Comparison Between Definitive Chemoradiotherapy and Esophagectomy in Patients With Clinical Stage I Esophageal Squamous Cell Carcinoma Sachiko Yamamoto MD, Ryu Ishihara MD, Masaaki Motoori MD, Yoshifumi Kawaguchi MD, Noriya Uedo MD, Yoji Takeuchi MD, Koji Higashino MD, Masahiko Yano MD, Satoaki Nakamura MD and Hiroyasu Iishi MD Am J Gastroenterol 2011; 106:1048–1054 R1 Jong Kyu Byun/ Prof. Jae Young Jang

INTRODUCTION Esophageal cancer is the sixth most common causes of cancer- related mortality worldwide. Squamous cell carcinoma remains the most common tumor type. Stage I (UICC-TNM classification: T1N0M0) esophageal cancer, defined as mucosal or submucosal cancer without lymph node or distant metastasis Esophagectomy has been the mainstay of treatment for esophageal cancer Esophagectomy is associated with significant mortality and substantial morbidity. Chemoradiotherapy (CRT) has been proposed as an alternative to esophagectomy, because of its favorable survival rate and mild toxicity To compare the overall survival of two cohorts of patients with clinical stage I esophageal squamous cell carcinoma treated with either CRT or conventional esophagectomy. Esophageal cancer is the sixth most common causes of cancer-related mortality worldwide. Although the incidence of esophageal adenocarcinoma is rapidly increasing in Europe and North America squamous cell carcinoma remains the most common tumor type. The overall survival of patients with esophageal cancer remains poor . Stage I esophageal cancer, defined as mucosal or submucosal cancer without lymph node or distant metastasis, Esophagectomy has been the mainstay of treatment for esophageal cancer, with chemoradiotherapy (CRT) or chemotherapy adding a modest survival benefit in some studies. Esophagectomy is only possible in those patients who are able to tolerate the procedure, and is associated with significant mortality and substantial morbidity. CRT for clinical stage I esophageal cancer has been proposed as an alternative to esophagectomy, because of its favorable survival rate and mild toxicity However, no comparative studies of esophagectomy and CRT have been reported in clinical stage I esophageal squamous cell carcinoma patients. The aim of this study was to compare the overall survival of two cohorts of patients with clinical stage I esophageal squamous cell carcinoma treated with either CRT or conventional esophagectomy.

METHODS Patient population and staging system Retrospective cohort study of patients with clinical stage I esophageal squamous cell carcinoma, untreatable by endoscopic therapy. Submucosal cancers or widespread cancers larger than 5 cm or with a circumferential spread more than 2/3 were referred for CRT or esophagectomy Diagnostic tool T-category - endoscopy, endosonography N-category - CT. Let me show you the Methods This was a retrospective cohort study of patients with clinical stage I esophageal squamous cell carcinoma, untreatable by endoscopic therapy Submucosal cancers or widespread cancers larger than 5 cm or with a circumferential spread more than two-third were referred for chemoradiotherapy or esophagectomy T-category was mainly diagnosed by endoscopy, which has demonstrated comparable diagnostic accuracy to endosonography for T1 esophageal cancer N-category was mainly diagnosed by CT.

METHODS Chemoradiotherapy Esophagectomy A total of 53 patients were treated with cisplatin and fluorouracil- based chemotherapy Concurrent radiotherapy using 10-MV X-rays was delivered at a dose of 2 Gy per day, five days a week, for a total dose of 60 Gy in 30 fractions. Esophagectomy Two- or three-field lymphadenectomy via right- thoracotomy Chemoradiotherapy -> A total of 53 patients were treated with cisplatin and fluorouracil- based chemotherapy Concurrent radiotherapy using 10-MV X-rays was delivered at a dose of 2 Gy per day, five days a week, for a total dose of 60 Gy in 30 fractions. Esophagectomy The most frequently used procedure was esophagectomy with two- or three-field lymphadenectomy via right thoracotomy

METHODS Follow-up evaluation and pattern of recurrence CRT 1–2 months after CRT and then every 3–6 months for the first 2 years, and every 6 months thereafter. PEx , blood test, endoscopy of the esophagus with iodine staining, and CT scan of the neck, chest, and abdomen. Esophagectomy every 6 months for 5 years. PEx, blood test, and CT scan of the neck, chest, and abdomen. Endoscopy was performed annually. Local recurrence included the recurrence or progression of the primary tumor, and metachronous esophageal cancer. Non-local recurrence included recurrence in the lymph nodes or any site beyond the primary tumor. Follow-up evaluations for patients who received CRT were performed 1–2 months after CRT and then every 3–6 months for the first 2 years, and every 6 months thereafter. Biopsy of the primary tumor site was performed when abnormal findings were detected in the esophagus. Follow-up evaluations for patients who underwent esophagectomy were performed every 6 months for 5 years. Patterns of treatment failure were defined as the site of recurrence. Local recurrence included the recurrence or progression of the primary tumor, and metachronous esophageal cancer. Non-local recurrence included recurrence in the lymph nodes or any site beyond the primary tumor. When metastasis was observed in patients with a second primary cancer other than at the esophagus, the origin of metastasis was decided on the basis of the histology and/or distribution of the metastatic cancer

