A Phase II, Multi-Center Study of Interventional Spray Cryotherapy for Early-Stage 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.