Narrow Band Imaging for Gastric Neoplasia

1 BACKGROUND

Precursor Lesions

Gastric cancer is the fourth most common cancer and second leading cause of malignant death
in the world. It often presents only with vague symptoms of dyspepsia and consequently is
frequently diagnosed at advanced stages.

Gastric cancer develop in a series of steps beginning with H. pylori infection. 2-4 It
induces an inflammatory reaction with the surrounding gut epithelium which is theorized to
drive a subsequent progression in some patients to mucosal atrophy, intestinal metaplasia,
dysplasia, and finally gastric adenonocarcinoma.

Systematic biopsy protocols

In the evaluation for precancerous gastric lesions and Helicobacter pylori, experts
recommend that biopsies be obtained from the antrum (3cm from pylorus), body (8cm from the
pylorus), and insisura/angle. Both the greater and lesser curvature should be sampled.
Additionally, recently developed staging systems including OLGIM (operative clinic on
intestinal metaplasia) scores require histologic assessment (via the updated Sydney score)
from two sites (antrum and corpus).

Narrow Band Imaging in endoscopy

Patients with H. pylori gastritis, gastric atrophy, intestinal metaplasia most commonly have
no visible lesions on white-light endoscopy, although endoscopic findings may include antral
nodularity, absent rugae, prominent gastric vessels white mucosal deposits. However, the
sensitivity and specificity of these gross findings for underlying histological findings is
poor. Therefore a number of image-enhancement techniques including chromoendoscopy using
mucosal dyes or endoscopy-based virtual chromo-endoscopy (e.g., narrow band imaging) have
been proposed. Narrow band imaging is the most widely investigated.

Narrow band imaging is an electronic, noninvasive technique in which the illuminating light
from the endoscope is filtered to enable passage primarily of two narrow bands of light,
415nm and 540nm. These wavelengths correspond to the hemoglobin absorption wavelength in the
capillaries and submucosal vessels respectively. This enhances evaluation of the mucosal
surface patterns and vascular irregularities. NBI has been shown to be useful in the
detection of dysplasia in Barrett's esophagus and characterization of small colonic
adenomas.

Recently, a simple NBI classification using high-definition white light endoscopy was
proposed for gastric mucosal examination.18 The NBI interpretation using this classification
was compared with histological examination of mucosal biopsies, with both NBI and histology
determined in blinded fashion. This classification which defines the mucosal pattern of the
stomach had an accuracy exceeding 80% and excellent interobserver agreement (kappa=0.75) for
normal mucosa, intestinal metaplasia, and dysplasia. However, the study was done at a
referral center where 34% of patients had dysplasia and NBI was not compared with a white
light assessment or standardized gastric biopsy protocol. Additionally, the results were not
provided on a per patient basis, which is the most relevant endpoint in clinical practice.

2.0 OBJECTIVES AND PURPOSE Prompt detection of gastric cancer precursors enables early
detection and less invasive treatment options such as endoscopic resection. Narrow band
imaging is a completely noninvasive technique which uses filtered light to enhance
assessment of mucosa. Our aim is to gauge whether biopsies targeted by narrow band imaging
improves the detection of gastric intestinal metaplasia and gastric dysplasia relative to
standard white light techniques on a per patient basis. A secondary aim will be to assess
whether the technique is amenable to standardization so that it might be used more broadly
to identify patients with early gastric neoplasia. While NBI is built into the vast majority
of endoscopes in use few physicians are aware of its potential use.

3.0 STUDY DESIGN

The study will be a prospective tandem endoscopy trial. All EGDs will have already been
planned as part of standard clinical care.

High definition white light endoscopy will initially be performed. The specific location of
all mucosal findings in the stomach such as ulceration or nodularity which require biopsy
will be noted by the endoscopist and research coordinator but will not be biopsied until
after NBI. This is done so that blood will not distort or bias NBI assessment. Any abnormal
findings in other parts of the GI tract examined using the scope (esophagus and duodenum)
will be noted and biopsied.

At the completion of the white light exam, while the scope is in the stomach, the white
light endoscopist will press a button on the scope which changes the view to the narrow band
imaging.

At this point the NBI endoscopist who is initially blinded to the white light findings will
enter the procedure room and examine the stomach using NBI. The type and location of NBI
abnormalities will be noted and biopsies obtained.

At the end of the NBI exam the NBI endoscopist will switch the scope view back to white
light mode. The white light endoscopist will return to the room and biopsy any sites
identified and recorded during the initial white-light endoscopy. A research coordinator
present for the entire procedure will verify and record that all sites identified during the
initial white light exam are biopsied.

Subsequently, random biopsies will be performed by taking 2 biopsies from the lesser
curvature (body and antrum), 2 biopsies from the greater curvature (body and antrum), and
one from the angle.

The biopsies obtained by white light exam, narrow band imaging exam, and random sampling
will be separately coded and submitted to pathology. Histologic analysis will be performed
by expert GI pathologists blinded to the acquisition approach.

Short 10 second video clips of each site targeted for biopsy by white light narrow band
imaging will be recorded. They will be matched with the final biopsy results and stored
WITHOUT personal health identifiers. These short videos may be used for training and shared
with collaborators to assess inter-observer variability and standardize the interpretation
of NBI of the stomach.

The primary outcome measure will be yield of NBI, high definition white light endoscopy, and
random biopsy for the detection of atrophic gastritis, IM and dysplasia on a per patient
basis. A secondary endpoint will be the number of regions found by each method to exhibit
atrophic gastritis, IM, and dysplasia (per lesion (region) yield). The yields of H. Pylori
by method and the total number of biopsies guided per method will be additional outcomes.

Patients will be enrolled at the Los Angeles County Hospital of the University of Southern
California as well as the Gastroenterology Unit at the University of Porto in Porto
Portugal. The protocol originates from and statistical analysis will be done at the
University of Southern California. No personal health identifiers will be exchanged at any
point between the two institutions.

Prior to the formal initiation of the study there will be a lead in period of 10-20 patients
with gastric symptoms. The initial patients will be examined using the white light, NBI, and
gastric biopsy protocol. After this the images will be discussed by the investigators at the
two centers to make certain that NBI interpretation of gastric premalignant changes is
standardized. The LAC+USC investigators will also review the Portugese video training
library on gastric NBI. Any changes in performance of the lead in versus the study will be
noted to address the secondary aim of developing a standardized approach to NBI which may
help this technique be used widely to identify patients with early gastric neoplasia.

4 STATISTICAL CONSIDERATIONS

The Fisher's exact chi squared test will be used for dichotomous outcomes such as the
accurate detection of the highest level histology and number of biopsies. Adverse reactions
will be reported in a descriptive manner.

Based on previous research which showed 74% correction detection of gastric cancer
precursors with white light endoscopy versus 89% with NBI and given our anticipated gastric
cancer prevalence of 20% we performed preliminary sample size estimates for a range of OR
using G*Power (alpha=0.05, beta =0.20). We anticipate an N of 200 will be sufficient to show
a significant difference between methods.

Inclusion Criteria:

- presenting for upper endoscopy for gastric indications

- gastric indications include upper abdominal pain dyspepsia abnormal gastric imaging
iron deficiency anemia gastric ulcer management of GI blood loss without active
bleeding reflux weight loss.

Exclusion Criteria:

- Subjects who are incarcerated, younger than 18, or unable to give informed consent
will be excluded.

- Patients who have evidence of active gastrointestinal bleeding will be excluded

- Patients taking anti-thrombotic agents including clopidogrel, ticlopidine, coumadin,
heparin, enoxaparin, and direct II or Xa inhibitors

- Patients with INR >1.5, platelet count <75,000