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 (Velban), vindesine (Eldisine), vinorelbine
(Navelbine), or paclitaxel (Taxol) have yielded response rates of 15% to
35%[1-6] and 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 (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
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
- 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 exceeding 550 mg/m² or 900 mg/m² of 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.
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