NEW YORKCombination chemotherapy with doxorubicin and
docetaxel (Taxotere) resulted in objective major responses in 32 of
51 patients with previously untreated metastatic breast cancer,
setting the stage for a large-scale comparison of the combination
against doxorubicin and cyclophosphamide.
The regimen resulted in 3 complete responses and 29 partial responses
for an overall response rate of 63%. At a median follow-up of 9
months, the median duration of response has not been reached. There
was no apparent increased risk of cardiotoxicity.
New Study Initiated
This regimen was the most effective we have tested against
advanced breast cancer over the past 5 years, said Joseph
Sparano, MD, director of Breast Medical Oncology, Albert Einstein
Medical Center, New York. On the basis of these results, the
Eastern Cooperative Oncology Group [ECOG] has initiated a study to
compare the regimen with doxorubicin and cyclophosphamide. The
new study will involve 3,000 women with early-stage node-positive and
high-risk node-negative breast cancer.
In his presentation at the 21st Annual San Antonio Breast Cancer
Symposium, Dr. Sparano said that the rationale for the study evolved
in part from previous studies of the combination of doxorubicin and
paclitaxel (Taxol), which achieved high response rates.
The rationale for combining doxorubicin and docetaxel derives from
the fact that docetaxel does not increase the risk of congestive
heart failure and does not affect the pharmacokinetics of
doxorubicin, he said.
The regimen employed in the study consisted of doxorubicin, 60
mg/m²; docetaxel, 60 mg/m², given 1 hour after doxorubicin;
G-CSF, 5 µg/kg, beginning on day 2; and dexamethasone
premedication. The regimen was repeated every 3 weeks for a maximum
of eight cycles, followed by docetaxel alone (100 mg/m²) until
disease progression or prohibitive toxicity.
Ejection fraction was assessed after six cycles of therapy, and, if
heart function remained within normal limits, the patient received an
additional two cycles of the combination.
None of the patients had a history of anthracycline therapy or
treatment for metastatic disease. A majority of patients had visceral
involvement, and about 40% had involvement of at least three organ systems.
Three-fourths of the patients had grade 3-4 neutropenia. Two
treatment-related deaths occurred, one due to neutropenic sepsis and
the other due to sepsis accompanied by gastrointestinal hemorrhage.
Both patients had liver metastases and other clinical features that
placed them at high risk, Dr. Sparano said.
Other grade 3-4 hematologic toxicity included a 15% incidence of
thrombocytopenia, a 9% incidence of anemia, and an 11% incidence of
febrile neutropenia. Grade 3-4 nonhematologic toxicity included
stomatitis in 6% of patients, diarrhea in 8%, glucose intolerance in
8%, neurosensory toxicity in 8%, severe fatigue in 6%, and neuromotor
toxicity in 4%.
Cardiotoxicity included two cases of heart failure, both of which
involved patients who received cumulative doxorubicin doses of 400
mg/m². Both patients responded to medical therapy. Additionally,
10 cases of asymptomatic decline in ejection fraction occurred, all
at doxorubicin doses of 300 mg/m² or greater.
The combination of doxorubicin and docetaxel, at the doses and
schedule used in this trial, is an active regimen for metastatic
breast cancer, Dr. Sparano said. The responses appear to
be unusally durable.
With the use of G-CSF, the rate of serious infections is low, and
other serious toxicity is uncommon, he said, emphasizing that
there is no evidence of an increased risk of cardiotoxicity
with this regimen. Subclinical and clinical cardiac damage occurred
almost exclusively in patients treated with a doxorubicin dose that
would not be exceeded if this regimen were used in the adjuvant setting.