Trial Information

Barrett's Esophagus Study (BEST) Trial - a Multi-Center and Endoscopic Outcomes Project

Barrett's esophagus (BE) is defined as a change in the esophageal mucosa from normal
squamous epithelium to columnar epithelium with intestinal metaplasia (1). There is
compelling evidence that BE is a precursor lesion for adenocarcinoma of the esophagus (2).
There is also evidence that the prevalence of BE is much higher than was initially
suspected, and that the true incidence rate of cancer in patients with BE is much lower than
previously estimated. Endoscopic surveillance of all patients with BE is not likely to be
cost effective, or save many lives. Therefore, it is important to understand which patients
with BE are likely to progress to malignancy, and equally important to determine which
patients are not likely to progress.Because progression is an uncommon event, definitive
studies of natural history including evaluation of numerous risk factors require large
numbers of patients, that can only be accomplished in the context of a multicenter study.
This model will be a useful tool leading to a reduction in overall health care costs.

An Opportunity to Generate the Essential Knowledge for Intervention. We have established an
initial network of investigators interested in the 'Barrett's Esophagus Study' (a long term,
longitudinal, prospective study) and collected preliminary data in patients with BE. To
date, 1376 patients from 4 centers have been entered into a central databank. We have
presented preliminary data on the incidence and prevalence rates of high-grade dysplasia and
cancer at national meetings. We now propose the creation of a formal consortium to perform a
cohort study with the ultimate primary aim of defining risk factors for the development of
high-grade dysplasia and adenocarcinoma in patients with BE. Such a multi-center,
prospective, cohort, multi-disciplinary approach to BE was endorsed by the "NIH PRG on
stomach and esophageal cancers" (May 2002).

BACKGROUND & CLINICAL SIGNIFICANCE Barrett's Esophagus the pre-malignant lesion for
esophageal adenocarcinoma - a Condition of Rapidly Increasing Incidence. Patients with BE
are at an increased risk for the development of esophageal adenocarcinoma and
esophagogastric junction adenocarcinoma. Adenocarcinoma of the esophagus is believed to
arise from BE in a step-wise progression from low-grade dysplasia to high-grade dysplasia,
finally leading to frank adenocarcinoma (4,5). The cost effectiveness of surveillance
endoscopy in patients with BE is very sensitive to the incidence of cancer (11). The exact
incidence of adenocarcinoma in patients with BE is not known and has been reported to vary
from 1 in 50 patient-years of follow up to 1 in 285 patient-years of follow up (18-22). The
published incidence data from existing cohorts of patients with BE have been influenced by
the small number of patients being evaluated, short duration of follow-up as well as by the
demographics of the population being studied (e.g. older patients, male sex). To date, the
maximum number of patients included in a published study determining the incidence of
adenocarcinoma has been only 327 patients (23,24). The ultimate goal of the proposed study
is to establish a large cohort of patients with BE to address issues of incidence,
progression and risk factors influencing progression. Such an approach was recently endorsed
by the "NIH 2002 PRG on stomach and esophageal cancers".

Factors predicting the development of dysplasia and cancer in BE patients are unknown. A few
possible factors have been associated with esophageal adenocarcinoma, but not studied in BE
patients. These include GERD symptoms, obesity, diet, smoking, prior cholecystectomy, drugs
and H pylori infection (negative association) (25-36). The presence of hiatal hernia and BE
length have been associated with dysplasia and cancer development in BE patients in a
preliminary single center study (37). Reflux symptoms have also been reported to be
significantly more prevalent among parents and siblings of patients with BE and esophageal
adenocarcinoma than spouse control relatives (38). A few uncontrolled reports have provided
conflicting results on the role of anti-reflux surgery and the use of acid suppressive
medications (proton pump inhibitors, H2 receptor antagonists) and their effect on the
neoplastic progression in BE patients (39-43). However, all the studies to date in BE
patients have been limited by small sample sizes, univariate analysis, short duration of
follow-up, lack of adjustment for confounding variables etc. In this proposed study, risk
factors and mechanisms of capturing data at each site and data transfer to the main study
database will be discussed and implemented. Sample size calculations for appropriate
univariate and multiple logistic regression analysis will be performed.

Proposed Study will Fill Significant Gaps in Knowledge. In the recent "NIH PRG on stomach
and esophageal cancers (May 2002)" and a workshop sponsored by the NIH & The American
Digestive Health Foundation on endoscopic priorities (44), experts in the field acknowledged
that there was a need for multi-center, longitudinal, studies and there were significant
gaps in the knowledge base of BE including:

1. Risk stratification of cancer risk

2. Appropriate method of surveillance and technique for identifying dysplasia

3. Frequency and benefits of surveillance

4. Optimal management of BE such as acid suppression and endoscopic reversal techniques
The ultimate goal of the BE Study is to address issues #1 and #3 i.e. risk
stratification of Barrett's patients, and by developing a large, multi-site database,
will prepare the way for future studies that can address the other key issues.

The information gained will be clinically useful. We will define the natural history of
progression of BE patients and to determine factors involved in this progression to
high-grade dysplasia and cancer. The potentially unique answers obtained from the study
would have major clinical relevance in

- Defining the natural history of dysplasia/cancer in BE patients and to identify risk
factors involved in progression to dysplasia/cancer.

