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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.
Study population Inclusion Criteria
- 18-80 years
- Patients must be able to provide written informed consent
- Patients referred for endoscopy for screening/surveillance of BE or for endoscopic
treatment of BE with early mucosal neoplasia Exclusion Criteria
- Current use of aspirin, non-steroidal anti-inflammatory agents (NSAIDs), or chronic
anticoagulants that cannot be discontinued prior to the procedure
- Inability to provide written informed consent
- Significant thrombocytopenia or coagulopathy
- Any significant co-morbid condition that would prevent the safe administration of
conscious sedation.
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 (Appendix A).
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 (10, 11). Details of endoscopy findings and digital video recordings will be
entered into an endoscopy form (Appendix B).
Step I - Perform video recording of Barrett's esophagus according to the Prague
C&M-classification.
Step II
- Obtain a high quality video recording, utilizing standard endoscopy and HRE, of areas of
interest for at least 30 seconds. For lesions localized at the lower end of the Barrett
segment, obtain an additional video recording with the endoscope in the retroflexed position
(again for at least 30 seconds).
Step III
- Obtain a 30 second video recording with NBI.
- Document macroscopic findings, localization of the area, and biopsy number on the image
recording form.
Step IV.
- Before spraying 0.4-0.8% indigo carmine solution over the macroscopic lesion, clean the
esophagus using tap water or mucomyst.
- Obtain a 30 second video recording with indigo carmine chromoendoscopy. Step V
- Obtain at least two biopsies and EMR/tissue ablation (if mucosal and/or vascular
pattern suggestive of dysplasia) from the site just imaged, and send the specimens in
separate containers for histopathological assessment.
Histology All biopsy specimens will be fixed in Bouin's solution, embedded in paraffin, and
sectioned at 4μm thickness at multiple levels in a routine fashion. Sections will be stained
with hematoxylin and eosin and if required, alcian blue stain at pH 2.5 will be used to
confirm the presence of intestinal metaplasia. The presence of dysplasia/EAC will be
assessed and classified on the basis of the revised-Vienna classification as negative for
dysplasia, low-grade dysplasia (LGD), HGD, or EAC. In this classification; HGD and
intramucosal EAC are categorized into one group (22). The pathologist will be blinded to the
endoscopy results. Specimens obtained by EMR will be reviewed by multiple pathologists.
Digital image processing and digital video-recording Digital tape recordings of all
procedures will be sent by courier to a QPC (a central computer software agency in Sweden)
for transcription and formatting. Digital still images will be copied onto CD-ROM and sent
by courier to QPC together with the completed image recording form. Digital data will be
distributed by courier to study investigators at the four study sites. No patient
identification or names will be utilized at any time. All data included digital tape
recordings and digital still images will be stored in a secure fashion such that only study
personnel will have access to the data.
D. DATA MANAGEMENT All data will be collected by one of the study investigators. The data
will be transferred to an Access spreadsheet. All images and video clips will be password
protected. They will be stored at a central site where they will be coded and then
anonymized by the deletion of all printed information recorded with the endoscopic images
and video-recordings. This code will not be broken until all analyses have been completed.
E. STATISTICAL POWER AND DATA ANALYSIS Based on the experience from earlier studies in this
field by the IWGCO, and the aforementioned numbers, it may be expected that 80 to 90
patients will have to be included to obtain the required number of videos and still images.
Patients will be included from the following four centers: Amsterdam, Mainz, Wiesbaden and
Kansas City. It is estimated that patient inclusion will require a period of at least 12 to
18 months.
The statistical software program (SAS, version 9.1; SAS Institute Inc., SAS Campus Drive,
Cary, N.C.) will be used for all data analysis.
For all lesions both a high-quality standardized pull-back maneuver and a detailed video
recording of the lesion of interest should be available, as well as the corresponding
histology.
A. Videos collected during step I - IV will be used for the following purposes:
1. To create a video-atlas of non-dysplastic and dysplastic/early neoplastic lesions in
patients with BE for teaching purposes and assessment of learning curves.
2. For testing the intra- and interobserver variability of the mucosal and vascular
patterns for BE using novel imaging technologies.
