Neel Bhalala (2009) Sofia Medical University

Background  Erythropoiesis-stimulating agents are man-made versions of a natural protein known as erythropoietin. Erythropoietin is made by the kidney and stimulates the primitive cells in the bone marrow to produce red blood cells, the main oxygen- carrying cells in the blood. An increase in the number of red blood cells is commonly indicated by an increase in the laboratory measures known as the blood hemoglobin level and the blood hematocrit. An abnormally low hemoglobin or hematocrit value is one of the hallmarks of anemia. 

Background  Multiple conditions may cause anemia, including the loss of erythropoietin due to the destruction of kidney function by chronic kidney disease. Other conditions that may cause anemia are generally unrelated to a deficiency of erythropoietin and are exemplified by anemias due to iron deficiency, certain vitamin deficiencies, hemorrhage, and various intrinsic bone marrow disorders. Generally, regardless of the cause of anemia, blood transfusions may be necessary to relieve patient symptoms and maintain life when the anemic condition becomes severe. The main goal of treatment with ESAs is to increase the number of red blood cells in patients with the specific types of anemia that are responsive to the ESAs so that blood transfusions are not needed.

Mechanism of action  ESA’s stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. A primary growth factor for erythroid development, erythropoietin is produced in the kidney and released into the bloodstream in response to hypoxia. In responding to hypoxia, erythropoietin interacts with progenitor stem cells to increase red blood cell (RBC) production. Production of endogenous erythropoietin is impaired in patients with chronic renal failure (CRF), and erythropoietin deficiency is the primary cause of their anemia. Increased hemoglobin levels are not generally observed until 2 to 6 weeks after initiating treatment with ESA’s.

BEST (Breast Cancer Erythropoietin Survival Trial)  Study Objective The primary objective of the Breast Cancer Erythropoietin Survival Trial (BEST) was to determine the effect of maintaining Hb 12 to 14 g/dL with epoetin alfa versus placebo on 12- month overall survival. Additional efficacy variables included change in Hb level from baseline to study completion, proportion of patients receiving RBC transfusion, tumor response rate, and time to disease progression (TTP).

Results

 The results from the recent survival studies raises the question about whether erythropoietic agents may negatively affect survival, especially at high Hb levels. In this study, almost twice as many patients in the epoetin alfa group than the placebo group exceeded the target Hb range (Hb > 14 g/dL) at some point during the study. Although speculative, it may be that the relationship between Hb and survival is a U-shaped curve, with increased risks at more extreme Hb levels. It has been suggested that, in certain tumor cell lines and xenografts that express both erythropoietin and its receptor, erythropoietin signaling may promote cancer progression several investigators have suggested a link between erythropoietin receptor expression and tumor proliferation. However, many studies showing such signaling required suprapharmacologic concentrations of erythropoietic agents to obtain the response and most in vitro studies have shown no such relationship. No causal relationship between epoetin alfa and cancer progression in humans has been shown.

Conclusion  Conclusion:  After reviewing the data it shows that ESA’s increased the risk for death and serious cardiovascular events when administered to target a hemoglobin of greater than 12 g/dL. Hence, it is advised that physicians should use the lowest ESA dose that will gradually increase the hemoglobin level to a concentration sufficient to avoid the need for blood transfusions. Based upon the new data which emphasizes the evidence for increased rate of tumor progression it is indicated that an ESA may offer no benefit and may cause serious harm in treating anemic cancer patients not currently on chemotherapy. When ESA's were used to attain hemoglobin levels in excess of the 12 g/dL level there was an increased risk for serious cardiovascular and thrombotic complications in chronic renal failure (whether or not receiving dialysis).  ESA's are not indicated for use in specific tumor types (breast cancer, head and neck cancer, and non-small cell lung cancer). The drug should define a hemoglobin level in asymptomatic patients at which ESA should be initiated and the hemoglobin level at which dosing should be suspended that is >12mg/dl. The ESAs should be discontinued following the completion of a chemotherapy regimen and re-evaluation of the degree of anemia with subsequent chemotherapy regimen(s) be done.