Erythropoietin stimulating agents (ESA) have been successfully used in the management of cancer and treatment-related anaemia for more than 15 years. Since the first published study showing their efficacy (Ludwig, 1990), several studies have demonstrated the ability of ESA to increase haemoglobin levels and reduce the need for red-cell transfusions, leading to an improvement in patient quality of life (Glaspy et al, 1997; Siedenfeld et al, 2001; Hedenus et al, 2003). However, the impact of anaemia improvement on overall survival is not clear (Glaspy, 2002). Although a small number of studies have suggested a trend toward improved survival with administration of ESA (Littlewood et al, 2001), other studies have not confirmed this finding (Osterborg et al, 2005). Furthermore, a recently published large meta-analysis showed no clear survival benefit (Bohlius et al, 2006). This meta-analysis also demonstrated that ESA increase the relative risk for venous thrombosis, raising further concerns about the use of these agents (Bohlius et al, 2006). A recent meta-analysis (Bennett et al, 2008) confirmed that ESA are associated with increased risk for deep vein thrombosis and showed, in addition, that these agents are associated with increased mortality risk. Several recent studies have also addressed the possible negative impact of ESAs on overall survival, particularly in patients with solid tumours (Henke et al, 2003; Leyland-Jones et al, 2005; Goldberg, 2007; Wright et al, 2007), although the mechanisms that explain the possible negative impact of ESA on overall survival have not yet been clarified. Henke et al (2006), suggested that tumour cells bear functional erythropoietin receptors (EPOR). However, a later study questioned this observation, demonstrating in vitro that EPOR on tumour cell lines are not functional (Laugsch et al, 2007). Furthermore, the currently available anti-EPOR antibodies are not of sufficient quality to detect EPOR on tumour cells and the data are not convincing enough to support the correlation of EPOR status with the clinical outcome in patients treated with ESA (Sinclair et al, 2007). In March, 2007, the United States Food and Drug Administration (FDA), based on the four published studies on solid tumours (Henke et al, 2003, 2006; Leyland-Jones et al, 2005; Goldberg, 2007; Wright et al, 2007), as well as on two unpublished studies (the Anemia of Cancer Study and the Lymphoid Cancers Anemia Study) instituted the addition of a black-box warning about the potential for tumour promotion and thromboembolic events. FDA instructions required ESA to be withheld from patients whose haemoglobin level exceeded 120 g/l until the level fell below 110 g/l. Furthermore, as discussed and suggested at a meeting of the FDA’s Oncologic Drugs Advisory Committee (2007) in May 2007 (http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4301b2-00-index.htm), the risks associated with raising and maintaining haemoglobin levels at a point higher than is needed in order to avoid transfusions should be considered “unacceptable.” The recently updated American Society of Clinical Oncology/American Society of Haematology (ASCO/ASH) 2007 clinical practice guidelines on the use of epoetin and darbepoetin in cancer-related anaemia, following the FDA instructions, suggested that haemoglobin levels should not exceed 120 g/l (Rizzo et al, 2008). They also addressed the fact that clinicians should carefully weigh the risks of thromboembolism in patients for whom epoetin or darbepoetin are prescribed, especially when ESA are administered concomitantly with the combination of immunomodulatory drugs (thalidomide or lenalidomide) and dexamethasone or anthracyclines, as is usually the case in patients with multiple myeloma. These guidelines underscore the fact that physicians caring for patients with non-myeloid haematological malignancies should consider starting with chemotherapy and follow the haematological outcomes achieved through tumour reduction before deciding on ESA administration (Rizzo et al, 2008).
Factors that influence responsiveness to ESA are the type and stage of the underlying malignancies, the type of therapy, and the co-existence of other causes of anaemia. The updated ASCO/ASH 2007 clinical practice guidelines suggest that continuing epoetin or darbepoetin treatment beyond 6–8 weeks in the absence of response (e.g. 10–20 g/l rise in Hb or no attenuation of clinical conditions requiring blood transfusion) does not appear to be beneficial, and thus ESA therapy in this case should be discontinued. Patients who do not respond should be investigated for underlying tumour progression, iron deficiency, or other aetiologies for anaemia (Rizzo et al, 2008).
One of the most important causes of ESA unresponsiveness is iron-restricted erythropoiesis or functional iron deficiency (FID), which is defined as an imbalance between iron requirements and iron supply to the erythroid marrow in the presence of adequate iron stores in the reticuloendothelial system (Goodnough, 2007). Iron-restricted erythropoiesis may occur at diagnosis as a result of the shift of the circulating iron into the reticuloendothelial system due to inflammatory cytokines and the hormone hepcidin (Weiss & Goodnough, 2005), or during ESA treatment due to the excess of stimulation of erythropoiesis (Cavill, 2002; Goodnough, 2007). Several studies have suggested benefits for the use of IV iron concomitant with ESA therapy in anaemia of cancer (Auerbach et al, 2004; Hedenus et al, 2007; Henry et al, 2007).