Elsevier

European Journal of Cancer

Volume 40, Issue 15, October 2004, Pages 2201-2216
European Journal of Cancer

Guidelines
EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer

https://doi.org/10.1016/j.ejca.2004.07.015Get rights and content

Abstract

Anaemia is frequently diagnosed in patients with cancer, yet it is difficult to identify a single cause due to its multifactorial aetiology. We conducted a systematic literature review (1996–2003) to produce evidence-based guidelines on the use of erythropoietic proteins in anaemic patients with cancer (see Table 4). Level I evidence exists for a positive impact of erythropoietic proteins on haemoglobin (Hb) levels when administered to patients with chemotherapy-induced anaemia or anaemia of chronic disease, when used to prevent cancer anaemia, in patients undergoing cancer surgery and following allogeneic bone marrow transplantation. The Hb level at which erythropoietic protein therapy should be initiated is difficult to determine as it varied between studies; a large number of Level I studies in patients with chemotherapy-induced anaemia or anaemia of chronic disease enrolled patients with a Hb concentration ⩽105 g/L, but none compared the effect of different baseline Hb levels on the response to treatment. Similarly, several studies defined the target Hb concentration as 120–130 g/L following treatment with erythropoietic proteins, but none specifically addressed the correlation between target Hb level and clinical benefit in a randomised fashion. Level I evidence shows that red blood cell (RBC) transfusion requirements are significantly reduced with erythropoietic protein therapy in patients with chemotherapy-induced anaemia or when used to prevent cancer anaemia (approximately 20% reduction compared with controls). We found indirect Level I and III evidence that patients with chemotherapy-induced anaemia or anaemia of chronic disease initially classified as non-responders to standard doses proceed to respond to treatment following a dose increase (absolute increases in response rate ranged from 8% to 18%). However, none of these studies examined the effect on response rates of a longer treatment period at the lower dose, or performed a randomised comparison of a dose increase versus an unchanged dose. There is Level I evidence to show that quality-of-life (QOL) is significantly improved in patients with chemotherapy-induced anaemia and in those with anaemia of chronic disease, particularly in patients achieving a Hb response to erythropoietic protein therapy. There are insufficient data to determine the effect on survival following treatment with erythropoietic proteins in conjunction with chemotherapy or radiotherapy. There is Level I evidence that dosing of erythropoietic proteins less frequently than three times per week (TIW) is efficacious when used to treat chemotherapy-induced anaemia or prevent cancer anaemia. There is Level III evidence that initial doses of erythropoietic proteins considered to be higher than current standard practice produce higher haematological responses in patients with chemotherapy-induced anaemia or anaemia of chronic disease. Level I evidence demonstrates that several baseline patient parameters (e.g., low endogenous erythropoietin [EPO] concentration, age <60 years, Hb concentration ⩾90 g/L) impact upon the response to erythropoietic proteins when used to treat chemotherapy-induced anaemia or prevent cancer anaemia. Evidence indicates that endogenous EPO concentration impacts on response in patients with lymphoproliferative malignancies, but is not a valid parameter in patients with solid tumours. There is Level I evidence that fixed doses of erythropoietic proteins can be used at the start of therapy to treat patients with chemotherapy-induced anaemia, but maintenance doses should be titrated individually. There is no evidence that pure red cell aplasia (PRCA) occurs following treatment with erythropoietic proteins in patients with chemotherapy-induced anaemia or when used prophylactically in patients with cancer. There is Level I evidence that the risk of thromboembolic events and hypertension are slightly elevated in patients with chemotherapy-induced anaemia receiving erythropoietic proteins. Level I evidence supports the effectiveness of erythropoietic proteins to prevent anaemia in non-anaemic cancer patients receiving chemotherapy or radiotherapy or in those undergoing cancer surgery. However, these are non-licensed indications and we do not currently recommend the prophylactic use of erythropoietic proteins to prevent anaemia in patients who have normal Hb values at the start of treatment.

Additional trials are warranted, especially on the issues of iron replacement and cost-effectiveness of erythropoietic protein therapy, as well as on tumour response/progression and survival.

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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