- Helping clarify what predisposes only a small subset of BE patients to develop
dysplasia/cancer. Rigorous examination of a number of risk factors may define this
patient group, thereby focusing our limited health care resources to the patient subset
at increased risk for the development of dysplasia/cancer - "reduction in health care
costs"

- Potential to change our current costly clinical practice of endoscopic surveillance of
all BE patients, by limiting surveillance to the 'high-risk group' - "improve clinical
decision making"

- Providing better and accurate information to our BE patients regarding their 'true'
risk for dysplasia and cancer.

PRELIMINARY STUDIES At this time, preliminary data have been collected from the 4
participating centers, and merged into one single databank. These preliminary results were
presented at the plenary sessions (45,46) of the American Gastroenterological Association
(AGA) annual meeting in Atlanta, GA (May 2001) and at the American College of
Gastroenterology (ACG) annual meeting in Las Vegas, NV (October 2001), indicating a common
interest amongst the investigators and capability of working together.

Distribution of Degree of Dysplasia. From the four participating centers, 1376 patients have
met the study criteria and had at least one endoscopy with biopsy revealing intestinal
metaplasia, thus confirming the diagnosis of BE. At the initial endoscopy, the distribution
of dysplasia was as follows:

Diagnosis Number of pts. Prevalence Low-grade dysplasia (LGD) 101 7.3% High-grade dysplasia
(HGD) 42 3% Esophageal adenocarcinoma 91 6.7% Incidence and progression to low-grade
dysplasia, high-grade dysplasia and esophageal adenocarcinoma. 1376 patients were enrolled
in the prevalence phase of the study. To date, 618 patients (95% Caucasians, 14% Females)
have had follow-up endoscopic procedures to examine the incidence of dysplasia/cancer. They
have been followed for a total of 2546 patient-years; mean follow up 4.12 patient-years
(range: 1-22.5 yrs). Twelve patients developed cancer during follow up for a cancer
incidence of 1 in 212 patient-years of follow up or 0.5% per year. The mean time to
development of cancer was 5.3 yrs (range: 2.4-11.2 yrs). Of interest, 7 of 12 patients had
high-grade dysplasia before cancer development while 2 had only low-grade dysplasia; 3
developed cancer from BE without dysplasia documented at any point. 22 patients developed
high-grade dysplasia during follow up for an estimate of high-grade dysplasia incidence of 1
in 116 patient-years of follow up or 0.9% per year. The mean time to high-grade dysplasia
development was 3.8 yrs (range: 1.2-7.9 yrs). 11 of 22 patients developed high-grade
dysplasia from BE without documented dysplasia, whereas the remaining 11 went from low-grade
dysplasia to high-grade dysplasia.

Risk Factors for BE and adenocarcinoma. The epidemiology and natural history of BE has been
poorly studied. Some factors have been associated with an increased risk for esophageal
adenocarcinoma in the general population (see Table 1), but risk factors for progression in
BE patients are not clear. A number of risk factors have been suggested as factors of risk
in BE patients including age, gender, ethnicity, GERD symptoms, family history of BE/cancer,
alcohol, tobacco, dietary factors (fat intake, cereal fiber, calcium etc.) acid suppressive
medications, biomarkers, genetic markers etc. Given this long list of possible risk factors,
we propose to convene a panel of experts in a planning committee to serve as jury in order
to determine which of the potential risk factors should be measured in a prospective study
and how they should be measured. This would narrow and refine the list of risk factors for
the prospective study.

There are a lot of purported risk factors to be evaluated. Thus, there is a long list (see
below) of potential factors of risk in patients with BE associated with progression to
dysplasia and/or cancer:

(1) Age (2) Gender (3) Ethnicity (4) Reflux symptoms (5) Smoking (6) Alcohol (7) Dietary fat
(8) Dietary fiber, vegetables, fruits (9) Dietary calcium (10) Obesity (11) Family history
of reflux, BE or esophageal cancer (12) Use of aspirin, non-steroidal anti-inflammatory
drugs (13) Use of lower esophageal sphincter relaxing medications (14) Use of acid
suppressive medications (15) Cholecystectomy (16) Anti-reflux surgery (fundoplication) (17)
Length of BE (18) Hiatal hernia (19) Helicobacter pylori infection (20) Low-grade dysplasia
on biopsy This proposal will make it feasible to narrow on the factors to be studied in the
prospective trial.

Statistical Analysis Prevalence and incidence rates: We expect to increase the
baseline-screened population from 1376 to more than 2500 individuals in the final study. The
number of patients we expect to enroll each year will be calculated and the expected number
of new prevalence cases using the 9.7% prevalence rate with the preliminary study data will
be estimated. In the preliminary study to date 618 patients have had at least one follow-up
visit. Including the remaining 700 patients from the preliminary study and assuming a 10%
rate for loss to follow up, we will have 6100-7450 patient years of follow up. The expected
number of new incidence cases using the 1.3% incidence rate with the preliminary study data
will be estimated.