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Dose-finding study of epidoxorubicin and docetaxel as first-line chemotherapy in patients with advanced breast cancer

Pagani, O. ; Sessa, C. ; Martinelli, G. ; Crivellari, D. ; Buonadonna, A. ; Thürlimann, B. ; Hess, D. ; Borner, M. ; Bauer, J. ; Zampino, G. ; Zimatore, M. ; Graffeo, R. ; Riva, A. ; Goldhirsch, A.

In: Annals of Oncology, 1999, vol. 10, no. 5, p. 539-545

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    Title
    • Dose-finding study of epidoxorubicin and docetaxel as first-line chemotherapy in patients with advanced breast cancer
    Author
    • Pagani, O.. Istituto Oncologico delta Svizzera Italiana, Ospedale S. Giovanni Bellinzona, Switzerland
    • Sessa, C.. Istituto Oncologico delta Svizzera Italiana, Ospedale S. Giovanni Bellinzona, Switzerland
    • Martinelli, G.. Division of Medical Oncology and Clinical Oncology-Hematology Unit, European Institute of Oncology Milan
    • Crivellari, D.. Divisione di Oncologia Medica, Istituto Nazionale Tumori Aviano, Italy
    • Buonadonna, A.. Divisione di Oncologia Medica, Istituto Nazionale Tumori Aviano, Italy
    • Thürlimann, B.. Medizinische Klinik C, Kantonspital St. Gallen
    • Hess, D.. Medizinische Klinik C, Kantonspital St. Gallen
    • Borner, M.. Institute of Medical Oncology Inselspital, Bern
    • Bauer, J.. Centre Pluridisciplinaire d'Oncologie, CHUV Lausanne, Switzerland
    • Zampino, G.. Division of Medical Oncology and Clinical Oncology-Hematology Unit, European Institute of Oncology Milan
    • Zimatore, M.. Division of Medical Oncology and Clinical Oncology-Hematology Unit, European Institute of Oncology Milan
    • Graffeo, R.. Istituto Oncologico delta Svizzera Italiana, Ospedale S. Giovanni Bellinzona, Switzerland
    • Riva, A.. Research & Development, Rhone-Poulenc Rorer Antony, France
    • Goldhirsch, A.. Istituto Oncologico delta Svizzera Italiana, Ospedale S. Giovanni Bellinzona, Switzerland
    Document Type
    • Postprint
    OAI-PMH Identifier
    • oai:doc.rero.ch:292941
    Summary
    Background: Anthracyclines and taxanes are the most active drugs against breast cancer and the search after their optimal combination is under intensive investigation in both the advanced and early disease settings. A dose-finding study of epidoxorubicin (E) and docetaxel (D) was conducted in advanced breast cancer (ABC) to define the maximum tolerated dose (MTD) of the combination with and without granulocyte colony-stimulating factor (G-CSF) support and to characterise its toxicity and activity profile. Patients and methods: Forty-two patients who received neither palliative chemotherapy nor adjuvant anthracyclines (55% with dominant visceral disease and 66% with ≥2 sites involved) with measurable/evaluable lesions, were treated at four dose levels starting from E 75 mg/m2 and D 75 mg/m2 to E 120 mg/m2 and D 85 mg/m2. A maximum of four cycles of the combination was given every three weeks and four additional cycles of single agent D were allowed in responding patients. Cardiac function was monitored at baseline and at every second course by echocardiography. Results: Febrile neutropenia (two patients) and prolonged, severe neutropenia (absolute neutrophil count (ANC) <0.1 times 109/l for more than three days; one patient) defined the MTD of the combination without G-CSF support at E 90 mg/m2and D 75 mg/m2. G-CSF was then routinely administered from the subsequent dose level of E 120 mg/m2 and D 75 mg/m2. The MTD with G-CSF support was established at E 120 mg/m2 and D 85 mg/m2 (one patient with neutropenic fever together with failure of ANC recovery at day 21, three patients with ANC less than 0.1 × 109l for more than three days, one patient with both and one patient with grade 4 thrombocytopenia and toxic death from typhlitis while neutropenic). No severe neurotoxicity, mucositis, or fluid retention were observed and there were no clinical signs of cardiotox-icity. Antitumour activity was not a primary endpoint of the study: the overall response rate (ORR) in 40 evaluable patients was 60% (95% confidence interval: 43%-75%, 58% in liver disease, 84% in soft tissue) with no apparent dose-related effect. After a median follow-up of 19 months (range 2-30$), the overall time to progression (TTP) in nine patients without maintenance hormonal therapy was five months. Conclusions: The combination of E and D proved to be an effective and safe regimen in poor- prognosis patients with ABC. G-CSF support allowed higher doses to be delivered safely but dose escalation did not translate into improved response rates (RR). The MTD without growth factors support was used, in a phase II trial, which also included patients with previous anthracycline-containing adjuvant regimens