Examining the Involvement of Erythropoiesis-Stimulating Agents in Tumor Proliferation (Erythropoietin Receptors, Receptor Binding, Signal Transduction), Angiogenesis, and Venous Thromboembolic Events

Anemia is frequent in cancer patients and its incidence increases with chemotherapy. The probability of requiring transfusions also increases with chemotherapy. Anemia negatively impacts survival and accentuates fatigue in cancer patients. Cancer promotes inflammatory cytokine production, which suppresses erythropoiesis and erythropoietin (EPO) production. Erythropoiesis-stimulating agents (ESAs) improve erythropoiesis and reduce transfusion needs in anemic cancer patients receiving chemotherapy. However, meta-analyses have shown an increased risk of thromboembolic (TE) events with ESA use during chemotherapy, but not increased on-study mortality or reduced overall survival. Three reasons have been proposed to explain why ESAs might have adverse effects in anemic cancer patients: tumor progression due to stimulation of tumor cell EPO receptors; increased risk of TE; and reduced survival. However, erythropoietin is not an oncogene, nor is the EPO receptor. It has also been demonstrated that erythropoietin does not stimulate tumor proliferation. Increased TE risk associated with ESAs is probably a consequence of increased blood viscosity due to excessive RBC mass elevation with concomitant plasma volume contraction, nitric oxide scavenging, and endothelial cell activation. Increased ESA dosing may also impact survival negatively because EPO contracts the plasma volume and stimulates inflammatory cytokine production independently of increasing erythropoiesis. Furthermore, transfusions themselves are associated with an increase in TE and plasma volume contraction, and these events are potentiated when ESAs are given with transfusions. An update on the management of anemia in oncology, the potential adverse events of ESAs, the benefits and risks of transfusions, and QoL are discussed in this paper. The

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“…Joachim Fandrey and Mario Dicato discuss ESAs and tumor proliferation in further detail in their manuscript in this supplement [38].…”

Section: Tumor Progression Resulting From Stimulation Of Tumor Cell Ementioning

confidence: 99%

Anemia Management in Oncology and Hematology

2009

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“…This latter aspect has been investigated with immunehistochemistry techniques using an antibody (C20, Santa Cruz, California) and many authors doubt the specifi city of the technique: the test shows the same cellular/tissue pattern in mice whether they are normal or EpoR knock out [2]. It appears that the antibody, not very specifi c for EpoR measures or heat shock proteins (HSPs), and hence its positivity in tumour samples correlates with poor prognosis not because of Epo or EpoR, but because elevation of HSP is a feature of poor prognosis [2].…”

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confidence: 99%

Erythropoiesis-stimulating agents: the present situation

Dicato

2011

Clin Transl Oncol

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“…However, following various FDA and EMEA meetings in 2004,2007, and 2008 to discuss safety concerns with ESAs in oncology and nephrology, the FDA, Committee for Medicinal Products for Human Use, and EMEA introduced ESA label changes. These safety questions, relating to venous thrombotic events (VTEs), including shorter survival in some studies and the debate about erythropoietin receptors, are discussed in detail by Joachim Fandrey and Mario Dicato in this issue [8]. Jerry Spivak, Pere Gascón, and Heinz Ludwig discuss the impact of anemia on survival and QoL and provide some fascinating insights into the role inflammatory cytokines play in anemia [9].…”

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confidence: 99%

“…The problem with EPORs identified on tumor cells using an unspecific antibody is that there is no proof that they are functional, nor that they are not confused with other entities like heat shock protein [8]. There is no evidence of clinical tumor progression when ESAs are used within the approved indication, in cancer patients receiving chemotherapy [8].…”

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confidence: 99%