CHICAGOAdjuvant therapy with epirubicin (Ellence)
followed by cyclophosphamide, methotrexate, and 5-fluorouracil (ECMF) prolongs
relapse-free survival and overall survival with only modest toxicity in
patients with early-stage breast cancer and should replace upfront CMF as
standard therapy in that setting, Christopher J. Poole, MD, said at the 39th
Annual Meeting of the American Society of Clinical Oncology (ASCO abstract 13).
Dr. Poole reported combined phase III data on behalf of the
National Epirubicin Adjuvant Trial (NEAT) in England and the Scottish Cancer
Trials Breast Group in Scotland (SCTBG BR9601, also known as "McNEAT").
"Arguably, these data suggest that there is now no routine place for
upfront CMF in adjuvant therapy of early breast cancer," he said.
Dr. Poole said that the background for design of this
protocol included controversy over the role of anthracyclines as adjuvant
therapy for early-stage breast cancer and poor design of some earlier trials
exploring this question. "The use of anthracyclines has been based more on
hope than on science," he said.
The two protocols were designed so that results could be
combined for greater power. Patients randomized to the experimental arm on both
studies received four cycles of epirubicin (100 mg/m2) followed by
CMF, while those on the control arm received CMF alone.
The CMF regimens varied slightly. Patients on the NEAT trial
received epirubicin plus four cycles of classical CMF and were compared with
patients receiving six cycles of classical CMF. Patients on the experimental
arm in McNEAT received epirubicin followed by four cycles of IV dose-modified
CMF (cyclophosphamide 750 mg/m2, methotrexate 50 mg/m2,
fluorouracil 600 mg/m2) given every 3 weeks. Patients on the McNEAT
control arm received eight cycles of IV dose-modified CMF given every 3 weeks.
Dr. Poole reported data from a pre-planned interim analysis
after 450 events. The analysis included data for 2,391 of the 2,401 randomized
The investigators were able to deliver good dose intensity
for both regimens, but it was significantly higher for ECMF (94% of planned
doses vs 92% for CMF, P = .0003).
There were significantly fewer deaths on the ECMF arm (4 vs
13 with CMF, P = .05). "All of the deaths occurred during the CMF
phase of treatment, not during the epirubicin treatment," Dr. Poole said.
"All were due to neutropenic sepsis, and I would like to point out that,
at the time of this study, prophylactic antibiotics and growth factors were not
routinely used in the UK." There was no difference in the rate of febrile
neutropenia between ECMF and CMF.
As expected, epirubicin caused more severe nausea/vomiting,
stomatitis, alopecia, and constipation (all P < .0001). However, the
data were reassuring with regard to concern about leukemia risk. "We have
yet to identify any cases of acute leukemia," Dr. Poole said.
Quality of life was slightly worse on ECMF due to the acute
toxicities, but Dr. Poole said that there were no differences in Global Health
Status. Quality of life differences were no longer apparent by 1 year after
Recurrence-free survival at 37 months of follow-up was
significantly better for ECMF, with a hazard ratio (HR) of 1.59. "There is
also a clear and significant reduction in risk of death with ECMF in all
categories of patients, regardless of lymph node status or age older or younger
than 50," Dr. Poole said. The HR of 0.65 for overall survival is
equivalent to a 35% reduction in odds of death.
The investigators concluded that ECMF prolongs
recurrence-free survival and overall survival, and is feasible, with better
dose delivery than classic CMF, fewer treatment-related deaths, and no increase
in second primary tumors.
In commenting on this paper, discussant Clifford Hudis, MD,
chief, Breast Cancer Medical Service, Memorial Sloan-Kettering Cancer Center,
said, "There is a clear improvement in disease-free survival with the
addition of epirubicin at the 100 mg/m2 dose, and this translated
into an overall survival advantage. The heterogeneous subjects in this study
are a strength, and the benefit can be said to be global, not confined to any
Nominal Price to Pay in Toxicity
Dr. Hudis noted that "there was a nominal price to pay
in toxicity for the addition of epirubicin, including an extraordinarily low
rate of acute myelogenous leukemia/myelodysplastic syndrome. I would wait for
longer follow-up before reaching conclusions about that, since I think it is
highly unlikely that there would be zero leukemias in a trial such as this