Erythropoietin or Darbepoetin for patients with cancer

University of Cologne, Köln, North Rhine-Westphalia, Germany
Cochrane database of systematic reviews (Online) (Impact Factor: 6.03). 02/2006; 3(3):CD003407. DOI: 10.1002/14651858.CD003407.pub4
Source: PubMed


Anaemia associated with cancer and cancer therapy is an important clinical factor in the treatment of malignant diseases. Therapeutic alternatives are recombinant human erythropoietin (Epo), darbepoetin (Darbepo) and red blood cell transfusions.
The aim of this systematic review was to assess the effects of Epo or Darbepo to either prevent or treat anaemia in cancer patients.
We searched the Central Register of Controlled Trials, MEDLINE and EMBASE and other data bases. Searches were done for the periods 01/1985 to 12/2001 for the first review and 1/2002 to 04/2005 for the update. We also contacted experts in the field and pharmaceutical companies.
Randomised controlled trials on managing anaemia in cancer patients that compared the use of Epo/Darbepo (plus transfusion if needed) with observation until red blood cell transfusion was required.
Several reviewers independently assessed trial quality and extracted data.
This update of the systematic review included a total of 57 trials with 9,353 patients. Of these, 27 trials with 3,287 adults were also included in the first Cochrane Review. Thirty trials with 6,066 patients were added during the update process. Use of Epo/Darbepo significantly reduced the relative risk of red blood cell transfusions (RR 0.64; 95% CI 0.60 to 0.68, 42 trials, n = 6,510). On average participants in the Epo/Darbepo group received one unit of blood less than the control group (WMD -1.05; 95% CI -1.32 to -0.78, 14 trials, n = 2,353). For participants with baseline haemoglobin below 12 g/dL haematological response was observed more often in participants receiving Epo/Darbepo (RR 3.43; 95% CI 3.07 to 3.84, 22 trials, n = 4,307). There was suggestive evidence that Epo/Darbepo may improve Quality of Life (QoL). The relative risk for thrombo embolic complications was increased in patients receiving Epo/Darbepo compared to controls (RR 1.67, 95% CI 1.35 to 2.06; 35 trials, n = 6,769). Uncertainties remain whether and how Epo/Darbepo effects tumour response (fixed effect RR 1.12; 95% CI 1.01 to 1.23, 13 trials, n = 2,833; random effects: RR 1.09; 95% CI 0.94 to 1.26) or overall survival (unadjusted and adjusted data: HR 1.08; 95% CI 0.99 to 1.18; 42 trials, n = 8,167).
There is consistent evidence that administration of Epo/Darbepo reduces the relative risk for blood transfusions and the number of units transfused in cancer patients. For patients with baseline haemoglobin below 12 g/dL (mild anaemia) there is strong evidence that Epo/Darbepo improves haematological response. There is suggestive evidence that Epo/Darbepo may improve QoL. However, there is strong evidence that Epo/Darbepo increases the relative risk for thrombo embolic complications. Whether and how Epo/Darbepo effects tumour response and overall survival remains uncertain.

