Using ESAs in patients with cancer-related anemia
The pathophysiology of cancer-related anemia is multifactorial.1 In addition to other potential causes (eg, iron deficiency, gastric ulcer), the myelosuppressive effects of chemotherapy and radiation therapy may cause anemia to develop in patients with cancer. Anemia is defined as a deficiency in red blood cells (RBCs).
The presence and severity of anemia symptoms varies depending on the degree of anemia, the rapidity of onset, and the age and physiologic status of the patient. Mild to moderate anemia can cause symptoms such as headache, palpitations, dizziness, tachycardia, and shortness of breath.2 Fatigue is commonly associated with anemia, and patients report it as the most disturbing symptom affecting their quality of life.3 Anemia is also associated with worse prognosis in certain cancers.4
A full workup to determine the etiology of anemia should be performed, and any potential causes not related to cancer treatment should be treated. The goal of anemia treatment is to improve oxygen-carrying capacity, thereby increasing oxygenation to tissues. There is no evidence or strict recommendation for targeting specific hemoglobin (Hgb) values. The treatment options for chemotherapy-related anemia include blood transfusions and erythropoietin-stimulating agents (ESAs) in conjunction with iron supplementation as appropriate. Packed red blood cell (PRBC) transfusion is the fastest method for alleviating symptoms of anemia and increasing Hgb. However, ESAs and PRBC transfusions are not free of risks. Potential complications of PRBC transfusion include transmission of infectious disease, transfusion reactions, iron overload, overtransfusion, and increased morbidity. Treatment with ESAs may incur increased risk of venous thrombotic events (VTEs), decreased survival time, and shortened time to tumor progression.5
Currently available erythropoietin-stimulating agents indicated for the treatment of chemotherapy-induced anemia are epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp). Both epoetin alfa and darbepoetin alfa exert the same biologic effects as endogenous erythropoietin. Erythropoetin stimulates the division and differentiation of committed erythroid progenitor cells in the bone marrow, increasing the production and differentiation of red blood cells. The half-life of darbepoetin alfa is approximately three times longer than epoetin alfa, allowing a 3-week administration cycle. Comprehensive reviews have shown there is no difference in safety or efficacy between epoetin alfa and darbepoetin alfa.6
BENEFITS AND RISKS ASSOCIATED WITH ESAs
Randomized controlled trials and meta-analyses have consistently shown that ESAs reduce the number of RBC transfusions; however, data showing that ESA use reduces fatigue or improves quality of life are insufficient at this time.6 Risks versus benefits of ESA use and PRBC transfusion should be individually determined for each patient.
Meta-analyses indicate that ESAs increase mortality, tumor progression, and thromboembolism.6 In 2007, the FDA issued a black box warning for ESAs regarding the risk of increased mortality and tumor progression based on eight randomized studies that individually demonstrated a decrease in overall survival and/or decreased locoregional disease control in patients with advanced breast, cervical, head and neck, lymphoid, and non-small cell lung cancers who received an ESA7-14 (Table 1). Multiple meta-analyses evaluated mortality rates in cancer patients receiving ESAs after the FDA's initial warning. A large meta-analysis that included 53 studies involving 13,933 patients evaluated mortality in all cancer patients in the studies. Results of this meta-analysis showed ESAs increased mortality by a factor of 1.17 and worsened overall survival. A subgroup analysis evaluated data on patients receiving chemotherapy and showed mortality and overall survival outcomes were not statistically significant.15 Similarly, a second meta-analysis evaluated survival among 13,611 patients with cancer who were treated in 51 phase III trials. These results showed an increased rate of mortality of 1.10 for patients who were treated with an erythropoietin-stimulating agent compared with those treated with a placebo.16 These findings prompted the FDA mandated black box warning that "ESAs are not indicated for patients receiving myelosuppressive chemotherapy where the outcome is cure."17-19
Erythropoietin-stimulating agents have also been associated with an increased risk of VTE, which is due to multiple factors. The presence of the tumor increases baseline risk independently of ESA use. In addition, the classic risks of Virchow triad (circulatory stasis, hypercoagulability, and endothelial injury) associated with thrombosis are typically present in this patient population. However, the risk of thrombosis is heightened when ESAs are administered. This outcome has been evidenced in multiple meta-analyses with an estimated 1.57-fold increased risk of VTE in patients receiving ESAs.16 Caution should be used when administering ESAs to patients who have additional risk factors for VTE (ie, previous history of VTE; prolonged periods of immobility; surgery; or receiving medications such as thalidomide, lenalidomide, corticosteroids, or doxorubicin).
The studies discussed above targeted higher Hgb levels than currently recommended, which is an important consideration. In these studies, ESA treatment was initiated when Hgb levels were lower than normal for a healthy adult (rather than the recommended less than 10 g/dL). Data do not support initiating ESAs at Hgb levels higher than 10 g/dL, and despite multiple studies on the agents, an optimal target Hgb level cannot be definitively determined.1,6 Delaying treatment and targeting lower Hgb levels may minimize patient exposure to the risks associated with ESA use and ensure that patients who receive ESAs are those who benefited in studies.
GUIDELINES AND RECOMMENDATIONS FOR USE
The National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology/American Society of Hematology (ASCO/ASH) developed recommendations and guidelines for the ESA use in adult patients with cancer. Evidence-based guidelines recommend that ESAs be reserved for oncology patients undergoing myelosuppressive chemotherapy who have an Hgb level of less than 10 g/dL; in addition, ESAs should not be used until after their potential harms and benefits and a comparison of the potential harms of PRBC transfusions are discussed with the patient.6