Docetaxel (Taxotere) is reported to have excellent activity against anthracycline-resistant metastatic breast cancer. In a series of 4 multicenter phase II trials, 100 mg/m² of docetaxel(Drug information on docetaxel) administered as a 1-hour intravenous infusion once every 3 weeks produced an overall response rate of 47% (range: 41% to 58%; 95% confidence interval), with a median time to progression of 4 months and survival of 10 months.[1-5]
These results are higher than those reported with doxorubicin(Drug information on doxorubicin) (Adriamycin) monotherapy, which is considered to be the most active single agent in second-line therapy for patients with metastatic breast cancer. Response rates associated with doxorubicin in the second-line treatment of metastatic breast cancer have ranged from 25% to 33%, with a median time to progression of 3.6 months and a median survival of 8.9 months.[6-13]
Because docetaxel has shown significant second-line activity in phase II trials, a phase III study was performed to compare the effects of docetaxel and doxorubicin in patients with metastatic breast cancer in whom prior alkylating chemotherapy failed. This preliminary analysis presents comparative data on the median time to progression after treatment, response rates, and toxicity profiles following treatment with docetaxel and doxorubicin. Data are presented on 200 of the 326 recruited 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: a performance status of at least 60% (Karnofsky index); no previous therapy with anthracyclines, anthracenediones, or taxanes; and failure after alkylating chemotherapy. Prior treatment with hormonal therapy for either advanced disease or in the adjuvant setting was permitted, as was radiation therapy.
Response after alkylating chemotherapy was defined as:
- Primary resistant--patients who relapsed during adjuvant chemotherapy or disease progression as the best response to chemotherapy for metastatic breast cancer
- Secondary resistant--patients who relapsed within 12 months after adjuvant chemotherapy or disease progression on chemotherapy for metastatic breast cancer after an initial response
- Not resistant--patients who relapsed at least 12 months after receiving adjuvant (first-line) chemotherapy or had disease progression at least 30 days after chemotherapy for metastatic breast cancer.
Laboratory entry criteria included the following values: absolute neutrophil count ³ 2.0 or greater × 109/L; a platelet count ³ 100.0 × 109/L; total bilirubin £ 1.25 or less × upper normal limit (UNL); aspartate aminotransferase (ASAT) or alanine aminotransferase (ALAT) £ 3 × UNL; alkaline phosphatase £ 6 × UNL; ASAT or ALAT or both £ 1.5 × UNL associated with alkaline phosphatase £ 2.5 × UNL; serum creatinine £ 1.5 × UNL; and a resting left ventricular ejection fraction above the lower normal limit of the institution, as measured by echocardiography or radionuclide angiocardiography.
Specific criteria for exclusion were: local recurrence within partially resected breast or locally advanced inoperable breast cancer (stage IIIB) as the only manifestation of the disease; more than 1 line of chemotherapy for advanced or metastatic disease; history or 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, osteoblastic skeletal lesions, a single osteolytic lesion, lymphedema, pulmonary lymphangitic metastases, pleural effusion, or ascites as the only site of disease; and symptomatic peripheral neuropathy of at least grade 2 according to National Cancer Institute (NCI) Common Toxicity Criteria.
Patients were recruited from 42 centers worldwide. Ethics committee approval and informed patient consent were obtained before the start of the trial.
Study Design and Treatment Plan
This was a nonblinded, randomized, multicenter phase III study. The randomization was stratified by center, and patients were assigned randomly to receive an intravenous infusion of either docetaxel, 100 mg/m², for 1 hour once every 3 weeks, or doxorubicin, 75 mg/m², for 15 to 20 minutes once every 3 weeks. Premedication was specified for patients in the docetaxel group only, and was comprised of 8 mg of oral dexamethasone(Drug information on dexamethasone), given 13 hours, 7 hours, and 1 hour before docetaxel infusion, and for an additional 4 days at a dose of 8 mg twice daily, starting immediately after docetaxel infusion.
The maximum duration of treatment was 7 cycles for both groups, unless progression or unacceptable toxicity occurred. If a patient failed to respond to the assigned treatment, further treatment was at the discretion of the investigator. Patients withdrawn from the study before disease progression could not receive other antitumor therapy until progression was documented, unless deemed necessary by the investigator. Patients were observed for 1 month after their last study treatment infusion to document any late adverse events, with a follow-up every 3 months until death, to document time to progression and survival.
Dose reductions were permitted for severe hematologic and nonhematologic toxicities other than alopecia and anemia, graded according to NCI Common Toxicity Criteria. A maximum of 2 dose reductions were allowed per patient--ie, from 100 to 75 mg/m² and from 75 to 55 mg/m² for docetaxel, and from 75 to 60 mg/m² and from 60 to 45 mg/m² for doxorubicin.
Concomitant bisphosphonate treatment was not allowed unless initiated more than 3 months before the start of the study.
A complete tumor assessment was performed during the 3 weeks before the first infusion of study medication, and included chest x-ray, bone scintigraphy and bone radiological examination, abdominal computed tomography scan, or ultrasound and physical examination. Bone scintigraphy could be performed 4 weeks before the first infusion of study medication. All evaluable and nonevaluable lesions were to be assessed at least every 2 treatment cycles.
The primary efficacy variable was time to progression, calculated from the date of randomization to the first progression. Response rate, defined as the percentage of patients in the group who achieved a complete or partial response, was a secondary efficacy variable. Patients with disease progression before the end of the second treatment cycle were considered to have early progression, whereas patients who received at least 2 cycles of therapy had their response to treatment classified as follows: complete response, partial response, stable disease, or progressive disease, according to the World Health Organization response criteria.
Weekly blood counts were performed. An initial assessment of left ventricular ejection fraction was made during the 2 weeks before study entry, using a multiple-gated acquisition scan or echocardiography; left ventricular ejection fraction was reassessed after a 400 mg/m² cumulative dose in the doxorubicin group, and at the end of the study in both treatment groups. Two types of analysis were performed on left ventricular ejection fraction: relative decrease in left ventricular ejection fraction from baseline according to NCI Common Toxicity Criteria, and absolute decrease in left ventricular ejection fraction from baseline according to the Schwartz criteria-- ie, a decrease in left ventricular ejection fraction of at least 10 absolute percentage points and below the lower normal limit.
A two-tailed log-rank test was used to compare differences in the median time to progression between treatment groups. A significance level of 0.001, according to Peto sequential procedure, was used for this preliminary evaluation, which was performed after patient accrual was completed. Patients were required to have received at least 2 cycles of treatment and to have had at least 1 follow-up tumor assessment to be evaluable for efficacy, unless disease progression occurred.
Two subpopulations were analyzed for efficacy: a second-line population comprised of patients who relapsed during treatment or within 12 months of the end of adjuvant chemotherapy containing an alkylating agent, or patients who had received 1 previous alkylating chemotherapy regimen for advanced or metastatic disease; and a first-line population, comprised of patients who relapsed more than 12 months after the end of adjuvant chemotherapy containing an alkylating agent and who had not received chemotherapy for advanced disease. All patients who received at least 1 infusion of study medication were evaluable for safety. Times-to-event variables were analyzed by the Kaplan-Meier method. All analyses were performed at least on the randomized (intent- to-treat) population.