Professor for Medical Oncology
Medical University of Vienna
Anaemia is a commonly observed side-effect in patients with cancer. Potential symptoms associated with anaemia are wide-ranging and include debilitating fatigue, anorexia, exertional dyspnoea and increased risk of life-threatening cardiac failure. Other anaemia symptoms are tachycardia, chest pain, decreased exercise tolerance, insomnia, dizziness and impaired concentration. Most of these symptoms adversely affect the quality of life (QOL) of patients by interfering with their normal activities, including the ability to work, carry out household chores, exercise and interact socially.(1,2) In addition, anaemia can have a negative impact on the outcome of cancer treatment. Despite these numerous negative consequences, cancer-related anaemia is often underdiagnosed and undertreated.(1,3–6)
The causes of anaemia in patients with cancer are generally multifactorial. Anaemia may be related to the cancer itself (due to tumour infiltration of the bone marrow and/or inflammatory cytokines that reduce the production and effect of erythropoietin) and/or the myelosuppressive effects of chemotherapy and radiation therapy.(1,7) In addition, incidence and severity of anaemia are highly dependent on the type of cancer, stage of disease, patient age and the type of treatment.(5,8) Prevalence and incidence of anaemia in cancer patients have recently been analysed by Knight and Wade.(7) They performed a systematic review of the literature and found that 30–90% of patients with cancer suffer from anaemia. Furthermore, the European Cancer Anaemia Survey (ECAS)(5) analysed data from more than 13,600 cancer patients in 24 European countries: prevalence on enrolment was 39%, increasing to 67% during the survey; the incidence of anaemia was 54%.
Erythropoietic proteins in the treatment of cancer-related anaemia
Until the 1980s, red blood cell (RBC) transfusion was the principal means of correcting cancer-related anaemia. However, transfusions were associated with a risk of infection and transfusion reactions, and therefore the need for alternative approaches was high. In 1983, the introduction of recombinant human erythropoietin (rHuEPO) changed the management of cancer-related anaemia, especially in terms of providing a more sustained correction and an improved risk/benefit profile.(9) Today, transfusion is considered mainly for patients with severe or acute anaemia (eg, haemogloblin [Hb] levels ≤7–8 g/dl).(10)
Three erythropoiesis-stimulating proteins (ESPs) are currently available for the management of cancer-related anaemia: epoetin alfa and epoetin beta (both rHuEPOs) and darbepoetin alfa. Epoetin alfa and beta differ in their molecular composition and formulation but have similar pharmacokinetics and pharmacodynamics.(11) Darbepoetin alfa is a unique erythropoietic protein that has the same mechanism of action as endogenous erythropoietin and rHuEPO. However, related to a biochemical modification (two additional amino-linked carbo‑hydrate chains(12)), its serum half-life after subcutaneous administration is extended to more than 70 hours, leading to an increased biological activity of this molecule in vivo. Based on these specific pharmacokinetic characteristics, darbepoetin alfa can be dosed less frequently (ie, once every one to three weeks) than conventional rHuEPOs (only once every week). In addition to reducing the expenditure of time for both patients and practitioners, such an optimised anaemia management would make synchronisation of the chemotherapy regimen and ESP administration possible.(1)
Less frequent dosing protocols with darbepoetin alfa have been tested in a dose-finding study(13,14) and two phase III studies.(15,16) In one of the latter studies,(15) anaemic patients (Hb ≤11 and ≥9g/dl) with non‑myeloid malignancies received chemotherapy once every three weeks and 6.75μg/kg darbepoetin alfa once every three weeks. Patients were randomised to receive darbepoetin alfa one week before chemotherapy (asynchronous group; day 15) or on the same day as chemotherapy (synchronous group; day 1) to evaluate whether timing of darbepoetin alfa administration in relation to chemotherapy has an effect on efficacy of darbepoetin alfa once every three weeks. In both groups, a mean change in Hb of 1g/dl after six weeks of treatment and a mean haematopoietic response of 74% could be observed. In addition, the efficacy of once-every-three-weeks darbepoetin alfa was unaffected by the timing of administration. In a noninferiority study, the efficacy of once-a-week darbepoetin alfa (2.25μg/kg) dosed per body weight was compared with the fixed dose of once-every- three-weeks darbepoetin alfa (500μg).(16) Fixed dose once every three weeks was as effective and safe as by-weight dosing once a week. However, requirement for transfusions tended to be lower in the once-every-three- weeks arm, and the number of injections was five instead of 14 in this arm. These results, together with those from the phase II studies,(13,14) support the possibility of administering darbepoetin alfa once every three weeks.
