Dose-finding study and pharmacokinetics of epirubicin and paclitaxel over 3 hours: A regimen with high activity and low cardiotoxicity in advance breast cancer

Pier Franco Conte, Editta Baldini, Alessandra Gennari, Andrea Michelotti, Barbara Salvadori, Carmelo Tibaldi, Romano Danesi, Federico Innocenti, Alfonso Gentile, Rita Dell'Anna, Ombretta Biadi, Mario Mariani, Mario Del Tacca

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Abstract

Purpose: To determine the maximum-tolerated dose (MTD) of paclitaxel over 3 hours with a fixed dose of epirubucin, to investigate the plasma pharmacokinetics of this combination, and to evaluate the toxicity and the activity in previously untreated metastatic breast cancer patients. Patients and Methods: Fifty patients with metastatic breast cancer, measurable disease, and normal left ventricular ejection fraction (LVEF) were eligible. Epirubicin was administered as an intravenous (IV) bolus at the fixed dose of 90 mg/m2 before the infusion of paclitaxel over 3 hours. The initial dose of paclitaxel was 135 mg/m2 and was increased by 20 mg/m2 in subsequent cohorts of six patients until dose-limiting toxicity (DLT). Plasma pharmacokinetics of paclitaxel and epirubicin was performed at cycle 1 in least two patients per dose level of paclitaxel (175 up to 225 mg/m2). Results: The DLT of this combination was febrile neutropenia in two of eight patients who received paclitaxel at 225 mg/m2. The mean peak plasma concentration of paclitaxel ranged between 5.1 and 6.2 μmol/L at doses of 175 to 225 mg/m2. The concentration of epirubicinol decreased from 47.3 ± 9.4 to 37.9 ± 7.5 ng/mL in a patients treated with paclitaxel 175 and 225 mg/m2. The most relevant toxicity was grade 4 neutropenia (61% of all courses). The pharmacokinetic data of paclitaxel, in particular the time above the treshold level of 0.05 μmol/L, were not significantly related to myelosuppression. Cardiac toxicity was mild: three patients (6%) developed mild congestive heart failure that was responsive to therapy. Among 49 assessable patients, 41 responses (84%; 95% confidence interval [CI], 70% to 92% were observed, and nine (18%) of these were complete. Conclusion: Our study demonstrates that (1) the MTD is epirubicin 90 mg/m2 and paclitaxel 200 mg/m2; (2) no clear relationship exists between pharmacokinetic data of paclitaxel and myelosuppression, while the increase in the dose of paclitaxel is associated with a reduction in epirubicinol plasma levels; and (3) the association is feasible, with low cardiotoxicity, and has a high activity in metastatic breast cancer.

Original languageEnglish
Pages (from-to)2510-2517
Number of pages8
JournalJournal of Clinical Oncology
Volume15
Issue number7
Publication statusPublished - Jul 1997

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Epirubicin
Paclitaxel
Pharmacokinetics
Breast Neoplasms
Maximum Tolerated Dose
Cardiotoxicity
Febrile Neutropenia
Neutropenia
Stroke Volume
Heart Failure

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Dose-finding study and pharmacokinetics of epirubicin and paclitaxel over 3 hours : A regimen with high activity and low cardiotoxicity in advance breast cancer. / Conte, Pier Franco; Baldini, Editta; Gennari, Alessandra; Michelotti, Andrea; Salvadori, Barbara; Tibaldi, Carmelo; Danesi, Romano; Innocenti, Federico; Gentile, Alfonso; Dell'Anna, Rita; Biadi, Ombretta; Mariani, Mario; Del Tacca, Mario.

In: Journal of Clinical Oncology, Vol. 15, No. 7, 07.1997, p. 2510-2517.

