A phase I/II dose-escalation study of weekly paclitaxel in combination with 5'-deoxy-5-fluorouridine for advanced or recurrent breast cance

Abstract

698 Background: Paclitaxel is one of effective agents for breast cancer treatment. The weekly schedule of paclitaxel is a common regimen around the world. Oral 5'-deoxy-5-fluorouridine (5'-DFUR) is an intermediate metabolite of Capecitabine. Thymidine phosphorylase (dThdPase) is an essential enzyme for the activation of the cytostatics 5'-DFUR / Capecitabine to 5-fluorouracil in tumors. Paclitaxel reportedly increased dThdPase levels in tumors in vivo study. To assess the dose-limiting toxicities (DLT), maximum tolerated dose (MTD) and anti-tumor activity of paclitaxel in combination with 5'-DFUR in patients with advanced or recurrent breast cancer. Methods: Eligible patients had measurable and/or evaluable metastatic lesions and were aged 20–75 years with a WHO performance status of 0–1. Those who had taken paclitaxel before and had peripheral neuropathy were excluded. Dose escalation schema was shown below. The main toxicities (NCI-CTC version 2) in the dose-escalation step were as follows: Grade (G) 4 neutropenia (for 4 days), febrile neutropenia, G 4 thrombocytopenia and G 3 nonhematological toxicity without nausea and vomiting were considered to be dose limiting. Results: Fifteen patients with a median age of 56 years (range 43–69) were included. Anti-tumor activity was assessed in total 15 patients, as 2 CR, 5 PR, 2 NC, 4 PD and 2 NE (response rate; 46.7%). At Level 1, one of six patients had DLT (febrile neutropenia). However, six patients did not reach DLT at Level 2 and 3. Then two patients had DLT at Level4, so it was regarded as MTD. Conclusions: Weekly paclitaxel in combination with 5'-DFUR did not increase hematological and nonhematological toxicity. Level 4 (paclitaxel 100 mg/m2 and 5'-DFUR 1,200 mg/body) was MTD. We decided that the recommended dose is Level 3 (paclitaxel 80 mg/m2 and 5'-DFUR 1200 mg/body). No significant financial relationships to disclose.