Results from a trial of patients with early-stage breast cancer have reignited discussions over the use of erythropoiesis-stimulating agents (ESAs) for chemotherapy-induced anemia, but experts remain unconvinced by the findings.
A decade ago, it was popular to treat cancer patients with ESAs; however, that practice was severely restricted after they were associated with an increased risk for death.
A black box warning was added to ESAs by the US Food and Drug Administration in 2007. The agency also restricted the use of these products in cancer patients to the treatment of chemotherapy-induced anemia, and warned against using them at all in patients who were being treated with a curative intent.
Data from a trial of an ESA in such a group of patients, which began before the restrictions came into force, are now available. The results were published in the July 17 issue of theJournal of the National Cancer Institute.
The trial, known as AGO-ECT, was headed by Volker Moebus, MD, from Klinikum Frankfurt Höchst in Frankfurt , Germany. The researchers evaluated epoetin alfa (Epogen, Amgen) for the prevention of chemotherapy-induced anemia in 1284 patients with early-stage breast cancer for whom the anticipated treatment outcome was a cure.
All patients received chemotherapy with epirubicin, paclitaxel, and cyclophosphamide, administered in either a conventional or an intense dose-dense (IDD) schedule, and all received the growth factor filgrastim to protect against myelosuppression. Patients were randomized to receive the ESA epoetin alfa to protect against anemia or placebo.
The ESA prevented the chemotherapy-induced decline in hemoglobin levels seen in the placebo group. In addition, the need for blood transfusions was much less in the ESA group than in the placebo group (12.8% vs 28.2%).
The ESA had no impact on overall or relapse-free survival, although the risk for thrombosis was higher in the ESA group than in the placebo group (7% vs 3%), the researchers note.
"We have shown a beneficial effect of epoetin alfa in the adjuvant treatment of breast cancer patients receiving IDD chemotherapy without deleterious effects on disease progression or mortality after almost 5 years of follow-up," the researchers conclude.
"This study provides important evidence that ESAs may be safe in the curative treatment of cancer," write 3 experts in an accompanying editorial.
"However, at the same time we must acknowledge that the data are insufficient to support the routine use of ESAs in this setting," say Chau Dang, MD, Clifford Hudis, MD, and Larry Norton, MD, from the breast cancer medicine service at the Memorial Sloan-Kettering Cancer Center in New York City.
The study numbers were small for survival data, and the requirement for blood transfusions, while reduced by ESAs, was still rather high, they note. The doubling of the venous thromboembolic event rate in this trial "may be unacceptably high," and there is the additional question of cost. "Can we justify adding ESAs as prevention when they do not improve relapse-free survival or overall survival or reduce the cost of care?" they ask.
Concept Is Killed
In another accompanying editorial, a medical oncologist involved with some of the earlier studies of ESAs in breast cancer provides some historic perspective and recalls the excitement over this group of agents.
Brian Leyland-Jones, MB BS, PhD, from Edith Sanford Breast Cancer Research in Sioux Falls, South Dakota, recalls how "at the end of the 1990s, there was much hope that ESAs would improve the survival of breast cancer patients."Preclinical studies showed that ESAs raise hemoglobin levels, improve oxygenation, increase the cytotoxicity of antineoplastics, and have beneficial effects on tumor regression, he notes. There were great expectations that these effects agents would improve survival, and 2 early trials did suggest an improvement.
However, subsequent clinical trials not only failed to show an improvement in survival, they also showed an increase in the risk for death in patients taking ESAs.
"Ten years later, in my humble opinion, there is no doubt," Dr. Leyland-Jones writes. Virtually all the meta-analyses of these clinical trials show worse survival with ESAs; even the trials that used ESAs within the labeling show very little, if any, impact on survival, he notes.
"I now truly believe that the concept of ESAs improving the survival of breast cancer patients is killed," he concludes.
The AGO-ETC trial was supported by Bristol-Myers Squibb, Amgen, Pharmacia, and Johnson & Johnson. Epoetin alfa was provided by Johnson & Johnson.
J Natl Cancer Inst. 2013;105:999-1001, 1001-1003, 1018-1026. Leyland-Jones editorial, Dang et al editorial, Abstract
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