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 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 (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
- 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
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,
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
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.
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