Purpose/Objectives: A prospective single arm trial was undertaken to determine the toxicity, the clinical and pathologic response rates and survival for patients with esophageal cancer treated with concurrent chemotherapy(CC) and accelerated hyperfractionated split course radiotherapy(AHFSCRT) followed by surgical resection.Materials and Methods: A prospective single arm trial was conducted between 1991 and 1995 for patients with T1-4, N0-1, M1(celiac or supraclavicular) adenocarcinoma or squamous cell carcinoma of the esophagus. A total of 74 patients entered onto the protocol, and 72 are eligible and evaluable. Neoadjuvant chemotherapy consisting of two cycles of Cisplatin(20mg/m2/day) and 5-fluorouracil (1000mg/m2/day) given concurrently with AHSCRT 1.5Gy BID (at least 6 hour between fractions) to 2400cGy and 2100cGy, with cycles 1 and 2 of chemotherapy respectively. Patients were staged/restaged with barium esophagram(BS), computerized tomograph of the chest(CAT), upper endoscopy(EGD) with ultrasound (EUS) and evaluated for surgical resection. A single adjuvant course of concurrent chemotherapy and AHSCRT was delivered for those patients who were pathologic partial responders(pPR).Results: Initial clinical staging revealed one patient stage I, 24 patients' stage IIA, 2 patients' with stage IIB, 34 patients' with stage III and 6 patients' with stage IV disease. Five patients could not be staged adequately. The toxicity to neoadjuvant therapy included nausea in 85% (grade 3 in 1%), esophagitis 90% (grade 3 in 18%), neutropenia grade 3 of 43% (with fever 17%), thrombocytopenia grade 4 in 10% and nephrotoxicity in 8%. There was one death due to neoadjuvant therapy. Of the 72 evaluable patients, 67 underwent surgery, and 65(90%) had a complete resection. Twenty-seven percent were pathologic complete responders, including 22% with adenocarcinoma and 36% with squamous cell carcinoma. Complete pathologic response after neoadjuvant therapy was accurately predicted by improvement of symptoms in 82%, resolution of abnormalities on barium swallow in 36%, CAT in 18%, EGD in 18% and EUS 9%. CR was predicted inaccurately by these means in 47%, 50%, 67%, 33% and 50% respectively. The median duration of follow-up is 24 months. There have been 35 deaths. Twelve of the deaths are attributable to distant metastatic disease. Twelve deaths were attributable to post-operative complications including 7 from respiratory distress and 7 from other causes. Seven patients died of unrelated causes while disease free. There have been no local failures in patients who have completed therapy. The Kaplan-Meier 3-year projected relapse-free and overall survival are 53% and 47% respectively. RFS and overall survival did not differ significantly when analyzed by cell type or response to induction therapy.Conclusions: The toxicity of the induction regime was moderate with one induction death, 1% grade 3 nausea, 18% grade 3 esophagitis, 43% grade 3 neutropenia and 10% grade 4 thrombocytopenia. Most treatment related mortality occurred perioperatively or postoperatively. It is unclear what contribution any one modality played in these deaths. The overall response rate was 55% with 27% being complete responders. The ability to predict complete responders based on clinical or radiographic means was not possible. Overall survival was encouraging, as was the absence of local failure in those who completed therapy. Future studies will be aim at decreasing the toxicity of the therapy, while maintaining excellent local control and hopefully improving overall survival.