosal abnormalities during chromo-endoscopy, NBI, FICE
or I-scan endoscopy will be taken. This is in concordance with the standard approach during
chromo-endoscopy directed screening colonoscopy for ulcerative colitis. The disposable
biopsy forceps are commercially available (Boston Scientific) and do not differ from the
ones used during normal endoscopic procedures.
A power analysis was performed to detect a statistical significance between group A and B,
group C and D and between group E and F. In a previous study dysplasia was found three times
more often using CE compared to white light endoscopy: 32/84 versus 10/81 patients. This wil
give an increase from approximate 10 to 30 percent. It is expected that in both study
groups the percentage of dysplasia equals.
Inclusion of 67 patients in each group will allow to detect a 20% increase of dysplasia
from 10 to 30% compared to white light endoscopy with a power of 80% (beta error 0.2; alpha
error 0.05). We expect to include a total of (67 x 6 =) 402 patients in the study.
Multiple factors will be used as co-variables
- Duration of disease
- Existence of PSC
- Use of medication
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject), Primary Purpose: Diagnostic
The difference in total number of neoplastic lesions detected by chromoendoscopy and virtual chromoendoscopy
The primary endpoint will be assessed in three subgroups comparing : 1 )Group A: HDTV Olympus colonoscopes and Chromo-endoscopy, methylene blue 0.1% to Group B: HDTV Olympus colonoscopes and Narrow band Imaging (NBI) 2) Group C: CCD Fujinon colonoscopes and Chromo-endoscopy, methylene blue 0.1% to Group D: CCD Fujinon colonoscopes and Fujinon Intelligent Color Enhancement 3) Group E: HD-Pentax colonoscopes and Chromo-endoscopy, methylene blue 0.1% to Group F: HD Pentax colonoscopes and I-scan As such this is not a comparison between different endoscopy systems, but a comparison of chromoendoscopy and virtual chromoendoscopy within each different system.
The primary endpoint can be assessed when pathology results are available : 2 weeks after endoscopy
Raf Bisschops, MD PhD
University Hospitals Leuven
Belgium: Federal Agency for Medicinal Products and Health Products