Guidelines for the use of erythropoietic proteins
As multiple ESPs and a wealth of data on different dosing regimens, indications and safety are available, guidelines to support physicians when determining appropriate use of ESPs are of major importance. In 2000, the American Society of Oncology (ASCO) and the American Society of Hematology (ASH) generated comprehensive clinical practice guidelines on the use of ESPs in patients with cancer that were updated in 2002.(17) Approaching the regional differences in clinical practices, the European Organization for Research and Treatment of Cancer (EORTC) developed specific guidelines for the European setting. They recommend initiation of treatment with ESPs in cancer patients with a Hb level of 9–11g/dl and support a target Hb of 12–13 g/dl.(9)
The high prevalence of tumour- and chemotherapy-induced anaemia, its potentially serious consequences and its impact on patient QOL make it clear that the management of anaemia is an important part of the treatment of cancer patients. As an effective and safe alternative to RBC transfusions, the introduction of ESPs represented a substantial improvement in the treatment of cancer-related anaemia.
The possibility of less frequent dosing (once every three weeks) of the ESP darbepoetin alfa means time-saving for practitioners, and it also increases the convenience for cancer patients through a reduced requirement for hospital visits and a reduced injection burden.
- Bokemeyer C, Foubert J. Anemia impact and management: focus on patient needs and the use of erythropoietic agents. Semin Oncol 2004;31:4-11.
- Curt GA, Breitbart W, Cella D, et al. Impact of cancer-related fatigue on the lives of patients: new findings from the Fatigue Coalition. Oncologist 2000;5:353-60.
- Curt GA, Johnston PG. Cancer fatigue: the way forward. Oncologist 2003;8 Suppl 1:27-30.
- Gordon MS. Managing anemia in the cancer patient: old problems, future solutions. Oncologist 2002;7:331-41.
- Ludwig H, Van Belle S, Barrett-Lee P, et al. The European Cancer Anaemia Survey (ECAS): a large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients. Eur J Cancer 2004;40:2293-306.
- Miller M, Kearney N. Institutional management of cancer-related fatigue: a comparison of clinical specialities. Eur J Oncol Nurs 2002;6:45-53.
- Knight K, Wade S, Balducci L. Prevalence and outcomes of anemia in cancer: a systematic review of the literature. Am J Med 2004;116 Suppl 7A:11S-26S.
- Groopman JE, Itri LM. Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst 1999;91:1616-34.
- Bokemeyer C, Aapro MS, Courdi A, et al. EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. Eur J Cancer 2004;40:2201-16.
- Sabbatini P, Cella D, Cleeland C, et al. NCCN Clinical Practice Guidelines in Oncology: cancer and treatment-related anemia, Version 2.2004. Available from: http://www.nccn.org/professionals/physician_gls/PDF/anemia.pdf
- Elliot S, Heatherington AC, Foote MA. Erythropoietic factors, clinical pharmacology and pharmacokinetics. In: Morstyn G, Foote MA, Lieschke GJ, editors. Cancer drug discovery and development. Hematopoietic growth factors in oncology: basic science and clinical therapeutics. Totowa, NJ, USA: Humana Press; 2004. p. 97-123.
- Egrie JC, Browne JK. Development and characterization of novel erythropoiesis stimulating protein (NESP). Br J Cancer 2001;84:3-10.
- Smith RE, Tchekmedyian NS, Chan D, et al. A dose and schedule-finding study of darbepoetin alpha for the treatment of chronic anaemia of cancer. Br J Cancer 2003;88:1851-8.
- Kotasek D, Steger G, Faught W, et al. Aranesp 980291 Study Group. Darbepoetin alfa administered every 3 weeks alleviates anaemia in patients with solid tumours receiving chemotherapy; results of a double-blind, placebo-controlled, randomised study. Eur J Cancer 2003;39:2026-34.
- Glaspy J, Henry D, Patl R. Effects of chemotherapy on endogenous erythropoietin levels and the
pharmacokinetics and erythropoietic response of darbepoetin alfa: a randomised clinical trial of synchronous versus asynchronous dosing of darbepoetin alfa. Eur J Cancer 2005;41:1136-45.
- Canon JL, Vansteenkiste J, Bodoky G, et al. Results of a randomized, double-blind, active-controlled trial of darbepoetin alfa administered once every 3 weeks for the treatment of anaemia in patients receiving multicycle chemotherapy. 10th Congress of EHA 2005; Abstract 1082.
- Rizzo JD, Lichtin AE, Woolf SH, et al. 2002. Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol 2002;20:4083-107.