GuidelinesEORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer
Introduction
Anaemia is frequently diagnosed in patients with cancer, yet it is difficult to identify a single cause due to its multifactorial aetiology. Treatment-induced anaemia occurs as a result of bone marrow damage; radiotherapy and most cytotoxic chemotherapeutic agents cause some degree of myelosuppression. Blood loss following radical cancer surgery can also trigger anaemia. The most common type of non-treatment-induced anaemia in patients with cancer occurs mainly as a result of the tumour and is referred to as the anaemia of chronic disease [1]. In such cases, activation of inflammatory cytokines is thought to result in inadequate erythropoietin (EPO) production [2], [3], impaired iron utilisation and suppressed proliferation of erythroid progenitor cells [4].
Allogeneic red blood cell (RBC) transfusions have been the mainstay of treatment for anaemia, and are still used in severe cases, but they do not provide long-term correction of anaemia. Cloning of the human EPO gene in 1983 [5] heralded the way forward for the treatment of cancer-related anaemia and allowed viable quantities of recombinant human erythropoietin (rHuEPO) to be produced commercially. rHuEPO was initially used for the correction of renal anaemia in 1986 [6] with the first pilot study published in anaemic patients with cancer in 1990 [7]. rHuEPO poses fewer risks to patients than RBC transfusions and provides a more sustained correction of anaemia, as well as being more convenient for patients. The efficacy of rHuEPO in anaemic cancer patients has been confirmed in numerous clinical trials, both in terms of increased haemoglobin (Hb) levels and decreased RBC transfusion requirements, and, more recently, improved quality-of-life (QOL). Some trials have reported a trend for improved survival following rHuEPO therapy [8], [9], however, recent randomised trials specifically designed for survival analyses have shown findings in the opposite direction in head and neck cancer patients undergoing radiotherapy [10] and in metastatic breast cancer patients receiving chemotherapy [11].
Clinicians today are faced with an expanding choice of erythropoietic proteins and a wealth of data on appropriate dosing regimens, approved indications and safety. In addition, the cost of erythropoietic protein therapy is significant, and not all patients respond to treatment; thus, guidelines on its use and the accurate selection of patients most likely to respond are vital. Suggested clinical guidelines for the treatment of cancer-related anaemia were first published by an American group in 1998 [1]. The National Comprehensive Cancer Network subsequently produced clinical practice guidelines on cancer and treatment-related anaemia in 2001, with an update published in 2003 [12]. The most comprehensive set of clinical practice guidelines for the use of epoetin in patients with cancer were published jointly in 2002 by the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH) [13]. These United States (US) evidence-based guidelines recommend the use of epoetin for patients with chemotherapy-associated anaemia and a Hb concentration ⩽100 g/L, with clinical circumstances determining the use of epoetin for patients with less severe anaemia (Hb concentration 100–120 g/L).
As the management of cancer anaemia continues to move at a rapid pace, and new drug therapies are approved, treatment guidelines must be reviewed and updated regularly. Indeed, since the release of the ASCO/ASH guidelines, a number of important studies have been published and another erythropoietic protein, darbepoetin alfa, with a longer serum half-life than rHuEPO [14], [15] has been approved in this field. An independent task force, endorsed by the European Organisation for Research and Treatment of Cancer (EORTC), was therefore established to systematically review the literature and produce up-to-date, evidence-based guidelines for the use of erythropoietic proteins in anaemic patients with cancer in Europe. These guidelines cannot account for inter-individual variation and clinicians should apply their best judgement when deciding on treatment options.
Section snippets
Patients and methods
The chosen database was MEDLINE due to its precise indexing and general availability. Electronic searches were conducted using the MEDLINE database for English language records from 1, January 1996 to 1, September 2003. The cut-off date of 1996 was chosen to follow-on from previous EORTC work conducted in this area [16]. Search terms were used to extract records limited to clinical studies with erythropoietic proteins in anaemic patients with cancer or lymphoproliferative malignancies aged ⩾18
Results
A total of 78 published studies (34 using epoetin alfa, 20 unspecified rHuEPO, 16 epoetin beta and 8 darbepoetin alfa) relating to the administration of erythropoietic proteins in anaemic patients with cancer were considered to be relevant from a total of 235 papers identified by the search. An additional 50 relevant abstracts were also identified (33 using epoetin alfa, 10 unspecified rHuEPO, 5 darbepoetin alfa and 2 epoetin beta). Criteria for exclusion included review articles, in vitro
Discussion
The results of this systematic literature review reveal an abundance of data on the use of erythropoietic proteins in cancer patients with chemotherapy-related anaemia, but limited data in the other therapeutic areas examined. Data were particularly sparse for the treatment of radiotherapy-induced anaemia where only one abstract was identified. The quality of the clinical trials varied greatly across the indications, with the majority of well-designed, large, controlled, randomised trials being
Conflict of interest
Dr. Bokemeyer has served as a consultant on advisory boards, and as a speaker at meetings, for Amgen, Hoffmann-La Roche Ltd and Janssen-Cilag. Dr. Aapro has received research grant support from, and served as a consultant to, Amgen, Hoffmann-La Roche Ltd and Ortho-Biotech. Dr. Osterborg has received research grant support from Amgen and Hoffmann-La Roche Ltd and served as a speaker for Amgen and Hoffman-La Roche. The remaining authors have no conflicts of interest to declare.
Acknowledgements
This work was performed by a committee of the EORTC Task Force Elderly, with a mandate to review the use of erythropoietic proteins in all anaemic patients with cancer, not only the elderly population. The task-force acknowledges the contributions of Drs. Yves Beguin, Tim Littlewood and Michael Gordon during the initial stages of this project. In addition, the task-force would like to thank Dr. Michael Gordon and representatives from Amgen, F. Hoffmann-La Roche Ltd and Ortho-Biotech for their
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