Warning flags for erythropoiesis-stimulating agents and cancer-associated anemia.

A recent U.S. Food and Drug Administration (FDA) alert has raised further concerns about potential adverse effects of erythropoiesis-stimulating agents (ESAs) in anemic cancer patients who are not receiving chemotherapy [1]. The warning was issued following interim analysis of an investigator-led phase III trial of 989 patients with head and neck cancers randomized to receive darbepoetin alfa (Aranesp; Amgen, Thousand Oaks, CA) or placebo (Danish Head and Neck Cancer Group [DAHANCA] 10 study, http://www. dahanca.dk). The enrolled patients were anemic but were not receiving chemotherapy. The trial data showed that darbepoetin alfa was associated with a higher mortality than with placebo (hazard ratio, 1.25; confidence interval [CI], 1.04–1.51) and, furthermore, darbepoetin alfa did not reduce the need for blood transfusion [2]. Hard on the heels of the darbepoetin alfa alert, Roche announced that it had temporarily suspended recruitment into its phase II dose-finding study with Continuous Erythropoietin Receptor Activator (CERA) in anemic patients with advanced nonsmall lung cell cancer (NSCLC) receiving chemotherapy [3]. Very recently, an unplanned safety analysis resulted in closure of a randomized placebo-controlled trial of epoetin alfa in NSCLC patients with disease-related anemia [4]. This analysis suggested poorer overall survival in patients with NSCLC treated with erythropoietin (Epo) [4]. Anemia in cancer patients has a multifactorial etiology. Anemia may develop secondary to impaired production of Epo or a blunted response of erythroid precursors to Epo [5]. Anemia may be exacerbated by chronic blood loss from tumor sites or be secondary to chemotherapy and radiotherapy. Debilitating fatigue, if it is secondary to anemia, can be managed by blood transfusions or ESAs to improve the quality of life (QOL) for anemic cancer patients. Interestingly, the effect of Epo therapy on QOL as a prospective outcome is not entirely consistent [6, 7]. Darbepoetin alfa is a hyperglycosylated Epo analog with an extended serum half-life [8] compared with available recombinant human Epos (epoetin alfa [Procrit, Ortho Biotech, Bridgewater, NJ; Epogen, Amgen; or Eprex, Janssen-Cilag Ltd, High Wycombe, U.K.] and epoetin beta [NeoRecormon, Roche, Basel, Switzerland]). CERA incorporates methoxy-polyethylene glycol polymers, which increase its mass to 60 kDa, twice that of Epo, and substantially prolong its half-life to about 135 hours. Darbepoetin alfa and CERA therefore have the therapeutic advantage of requiring less frequent administration for anemia management. Previous reports have suggested that ESA therapy may be harmful to some groups of cancer patients. Henke and colleagues [9] described the outcome of epoetin beta treatment in a randomized trial of 351 anemic head and neck cancer patients undergoing radiotherapy. The therapeutic goal was normalization of hemoglobin to 14 g/dl in men and 13 g/dl in women. Unexpectedly, locoregional progression-free survival was worse in the Epo treatment arm compared with placebo. In the same year, another random-