Is once‐weekly epoetin beta ‘highly effective’ in treating anaemia in patients with lymphoproliferative malignancy?
2004-03-08

Is once-weekly epoetin beta ‘highly effective’ in treating anaemia in patients with lymphoproliferative malignancy? Cazzola and colleagues suggest that this is the case in a recently published open-label, randomized, multicentre phase III study designed to assess the effectiveness of a once-weekly (q.w.) dosing regimen of epoetin beta (Cazzola et al, 2003). However, the arguments leading to such an optimistic conclusion do not appear to be fully supported by the data presented in the report. Additional clarification is required, as outlined below. First, Cazzola et al (2003) do not specify whether there was a prospective definition of a clinically acceptable difference between q.w. and three-times-weekly (t.i.w.) dosing for the primary efficacy endpoint [time-adjusted haemoglobin (Hb) area under the curve between weeks 5 and 16: Hb-AUC5--16]. Without a prospectively defined non-inferiority margin, it is not possible to determine whether the q.w. treatment group met prospectively defined criteria for non-inferiority. There also appear to be inconsistencies with regard to the size of the confidence intervals (CIs) for which the data are reported; while the study was powered to test at the 5% significance level and was designed to calculate both 90% and 95% CIs, only 90% CIs are reported for the primary efficacy variable, which equates to testing at the 10% significance level. If 95% CIs were computed, based on the standard deviations derived from the 90% CIs presented in the manuscript, the lower boundary for the 95% difference between treatment groups in the primary efficacy endpoint (Hb-AUC5--16) would be −0·58 g/dl. These data cannot therefore exclude the possibility of a 0·5 g/dl inferior result in the mean Hb increase achieved when using epoetin beta q.w.. The authors implied that there was no difference between the q.w. and t.i.w. study groups in terms of the median time to response (i.e. 71 and 57 d respectively) by providing a P-value of 0·57. However, this is inappropriate as the CI for the difference between treatment groups should be presented in the non-inferiority setting and the P-value may not be significant due to lack of power. Also of importance when considering the efficacy comparison between q.w. and t.i.w. groups is the fact that the dose of epoetin beta was doubled in patients with an inadequate response (≤0·5 g/dl Hb increase between baseline and week 5) or those requiring a red blood cell (RBC) transfusion during week 4. In the q.w. group, the resulting higher dose (60 000 IU) was given as 30 000 IU in two separate injections (i.e. twice weekly). Thus, the q.w. treatment group was not truly q.w.. There is no discussion of the proportion of subjects in the t.i.w. treatment group who had their dose doubled or in the q.w. group who had their dosing frequency increased. In addition, the article reports the mean weekly dose in IU/kg, which is not easily interpreted in a fixed dose study. Nevertheless, a difference between q.w. and t.i.w. arms was reported in the mean weekly epoetin beta dose; between weeks 5 and 16 this was 323 IU/kg in the q.w. group and 267 IU/kg in the t.i.w. group. The once-weekly to thrice-weekly dose ratio during this period was 1·21 (95% CI 0·90–1·61), indicating that, on average, 21% more drug was required by patients receiving the q.w. schedule. Finally, as the authors acknowledged, the patient population was carefully selected in order to ensure a high probability of response and was not therefore representative of a standard clinical population. Patients were required to have a low baseline endogenous erythropoietin concentration (≤100 mU/ml), and were excluded if they had received a RBC transfusion within the previous 2 months, suggesting the inclusion of only those patients with mild-to-moderate anaemia. This is supported by the mean baseline Hb concentration, which was >10 g/dl in both q.w. and t.i.w. treatment groups, and the low requirement for RBC transfusion throughout the study (9% in the q.w. group and 14% in the t.i.w. group). Based on these arguments, the conclusion that epoetin beta is highly effective following q.w. dosing does not appear to be as clearly demonstrated as the title of the report claims. Drs C. Bokemeyer, T. Littlewood and M. Aapro have all served as consultants to Amgen, Roche and Ortho-Biotech, producers of erythropoietic agents. They are, or will be involved with the European Organisation for Research and Treatment of Cancer Committee (EORTC) evaluating the use of erythropoietic agents in cancer patients. Dr Aapro is co-chair of the Steering Committee of the on-going ‘Breast cancer-anaemia and value of erythropoietin’ (BRAVE) study, which evaluates erythropoietin beta in patients with breast cancer.