Trial Information

Endoscopic Detection of Early Neoplasia in Patients With Barrett's Esophagus

B. BACKGROUND AND SIGNIFICANCE Burden of disease Barrett's esophagus (BE) is an acquired
condition resulting from chronic gastroesophageal reflux disease and is a well recognized
pre-malignant condition for the development of esophageal adenocarcinoma (EAC) (1, 2). BE is
defined as the displacement of the squamocolumnar junction proximal to the gastroesophageal
junction with the presence of intestinal metaplasia (15). This condition entails a 30 to 50
fold greater risk for the development of EAC and has an incidence of development of EAC that
approaches 0.5% annually (3, 4). EAC is a highly lethal cancer and is the most rapidly
increasing cancer in the United States and Western Europe with an incremental increase of
4-10% per year. Although survival rates have improved during the recent years in some
countries, the overall 5-year survival rate is still a dismal 10% in most Western
populations (5-7). Clinical strategies for preventing deaths from this cancer focus on
techniques for identification of esophageal neoplasms in an asymptomatic, early, and curable
stage. Therefore, endoscopic screening of subjects with chronic reflux symptoms has been
recommended as a method of detecting BE and early cancer (8). Patients with BE are then
routinely enrolled in surveillance programs in an attempt to identify those who might
benefit from treatment at a pre-invasive stage of EAC with an ultimate aim of reducing
cancer related deaths (8).

Limitations of current Barrett's surveillance protocol Current guidelines for surveillance
include taking biopsy specimens from endoscopically visible mucosal abnormality followed by
random 4-quadrant biopsies every 2 cm throughout the entire length of BE (15).
Unfortunately, the effectiveness of this strategy is hampered by numerous factors. Apart
from being labor intensive and time consuming for the patient; the accuracy of this protocol
is limited by sampling errors. Biopsy specimens from short segments or tongues of columnar
mucosa generally reveal intestinal metaplasia in only 40-60% of patients (16). In a study of
570 patients undergoing upper endoscopy, BE was suspected in 146 patients; however, only 60
patients had diagnosis confirmed by biopsy. Short segment BE (SSBE) was more frequently
suspected than long segment BE (LSBE) but was correctly diagnosed only 25% of the time
compared with 55% for LSBE (17). Similar to the distribution of the metaplastic tissue, the
presence of dysplasia or early adenocarcinoma within a Barrett's segment is patchy and
focal. Standard endoscopy and random biopsies might fail to detect these lesions. Early
neoplastic lesions are not visible to the eye of the endoscopist at standard endoscopy and
random biopsies sample only a small proportion of the epithelium at risk. Also, this "hit
and miss" nature of biopsy increases the cost of the procedure and limits the reliability of
histologic interpretation of dysplasia. The increasing use of endoscopy has led to more and
more patients being diagnosed with BE and offered surveillance. Also, the number of patients
being followed up, and to whom potentially curative therapy can be offered, have increased.
The advent of newer methods of endoscopic treatment of high-grade dysplasia (HGD) and early
EAC in the form of ablative therapy and EMR makes it highly desirable to diagnose dysplasia
and EAC early in the disease process. This may help in alleviating the morbidity and
mortality associated with esophagectomy for EAC. These compelling reasons coupled with the
limitations of current surveillance protocols make the development of new approaches aimed
at improving efficacy of Barrett's surveillance mandatory.

Novel imaging techniques and endoscopic therapies Significant effort has been expended on
development of new GI techniques in order to provide a precise and even a "real time"
endoscopic diagnosis. Chromoendoscopy is a technique that involves the application of agents
to improve characterization of the mucosa resulting in selective uptake or enhancement of
mucosal surface pattern (11). HRE units are equipped with charge-coupled devices with up to
a million pixels that allow clear visualization of fine mucosal details which may facilitate
the detection of early neoplastic lesions (9). NBI is a novel endoscopic technique that is
based on the optical phenomenon that the depth of light penetration into tissues is
dependent on the wavelength; the shorter the wavelength, the more superficial the
penetration. Use of blue light with narrow band filters enables detailed imaging of the
mucosal and vascular surface patterns within the BE segment with a high level of resolution
and contrast without the need for chromoendoscopy. The main chromophore in esophageal
tissues in the visible wavelength is hemoglobin, which has a maximum absorptive wavelength
near 415 nm. This is within the wavelength for NBI and responsible for revealing the
superficial vasculature (10).

