Spray Cryotherapy for Esophageal Cancer (ICE-CANCER)

Background

Endoscopic modalities have been reported to be effective in definitive treatment of early
stage esophageal cancer. A study comparing endoscopic treatment to surgery in early
esophageal cancer using the SEER (Surveillance Epidemiology and End Results) database showed
no difference in the relative hazard of death from esophageal cancer between the two groups.
The primary endoscopic therapies used in this study were endoscopic mucosal resection (EMR)
and photodynamic therapy (PDT). Estimated 1 and 3 year survival in this study were 92% and
75% in the endoscopic arm and 92% and 82% in the surgical arm. EMR, endoscopic excision of
superficial cancer, has also been shown to be highly effective in mucosal tumors in single
center studies. "Low-risk" lesions, defined as flat or raised mucosal tumors 2 cm or less
that are well-or moderately-differentiated without lymphovascular invasion, demonstrate
complete response was seen in 96.6% of patients with 5 year survival of 84%. However,
"high-risk lesions," defined as greater than 2 cm, poorly-differentiated, flat-ulcerated, or
invading into the submucosa, have a complete remission rate of only 59%.

Endoscopic resection is not possible in all mucosal cancers. Some cancers are not visible
endoscopically but detected only by endoscopic biopsy. In other cases, the EMR cannot be
done due to scarring from previous resection or other therapy, especially external beam
radiation. Management of these cases is problematic. PDT using porfimer sodium has been
extensively studied for Barrett's esophagus with high-grade dysplasia, however studies of
PDT for early stage esophageal cancer are limited. In a recent single site study using PDT
and EMR for mucosal cancers, overall survival was comparable to a group treated with
esophagectomy at the same center, with estimated 1 and 3 year survival of 98% and 95%. PDT
was used in 43% in combination with EMR in the endoscopic treatment group. Recurrent
carcinoma was detected in 16% of endoscopically treated patients. All recurrences were
intramucosal cancers, with all but one managed by EMR. Overall, endoscopic treatment was
well-tolerated. However, side effects of PDT are common and include photosensitivity,
esophageal stricture, chest pain, nausea, vomiting, and fever. In the U.S., PDT is no longer
commonly used in the esophagus due to availability of alternative treatment modalities with
less cost and side effects.

Endoscopic spray cryotherapy with liquid nitrogen has emerged as an alternative treatment in
stage I esophageal cancer in those not suitable for other therapies. A recent retrospective
review at 10 U.S. centers assessed outcomes in seventy-nine patients. Patients included
those with esophageal carcinoma who failed, refused, or were ineligible for conventional
therapy including chemotherapy, radiation, combination chemotherapy and radiation,
esophagectomy, and endoscopic mucosal resection. The majority of patients (76%) had tumor
stage T1N0M0 with mean tumor length of 4 cm. All patients were treated with liquid nitrogen
spray cryotherapy, and forty-nine patients completed treatment. Complete response of luminal
disease occurred in 61.2%, including 18 of 24 (75%) with mucosal cancer. Follow-up averaged
10.6 to 11.5 months, and no serious adverse events were reported. Longer term follow-up was
reported recently in abstract form. Complete response was seen in 92% of patients with
mucosal cancer with median follow-up of 28 months and overall estimated survival at 1 and 3
years of 98% and 92% respectively.

Published studies have demonstrated spray cryotherapy to be safe and well-tolerated, with
low overall complication rates. Tolerance of the procedure is very good. All procedures are
performed on an outpatient basis. Primary side effects include chest pain, dysphagia, and
odynophagia, reported in about half of all procedures. Mean duration of symptoms was 3.6
days, and many patients had no side effects after treatment. Serious adverse events were
rare. Gastric perforation occurred in one patient with Marfan's syndrome. Benign esophageal
stricture was reported in 13% of patients treated for cancer, with previous esophageal
narrowing noted in 9/10. In combination with its relative cost-effectiveness and minimal
invasiveness, endoscopic spray cryotherapy is an appealing option for those with stage I
esophageal cancer who are ineligible or refuse conventional therapies.

