The use of erythropoiesis-stimulating agents (ESAs) in clinical trials has been shown to be an effective means of increasing hemoglobin (Hb) concentrations and reducing the need for red blood cell transfusions in patients with chemotherapy-induced anemia (CIA). Despite these findings, other recent trials have pointed to potential adverse events with ESA use, including an increased risk of mortality and disease progression. In fact, these trials spurred a black box warning on ESA labels by the Food and Drug Administration in 2007. Therefore, to reevaluate the benefits and risks of ESAs in clinical settings, Ludwig et al conducted the first pooled analysis of all randomized, placebo-controlled trials that involved the ESA darbepoetin alfa (DA).

This analysis included six studies and 2,122 patients with CIA, with lung and hematologic cancers being the most frequent primary tumor type. Of the total patient population analyzed, 1,200 patients received DA and 912 received a placebo. The study examined the following safety end points: overall survival, progression-free survival, and disease progression. According to statistical analysis, DA did not increase mortality or have any effect on disease progression, irrespective of baseline Hb levels. In addition, DA treatment was found to decrease the need for transfusion, an important finding that reaffirms the benefit of ESA use because, in this study, patients receiving transfusions were at a higher risk for mortality and adverse events.

This authors conclude that these results reaffirm the value of ESAs in clinical settings, and also suggests further reasons why other trials have shown contradictory results. For one, these studies have primarily initiated ESA therapy at higher Hb baselines and targeted higher overall Hb levels, which has been shown to be associated with adverse events. Patients who do not respond well to ESAs often have higher target Hb levels, and therefore may not represent an accurate outcome of ESA treatment. Also, patients undergoing transfusion typically have other, underlying health problems that could contribute to adverse events and confound the positive effects of ESA treatment. However, the authors contend that until the risks and benefits of ESA use are better understood, health care providers should continue to follow prescribing information and to administer ESAs cautiously according to patient need.

Ludwig H, Crawford J, Osterborg A, Vansteenkiste J, Henry DH, Fleishman A, Bridges K, Glaspy JA. Pooled analysis of individual patient-level data from all randomized, double-blind, placebo-controlled trials of darbepoetin alfa in the treatment of patients with chemotherapy-induced anemia. J Clin Oncol. 2009 Jun 10;27(17):2838-47.

NAAC Expert Commentary
In patients undergoing treatment for cancer, recent studies suggest an increased risk of death for patients treated with erythropoiesis-stimulating agents (ESAs) used in the treatment of anemia. This risk was confirmed by two meta-analyses.^1,2 In the present study, Ludwig et al performed a meta-analysis of six randomized, controlled studies of darbepoetin alfa (DA) in patients receiving chemotherapy. They reached two important conclusions:

1. Darbepoetin alfa was associated with increased risk of thromboembolic complication
2. Darbepoetin alfa was not associated with increased risk of death or tumor progression

These findings may certainly bring some comfort to practitioners facing the devastating effects of anemia in cancer patients, because they conclusively demonstrated that DA does not seem to alter the natural course of cancer in the majority of patients receiving chemotherapy and because it can be safely administered to these patients with a Hb level up to 12 g/dL.

Nonetheless, it is important to identify some problems within the study. Firstly, the study did not include patients receiving the other ESA (epoetin alfa) and no explanation was provided by the authors. Whether these patients were not included because the authors did not have access to the data or because the use of epoetin alfa would have increased mortality rate, the reader is entitled to an explanation. Secondly, as the authors themselves state, time to progression (TTP) was an end point in only one of the 6 studies. In the other five studies, the TTP was deduced from clinical data. Thus, some small differences in TTP might have been missed.

Despite these limitations, the study clearly indicates that the risk of ESA use in patients receiving chemotherapy has been overemphasized and that it may be the appropriate time to reassess the issue.

References

1. Bennett CL, Silver SM, Djulbegovic B, Samaras AT, Blau CA, Gleason KJ, Barnato SE, Elverman KM, Courtney DM, McKoy JM, Edwards BJ, Tigue CC, Raisch DW, Yarnold PR, Dorr DA, Kuzel TM, Tallman MS, Trifilio SM, West DP, Lai SY, Henke M. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA. 2008 Feb 27;299(8):914-24. Link.
2. Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, Zwahlen M, Clarke M, Weingart O, Kluge S, Piper M, Rades D, Steensma DP, Djulbegovic B, Fey MF, Ray-Coquard I, Machtay M, Moebus V, Thomas G, Untch M, Schumacher M, Egger M, Engert A. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet. 2009 May 2;373(9674):1532-42. Link.

Last Updated: July 14, 2009