A dose-finding study of epirubicin in combination with paclitaxel in the treatment of advanced breast cancer.
We performed a dose escalation study to evaluate the maximum tolerated dose of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given over 3 hours plus bolus epirubicin 90 mg/m2. The starting dose of paclitaxel, 135 mg/m2, was escalated by 20-mg/m2 increments in cohorts of three to six patients. Courses were repeated every 3 weeks. Filgrastim (5 micrograms/kg/d) was administered to shorten the duration of grade 4 neutropenia lasting longer than 72 hours. Twenty-nine patients have been treated, 86% of whom had failed adjuvant chemotherapy (with anthracyclines in 14 cases). One hundred forty-eight courses have been administered, and the paclitaxel dose has been escalated to 225 mg/m2 without reaching the maximum tolerated dose. The most frequent dose-related toxicity has been grade 4 neutropenia, which occurred in 59% of courses. The median duration of grade 4 neutropenia was 4 days, which was shortened with filgrastim only in patients treated with paclitaxel 225 mg/m2. Eleven episodes of febrile neutropenia (7% of courses) have been observed. Nonhematologic toxicities were mild or moderate: grade 1 or 2 peripheral neuropathy was reported by 41% and 10% of patients, respectively. The cardiac toxicities of this regimen were surprisingly low: median left ventricular ejection fraction was 57% at study entry and 56% after six courses. Only two patients showed a decrease of left ventricular ejection fraction below 50% after six courses, and no signs of anthracycline-induced congestive heart failure were noted. The activity of this novel combination is encouraging: the overall response rate is 80%, with 16% complete responses. We have demonstrated that the combination of epirubicin plus paclitaxel given over 3 hours is feasible with acceptable toxicities, does not appear to be associated with clinically relevant cardiotoxicity, and is active in a population of patients who have failed adjuvant chemotherapy.
Division of Medical Oncology, St Chiara Hospital, Pisa, Italy.
P F
PF
Conte
A
A
Michelotti
E
E
Baldini
B
B
Salvadori
A
A
Gennari
M
M
Da Prato
C
C
Tibaldi
E
E
Salzano
A
A
Gentile
D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D017024:Chemotherapy, Adjuvant; D015331:Cohort Studies; D004361:Drug Tolerance; D015251:Epirubicin / Q000008:administration & dosage* / Q000009:adverse effects; D005240:Feasibility Studies; D005260:Female; D005334:Fever / Q000139:chemically induced; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000627:therapeutic use; D006321:Heart / Q000187:drug effects; D006333:Heart Failure / Q000139:chemically induced; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced / Q000188:drug therapy; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D011994:Recombinant Proteins; D012074:Remission Induction; D013318:Stroke Volume / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D015251:Epirubicin; D017239:Paclitaxel; D000069585:Filgrastim