Regarding “Randomized Comparison of Epoetin Alfa and Darbepoetin Alfa in Anemic Patients with Cancer Receiving Chemotherapy”

I read with interest the publication by Waltzman and colleagues in The Oncologist [1] that reports the first randomized, prospective, head-to-head trial of erythropoietic proteins (EPOs) in patients with anemia and solid tumors. Notably, this trial was designed and powered to detect a statistical difference between two EPO therapies using an early hemoglobin (Hb) response (≥1 g/dl increase after 4 weeks’ treatment) as the primary measurement of efficacy. In this study, the authors reported that epoetin alfa at a dose of 40,000 IU s.c. once weekly was superior to darbepoetin alfa at a dose of 200 μg s.c. every 2 weeks, with nearly half of all epoetin alfa-treated patients achieving a ≥1 g/dl increase in Hb after 4 weeks (47% vs. 33%, respectively; p = .0078). The median time to this early Hb rise was also significantly quicker with epoetin alfa in these patients (35 days compared with 46 days; p = .0057). The dosing regimens selected for comparison represent the two most commonly used in the U.S. clinical setting. I agree with the authors’ choice of early response as the primary endpoint. An early Hb response is important because of the need to gain the benefits of EPO treatment as soon as possible in a finite course of chemotherapy. An early response may be associated with better clinical outcomes, specifically a greater reduction in the need for blood transfusions and improvements in quality of life [2]. Early responders also show a more favorable long-term hematological profile; in the present study, patients treated with epoetin alfa had consistently greater weekly Hb increases from week 3 to study end at week 16 (p ≤ .023). Given that the duration of concomitant EPO treatment is often short (8–10 weeks) [1], a rapid response is therefore highly desirable in patients with cancer and anemia. Furthermore, the decision to assess response after 4 weeks (i.e., at week 5) meant that the results were not influenced by dose increases (which did not occur until weeks 5 and 7 in the epoetin alfa and darbepoetin alfa groups, respectively). By comparison, epoetin beta also produces a rapid Hb increase [3, 4], as shown in a recent meta-analysis of data from three prospectively randomized clinical trials [5]. In this meta-analysis, which included patients with solid tumors, a mean Hb increase from baseline of 1 g/dl after 4 weeks was seen with epoetin beta at a dose of approximately 10,000 IU three times a week irrespective of whether the patients received platinum- or nonplatinum-based chemotherapy (Fig. 1). In another study, which included patients with hematological malignancies, the correction of anemia occurred with equal rapidity and efficacy, whether epoetin beta was administered at 30,000 IU weekly or 10,000 IU three times a week [4]. Although a well-designed, controlled, clinical trial directly comparing epoetin beta with darbepoetin alfa is needed, it could be hypothesized that epoetin beta at the above-mentioned dosages is superior to darbepoetin alfa at a dose of 200 μg every 2 weeks in producing a rapid Hb response. Mean change in hemoglobin (Hb) after 4 weeks’ treatment in patients with solid tumors receiving platinum and nonplatinum chemotherapy: results from meta-analysis From [5]. Perhaps one potential criticism of the present study is the decision to assess the change in transfusion need from week 5 to study end. It is often standard procedure to discount the first 4 weeks of treatment with EPO to evaluate its effects on transfusion need. However, transfusions are costly with risk implications and represent a significant burden to both the patient and healthcare provider [6–8]. Furthermore, given the short average duration of EPO therapy in patients with cancer, perhaps transfusion need should be assessed from study start as opposed to from week 5. The author indicates no potential conflicts of interest.