Doxorubicin-Docetaxel Produces Major Responses in Metastatic Breast Cancer

NEW YORK—Combination 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.

Durable Responses

“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.”