Darbepoetin Alfa Controversies, From Dosage Issues to Safety Concerns: the Larger Lesson

Our paper, “Darbepoetin Alfa Administered Every 2 Weeks Alleviates Anemia in Cancer Patients Receiving Chemotherapy,” at the time of its publication almost a decade ago, was impactful and frequently cited because it provided important information regarding the optimal dose of darbepoetin alfa to give every three weeks to anemic cancer patients receiving chemotherapy, and regarding the efficacy of that dosage of darbeopetin alfa as compared in a randomized trial to epoetin alfa, given at a dose of 40,000 units per week, with a dose increase to 60,000 units in non-responding patients. By 2002, oncologists had become interested in the use of erythropoiesis-stimulating agents (ESAs) to treat chemotherapy-induced anemia, with the dual goals of reducing red cell transfusion rates and improving the functional status of their patients.

Epoetin alfa, given at a dose of 40,000 units per week, with an increase to 60,000 units in non-responding patients, had become widely used for the treatment of chemotherapy-induced anemia. Darbepoetin alfa is an ESA with increased sialic acid content that was developed to provide an ESA with an increased half life. Darbepoetin alfa had been shown to have activity in the treatment of chemotherapy-induced anemia, but the every-two-week dose required to produce results similar to those of weekly epoetin alfa remained unclear and controversial.

Our paper reported the results of a trial in which patients with chemotherapy-induced anemia were randomly assigned to one of several treatments, including: epoetin alfa at a dose of 40,000 units per week, darbepoetin alfa at a dose of 3 mcg/kg every two weeks, darbepoetin alfa at a dose of 5 mcg/kg every two weeks, darbepoetin alfa at a dose of 7 mcg/kg every two weeks, and darbepoetin alfa at a dose of 9 mcg/kg every two weeks. The results suggested that the minimal effective doses of darbepoetin alfa given every two weeks were between 3 and 5 mcg/kg; higher doses were without additional benefit. The results with these 3- and 5-mcg/kg doses, in terms of hemoglobin response rate and observed transfusion risks, were similar to those observed in the patients who received epoetin alfa. At the time, this was the only systematic study of optimal doses of ESAs for the treatment of chemotherapy-induced anemia-and the results were controversial. The findings were ultimately confirmed in a very large, randomized clinical trial published subsequently.[1] Our October 2002 paper helped oncologists choose the appropriate dose and schedule of a particular ESA for the treatment of patients with chemotherapy-induced anemia.

Events over the last nine years have dramatically changed the landscape of oncology practice with respect to the use of ESAs, and a very different lesson emerges from a retrospective review of our paper. Over the intervening years, several clinical trials of ESAs in cancer patients have reported a lower survival and/or increased tumor progression in patients receiving ESAs than in untreated controls. In most of these trials, patients were either receiving ESAs to prevent, rather than treat, anemia (with hemoglobin concentrations increased to levels not relevant to ESA use for the treatment of anemia in clinical practice [a scenario in which hemoglobin levels had been maintained at 12 g/dL or less], or they were not receiving chemotherapy. Moreover, in some of the trials there were baseline imbalances in risk factors for tumor progression and/or mortality that favored the control group. The specifics of these trials and their limitations are beyond the scope of this commentary but are available in other reviews for the interested reader.[2,3] To date, there is no evidence that ESAs as used in our clinical trial-or in oncology practice generally-to treat, rather than to prevent, anemia in cancer patients receiving chemotherapy, is associated with any adverse effects on cancer outcomes.

Nonetheless, a lesson emerges that is important for all supportive care interventions in oncology. When a concern was raised regarding possible effects of ESAs on tumor outcomes in cancer patients, we did not have results from well-designed, appropriately balanced and stratified randomized trials available documenting the safety, with respect to cancer outcomes, of ESAs used to treat anemia in patients receiving chemotherapy. This deficit cannot be blamed on a lack of resources to underwrite such trials; at their peak, ESAs were the most financially successful pharmaceuticals in oncology. This data deficit has resulted in increasing restrictions being placed on the use of ESAs in oncology practice in the United States, restrictions that have had the effects of increasing the exposure of our cancer patients to red cell transfusions, decreasing their hemoglobin levels, and increasing their anemia symptoms. The clinical trials that will finally provide the much-needed definitive safety data are in progress, and when reported will help us again provide optimal treatment to our patients. While our paper represented a rational, systematic approach to the details of dose and dose frequency of ESAs in oncology practice, today it also reflects a failure on our part to appreciate the importance of pro-actively addressing the impact on cancer outcomes of supportive care agents widely utilized in oncology settings.

Today, ESAs are much less utilized in the management of anemic patients receiving chemotherapy than they were in 2002, and the results of our paper are of substantially less interest or importance. The controversy in the field of erythropoietic support has shifted from the specifics of which agent or which dose or what treatment interval to contentious interpretations of a safety database that supports several very divergent explanations, none of which can settle the debate.[4] Hindsight can be instructive. Moving forward, whenever a supportive care agent is being widely used in the treatment of cancer patients, it is important that we address, early on, the safety of the intervention with respect to tumor progression and survival outcomes in well-designed clinical trials that mimic the actual use of the agents in oncology practice. This is particularly true when the resources exist to support these perforce large, well-powered trials.

References:

REFERENCES:

1. 20030125 Study Group Trial, Glaspy J, Vadhan-Raj S, et al. Randomized comparison of every-2-week darbepoetin alfa and weekly epoetin alfa for the treatment of chemotherapy-induced anemia: the 20030125 Study Group Trial. J Clin Oncol. 2006;24:2290-7.

2. Glaspy JA. Erythropoiesis-stimulating agents in oncology. J Natl Compre Canc Netw. 2008;6:565-75.

3. Glaspy J. Hematology: ESAs to treat anemia-balancing the risks and benefits. Nat Rev Clin Oncol. 2009;6:500-2.

4. Glaspy JA. Erythropoietin in cancer patients. Annu Rev Med. 2009;60:181-92.