ABSTRACT
AIM: To define the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of the carboplatin-vinorelbine combination in pretreated patients with advanced breast cancer. PATIENTS AND METHODS: Patients with histologically confirmed metastatic breast cancer relapsing or progressing after prior taxane and anthracycline containing chemotherapy were enrolled. Cohorts of 3-6 patients were treated at successive dose levels (DLs) with escalated doses of carboplatin [range, area under the curve (AUC) 4-6] on day 1 and vinorelbine (range, 20-35 mg/m(2)) on days 1 + 8 recycled every 28 days. RESULTS: Twenty-seven patients with a median age of 58 years and performance status (WHO) of 0-2 were treated at 6 DLs. All patients were assessable for toxicity and 20 for response. DLT was reached at carboplatin 6 AUC and vinorelbine 35 mg/m(2), and therefore, this was considered as the MTD. Prophylactic G-CSF administration could not allow further dose escalation. The recommended dose for further phase II testing was defined at carboplatin 6 AUC on day 1 and vinorelbine 30 mg/m(2) on days 1 and 8. Among 98 administered treatment cycles 41 (42%) and 7 (7%) were complicated with grades 3 and 4 neutropenia and thrombocytopenia, respectively. Nonhematologic toxicities included grade 2 peripheral neuropathy in 3 cycles and grades 2 and 3 fatigue in 32 (32%). CONCLUSION: The present study determined the feasibility of the combination of carboplatin at AUC 6 (day 1) and vinorelbine at 30 mg/m(2) (days 1 and 8 ) without G-CSF support in patients with taxane and anthracycline pretreated advanced breast cancer. Phase II studies at these doses should follow in order to determine the activity of the regimen.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/drug therapy , Vinblastine/analogs & derivatives , Adult , Aged , Antibiotics, Antineoplastic/administration & dosage , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/adverse effects , Breast Neoplasms/pathology , Carboplatin/administration & dosage , Carboplatin/adverse effects , Drug Administration Schedule , Feasibility Studies , Female , Humans , Middle Aged , Paclitaxel/administration & dosage , Treatment Outcome , Vinblastine/administration & dosage , Vinblastine/adverse effects , VinorelbineABSTRACT
PURPOSE: To determine the maximum tolerable dose (MTD) and the dose-limiting toxicity (DLT) of docetaxel (D) in combination with epirubicin (Epi) in patients with advanced breast cancer. PATIENTS AND METHODS: Forty-seven chemotherapy-naïve metastatic breast cancer patients aged < 75 years with PS (WHO) 0-2 and adequate bone marrow, renal, liver and cardiac function, were enrolled in the study. Epi was given as a five-min bolus i.v. infusion on day 1 (d1) in escalated doses with increments of 10 mg/m2; D was given in a one-hour infusion after appropriate premedication on either day 1 or on day 2 in escalated doses with increments of 10 mg/m2. The patients' median age was 60 years, 42 (89%) had a PS (WHO) 0-1, 16 (34%) were premenopausal and 25 (53%) had visceral disease. RESULTS: When the two drugs were given on the same day, the MTD1 was reached at the doses of Epi 60 mg/m2 and D 80 mg/m2; administration of G-CSF could not result in a dose intensification. When the drugs were given on two consecutive days, the MTD2 was reached at the doses of Epi 80 mg/m2 (d1) and D 90 mg/m2 (d2). The dose-limiting events were febrile neutropenia and grade 4 neutropenia, which developed in 30 (64%) patients during the study; among 227 delivered cycles grade 3-4 neutropenia occurred in 64 (28%) cycles but only 22 (10%) of them were complicated by fever. There were no septic deaths. Grade 1-2 neurosensory toxicity occurred in nine (19%) patients, mild edema in eight (17%) and allergic reactions in five (11%). Four (9%) patients presented a greater than 10% decrease of LVEF and treatment discontinuation was required in two of them; none of the patients developed congestive heart failure. Nevertheless, one patient suddenly died 10 days after treatment initiation of myocardial ischemia, and this death is considered treatment-related. Five (14.7%) complete and thirteen (38.2%) partial responses (ORR: 53.9%; 95% confidence interval: 36.1%-69.7%) were observed in 34 evaluable patients. Ten (29.4%) and six (17.6%) patients had stable and progressive disease, respectively. The median duration of response and time to tumor progression were five and seven months, respectively. The median survival has not yet been reached. CONCLUSIONS: The combination of epirubicin and docetaxel is a feasible and well tolerated regimen, but the MTD depends on the administration schedule of the drugs.
