RESUMEN
OBJECTIVE: The 7-year follow-up of the US oncology 9735 trial demonstrated the superiority of TC [docetaxel (DTX)/cyclophosphamide (CPA)] to doxorubicin/CPA therapy. To introduce TC therapy in Japan, the verification of the safety and tolerability is essential. We performed a collaborative prospective safety study with Okayama University to introduce TC therapy. METHODS: The subjects were 53 patients aged from 33 to 67 years at intermediate risk based on the St Gallen risk classification who underwent radical surgery for primary breast cancer between August 2007 and December 2008. As post-operative adjuvant chemotherapy, four cycles of TC (DTX 75 mg/m(2) + CPA 600 mg/m(2)) were administered at 3-week intervals. Adverse events were evaluated based on National Cancer Institute-Common Terminology Criteria for Adverse Events ver. 3.0. The safety and completion rate were evaluated as the primary and secondary endpoints, respectively. RESULTS: Regarding hematological toxicity, Grade (G) 4 neutropenia occurred in 71.7% and G3 in 26.4%. G3-4 leukopenia developed in 32.1% and 56.6%, respectively, G4 anemia in 1.9% and G1-2 anemia in 26.4%. Regarding non-hematological toxicity, systemic malaise, skin eruption, edema, myalgia, arthralgia and nausea were noted in most patients. The completion rate was 94.3%, dose reduction was necessary in 7.5% and granulocyte colony-stimulating factor (G-CSF) support was required in 17.0%. On comparison between patients aged 65 years or older and younger than 65 years, the completion rate, dose reduction and incidence of febrile neutropenia (FN) were higher in the elderly patients. G-CSF support was more often needed in this subgroup. CONCLUSIONS: TC therapy is tolerable for Japanese patients, but attention should be paid to the development of FN and neutropenia. The completion rate was lower in the elderly patients, showing that tolerability was not necessarily favorable.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anciano , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Ciclofosfamida/administración & dosificación , Docetaxel , Estudios de Factibilidad , Femenino , Humanos , Japón , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Tasa de Supervivencia , Taxoides/administración & dosificación , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: The primary purposes of this study were to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD), to recommend a dose for phase II studies, and to analyze the pharmacokinetics of KW-2170. A secondary purpose was to assess tumor response to KW-2170. EXPERIMENTAL DESIGN: KW-2170 was given as a 30-min i.v. infusion every 4 weeks. Doses were escalated from 1.0 mg/m2 according to a modified Fibonacci method. RESULTS: A total of 45 cycles of KW-2170 were delivered to 41 patients at doses ranging from 1.0 to 53.0 mg/m2. The primary DLT was neutropenia which was observed in two of six patients treated at 32.0 mg/m2 and in two of two patients treated at 53.0 mg/m2; therefore, the MTD was 53.0 mg/m2. Although no patients showed a complete response (CR)or partial response (PR), 15 patients were evaluated a shaving freedom from progression at the 1-month time-point, with two demonstrating slight tumor shrinkage in their metastatic lesions. None of the patients experienced significant cardiotoxicity. The plasma concentration of KW-2170 declined in a triphasic manner. The half-life, total clearance (CLtot) and volume of distribution (Vdss) were nearly constant and independent of dose, and showed a relatively small interpatient variability. A linear relationship was observed between dose and maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC 0-infinity). In addition, there was a good correlation between neutropenia and AUC 0- infinity. This suggests that toxicity may be dependent on systemic exposure to the drug. Two oxi-dative metabolites were observed in the patients' plasma and urine. CONCLUSIONS: The primary DLT of KW-2170 in this study was neutropenia, with a MTD of 53 mg/m2.A significant linear relationship was observed between neutropenia and AUC 0- infinity. We estimate the recommended dose for phase II studies to be 41.0 mg/m2.