Challenges in Treating Chemotherapy-Induced Anemia

Rickey C. Miller, PharmaD, BCPS, BCOP
Published: Friday, Mar 04, 2011
Practicing clinicians and healthcare administrators face many challenges in treating cancer patients, including management of chemotherapy-induced anemia. Information on how to best treat these patients comes from a variety of sources: clinical guidelines provide direction based on evidence-based literature, the US Food and Drug Administration (FDA) provides guidance on safe administration and use of erythropoiesis-stimulating agents (ESAs), and insurance providers drive treatment based on evidence and policy. With all of the directives on how to treat chemotherapy-induced anemia, integration of concepts and current data must be completed to determine the appropriate use of ESAs in cancer. The landscape surrounding erythropoietin agents is shifting as questions surround the safety and appropriate use of these agents in cancer patients. The clinical decision between blood transfusions and use of ESAs has become more difficult, as there are safety warnings concerning ESAs and questions regarding the safety of blood transfusions.

SAFETY

The American Society of Hematology (ASH)/American Society of Clinical Oncology (ASCO) has called for a meta-analysis of data to determine factors contributing to (1) the risks surrounding transfusions or adverse event of ESAs, or both; (2) faster tumor progression or shorter survival in some ESA-treated patients; and (3) a better understanding of effectiveness of ESAs for anemia not related to chemotherapy (anemia of cancer) and eventually help guide the design of new clinical trials. The Erythropoiesis Stimulating Agents in Cancer Patients: Individual Patient Data Meta-Analysis Collaborative Group presented a meta-analysis at the December 2008 ASH meeting. Their timely efforts analyzed data for 13,933 patients from 53 studies. ESAs increased on-study mortality by 17% (hazard ratio [HR], 1.17; 95% confidence interval [CI], 1.06-1.30; P= .002) and worsened overall survival by 6% (HR, 1.06; 95% CI, 1.00-1.12; P= .005). Chemotherapy patients also had worse outcomes, with on-study mortality increasing by 10% (HR, 1.10; 95% CI, 0.98-1.24; P= .12) while overall survival decreased by 4% (HR, 1.04; 95% CI, 0.97-1.11; P= .26). Since the CI crossed 1 in the chemotherapy subset, it appears from this meta-analysis that ESAs decrease survival in chemotherapy patients, but caution should be used in all patients using ESAs.1-3

From the meta-analysis, Bohlius et al2 determined the number needed to harm (NNH) for cancer patients with various prognoses. For low-risk patients who have a 5% chance of mortality within the next 4 months, the NNH was 121 (95% CI, 69-343). For medium-risk patients who have a 20% risk of mortality within months, the NNH was 34 (95% CI, 19-94). Finally, for high-risk patients with a 70% risk of mortality within 4 months, the NNH was 24 (95% CI, 14-67).3

These data confirmed the FDA warnings issued in March 2007 and proposed a framework for the ASH/ASCO 2007 guidelines. The guidelines included warnings derived from prior published or presented data that were then solidified as black box warnings in ESA labeling which: (1) shortened the time to tumor progression in patients with advanced head and neck cancers receiving radiation therapy when administered to target a hemoglobin level >12 g/dL (Ezetimibe and Simva­statin in Hypercholesterolemia Enhances Atherosclerosis Regres­sion [ENHANCE] and Danish Head and Neck Cancer Study [DAHANCA] Group, 10 trials); (2) shortened overall survival and increased mortality attributed to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to target a hemoglobin level >12 g/dL (Breast Cancer Erythropoietin Trial [BEST]); and (3) increased the risk of death when administered to target a hemoglobin level of 12 g/dL in patients with active malignant disease receiving neither chemotherapy nor radiation therapy (Randomized Trial of Epoetin Alfa in Patients With Advanced Non-Small Cell Carcinoma of the Lung [EPO-CAN-20] and Amgen 20010103 trials). The FDA warning established that treating patients to a hemoglobin level >12 g/dL can lead to negative consequences.4-9

The Oncology Drug Advisory Committee (ODAC) of the FDA met after the letter in March 2007 to further analyze the safety data and clarify safety directives. It restated that patients with advanced breast, head and neck, lymphoid, and non–small-cell lung cancers (when hemoglobin levels are targeted at >12 g/dL), survival can be shortened and tumor progression more likely. Further warnings of changes in survival and tumor progression were made for ESAs at any targeted hemoglobin level (specifically <12 g/dL). Dosing should be targeted at the lowest dose to avoid blood transfusions. Anemia as a result of chronic disease is addressed as a nonindication. In March 2008, this information was added to the product labeling.10,11


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