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Available from: Benjamin Djulbegovic, Dec 19, 2013
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    • "The authors concluded that insufficient data exist to support an effect of ESAs on tumor progression (RR 1.02, 95% CI 0.98–1.06) and warrant further research into cellular mechanisms and pathways (Tonia et al. 2012). Hence, the matter of debate whether EPO can promote tumor growth and induces cancer-therapy resistance continues (Jelkmann 2007). "
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    ABSTRACT: Erythropoietin (EPO) is a hematopoietic growth factor stimulating the formation of red blood cells. EPO is notoriously known as a doping substance in high-performance sports, and in cycling in particular. In the clinical setting, this erythropoiesis-stimulating agent is utilized to treat anemia, especially if caused by a lack of endogenous EPO production due to chronic renal failure. In recent years, the non-hematopoietic functions of EPO, also known as pleiotropic functions, have been intensively investigated. Of interest for orthopedics and musculoskeletal tissue engineering, the non-hematopoietic capabilities of EPO include osteogenic and angiogenic potencies. The objectives of the present thesis were to address and investigate the efficacy of EPO in regenerating bone and facilitating bone healing. The first paper investigated the effectiveness of continuous low-dose systemic EPO administration to enhance bone formation in an autograft posterolateral spinal fusion model in rabbits. We observed an increased bone volume and neovascularization compared with saline-treated controls after six weeks of observation. The second paper set out to investigate the cellular mechanisms of the osteogenic action of EPO and to describe the dose-response relationship in vitro. Human mesenchymal stromal cells (hMSCs) were exposed to a wide range of EPO-concentrations for up to three weeks. The lowest effective dose was 20 IU/ml EPO, and a proportional dose-response relationship was observed. Hence, the highest tested concentration of 100 IU/ml EPO yielded the most pronounced osteogenic effect. Regarding the cellular ways of action, two cell membrane receptors were observed, namely the EPO receptor (EPOR) and the cytokine receptor common beta subunit (CD131). Furthermore, the osteogenic effect was mediated via three intracellular signaling pathways: TOR serine-threonine kinase (mTOR), Janus kinase 2 (JAK2), and phosphatidylinositol 3-kinase (PI3K). The third paper was designed to accelerate clinical progress. Before the clinical implementation of EPO it was necessary to test EPO in a large-animal model. Systemic EPO administration can cause severe adverse events such as thromboembolisms. A single, locally administered, low-dose approach was therefore chosen. Bone formation was assessed in a porcine calvarial defect model. The defects were treated with EPO or placebo and in combination either with autologous bone graft, a commercially available collagen carrier, or a polycaprolac-tone scaffold. After five weeks of observation, an increased bone volume after EPO treatment was observed in the collagen carrier group. The excellent regenerative potential of the autograft was underlined by the fact that the bone volume did not significantly differ from that of the healthy reference bone. At the other end of the spectrum, bony ingrowth into the PCL scaffold was sparse both with and without EPO, which suggests the need to investigate other types of scaffold material or modified PCL constructs. In conclusion, bony ingrowth and vascularization of three-dimensional scaffolds for bone tissue regeneration remains a challenge. The described pleiotropic functions of EPO may overcome this limitation of skeletal tissue engineering in the future. EPO could potentially facilitate neovascularization, and the migration of cells that are directed into the core of the scaffold will facilitate bony ingrowth. Moreover, EPO promotes a direct and indirect osteogenic stimulation of hMSCs. A clinically safe dose enhanced bone healing in a large-animal model. This is encouraging news for the potential direct clinical utilization of EPO. EPO is therefore a promising growth factor in regenerative medicine.
    Full-text · Article · Feb 2014 · Acta Orthopaedica
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    • "Clinical trials with ESAs have reported an improved QoL and decreased treatment-related anemia (including numbers of blood transfusions) [33]. Other studies suggested an improvement in survival outcome of cancer patients that received rHuEPO for anemia [33]. "
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    ABSTRACT: Traditionally, erythropoietin (EPO) is described as a hematopoietic cytokine, regulating proliferation and differentiation and survival of the erythroid progenitors. The recent finding of new sites of EPO production and the wide spread distribution of EPO receptors (EPO-R) on endothelial cells, cardiomyocytes, renal cells as well as the central and peripheral nervous system raised the possibility that EPO may exert pleiotropic actions on several targets. Indeed studies (mainly preclinical) have documented protective, non-hematopoietic, abilities of EPO in a variety of tissue. However, the data obtained from clinical studies are more skeptical about these properties. This article provides a comprehensive overview of EPO and its derivatives.
    Full-text · Article · Nov 2011 · Medical science monitor: international medical journal of experimental and clinical research
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    • "The use of EPO has been shown to worsen outcome in certain cancers due to increased thromboembolic risk and possibly EPO-induced tumour progression [103]. This observation raises concerns over EPO use in patients with malignancies who develop sepsis. "
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    ABSTRACT: Sepsis is the systemic inflammatory response to infection and can result in multiple organ dysfunction syndrome with associated high mortality, morbidity and health costs. Erythropoietin is a well-established treatment for the anaemia of renal failure due to its anti-apoptotic effects on red blood cells and their precursors. The extra-haemopoietic actions of erythropoietin include vasopressor, anti-apoptotic, cytoprotective and immunomodulating actions, all of which could prove beneficial in sepsis. Attenuation of organ dysfunction has been shown in several animal models and its vasopressor effects have been well characterised in laboratory and clinical settings. Clinical trials of erythropoietin in single organ disorders have suggested promising cytoprotective effects, and while no randomised trials have been performed in patients with sepsis, good quality data exist from studies on anaemia in critically ill patients, giving useful information of its pharmacokinetics and potential for harm. An observational cohort study examining the microvascular effects of erythropoietin is underway and the evidence would support further phase II and III clinical trials examining this molecule as an adjunctive treatment in sepsis.
    Full-text · Article · Aug 2010 · Critical care (London, England)
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