Erythropoetic-stimulating agents: where do we stand?

Abstract

At present three erythropoietic-stimulating agents (ESAs) are available, these being epoietin alpha, epoietin beta and darbepoietin. In oncology the marketing licence given in the early 1990s was and still is for reduction of red blood cell (RBC) transfusion in chemotherapy-induced anaemia (CIA) in non-haematological neoplasia. Regulatory bodies as well as various scientific societies have issued guidelines and updated these regularly in accordance with additional data from numerous studies published since first marketing. Over the past few years, worrisome data have shown adverse effects in trials comparing ESAs with controls (transfusion or placebo). In fact reviewing the published literature closely does not allow at the time of writing (March 2008) the exclusion of a survival decrease due to an effect of ESAs on the cancer itself. Haemoglobin (Hb) target dosing has been an issue and is addressed in the dosing of ESAs in patients on therapy. In addition to survival and tumour progression, published articles also address at length thromboembolic diseases (TEDs), these being more frequent in ESA-treated patients compared with the controls in various studies. The three agents epoietin alpha, epoietin beta and darbepoietin can be considered as the same pharmacological class as regards indications of CIA, Hb limits and dose adjustments, as well as regards warnings in respect of adverse effects. The purpose of this paper is not to to be a substitute for recommendations or official recently published guidelines (ASCO, ASH, ESMO, EORTC, NCCN, etc.) but to present an overview of the data which have motivated ongoing regulatory authorities’ assessments and reviewing of guidelines. An updated Cochrane review is underway, and the regulatory authorities such as the Food and Drug Administration (FDA) after the recent ‘Oncology drug advisory committee to the FDA’ (ODAC) of March 15, 2008, and the EMEA will most probably refine the present safety recommendations. Various aspects and adverse effects are to be considered here. (i) The realization that TED is a major issue in routine treatment. (ii) The fact that several studies have shown progression of disease and/or decreased survival in the ESA-treated group of patients compared with controls. Erythropoietin receptor (EpoR) data on malignant cells from a ‘Head and Neck Cancer’ trial with radiotherapy treatment and a target Hb beyond 14 g/ dl have been and still are largely commented on in the medical literature [1]. (iii) Furthermore, quality of life (QoL) has been considered as an additional benefit of ESA therapy, and the latest analyses cast doubts on the validity of this presumed benefit [2].