TORONTOEpirubicin (Ellence) and doxorubicin (Adriamycin) in
combination regimens for adjuvant treatment of breast cancer will be
compared in a major randomized controlled trial sponsored by the
National Cancer Institute of Canada (NCIC), according to Maureen
Trudeau, MD, head of systemic therapy at Sunnybrook Regional Cancer
Centre in Toronto, Ontario. Dr. Trudeau described the reasoning
behind and the design of NCIC CTG-MA.21 at a clinical
investigators workshop sponsored by the University of Texas M.
D. Anderson Cancer Center and Pharmacia Oncology.
Canadian study will compare cyclophosphamide
(Cytoxan)/epirubicin/5-fluorouracil (CEF) to doxorubicin
(Adriamycin)/cyclophosphamide (AC) plus paclitaxel (Taxol) and to
epirubicin/cyclophosphamide (EC) plus paclitaxel in patients who have
node-positive or high-risk node-negative breast cancer and have had
total or partial mastectomies (see Figure 1).
While AC plus paclitaxel is commonly used in the United States and
CEF in Canada, many European centers favor EC as standard adjuvant
therapy, according to Dr. Trudeau. One reason for this is the lower
risk of cardiac toxicity associated with epirubicin. A number of
studies have compared combinations including epirubicin and
doxorubicin at equal doses. The FEC-50 regimen (5-FU, epirubicin 50
mg/m², cyclophosphamide) has been tested against the standard
doxorubicin-containing FAC-50 regimen for metastatic breast cancer in
several trials. According to Dr. Trudeau, response rates and median
survival were comparable. The most important difference in
these studies was the much lower cardiac toxicity associated with the
epirubicin-containing regimens, she said.
In 1998, Ontario cancer specialists reviewed the clinical trials
comparing epirubicin and doxorubicin in women with metastatic breast
cancer. There were no significant differences in response rates
or in median survival, and we concluded that these two agents are
equally efficacious. Toxicity was significantly less with FEC than
with FAC, Dr. Trudeau said. She also pointed out that it is
possible to increase the epirubicin dose without being limited by the
cardiac toxicity and hand-foot syndrome associated with high doses of doxorubicin.
Comparing Package Regimens
overview inspired the development of the NCICs MA.5 trial,
which directly compared CEF to CMF (cyclophosphamide, methotrexate,
5-fluorouracil) in patients with breast cancer. This trial is
not comparing drug to drug, but package regimen to package
regimen, Dr. Trudeau said (see Figure 2). The 710 patients were
stratified by total vs partial mastectomy, hormone receptor status,
and number of positive lymph nodes. Patients were randomized either
to six 4-week cycles of CEF or CMF.
Dr. Trudeau reported that 5-year survival was significantly better
with CEF than with CMF (77% vs 70%, P = .03). This
represents a 19% reduction in the risk of death, she said.
CEF was associated with more neutropenia, fever or infection,
thrombocytopenia, alopecia, and vomiting during the courses of
treatment. The epirubicin-containing regimen was also associated with
late adverse events Dr. Trudeau described as a bit
disconcerting. These included congestive heart failure (1.1% vs
0.3% of patients), acute myelogenous leukemia (1.1% vs 0.3%), and
acute lymphocytic leukemia (0.3% vs 0%).
Dr. Trudeau said that most patients in this trial were given
trimethoprim-sulfamethoxazole as a prophylactic measure, and the
researchers wonder if this antifolate might have contributed to the
leukemia risk. Most patients now use ciprofloxacin (Cipro), and
no further leukemias have been documented, she said.
Survival Higher with CEF
Relapse-free survival and overall survival were significantly
improved in patients treated with CEF compared with CMF, Dr.
Trudeau announced. CEF corresponded with a 29% risk reduction
in recurrence and a 19% risk reduction in mortality, compared with
CMF. Acute and delayed toxicities were manageable, and quality of
life was clinically similar between the two treatments.
Consequently, the CEF regimen was used as the first arm in the new
NCIC study. The second is the AC plus paclitaxel regimen reported in
Cancer and Leukemia Group B (CALGB) 9344. The third is EC followed by
paclitaxel. About 1,500 patients will be randomized among these three arms.
Previous studies showed that CEF is superior to CMF, that AC
followed by paclitaxel is superior to AC, and that CEF is probably
equivalent to AC followed by paclitaxel, Dr. Trudeau said.
Adding a taxane after 6 months of CEF was too difficult.
Studies also suggest that 3 months of EC with G-CSF support is
equivalent to 6 months of CEF. The new EC treatment uses dose-dense,
dose-intense chemotherapy with a sequenced taxane and will be
compared to the standard US and Canadian aggressive treatments, CEF
and AC followed by paclitaxel, Dr. Trudeau concluded.