Trial Information

Endoesophageal Cryotherapy: A New Technique For Ablating Barrett's Esophagus And Early Stage Esophageal Cancer

Baseline evaluation will include the following ( all are considered standard of care except
# 8 ):

1. Informed consent.

2. Evaluation of inclusion/exclusion criteria

3. Demographics- date of birth, age, gender, ethnicity

4. Medical history and physical exam

5. Imaging (groups 2, 3 and 4) i. CT scan of the chest and abdomen with oral and
intravenous contrast (if not allergic) ii. Endoscopic Ultrasound, with evaluation of
the esophageal wall and mediastinum and upper abdomen for evidence of abnormal lymph
nodes. Suspicious lymph nodes (round, hypoechoic, homogeneous, > 5mm) will undergo
EUS-guided fine needle aspiration if appropriate, as deemed by the principal
investigator.

6. Pathology review (groups 2 and 4) - two independent reviewers, including at least one
from the WRAMC Pathology Department, will review the pathology slides from esophageal
biopsies. This review will serve to confirm the diagnosis of Barrett's esophagus with
high grade dysplasia and/or IMCA for agreement of the diagnosis of adenocarcinoma and
the degree of dysplasia.

7. Presentation at Tumor Board prior to entering the protocol (groups 2, 3 and 4).

8. Dysphagia score (see Appendix 4) is for research purposes.

Prior to cryotherapy:

As part of the research protocol, all patients will be treated with high dose proton pump
inhibitor (PPI) (lansoprazole 30mg, esomeprazole 40mg, pantoprazole 40mg, omeprazole 40mg or
rabeprazole 40mg) BID for maximal acid suppression until complete ablation is achieved or
the patient exits the study. All of these agents are considered equally effective at the
doses listed with no one agent considered superior. Treatment with these research doses
will begin at least one week prior to the first cryotherapy session. Pre-enrollment
standard doses of PPI will be restarted once the patient enters the surveillance phase or
exits the study. Care will be taken to avoid, if possible, any potentially toxic medications
to the esophageal mucosa (i.e. non-steroidal anti-inflammatory drugs, bisphosphonates,
potassium supplements).

EGD/Cryotherapy Patients will be scheduled for EGD with cryotherapy on designated days when
support for the cryotherapy device is available according to the study timeline (Appendix
2). A commitment from the CSA Medical Inc. (Baltimore, MD) will provide technical support
for sessions to allow patients timely treatment.

Patients will prepare for EGD in the standard fashion using an overnight fast with only sips
of clear liquids and required medications allowed up to 2 hours before the procedure.
Patients will be interviewed prior to the procedure using a standardized questionnaire
(Appendix 3). This questionnaire will assess overall sense of well-being, general state of
health, ability to perform activities of daily living, and ability to eat. It will
specifically solicit symptoms of chest pain, irregular heart rate, shortness of breath,
dysphagia or odynophagia. A dysphagia score will also be measured (appendix 4).

Moderate sedation with intravenous meperidine or fentanyl and midazolam will be administered
and staff investigators will perform the EGD using a therapeutic upper endoscope with
adherence to standard protocol. A 14 to 18 French nasogastric tube which has been modified
with decompression ports spanning the distal 12 inches of the tube (to allow decompression
of both the stomach and the esophagus) will be placed into the stomach under direct
visualization. This is connected to continuous suction to allow decompression during the
cryotherapy procedure. During the procedure an assistant will monitor and record the heart
rate, blood pressure and oxygen saturation per WRAMC moderate sedation guidelines.

All subjects will be treated with narcotic analgesics and anti-emetics as needed after each
procedure.

Groups 1, 2 and 4 At the first procedure, the most proximal edge of the squamocolumnar
junction (SCJ) and the tips of the gastric folds (gastroesophageal junction of GEJ) will be
marked with a submucosal tattoo of India ink (SPOT, GI Supply, Camp Hill, PA) using a
standard sclerotherapy needle (if not already performed). The ink tattoo will guide
measurement of response to ablation and sampling the neo-squamous segment for residual
Barrett's during follow up exams. For severe esophageal squamous dysplasia, the tattoo will
be applied at the proximal and distal margins of the dysplastic area. If not allergic to
iodine, Lugol's solution will be used to stain the squamous mucosa during the exam to
outline the area of severe squamous dysplasia and guide the tattoo placement. Lugol's is
chosen since normal squamous, but not dysplasia or carcinoma stains with this vital stain.
These marks are placed for research purposes only and help to ensure that accurate
measurements to assess the change of Barrett's segment with therapy are recorded. (30) The
location of the squamocolumnar junction (SCJ), the esophagogastric junction (EGJ) and
diaphragmatic hiatus (DH) will be documented in terms of centimeters from the incisors. Any
islands of squamous tissue within the Barrett's segment will be photographed, measured, and
recorded. If the SCJ is not well visualized, chromoendoscopy with Lugol's solution, which
highlights the squamous epithelium, will be performed.