Esophagectomy was considered as the criterion standard for treatment of patients with early
EAC. However, it is associated with significant morbidity and mortality, even in experienced
surgical hands and high-volume surgical centers. EMR has been used increasingly to replace
surgery as a curative treatment modality for early EAC in patients with BE (12, 13). It
allows effective local treatment of early cancer, histological analysis of all resected
specimens and thus confirmation of diagnosis and complete resection of the lesion. Ablative
therapies in BE patients have provided promising results as well (18, 19).

C. PRELIMINARY DATA Our group recently assessed the potential of NBI for the prediction of
histology during screening and surveillance endoscopy in BE patients (10). Images obtained
by this system were classified according to the mucosal (ridge/villous, circular,
irregular/distorted) and vascular (normal, abnormal) patterns and correlated with histology
in a prospective and blinded fashion. The sensitivity, specificity, and positive predictive
value of the ridge/villous pattern for the diagnosis of intestinal metaplasia without
high-grade dysplasia (HGD) were 93.5%, 87%, and 95% respectively. The sensitivity,
specificity, and positive predictive value of the irregular/distorted patterns for HGD were
100%, 99%, and 95% respectively. These promising results have been validated by other
investigators. Similarly, Dr. Sharma has published several studies involving the use of
chromoendoscopy in patients with BE. In a study of 80 patients with columnar lined esophagus
using indigo carmine dye and 115x magnification endoscopy, three mucosal patterns as stated
above were identified. The presence of ridge/villous pattern for detecting intestinal
metaplasia had high sensitivity, specificity, and positive predictive value (97%, 76%, and
92% respectively). Six patients had an irregular/distorted pattern and biopsies revealed HGD
in all these patients (11). Our group has been active in evaluating the role of ablative
therapies in patients with BE.

We recently assessed the long-term efficacy of achieving complete reversal (endoscopic and
histologic) between multipolar electrocoagulation and argon plasma coagulation in patients
with BE and assessed factors influencing successful ablation. A total of 35 BE patients were
followed for at least 2 years following ablative therapy and complete reversal of BE was
achieved in 70% of the patients, regardless of the ablative technique (19). The
International Working Group on the Classification of Oesophagitis has been at the forefront
for the classification and grading of acid-peptic related esophageal diseases such as
erosive esophagitis and BE. Sharma et al developed and validated an endoscopic grading
system for BE (Prague C & M criteria). The criteria includes assessment of the
circumferential (C) and maximal (M) extent of the endoscopically visualized BE segment along
with endoscopic landmarks. This grading system demonstrated a high validity for the
endoscopic assessment of visualized BE lengths (20).

D. RESEARCH DESIGN AND METHODS Overview Patients with known / suspected BE Pre-registration,
informed consent

Standard endoscopy followed by HRE, NBI and chromoendoscopy

Digital video-recording of endoscopy findings (Subsequent de-identification of all patient
information)

Target biopsies of suspected lesions

Removal of abnormal lesions with EMR / mucosal ablation

Pathologist for histologic interpretation

This is a part of a multicenter study initiated at Kansas City. Patients will be recruited
from Amsterdam, Mainz, Wiesbaden and Kansas City.

Methods Physical examination and questionnaire All patients will complete a validated GERD
questionnaire (GERQ) (21) that records duration, severity, and frequency of heartburn and
regurgitation with supplemental information on medications such as acid suppressive therapy,
aspirin, NSAIDs, etc. Demographic information and clinical findings such as height, weight
and waist circumference will be recorded .

Endoscopic procedure The endoscopic procedures will be performed with a high-resolution
endoscope (Olympus GIF-Q240Z, GIF-Q160Z, or more recent versions) that has the capability of
performing NBI with the push of a switch. Standard methods of conscious sedation and
cardiopulmonary monitoring will be used during each procedure. The distal esophagus will be
carefully inspected for the presence of erosions, nodules and plaques. The presence and size
of hiatal hernia will be recorded. A plastic disposable distal attachment cap (e.g. Olympus
D-201-11802) with a free distal distance of 2-3 mm will be attached to the endoscope in
order to fix mucosal areas of interest until images and biopsies have been taken. The
endoscopist will be blinded to the previous BE histology of the patient. The classification
of mucosal and vascular patterns will be performed in a standardized manner into groups as
described above. Details of endoscopy findings and digital video recordings will be entered
into an endoscopy form .