PISA, ItalyAnthracycline/taxane combinations given upfront should be the new standard of care for metastatic breast cancer, Pierfranco Conte, MD, said at a clinical investigators workshop sponsored by the University of Texas M. D. Anderson Cancer Center and Pharmacia Oncology. Dr. Conte is chief of the Division of Medical Oncology at St. Chiara Hospital in Pisa, Italy.
Doxorubicin plus paclitaxel(Drug information on paclitaxel) in advanced breast cancer has a response rate of 83% to 94% and a complete remission rate of 24% to 41%, Dr. Conte said, based on a review of a series of trials of doxorubicin(Drug information on doxorubicin) (Adriamycin)/taxane combinations. The combination, however, also has an unacceptably high risk of congestive heart failure [CHF] of 20%, he added. It is recommended that the maximum cumulative dose of doxorubicin be 360 mg/m² when combined with paclitaxel.
Substituting Epirubicin(Drug information on epirubicin)
Dr. Contes group substituted epirubicin (Ellence) plus paclitaxel (Taxol) for doxorubicin plus paclitaxel as a way around the cardiotoxicity problem. Dr. Conte said that paclitaxel also induces an increase in plasma concentrations of epirubicinol, an active metabolite of epirubicin.
In this study, 50 patients with metastatic breast cancer were treated with cycles of epirubicin 90 mg/m² plus paclitaxel 200 mg/m² as a 3-hour infusion. The response rate was 84%, which included complete remissions in 19% of patients. Median progression-free survival was 10 months and median overall survival was 25 months.
Epirubicin/paclitaxel does induce a low incidence of CHF, about 9%, but this occurs mostly at cumulative epirubicin doses greater than 900 mg/m², Dr. Conte said. He recommended limiting the cumulative dose of epirubicin to 720 mg/m² in patients with pre-existing cardiac risk factors and to 900 mg/m² in those with no cardiac risk factors.
Combined with Docetaxel(Drug information on docetaxel)
Epirubicin can also be combined with docetaxel (Taxotere) for treatment of advanced breast cancer, but Dr. Conte warned that the usual dose of one or both drugs must be reduced to prevent toxicity problems. Overall response rates with this combination were 80% in patients with locally advanced breast cancer and 60% in patients with metastatic breast cancer.
The combination of epirubicin plus Taxotere is feasible with acceptable toxicity, He stated. The most relevant dose-limiting toxicities are febrile neutropenia and grade 4 neutropenia. Maximum tolerated doses are 90 mg/m² epirubicin with 60 mg/m² Taxotere, or 75 mg/m² epirubicin with 80 mg/m² Taxotere [the recommended dose]. The maximum tolerated dose has not been reached when the combination was given with G-CSF, and this group arm is at dosing level 90 mg/m² epirubicin plus 100 mg/m² Taxotere. Dr. Conte added.
Increased Response with Taxanes
A review of previous studies with anthracycline/taxane combinations in advanced breast cancer shows increased response rates for taxane-containing combinations, Dr. Conte said. Four of seven randomized trials showed a significant advantage for anthracycline/taxane combinations in terms of response rate. Four of five reported improved progression-free survival, and one of three showed a significant overall survival advantage. There is clear evidence that upfront anthracycline/taxane should be the standard of care for metastatic breast cancer, but the question remains as to whether the drugs should be given together or in sequence.
That question is being addressed in the ongoing North-West Oncology Group (Gono)-MIG 6 trial. The trial randomizes patients either to eight courses of epirubicin 90 mg/m² and paclitaxel 200 mg/m² given together, or to four courses of epirubicin 120 mg/m² followed by four courses of paclitaxel 250 mg/m².