Study Device: truFreezeTM System, CSA Medical Inc., Baltimore, MD

Study Objective: The objective of this study is to evaluate the safety and efficacy of
endoscopic spray cryotherapy using the CSA Medical, Inc. truFreeze™ System for patients with
early-stage esophageal cancer (T1a, N0, M0) who are ineligible or refuse conventional
therapy including surgery, chemotherapy, radiation therapy, and endoscopic resection.

Study Design: Multi-center phase II study.

Study Population: Patients with early-stage esophageal cancer (stage T1aN0M0)

Study Duration: It is estimated that enrollment will take approximately two years. Each
subject will remain in the study for up to one-year of treatment and for three years
post-treatment. It is expected to take five years to collect all required data for this
study.

Sample size: 40

Treatment

Participant receives liquid nitrogen spray cryotherapy every 4 - 8 weeks x no more than 8
cycles. Those with complete response to therapy will proceed to surveillance. Those with
stable or responding disease will continue with cryotherapy. Those with progression of
disease will discontinue protocol. For responding or stable disease after 8 cycles, continue
treatment beyond 8 cycles until tumor progression or unacceptable toxicity. Discontinue
protocol therapy for disease progression or unacceptable toxicity.

Follow-Up Evaluations and Data Collection

Patients will return for surveillance EGD (esophagogastroduodenoscopy) procedures with
biopsies at 3, 6, 9, 12, 18, 24, 30, and 36 months (± 4 weeks) after the last cryotherapy
treatment. An estimate of tumor size and response compared to baseline will be made at each
endoscopy. Biopsies will be performed using large capacity forceps. In the area where tumor
was present, biopsies will be taken every 1 cm in each quadrant. Directed biopsies will be
performed in any areas that appear suspicious for cancer.

CT scan of the chest, abdomen, and pelvis (with oral and intravenous contrast if possible)
will be performed every 6 months during the follow-up period. Full body PET/CT may also be
performed instead of CT scanning.

Endoscopic ultrasound will be performed 6 months after treatment completion to assess for
lymphadenopathy.

At the conclusion of this protocol, regardless of the outcome, patients will continue to
require periodic surveillance endoscopies for re-emergence of esophageal cancer consistent
with the standard surveillance guidelines. This monitoring will be performed at the
investigator's site unless otherwise desired by the patient.

Inclusion Criteria:

- T1aN0M0 esophageal cancer (tumor invades no deeper than lamina propria or muscularis
mucosa, no regional lymph node or distant metastases), with the following minimum
diagnostic workup:

- History/physical exam within 6 weeks prior to enrollment

- PET and CT scan of the chest and abdomen within 12 weeks prior to enrollment

- Endoscopy with histology or cytology confirming carcinoma

- Endoscopic ultrasound (EUS) with evaluation of the esophageal wall, mediastinum, and
upper abdomen for evidence of abnormal lymph nodes. Suspicious lymph nodes will
undergo EUS-guided fine needle aspiration if appropriate, as determined by the
investigator.

- Endoscopic resection of focal lesions with histologic confirmation of positive deep
margin or residual cancer within the esophagus

- Not a candidate for or refuses conventional therapies (surgery, radiation,
chemotherapy, endoscopic resection) as determined by evaluation by the investigator,
discussion with the patient, and review in Thoracic or Gastrointestinal Tumor Board.

- For females: not pregnant (negative pregnancy test within 14 days of starting study
treatment), on acceptable means of contraception (oral contraceptives, barrier
methods, approved contraceptive implant, long-term injectable contraception,
intrauterine device or tubal ligation), or not of child bearing potential. Patients
are considered not of child bearing potential if they are surgically sterile (they
have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy)
or they are postmenopausal.

- 18 years of age or older

- ECOG Performance Status 0 - 2

Exclusion Criteria:

- Medically unfit or other contraindication to tolerate upper endoscopy with ablation

- Contraindication to endoscopic spray cryotherapy as outlined in the directions for
use for the device

- Other malignancy (except nonmelanoma skin cancer) within the past 1 year

- Co-morbid illness expected to cause death within 6 months

- Esophageal stricture preventing passage of endoscope or catheter

- Concurrent enrollment in an investigational drug or device trial that clinically
interferes with this study's endpoints throughout the study

- Inability to provide informed consent or comply with this protocol

- Concurrent or previous cancer therapy for current esophageal malignancy by
esophagectomy, chemotherapy, radiation therapy, and photodynamic therapy