A Randomized Phase II Trial of Capecitabine Plus Cisplatin (XP) Versus Capecitabine Plus Paclitaxel (XT) as a First-line Treatment for Advanced or Recurrent Esophageal Squamous Cell Carcinoma

1. Introduction and Study Rationale

1.1 Esophageal squamous cell carcinoma Esophageal cancer is the seventh most common cancer in Korea, with almost 400,000 new patients diagnosed annually worldwide. There are large variations in the predominant histological type throughout the world but the majority of worldwide esophageal cancers are squamous cell carcinoma arising from the upper and middle thirds of the esophagus. Esophageal cancer is a highly virulent disease with a five-year survival rate of 10-15% . Metastatic esophageal carcinoma is an incurable disease with median survival duration of 6 to 8 months .

1.2 5-FU plus Cisplatin (FP) combination chemotherapy Cytotoxic chemotherapy has been used to control tumor growth, improve quality of life and prolong survival although a survival advantage for chemotherapy over best supportive care alone in patients with metastatic cancer of the esophagus has not been proven in randomized trials. Although there is no standard chemotherapy regimen for metastatic esophageal cancer, various kinds of chemotherapy regimens have been used to alleviate symptoms caused by cancer and prolong survival and improve quality of life. Various phase-II trials have been performed to evaluate the effect of such chemotherapy. The activity of conventional single agent chemotherapy has been studied for cisplatin, 5-FU and mitomycin, which induced response rates of 15-30% . In most of these studies, the chemotherapy regimen consisted of a combination of cisplatin with another agent such as 5-FU or etoposide for both squamous cell carcinoma and adenocarcinoma. The most commonly used chemotherapy regimen for patients with advanced esophageal cancer is a combination of 5-FU and cisplatin, with response rates ranging from 15% to 45%, however, the effect on survival remained undetermined.

1.2 Capecitabine for esophageal cancer Capecitabine is a novel, orally administered fluoropyrimidine carbamate that is absorbed readily by the gastrointestinal tract and is metabolized by the liver, where it is converted initially to 5 -deoxy-5-fluorocytidine (5 -DFCR) and subsequently, to 5 -deoxy-5-fluorouridine (5 -DFUR). Designed to mimic continuous intravenous (CIV) 5-FU, oral capecitabine predominantly concentrates in tumor tissue . Capecitabine currently is approved as a single agent for the adjuvant treatment of stage III colon cancer, as first-line treatment for metastatic colorectal cancer, and for metastatic breast cancer both as a single agent for patients and in combination with docetaxel. Whether oral fluoropyrimidines may be appropriately substituted, therefore making the therapy less burdensome to the patient and reducing the need for infusion catheters, is not fully investigated In patients with advanced esophagogastric cancer, capecitabine combinations have generally shown good antitumor activity and highlight the potential of capecitabine as a replacement of infusional 5-FU . Capecitabine has been investigated in combination with cisplatin and docetaxel in phase II trials in patients with advanced esophageal cancer with observed response rates of 47.1% and 46%, respectively . In a recent phase III trial comparing the efficacy of capecitabine/cisplatin (XP) versus FP in advanced gastric cancer, XP was not inferior to FP, in terms of progression-free survival (PFS), overall survival (OS), and response rate (RR) . In our experience, the combination of capecitabine and cisplatin for esophageal cancer showed encouraging response rate (59%) with tolerable toxicities and convenience.

1.3 Paclitaxel for esophageal cancer Paclitaxel in combination with cisplatin has shown favorable results for advanced esophageal carcinoma . A recent phase II study of bi-weekly administration of paclitaxel and cisplatin in 51 patients resulted in complete response in 4%, partial response in 39%, stable disease in 43% and progressive disease in 14% of patients, and a one-year survival of 43% . Several phase II trials have assessed combinations of taxanes (paclitaxel and docetaxel) and cisplatin and other agents, with response rates of 40-56% .