The cryocatheter is passed into the therapeutic channel of the endoscope and extended one cm
beyond the distal tip of the scope. Liquid nitrogen is sprayed through the cryocatheter,
which causes a white frost (cryoburn) on the adjacent mucosa. The most distal aspect of the
Barrett's esophagus segment is treated first and the endoscope is slowly withdrawn
proximally, maneuvering the tip of the cryocatheter such that the cryoburn is extended to
"paint" a white frost cryoburn circumferentially. The spray will be applied for duration of
10 seconds as measured by the integrated device timer. During each cryotherapy session, the
process will be repeated up to four times in piecemeal fashion such that for any given area
treated it will be maintained in a frozen state for a total of 40 seconds. A frozen state
will be defined as mucosa appearing white.

At the completion of the endoscopic procedure, the patients are monitored in our recovery
area until completely awake, alert and able to be discharged according to our standard
conscious sedation policy. Following discharge from the endoscopy suite, patients will be
contacted in one week by telephone to assess for any immediate complications. A
questionnaire will be completed by the study physician or nurse (appendix 3). Patients will
be seen the same day in the clinic or endoscopy center for any serious concerns (patient or
study personnel).

Patients will return in 6 weeks (groups 1, 2 and 4) for reassessment with a repeat EGD and
cryotherapy for residual Barrett's mucosa. The interview questionnaire and dysphagia score
will be repeated before each EGD. The location of the SCJ, the EGJ and DH and dysplastic
region will be recorded and photographed to characterize the precise size and location of
any islands of squamous tissue within the Barrett's segment. If there is gross evidence of
mucosal injury due to the previous cryotherapy (any mucosal break including erosions, tears,
or ulcers) the procedure will be terminated and further ablation will be held for an
additional 2 weeks. If there is no gross evidence of esophageal mucosal injury, cryotherapy
will be repeated. The process will continue until complete ablation of the Barrett's mucosa
has been achieved or the maximum number of treatment sessions has been performed (8
treatments total).

When it appears endoscopically that all or nearly all of the mucosa has been replaced with
normal appearing squamous mucosa, a biopsy or several biopsies may be taken at the
discretion of the endoscopist of any suspicious areas to confirm that cryotherapy has been
completed. When such "quick look" biopsies have been taken, no cryotherapy will be
performed that day.

If the pathology results return revealing sub-squamous intestinal metaplasia or dysplasia,
cryotherapy may be resumed two weeks after the biopsies had been taken (to allow adequate
time for the mucosa to have healed). If the biopsy confirms resolution, the patient will
then be scheduled for post-cryotherapy surveillance.

Biopsies taken during these endoscopies will be used only for the clinical purpose of
assessing the patient's histologic response to cryotherapy. As such, no excess tissue will
be collected or stored for any purposes.

Group 3:

Group 3 patients will undergo cryotherapy with intent to ablate the neoplasia. Group 3
patients with long segment Barrett's esophagus will undergo ablation of only the nodular
areas and/or mass lesions. Flat Barrett's will not be treated. The mass lesion will be
treated in its entirety until frozen or up to 20 seconds. This will be repeated for a total
treatment time of 60 seconds.

Follow up endoscopy to allow repeat treatment with cryotherapy will be every two weeks until
the lesion is eradicated or is treated up to 8 times, whichever comes first. These patients
are being offered more aggressive therapy (every 2 weeks rather than every 6 weeks), due to
the presence of more advanced disease. Treatment will be withheld for evidence of active
ulceration and will not be resumed until this has healed. When it appears endoscopically
that the cancer has been eradicated and all or nearly all of the mucosa has been replaced
with normal appearing squamous mucosa, a biopsy or several biopsies may be taken at the
discretion of the endoscopist of any suspicious areas to confirm that cryotherapy has been
completed. When such "quick look" biopsies have been taken, no cryotherapy will be
performed that day. If the pathology results return revealing sub-squamous intestinal
metaplasia, dysplasia or cancer, cryotherapy may be resumed. If the biopsy confirms
resolution, the patient will then be scheduled for post-cryotherapy surveillance.

Biopsies taken during these endoscopies will be used only for the clinical purpose of
assessing the patient's histologic response to cryotherapy. As such, no excess tissue will
be collected or stored for any purposes. No blood will be drawn for this study.

The initial EGD procedures are estimated to require up to 45 minutes to perform due to the
possible need to perform Lugol's staining and/or India ink marking of the esophagus.
Subsequent re-treatment EGD's are estimated to require no more than 30 minutes to perform.
An EGD that reveals healing where only "quick look" biopsies are taken will take no more
than 10 minutes to perform.