Patients with cancer frequently develop a multifactorial anemia. The past decade has seen a dramatic improvement in understanding of the biology of the anemia of chronic disease, which has increased interest in studies of parenteral iron or antihepcidin strategies in these patients. Randomized trials have shown that therapy with erythropoiesis-stimulating agents (ESAs) is associated with a reduction in transfusion rates in patients with cancer undergoing chemotherapy. More recently, some studies have suggested that ESA therapy may increase the risk of tumor progression or reduce survival in patients with cancer. This topic was extensively reviewed previously. This update supplements prior reviews with data generated over the past 4 years. During this interval, interest in thrombosis and its role in cancer biology has increased, and concerns about the thrombotic risks of ESAs has moved to the fore-front. Until additional safety data are forthcoming, ESAs should be used only to treat chemotherapy-induced anemia, with the goal of preventing transfusions. Patients and physicians should be aware of the safety data for these products.
John A. Glaspy
Patients who have cancer, particularly those undergoing chemotherapy, frequently become anemic. Therapy with erythropoiesis-stimulating agents (ESAs) is associated with an increase in hemoglobin levels, a reduction in transfusion requirements, and, according to many clinical trialists and experienced clinicians, an improvement in functional status, productivity, and quality of life. Several randomized trials of ESAs in patients who have cancer have recently reported inferior outcomes in tumor progression or survival, raising appropriate concerns about the safety of ESAs in oncology. However, 3 important caveats to these reports exist. First, these clinical trials did not reflect the common use of ESAs in oncology practice (i.e., to treat, rather than prevent, anemia in patients undergoing chemotherapy). Second, the trials were seriously flawed and did not meet reasonable standards for cancer progression or survival trials. Third, during the same period, randomized trials were presented or published that showed no negative impact on tumor progression or survival; these trials have approximately the same shortcomings as trials that suggest a safety issue exists. The lack of definitive answers about the safety of ESAs for treating chemotherapy-related anemia has placed physicians, regulators, and most importantly patients in a difficult position that can only be addressed with additional data. This article reviews relevant preclinical and clinical available data to help improve understanding and guide decision making.
John A. Glaspy
Cancer patients are frequently anemic. Treatment of anemic patients with erythropoiesis-stimulating proteins (ESPs) such as epoetin and darbepoetin is associated with benefits that include a reduced transfusion risk and improved quality of life. The recent reports of two randomized trials in which ESP treatment was associated with a decreased survival raised valid concerns regarding the safety of these agents in oncology practice. Reports of erythropoietin receptors on non-hematologic human tumor cells have increased the level of concern and provided a relatively simple model for the effects of ESPs on tumor progression and resistance to treatment. This article reviews available data, which lead to a number of conclusions: 1) the two trials suggesting a negative impact on survival have serious methodologic issues that may compromise interpretation; 2) when used to treat rather than prevent anemia in cancer patients, ESPs show no significant negative impact on survival outcomes; 3) with the exception of erythroleukemia cell lines, the presence of functional erythropoietin receptors on human tumor cells has not been conclusively shown; and 4) a sound theoretical basis exists, supported by preclinical evidence, that any effect of ESP therapy on tumor outcomes may depend on baseline hemoglobin levels, with different effects when anemic and non-anemic individuals are treated. For the present, it is prudent to withhold ESP therapy unless hemoglobin concentrations fall below 12 g/dL and to titrate treatment to maintain a target of 12 g/dL, with adjustments in therapy to insure that levels do not exceed 13 g/dL.