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Docetaxel vs Mitomycin Plus Vinblastine in Anthracycline-Resistant Metastatic Breast Cancer

Docetaxel vs Mitomycin Plus Vinblastine in Anthracycline-Resistant Metastatic Breast Cancer

ABSTRACT: This nonblinded, multicenter, randomized phase III study compares the median time to progression (primary endpoint), response rate, and quality of life, safety, and survival of docetaxel (Taxotere) vs mitomycin (Mutamycin) plus vinblastine (Velban) in patients with metastatic breast cancer in whom previous anthracycline-containing chemotherapy has failed. Patients were randomized to receive an intravenous infusion of either 100 mg/m² of docetaxel for 1 hour every 3 weeks, or 12 mg/m² of mitomycin (Mutamycin) every 6 weeks plus 6 mg/m² of vinblastine every 3 weeks. This preliminary analysis presents data on 200 patients among 392 patients recruited. Median time to progression was longer in the group treated with docetaxel compared with the mitomycin/vinblastine group (17 vs 9 weeks). The overall response rates were higher with docetaxel (28% vs 13%, respectively), and fewer patients in the docetaxel group had progressive disease as their best overall response (29% vs 48%). As expected, thrombocytopenia was more common in the mitomycin/vinblastine group, and neutropenia occurred more frequently in the docetaxel group. Severe fluid retention in the docetaxel group (8.7%) resulted in treatment discontinuation in 5 patients (5%). Severe thrombocytopenia (12%) and constipation (6%) led to treatment discontinuation in 7 and 3 patients, respectively, in the mitomycin/vinblastine group. Based on this preliminary analysis, docetaxel appears to be equally as safe as and more active than mitomycin/vinblastine in patients with metastatic breast cancer in whom previous anthracycline-containing chemotherapy has failed. These results are subject to cautious interpretation because this analysis was conducted on the first 200 patients who finished the study treatments, and these preliminary results may underestimate response and overstate treatment discontinuation rates. Thus, the final analysis on the entire patient population is necessary to confirm these preliminary findings. [ONCOLOGY 11(Suppl 8):25-30, 1997]

Introduction

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.[1] 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.[1] So far, no large phase III study
comparing paclitaxel to another chemotherapy regimen in patients with anthracycline-resistant
advanced breast cancer has been reported.

Phase II Studies

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.

Patients and Methods

Patients

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 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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