Grossi et al Figure 1 Mechanism(s) of anemia in cancer patients. affect tumor response and overall survival. As for the disease outcome, the conclusion reflects the somewhat divergent results of a large randomized double blind versus placebo study suggesting a possible better outcome in patients treated with rHuEpo (Littlewood et al 2001), and those of two different studies that have shown a risk of worst outcome of cancer disease in patients treated with rHuEpo (Henke et al 2003; Leyland-Jones 2003). The expression of Epo receptor (EpoR) has been demonstrated on several nonerythroid tumor cells (Arcasoy et al 2005), but this does not invariably translate into the receptor activation. Moreover it has been shown that antibodies currently used in immunoblotting and immunostaining techniques lack specificity (Elliott et al 2006), therefore the results should be evaluated with caution. American Society of Hematology/American Society of Clinical Oncology (ASCO) (Rizzo et al 2002), National Comprehensive Cancer Network (NCCN) (2006), and European Organisation for Research and Treatment of Cancer (EORTC) (Bokemeyer et al 2004) proposed guidelines for the use of erythropoietic proteins (EPS) in anemia of cancer. These indicate that scope of the treatment is not only the erythropoietic response (hemoglobin increase), but also the improvement of QoL, negatively affected by the anemia, and prevention of transfusion. The target hemoglobin level should be 12–13 g/ dL in order to reduce the risk of hypertension and thromboembolic events associated with this therapy (Bokemeyer et al 2004). However the efficacy of EPS relies on the presence of adequate iron availability for the necessity of erythropoiesis, therefore preliminary evaluation and monitoring of transferrin saturation are mandatory. If transferring saturation is ≤20% intravenous should be administered (Auerbach et al 2004) 270 The spectrum of EPS includes a large variety of products, such as erythropoietin delta (Deicher and Horl 2004) and omega (Bren et al 2002), with registration limited to anemia of kidney failure, while pegylated Epo beta (Osterborg et al 2004) and a pegylated synthetic peptide, Hematide (Stead et al 2006), are still under clinical evaluation. The only approved and currently marketed EPS for treatment of anemia in cancer patients are rHuEpo alpha and beta, and darbepoetin alpha. Data on rHuEpo are briefly mentioned in this review, which will focus especially on the activity of darbepoetin in the treatment of patients with cancer anemia. rHuEpo Treatment with EPS in the setting of anemia of chronic disorders, including cancer, requires higher doses (3- to 4- fold) than in the treatment of anemia of kidney failure, due to the inhibition of endogenous Epo production, of bone marrow activity, or both. Therefore a typical schedule of 150 U/Kg (10 000U) of rHuEpo three times per week with rHuEpo alpha or beta is adopted in cancer patients instead of 40–50 ml/Kg used in chronic kidney failure. Response rate varies largely in relation to the disease. Commonly hemoglobin levels improve in 25% to 30% of patients with myelodysplastic syndrome (MDS) (Alessandrino et al. 2002), but in subgroups of patients with favourable characteristics (International Prognostic Scoring System [IPSS] low/intermediate 1 risk, reduced or no transfusion support, endogenous Epo levels <200 mU/ml) this rate can increasee to 50% with daily (ICSG 1998; Alessandrino et al 2002) or every other day (Ter pos et al 2003) administrations of 10 000 U. Hellstrom-Lindberg and colleagues (1998) demonstrated that the percentage of Therapeutics and Clinical Risk Management 2007:3(2)