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Local-regional carcinoma of the esophagus is often diagnosed in advanced stages because the diagnosis is established when symptoms are severe. The prognosis of patients with local-regional carcinoma of the esophagus continues to be grim. While preoperative chemoradiotherapy increases the fraction of patients who achieve pathologic complete response, that percentage is approximately 25%. In an attempt to increase the number of patients with either no cancer in the surgical specimen or only microscopic cancer, we adopted a three-step strategy. The current study utilized up to two 6-week cycles of induction chemotherapy with irinotecan (CPT-11, Camptosar) and cisplatin as step 1. This was followed by concurrent radiotherapy and chemotherapy with continuous infusion fluorouracil (5-FU) and paclitaxel as step 2. Once the patients recovered from chemoradiotherapy, a preoperative evaluation was performed and surgery was attempted. All patients signed an informed consent prior to their participation on the study. A total of 43 patients were enrolled. The baseline endoscopic ultrasonography revealed that 36 patients had a T3 tumor, five patients had a T2 tumor, and two had a T1 tumor. Twenty-seven patients had node-positive cancer (N1). Thirty-nine (91%) of the 43 patients underwent surgery; all had an R0 (curative) resection. A pathologic complete response was noted in 12 of the 39 patients. In addition, 17 patients had only microscopic (< 10%) viable cancer in the specimen. Therefore, a significant pathologic response was seen in 29 (74%) of 39 taken to surgery or 29 (67%) of all 43 patients enrolled on the study. With a median follow up beyond 25 months, 20 patients remain alive and 12 patients remain free of cancer. Our preliminary data suggest that the proportion of patients with significant pathologic response can be increased by using the three-step strategy.