PURPOSE We have previously identified paclitaxel as an active single agent in the treatment of esophageal cancer. We performed a phase II trial of paclitaxel in combination with cisplatin and fluorouracil (5-FU), conventionally used chemotherapy for esophageal cancer. The antitumor response, toxicity, and survival of patients treated with the three-drug regimen were evaluated. PATIENTS AND METHODS Sixty-one patients with advanced, surgically unresectable, or metastatic squamous cell or adenocarcinoma of the esophagus were treated. No prior chemotherapy was allowed. Thirty patients had adenocarcinoma and 31 patients had squamous cell carcinoma. The majority (47 patients; 77%) had metastatic disease and 14 patients (23%) had an unresectable primary or locally recurrent tumor. Patients received paclitaxel 175 mg/m2 by 3-hour infusion day 1; cisplatin 20 mg/m2 daily days 1 through 5, and 5-FU by continuous infusion at a dose of 1,000 mg/m2 daily days 1 through 5. Because of toxicity observed in the first 10 patients treated, the starting dose of 5-FU was subsequently reduced to 750 mg/m2 daily in the remaining patients. A planned attenuation of cisplatin to 15 mg/m2 daily was made after the first three cycles. Granulocyte colony-stimulating factor (G-CSF) was not routinely administered unless the patient had an episode of febrile neutropenia or prolonged grade 4 neutropenia. Treatment was recycled every 28 days. RESULTS Sixty-one patients completed a median of five cycles, and 60 patients were assessable for response. Major responses were seen in 29 patients (48%; 95% confidence intervals, 35 to 61), which included seven complete responses (12%). Comparable response rates were seen for patients with adenocarcinoma (46%) and those with squamous carcinoma (50%), and for patients with metastatic disease (22 of 46 patients; 48%) and those with locally advanced disease (seven of 14 patients; 50%). A significantly higher complete response rate was observed in patients with squamous carcinoma (20%) compared with those with adenocarcinoma (3%; chi2 P=.04). The median duration of response was 5.7 months (range, 1 to 18.6 months). Median survival was 10.8 months (range, 1.5 to 25 months). Toxicity was severe but manageable with dose attenuation, and included 18% of patients with grade 3 neurologic toxicity. Twenty-eight patients (46%) required a dose attenuation for toxicity, and 42 of 275 treatment cycles (15%) required a dose attenuation. Twenty-nine patients (48%) required hospitalization for toxicity, which included 11 patients for neutropenic fever (18%). There were no treatment-related deaths. CONCLUSION The combination of paclitaxel, cisplatin, and 5-FU has substantial antitumor activity in metastatic esophageal carcinoma, with a remarkable complete response rate noted in patients with squamous carcinoma. Paclitaxel is an important new agent in the treatment of esophageal carcinoma, and further evaluation of this agent in combination chemotherapy is warranted. Given the toxicity associated with the current regimen, the optimal dose and schedule of paclitaxel in combination chemotherapy remain to be established.