3. A video set to determine the detection rate of mucosal neoplasia by expert
endoscopists, experienced endoscopists, and trainees for each individual technique:
Endoscopists will review a set of video recordings of patients with both dysplastic and
non-dysplastic BE. They will be divided into a training set and a testing set. The training
set will be used to familiarize endoscopists with the various patterns associated with
normal and abnormal BE histology. Subsequently, in the testing set, for each video
recording: the presence/absence and location of the neoplastic lesion (both for depth of
insertion and circular orientation) will be recorded by the individual endoscopist.
B. EMR specimens will be reviewed by multiple pathologists and interobserver variability for
the diagnosis of dysplasia will be assessed.
F. IMPORTANCE OF CURRENT RESEARCH TO VETERANS GERD is known to be common in the adult
population, including the VA population. BE is a complication of chronic GERD and a well
recognized precursor of EAC, a cancer that is known to be increasing in incidence.
Application of newer technological advances to identify and resect early neoplastic lesions
may lead to a decrease in morbidity and mortality from EAC amongst veterans. The performance
of the current study will provide veterans access to the latest imaging tools that can
detect BE dysplasia at an early, potentially curable, stage. This will pave the way for
future routine use of novel imaging methods in the veteran population for the diagnosis of
precursor lesions to EAC, ultimately translating into avoidance of surgical resection,
chemotherapy and radiotherapy in its management. This will not only improve the quality of
life in veterans diagnosed with EAC, but also result in cost savings for the VA health care
system.
G. HUMAN SUBJECTS RESEARCH Informed consent For informed consent, research protocols will be
explained in detail to participants by appropriate staff and a copy of the approved
institutional review board (IRB) consent form will be provided to the participant for
reference and study. Consent will be documented by signing of the approved form by the
subject, the physician, and the appropriate witness. The study will be explained to the
subjects in lay language. Any subject who wishes to withdraw from this investigation on
his/her own accord and for whatever reason is entitled to do so without obligation and
prejudice to further treatment. Subjects will be assured that they may withdraw from the
study at any time for any reason.
Risk and Benefit to the Study Participant Careful data monitoring and quality control will
be maintained. After informed consent is obtained, BE patients enrolled in this study will
undergo endoscopy as described above, following the guidelines for endoscopy set forth by
the American College of Gastroenterology. During an endoscopic procedure required for the
patient's medical condition, biopsies and EMR of esophageal tissue will be obtained, which
will be placed in transport medium and processed in the histopathology laboratory to meet
the various objectives of this proposal.
Potential Risks:
Intravenous sedation: Bruising and minor discomfort where the needle is inserted are
possible. In addition, there is a small risk of breathing difficulty and heart rhythm
irregularities related to the medicine(s) given. All patients are monitored with automatic
reading of blood pressure, pulse, and oxygen saturation.
Endoscopy with biopsies: Minor complications include discomfort and gagging related to the
passage of the endoscope into the esophagus, and a slight sore throat post procedure. There
is a small risk (about 3 in 10,000) of perforation that could require surgery to repair and
an equally small risk (8 in 10,000) of inhaling saliva or stomach juices that could cause
aspiration pneumonia. In the event that any adverse events occur due to the endoscopy,
patients will be cared for at the medical center. There is no increased risk to patients by
using NBI or chromoendoscopy and the duration of the procedure is increased by 8-10 minutes.
Endoscopy with EMR and tissue ablation: In addition to the risks of endoscopy as noted
above, EMR is associated with a risk of bleeding of 5%, and a risk of perforation of 0.1%.
Bleeding can be easily controlled by deploying hemoclips or using bipolar cautery devices.
Transient side effects after treatment may include chest pain, difficulty swallowing, pain
with swallowing, throat pain, or fever. These can be managed as clinically appropriate by
the physician.
Phlebotomy: Bruising and minor discomfort where the needle is inserted for blood draw are
possible.
Protection against risk: The risks of endoscopy are minimized by careful monitoring of
patients with real time blood pressure, pulse, and oxygen saturation in addition to
monitoring by a trained registered nurse during the procedure. Endoscopic procedures will
be performed in the GI endoscopy unit (fully equipped and staffed with ACLS trained
personnel to intervene in the case of any medical emergency).
Potential benefits: Endoscopic surveillance of BE as practiced in this protocol is
considered the standard of care. Dysplasia may be identified early and removing early
neoplastic lesions with EMR has the potential to cure the patient and save exposure to a
surgical resection, chemotherapy and radiotherapy. This should lead to a decrease in
morbidity and mortality of patients with Barrett's esophagus and concurrent neoplasia. |