Objective: To evaluate, characterize, compare, and critique trials reporting increased tumor progression in patients with cancer who are receiving erythropoiesis-stimulating agents (ESAs) that led to Food and Drug Administration (FDA) actions for black box warnings and labeling changes.
Data sources: Literature was accessed through MEDLINE (1950-August 2008) and PubMed (1975-August 2008) using the search terms recombinant erythropoietin, darbepoetin, epoetin, anemia, neoplasms, and disease progression. Articles cited in MedWatch alerts, Oncologic Drugs Advisory Committee meeting briefs, and bibliographies from identified articles were also reviewed.
Study selection and data extraction: All studies published in English with data suggesting increased tumor progression or death due to disease progression in patients receiving ESAs were included.
Data synthesis: ESAs are approved for treatment of anemia in several different disease states, including chemotherapy-induced anemia. Ten trials investigating off-label use of ESAs in patients with cancer have reported an increased risk of tumor progression and/or treatment-associated death. Two of these trials reported worse overall survival with ESA treatment compared with placebo (28% vs 23% and 21.9% vs 16.4%), while another trial reported shorter time to death with treatment (68 vs 131 days; p = 0.04). Many of these studies had important limitations, including imbalanced groups at baseline and poor design. Moreover, none of these trials was designed to detect a statistically worse outcome with ESAs; thus, absolute conclusions regarding tumor progression cannot be drawn. As a result, better designed trials with safety as the primary outcome are ongoing.
Conclusions: Additional studies are needed and being undertaken to qualify and quantify the possible risk of tumor progression with use of ESAs. Prudent practice dictates that until results of these trials are available, ESAs should be used in accordance with FDA labeling.