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Phase I Trial of Escalating-Dose Irinotecan Given Weekly With Cisplatin and Concurrent Radiotherapy in Locally Advanced Esophageal Cancer

David H. Ilson, Manjit Bains, David P. Kelsen, Eileen O’Reilly, Martin Karpeh, Daniel Coit, Valerie Rusch, Mithat Gonen, Katie Wilson, Bruce D. Minsky

From the Gastrointestinal Oncology Service, Department of Medicine, and Departments of Surgery, Radiation Oncology, and Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY.

Address reprint requests to David H. Ilson, MD, PhD, 1275 York Ave, New York, NY 10021; email: ilsond{at}mskcc.org.

Purpose: To identify the maximum-tolerated dose and dose-limiting toxicity (DLT) of weekly irinotecan combined with cisplatin and radiation in esophageal cancer.

Patients and Methods: Nineteen patients with clinical stage II to III esophageal squamous cell or adenocarcinoma were treated on this phase I trial. Induction chemotherapy with weekly cisplatin 30 mg/m² and irinotecan 65 mg/m² was administered for four treatments during weeks 1 to 5. Radiotherapy was delivered weeks 8 to 13 in 1.8-Gy daily fractions to a dose of 50.4 Gy. Cisplatin 30 mg/m² and escalating-dose irinotecan (40, 50, 65, and 80 mg/m²) were administered on days 1, 8, 22, and 29 of radiotherapy. DLT was defined as a 2-week delay in radiotherapy for grade 3 to 4 toxicity.

Results: Minimal toxicity was observed during chemoradiotherapy, with no grade 3 or 4 esophagitis, diarrhea, or stomatitis. DLT caused by myelosuppression was seen in two of six patients treated at the 80-mg/m² dose level, thus irinotecan 65 mg/m² was defined as the recommended phase II dose. Dysphagia improved or resolved after induction chemotherapy in 13 (81%) of 16 patients who reported dysphagia before therapy. Only one patient (5%) required a feeding tube. Six complete responses (32%) were observed, including four pathologic complete responses in 15 patients selected to undergo surgery (27%).

Conclusion: Cisplatin, irinotecan, and concurrent radiotherapy can be administered on a convenient schedule with relatively minimal toxicity and an acceptable rate of complete response in esophageal cancer. Further phase II evaluation of this regimen is ongoing. A phase III comparison to fluorouracil or taxane-containing chemoradiotherapy should be considered.

Supported in part by a grant from Pfizer, New York, NY.

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