RESUMO
Doxorubicin and paclitaxel both display strong antitumor activity in the treatment of breast cancer. The optimal schedule of this combination, however, remains undefined. In this phase I and pharmacologic study, we administered weekly 12 mg/m2 doxorubicin as a bolus infusion immediately followed by a 1 h 80 mg/m2 paclitaxel infusion to patients with metastatic breast cancer. A total of 119 weekly courses were delivered to seven patients. Grade IV neutropenia was observed in two patients at the first dose level, thus already defining the maximum tolerated dose. Pronounced non-hematologic toxicities were mild neuropathy (grade I: 39%) and stomatitis (grade I: 19%, grade II: 8%). No signs of cardiac toxicity were observed with this dose schedule. Three partial responses were achieved in this group of heavily pretreated patients. The pharmacokinetics of paclitaxel, doxorubicin and Cremophor EL with this schedule were analyzed. Overall, the schedule was well tolerated and combined with its preliminary response rate justifies further evaluation in phase II studies.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/farmacocinética , Doxorrubicina/uso terapêutico , Paclitaxel/farmacocinética , Paclitaxel/uso terapêutico , Adulto , Alopecia/induzido quimicamente , Alopecia/complicações , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Relação Dose-Resposta a Droga , Doxorrubicina/toxicidade , Esquema de Medicação , Feminino , Glicerol/análogos & derivados , Glicerol/farmacocinética , Humanos , Infusões Intravenosas , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/complicações , Paclitaxel/toxicidadeRESUMO
Paclitaxel (Taxol(R)) is an active agent in platinum-refractory ovarian cancer. Since the available pharmacokinetic data of 135 mg m-2 paclitaxel administered by 3-h infusion are scarce and fragmented, we now describe a comprehensive pharmacologic study in a group of 13 patients who were pretreated with platinum for advanced ovarian cancer. The mean paclitaxel AUC was 10.3+/-2.4 h micromol l-1 (range 6.8-13.9 h micromol l-1). Quantification of the two major paclitaxel metabolites, 6alpha-hydroxypaclitaxel and 3'-p-hydroxypaclitaxel yielded AUCs of 0.44+/-0.30 h micromol l-1 and 0.31+/-0.20 h micromol l-1, respectively. The AUC of 3'-p-hydroxypaclitaxel was significantly different from that of patients with an altered hepatic function. The administration of 135 mg m-2 single-paclitaxel was safe, and the toxicities observed at higher doses in earlier studies were absent in this study. This is important, because the schedule and paclitaxel dose of 135 mg m-2 given by a 3-h infusion is expected to be used more frequently in combination with other cytotoxic agents with the aim of improving efficacy.