Patients with cancer commonly develop anaemia, even if they are not receiving chemotherapy or radiotherapy. Anaemia in these patients may be the result of blood loss, haemolysis, bone marrow malfunction because of invasion with tumour, or other factors. Frequently, however, the cause is the anaemia of chronic disease (Cartwright, 1966; Lee, 1983). Patients with anaemia of chronic disease have a shortened red blood cell survival for which erythropoiesis fails to compensate (Miller et al, 1990; Koeller, 1998); experimental evidence indicates that inflammatory cytokines are responsible for the disruption of normal erythropoiesis (Means et al, 1995; Jelkmann, 1988). This occurs through several characteristic mechanisms. Iron utilisation appears defective, as indicated by typically low serum iron in the presence of adequate or elevated iron stores (Lee, 1983; Means and Kranz, 1992; Moliterno and Spivak, 1996). In addition, bone marrow erythroid progenitor cells show a blunted response to erythropoietin, with insufficient proliferation and a low circulating reticulocyte count (Means and Kranz, 1992; Moliterno and Spivak, 1996; Nowrousian, 1998). Finally, the production of erythropoietin itself in response to anaemia is inadequate. Compared to patients without cancer who have iron-deficiency anaemia, anaemic cancer patients have a smaller increase in erythropoietin for their level of anaemia (Ozguroglu et al, 2000).
Although anaemia of chronic disease is often mild to moderate in severity, this degree of anaemia and the associated symptoms can have considerably adverse effects on the lives of patients already in poor health. Fatigue, dyspnoea, and weakness have been shown to significantly affect the quality of daily life in patients with cancer (Cella, 1997a; Vogelzang et al, 1997; Curt, 2000). Studies in patients who have low haemoglobin levels for extended periods due to chronic renal insufficiency point to untreated anaemia as an independent risk factor for cardiovascular disease (Foley et al, 1996). Treatment with recombinant human erythropoietin (rHuEPO) earlier in the course of renal failure and correction of haemoglobin to higher levels are topics of current debate and investigation within the renal disease community, as some evidence suggests this approach may prevent the development or worsening of cardiac damage including left ventricular hypertrophy (NKF Anemia Work Group, 1997; Obrador et al, 1999; Hayashi et al, 2000; Macdougall, 2000).
An initial study in patients with cancer who were not receiving chemotherapy indicated that rHuEPO can correct anaemia in this population as well, with 32% of patients achieving a haematocrit increase of 6% when rHuEPO was given at 100Ukg−1 three times weekly for 8 weeks (Abels et al, 1991). A significant reduction in red blood cell transfusions was not achieved at this dose and schedule; however, in a subsequent study using a higher dose of rHuEPO and longer duration of administration (150Ukg−1 three times weekly for up to 12 weeks) (Quirt et al, 2001), the percentage of nonchemotherapy patients requiring transfusions was significantly decreased by the second month of treatment. In the latter study, 48% of patients (39% of whom required a doubling of dose at week 5) met the definition for haemoglobin response (an increase in haemoglobin of at least 2gdl−1 without transfusion).
Darbepoetin alpha is a protein that stimulates erythropoiesis in the same manner as rHuEPO, but has an increased number of sialic acid residues. The sialic acid-containing carbohydrate of erythropoietin determines its serum half-life (Egrie et al, 1993), and darbepoetin alpha has demonstrated a two- to three-fold longer serum half-life than rHuEPO in animal models and in patients with chronic renal failure (MacDougall et al, 1999; Egrie and Browne, 2001). In cancer patients undergoing chemotherapy, darbepoetin alpha therapy increased haemoglobin concentration when administered weekly (QW), or every 2 (Q2W), 3 (Q3W), or 4 (Q4W) weeks (Hedenus et al, 2002; Kotasek et al, 2002; Glaspy et al, 2002).
The study described here was the first to evaluate the dose, schedule, and pharmacokinetic profile of darbepoetin alpha in patients with anaemia of cancer, a condition for which dosing at weekly intervals or greater would be valuable. Darbepoetin alpha was given at one of four QW doses (from 0.5 to 4.5μgkg−1); at 6.75μgkg−1 Q3W; and at 6.75 or 10.0μgkg−1 Q4W.