CHICAGO—Adjuvant therapy with epirubicin(Drug information on epirubicin) (Ellence) followed by cyclophosphamide(Drug information on cyclophosphamide), methotrexate(Drug information on 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.
CMF Regimens
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(Drug information on 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 patients.
Study Results
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 treatment.
Recurrence-Free Survival
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 subset."
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 one."
