Metastatic breast cancer is an incurable disease, and, to date, there is no standard chemotherapy for patients with metastatic breast cancer in whom anthracycline-containing chemotherapy has failed. Tubulin-binding agents, such as vinblastine(Drug information on vinblastine) (Velban), vindesine(Drug information on vindesine) (Eldisine), vinorelbine (Navelbine), or paclitaxel(Drug information on paclitaxel) (Taxol) have yielded response rates of 15% to 35%[1-6] and mitomycin(Drug information on mitomycin) (Mutamycin), another commonly used agent in second-line regimens, has achieved objective response rates ranging from 15% to 25% at doses of 10 to 20 mg/m² administered every 4 to 8 weeks.[7,8]
Before the approval of paclitaxel and docetaxel(Drug information on docetaxel) (Taxotere), mitomycin and vinblastine (bolus or continuous infusion), either alone or in combination, were the backbone of most combinations used in patients in whom a prior anthracycline-containing regimen had failed. Several authors regard the combination of mitomycin and vinblastine as producing the highest antitumor activity compared with each drug used as a single agent[7,9-16], even though no advantage in survival was observed. So far, no large phase III study comparing paclitaxel to another chemotherapy regimen in patients with anthracycline-resistant advanced breast cancer has been reported.
Data from numerous phase II studies indicate that 100 mg/m² of docetaxel administered as a 1-hour infusion once every 3 weeks produces response rates of up to 58% in this group of patients.[17-21] These results appear significantly superior to other single agents and at least equivalent to the various combination therapy regimens.
This present trial represents the first phase III randomized study comparing a taxane (docetaxel) to an accepted salvage regimen (mitomycin/vinblastine) in patients in whom an anthracycline-containing regimen has failed. This preliminary analysis performed on 200 patients among the 392 recruited presents comparative data on the median time to progression, response rates, and toxicity profiles following treatment with docetaxel or the mitomycin/vinblastine combination regimen.
Women aged 18 to 75 years who had histologically or cytologically proven progressive metastatic adenocarcinoma of the breast and measurable and/or evaluable disease were considered for study participation provided they met the following criteria: Karnofsky performance status of at least 60% and failure of previous therapy with an anthracycline-containing regimen defined as:
- Primary resistant--patients who relapse on adjuvant chemotherapy or whose disease progresses
- Secondary resistant--patients who relapse within 12 months after adjuvant chemotherapy or disease progression on chemotherapy for metastatic breast cancer after an initial response
- Not resistant--patients with progression of metastatic disease at least 30 days after chemotherapy for metastatic breast cancer or exposure to previous anthracycline in an adjuvant and/or neoadjuvant setting, provided that further chemotherapy was given for advanced disease.
Laboratory entry criteria included the following values: absolute neutrophil count ³ 2.0 × 109/L; a platelet count ³ 100.0 × 109/L; total bilirubin £ 27.5 µM/L (1.5 g/dL); aspartate aminotransferase (ASAT) or alanine aminotransferase (ALAT) £ 3 × upper normal limit (UNL); alkaline phosphatase £ 6 × UNL; ASAT or ALAT or both 1.5 or less × UNL associated with alkaline phosphatase £ 2.5 × UNL; serum creatinine £ 175 µM/L (2 mg/dL); normal cardiac function using multiple-gated acquisition scan or echocardiography in patients who have received cumulative doses of doxorubicin(Drug information on doxorubicin) exceeding 550 mg/m² or 900 mg/m² of epirubicin(Drug information on epirubicin).
Specific criteria for exclusion were: more than one line of chemotherapy for advanced or metastatic disease; presence of brain or leptomeningeal metastases; prior or concurrent malignancies, with the exception of adequately treated in situ carcinoma of the uterine cervix and cured nonmelanoma skin cancer, and/or an osteoblastic skeletal lesion, and/or a single osteolytic lesion, and/or lymphedema, and/or pulmonary lymphangitic metastases and skin lymphangitis, and/or pleural effusion, and/or ascites, as the only site of disease; symptomatic peripheral neuropathy of at least grade 2 according to National Cancer Institute (NCI) Common Toxicity Criteria; unstable heart disease requiring treatment; congestive heart failure; angina pectoris or significant arrhythmias; and history of myocardial infarction within 6 months of study entry.
Patients were recruited from 49 centers worldwide. Ethics committee approval and patient written informed consent were obtained before the start of the trial.