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,
Doxorubicin plus 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 (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.
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
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.