Statistical analysis overall survival, progression-free survival (PFS) Start : Day 1 of CRT or the date of esophagectomy End : The date of death or 31 March 2009, whichever occurred first. progression-free survival (PFS) Start : Day 1 of CRT or the date of esophagectomy, End : The date of recurrence or death, or 31 March 2009, whichever occurred first. For all analyses a two-sided P value of <0.05 was considered statistically significant. For analysis of overall survival, the start of follow-up was defined as day 1 of CRT or the date of esophagectomy, and the end was either the date of death or 31 March 2009, whichever occurred first. For analysis of progression-free survival (PFS), the start of follow-up was defined as day 1 of CRT or the date of esophagectomy, and the end was either the date of recurrence or death, or 31 March 2009, whichever occurred first. For all analyses a two-sided P value of less than 0.05 was considered statistically significant.

RESULTS SURG group CRT group Now I’m going to show you some tables ,figures which is related results. This Flow chart about patient recruitment. A total of 207(two hundreds seven) patients were initially treated by endoscopic resection, whereas 226 (two hundredstwenty six) patients were initially treated with modalities other than endoscopic therapy at Osaka Medical Center for Cancer and Cardiovascular Diseases between February 1995 and August 2008 . A total of 54(fifity four) patients underwent CRT and 116(one hundred sixteen ) patients underwent esophagectomy (SURG group) and included in this study. The baseline characteristics of these patients are summarized in next table SURG group CRT group

RESULTS Let’s show this table Patients in the CRT group were older and the lesions in the CRT group were larger than those in the SURG group

RESULTS Survival Follow up Observation period Death CRT group 100 % (54 patients) SURG group 99 % (115 of 116 patients ) Observation period CRT group 30 (4–77) months SURG group 67 (10–171) months Death CRT group 6 (3 deaths due to esophageal ca.) SURG group 30 (20 deaths due to esophageal ca.) All 54 patients (100%) in the CRT group and 115 of 116 patients (99%) in the SURG group were completely followed up until their death or until 31 March 2009. The median (range) observation period was 67 (10–171) months in the SURG group, which was significantly longer than 30 (4–77) months in the CRT group (P<0.0001). There were 30 deaths in the SURG and 6 in the CRT group during the follow-up period. Ten patients in the SURG group, and three in the CRT group died of esophageal cancer

Overall survival rates RESULTS in the SURG group The 1- and 3-year overall survival rates were 97.4% and 85.5 in the CRT group 98.1% and 88.7 in the SURG progression free survvial rate (non-local) rates were 93.9% and 81.9% in the CRT group 90.5% and 83.5% Overall survival rates PFS (non-local) rates SURG CRT 1- year 97.4% 98.1% 3-year 85.5% 88.7% SURG CRT 1- year 93.9% 90.5% 3-year 81.9% 83.5%

RESULTS In this table .Cox proportional hazards modeling showed that the overall survival was comparable between the two groups after adjusting for age, sex, and tumor size. The hazard ratio of CRT for overall survival was 0.95 In female and More than seventy years old group ,hazard ratio was higher

RESULTS The incidence of local recurrence, including metachronous esophageal cancer, was significantly higher in the CRT group than in the SURG group BUT Most local recurrences after CRT, including metachronous cancers, were mucosal cancers and were cured following treatment with no effect on survival Most local recurrences after CRT, were cured following treatment with no effect on survival.

Conclusion The overall survival rate Locally recurrent carcinoma was endoscopically treatable in most patients, with no effect on overall survival. CRT seems to be a viable alternative to esophagectomy in patients with clinical stage I esophageal cancer. Chemoradio Tx Esophagectomy Now let’s show conclusion The overall survival rate of patients with clinical stage I esophageal cancer treated with CRT was comparable to that in those treated with esophagectomy, despite a high local recurrence rate. Locally recurrent carcinoma was endoscopically treatable in most patients, with no effect on overall survival. CRT seems to be a viable alternative to esophagectomy in patients with clinical stage I esophageal cancer.