Docetaxel Plus Doxorubicin Ups Response in Metastatic Breast Cancer

SAN FRANCISCO—The addition of docetaxel (Taxotere) to an anthracycline (doxorubicin)-containing regimen may improve response rates in the first-line treatment of metastatic breast cancer. The findings come from a large international trial, TAX 307, presented at the 37th Annual Meeting of the American Society of Clinical Oncology (ASCO) in San Francisco.

The trial compared docetaxel/doxorubicin (Adriamycin)/cyclophosphamide (TAC) with 5-fluorouracil (5-FU)/Adriamycin/cyclophosphamide (FAC) in 484 patients, said lead investigator Jean-Marc Nabholtz, MD.

Dr. Nabholtz is professor of medicine and director of the Cancer Therapy Development Program and the Solid Tumor Program at the UCLA School of Medicine. He is also chairman of the Breast Cancer International Research Group (BCIRG).

At ASCO 1999 (Atlanta), Dr. Nabholtz presented a phase III study of Adriamycin/docetaxel (AT), TAX 306. In that trial, AT was significantly more effective than Adriamycin/cyclophosphamide (AC) in terms of response rate, time to progression, and time to treatment failure. Earlier trials had shown single-agent docetaxel to be superior to doxorubicin.

The current TAX 307 study randomized patients to 6 cycles every 3 weeks of docetaxel 75 mg/m2, doxorubicin 50 mg/m², and cyclophosphamide 500 mg/m² (TAC) or 5-FU 500 mg/m², doxorubicin 50 mg/m², and cyclophosphamide 500 mg/m² (FAC).

To date, the study has not reached the number of events (312) required for an analysis of time to progression and survival; therefore, only response rates and safety data were presented. As of April 15, 2001, there were 287 events.

The intent-to-treat analysis of 242 patients in each arm showed a significant improvement in overall response rates with TAC: 55% vs 42% with FAC (P = .008). This yielded an odds ratio of 1.6 in favor of  TAC. There were complete responses in 8% of TAC patients and 5% of FAC patients. Progressive disease occurred in 10% and 16%, respectively.

Almost three fourths of patients had visceral metastases, and over half had bone metastases. TAC maintained a more favorable response rate in all subgroups except those with liver metastases; response rates in both arms were equivalent in those patients. In patients with prior adjuvant chemotherapy, response rates were 56% for TAC and 36% for FAC.

Nonhematologic side effects were acceptable in both arms, and there was no added cardiotoxicity with TAC, compared with FAC, Dr. Nabholtz said. TAC was associated with significantly greater febrile neutropenia. Febrile neutropenia occurred in 29% of patients on TAC and in 6% of TAC cycles, compared with 4% of patients and 1% of cycles with FAC.

The incidence of grade 3-4 infection and septic death, however, was not increased with TAC. Infection occurred in 5% of patients and 1% of cycles with TAC vs 3% and 0.4%, respectively, with FAC.

He pointed out that the intent of the study was "proof of concept" that the integration of docetaxel and anthracyclines as first-line metastatic treatment is possible even in countries where G-CSF (Neupogen) is not commonly used.

Dr. Nabholtz commented on the implications of the study: "TAC and AT are valid options for the management of metastatic breast cancer, although it is still unclear whether to use the combination up front or to use an anthracycline followed by Taxotere."

He added that the results of TAC in phase III trials of metastatic breast cancer serve as encouragement that this combination may well prove effective in the adjuvant setting. Trials currently evaluating docetaxel/anthracycline-based adjuvant therapy include BCIRG 001, ECOG 2197, NSABP B-30, BCIRG 005, and BCIRG 006.