Research output: Contribution to journalArticle

Conte, PF, Baldini, E, Gennari, A, Michelotti, A, Salvadori, B, Tibaldi, C, Danesi, R, Innocenti, F, Gentile, A, Dell'Anna, R, Biadi, O, Mariani, M & Del Tacca, M 1997, 'Dose-finding study and pharmacokinetics of epirubicin and paclitaxel over 3 hours: A regimen with high activity and low cardiotoxicity in advance breast cancer', Journal of Clinical Oncology, vol. 15, no. 7, pp. 2510-2517.
Conte, Pier Franco ; Baldini, Editta ; Gennari, Alessandra ; Michelotti, Andrea ; Salvadori, Barbara ; Tibaldi, Carmelo ; Danesi, Romano ; Innocenti, Federico ; Gentile, Alfonso ; Dell'Anna, Rita ; Biadi, Ombretta ; Mariani, Mario ; Del Tacca, Mario. / Dose-finding study and pharmacokinetics of epirubicin and paclitaxel over 3 hours : A regimen with high activity and low cardiotoxicity in advance breast cancer. In: Journal of Clinical Oncology. 1997 ; Vol. 15, No. 7. pp. 2510-2517.
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abstract = "Purpose: To determine the maximum-tolerated dose (MTD) of paclitaxel over 3 hours with a fixed dose of epirubucin, to investigate the plasma pharmacokinetics of this combination, and to evaluate the toxicity and the activity in previously untreated metastatic breast cancer patients. Patients and Methods: Fifty patients with metastatic breast cancer, measurable disease, and normal left ventricular ejection fraction (LVEF) were eligible. Epirubicin was administered as an intravenous (IV) bolus at the fixed dose of 90 mg/m2 before the infusion of paclitaxel over 3 hours. The initial dose of paclitaxel was 135 mg/m2 and was increased by 20 mg/m2 in subsequent cohorts of six patients until dose-limiting toxicity (DLT). Plasma pharmacokinetics of paclitaxel and epirubicin was performed at cycle 1 in least two patients per dose level of paclitaxel (175 up to 225 mg/m2). Results: The DLT of this combination was febrile neutropenia in two of eight patients who received paclitaxel at 225 mg/m2. The mean peak plasma concentration of paclitaxel ranged between 5.1 and 6.2 μmol/L at doses of 175 to 225 mg/m2. The concentration of epirubicinol decreased from 47.3 ± 9.4 to 37.9 ± 7.5 ng/mL in a patients treated with paclitaxel 175 and 225 mg/m2. The most relevant toxicity was grade 4 neutropenia (61{\%} of all courses). The pharmacokinetic data of paclitaxel, in particular the time above the treshold level of 0.05 μmol/L, were not significantly related to myelosuppression. Cardiac toxicity was mild: three patients (6{\%}) developed mild congestive heart failure that was responsive to therapy. Among 49 assessable patients, 41 responses (84{\%}; 95{\%} confidence interval [CI], 70{\%} to 92{\%} were observed, and nine (18{\%}) of these were complete. Conclusion: Our study demonstrates that (1) the MTD is epirubicin 90 mg/m2 and paclitaxel 200 mg/m2; (2) no clear relationship exists between pharmacokinetic data of paclitaxel and myelosuppression, while the increase in the dose of paclitaxel is associated with a reduction in epirubicinol plasma levels; and (3) the association is feasible, with low cardiotoxicity, and has a high activity in metastatic breast cancer.",
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T1 - Dose-finding study and pharmacokinetics of epirubicin and paclitaxel over 3 hours

T2 - A regimen with high activity and low cardiotoxicity in advance breast cancer

AU - Conte, Pier Franco

AU - Baldini, Editta

AU - Gennari, Alessandra

AU - Michelotti, Andrea

AU - Salvadori, Barbara

AU - Tibaldi, Carmelo

AU - Danesi, Romano

AU - Innocenti, Federico

AU - Gentile, Alfonso

AU - Dell'Anna, Rita

AU - Biadi, Ombretta

AU - Mariani, Mario

AU - Del Tacca, Mario

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N2 - Purpose: To determine the maximum-tolerated dose (MTD) of paclitaxel over 3 hours with a fixed dose of epirubucin, to investigate the plasma pharmacokinetics of this combination, and to evaluate the toxicity and the activity in previously untreated metastatic breast cancer patients. Patients and Methods: Fifty patients with metastatic breast cancer, measurable disease, and normal left ventricular ejection fraction (LVEF) were eligible. Epirubicin was administered as an intravenous (IV) bolus at the fixed dose of 90 mg/m2 before the infusion of paclitaxel over 3 hours. The initial dose of paclitaxel was 135 mg/m2 and was increased by 20 mg/m2 in subsequent cohorts of six patients until dose-limiting toxicity (DLT). Plasma pharmacokinetics of paclitaxel and epirubicin was performed at cycle 1 in least two patients per dose level of paclitaxel (175 up to 225 mg/m2). Results: The DLT of this combination was febrile neutropenia in two of eight patients who received paclitaxel at 225 mg/m2. The mean peak plasma concentration of paclitaxel ranged between 5.1 and 6.2 μmol/L at doses of 175 to 225 mg/m2. The concentration of epirubicinol decreased from 47.3 ± 9.4 to 37.9 ± 7.5 ng/mL in a patients treated with paclitaxel 175 and 225 mg/m2. The most relevant toxicity was grade 4 neutropenia (61% of all courses). The pharmacokinetic data of paclitaxel, in particular the time above the treshold level of 0.05 μmol/L, were not significantly related to myelosuppression. Cardiac toxicity was mild: three patients (6%) developed mild congestive heart failure that was responsive to therapy. Among 49 assessable patients, 41 responses (84%; 95% confidence interval [CI], 70% to 92% were observed, and nine (18%) of these were complete. Conclusion: Our study demonstrates that (1) the MTD is epirubicin 90 mg/m2 and paclitaxel 200 mg/m2; (2) no clear relationship exists between pharmacokinetic data of paclitaxel and myelosuppression, while the increase in the dose of paclitaxel is associated with a reduction in epirubicinol plasma levels; and (3) the association is feasible, with low cardiotoxicity, and has a high activity in metastatic breast cancer.

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