BACKGROUND In patients with advanced esophageal adenocarcinoma, the efficacy and palliative role of systemic chemotherapy are not well defined. The primary objective of this Phase II trial was to evaluate the antitumor activity and toxicity of a multiday chemotherapy schedule of high dose cisplatin and etoposide in patients with unresectable or metastatic esophageal adenocarcinoma. A secondary objective was to assess the efficacy of this regimen in palliating dysphagia. METHODS Twenty-seven eligible patients with unresectable locoregional or metastatic esophageal adenocarcinoma were treated with cisplatin, 30 mg/m2/day, and etoposide, 60 mg/m2/day, intravenously daily for 5 days, every 3 weeks. After three cycles of chemotherapy, all patients were assessed for response. Patients with responding metastatic disease were given one additional cycle of chemotherapy, and patients with locoregional disease received radiation and concurrent continuous infusion of 5-fluorouracil at 300 mg/m2/day for the duration of radiation therapy. Patients were questioned about dysphagia symptoms initially and then weekly during chemotherapy. RESULTS The major toxicities included myelosuppression, nausea and vomiting, and peripheral sensory neuropathy, with one treatment-related death. Major responses were observed in 13 patients (48%; 95% confidence intervals, 36-74%), including 5 complete and 8 partial responses. Dysphagia relief occurred in 89% of 18 symptomatic patients within a median time of 16 days. The median survival duration for all patients was 9.8 months, and the actuarial 3-year survival rate was 22%. CONCLUSIONS Multiday chemotherapy with high dose cisplatin and etoposide is active in patients with advanced esophageal adenocarcinoma. Toxicities associated with this regimen are substantial but manageable.