In cancer patients, anemia is multifactorial, resulting from cancer treatment, anemia of malignancy, blood loss, impaired production of or response to erythropoietin(Drug information on erythropoietin), and dysregulation of iron metabolism (decreased dietary iron intake, absorption, and utilization). Clinical studies have found that erythropoietin stimulating agents (ESAs) increase hemoglobin (Hb) levels and reduce the need for blood transfusions by 40%, with ESA-treated patients receiving an average of 1 unit less of red blood cells (RBCs) than non-ESA-treated anemic cancer patients.[1,2]
Epoetin alfa (Procrit) and darbepoetin alfa(Drug information on darbepoetin alfa) (Aranesp) are approved to treat anemia in cancer patients receiving chemotherapy.[3,4] However, in everyday practice, ESAs are often prescribed not only at FDA-approved doses for cancer patients receiving chemotherapy but also for other cancer patients, or using unapproved dosing regimens. ESAs are now leading drugs used in oncology, with $11.9 billion in worldwide sales in 2006. Anemia has been associated with decreased overall survival in cancer patients. It was hypothesized that correction of anemia by ESAs would improve tumor oxygenation and thus the response to chemotherapy and radiation, resulting in improved overall survival.
Early studies evaluating use of ESAs to correct anemia were not powered to measure overall survival, but a meta-analysis summarizing the data from 27 clinical trials from 1985–2001 found a nonsignificant trend toward improved overall survival in ESA-treated patients. In 2006, a repeat meta-analysis which included additional trials conducted from 2001–2005 summarized the results of 57 clinical trials in which 9,353 cancer patients with anemia were randomized to an ESA or RBC transfusions alone.[1,2]The impact of ESAs on overall survival was inconclusive, however there was evidence that ESAs could, in certain circumstances, adversely affect survival in cancer patients. In addition, there were significant risks associated with ESA use, including thromboembolic complications (eg, transient ischemic attacks, stroke, pulmonary emboli, deep vein thrombosis, and myocardial infarction) and hypertension.[1,2]
EMERGING safety CONCERNS
Two large trials specifically designed to measure overall survival in cancer patients treated with ESAs to maintain Hb higher than the recommended level of 12 g/dL concluded ESAs had an adverse effect. Henke and colleagues demonstrated that patients with advanced head and neck cancer receiving radiation therapy had a higher risk of tumor progression if treated with an ESA to achieve a target Hb >14 g/dL in women and >15 g/dL in men. The BEST trial showed maintenance of an Hb of 12–14 g/dL in metastatic breast cancer patients undergoing first-line chemotherapy was associated with decreased overall survival.
In the past year, four additional clinical trials found a higher incidence of serious adverse effects and/or death with use of ESAs in unapproved dosing regimens or in patients not receiving chemotherapy.
In January 2007, the FDA was notified of the interim analysis of a clinical trial evaluating the use of ESAs to achieve a target Hb level of 12 g/dL in 989 patients with cancer-related anemia not receiving chemotherapy. In this study, the use of an ESA did not reduce the need for RBC transfusions, and it increased overall mortality (hazard ratio 1.25; 95% confidence interval: 1.04, 1.51).