Phase I study of a weekly schedule of a fixed dose of cisplatin and escalating doses of paclitaxel in patients with advanced oesophageal cancer

The objective of this study was to determine the toxicities and maximum tolerated dose (MTD) of a dose-dense schedule with a fixed dose of cisplatin and escalating doses of paclitaxel in patients with metastatic or irresectable squamous cell-, adeno-, or undifferentiated carcinoma of the oesophagus. Patients received paclitaxel over 3 h followed by a 3-h infusion of a fixed dose of cisplatin of 70 mg/m(2) on days 1, 8. 15, 29. 36 and 43. The starting dose of paclitaxel was 80 mg/m(2). Patients were re-treated if white blood cell count (WBC) was greater than or equal to 1 x 10(9) cells/l, except for day 29 when the WBC had to be greater than or equal to 3 x 10(9) cells/l. Six patients were treated at each dose level, The dose of paclitaxel was increased by 10 mg/m(2) per level. Of the 24 patients enrolled, 13 had adenocarcinoma, 10 had squamous cell carcinoma and one had an undifferentiated carcinoma. All patients were evaluable for toxicity and 22 of 24 patients were evaluable for response. The paclitaxel dose could be escalated to 110 mg/m(2). At this dose, 3 out of 6 patients developed dose-limiting toxicity (DLT) including neutropenic enterocolitis with sepsis. vomiting and diarrhoea. Diarrhoea grades 3 and 4 was seen in 4 (17%) patients. Two of these patients died of neutropenic enterocolitis. Neutropenia grades 3 or 4 was seen in 20 (83%) patients. but apart from the two patients with neutropenic enterocolitis no other infectious complications were seen. Mild to moderate sensory neurotoxicity was seen in 11 (46%) patients (grade I in 8 patients and grade 2 in 3 patients). Other toxicities were mild and easily manageable. Of the 22 evaluable patients. It (50%) patients achieved a partial or complete response with a median duration of 13 months. Ten patients with either locally advanced disease or supraclavicular or celiac lymph nodes received additional local treatment after response to chemotherapy, seven patients are still without evidence of disease after a median follow-up of 32 months. Paclitaxel at a dose 100 mg/m(2) infused over 3 h followed by a 3-h infusion of 70 mg/m2 cisplatin can be recommended for further studies in patients with metastatic or unresectable oesophageal cancer. Occurring diarrhoea should be handled with caution because it may be a sign of neutropenic enterocolitis. The response rate of this dose-dense schedule seems encouraging. (C) 2002 Elsevier Science Ltd. All rights reserved.