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Journal of Clinical Oncology, Vol 24, No 15 (May 20), 2006: pp. 2290-2297 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.8570 Randomized Comparison of Every-2-Week Darbepoetin Alfa and Weekly Epoetin Alfa for the Treatment of Chemotherapy-Induced Anemia: The 20030125 Study Group Trial
From the University of California Los Angeles School of Medicine, Los Angeles; Comprehensive Blood and Cancer Center, Bakersfield; Wilshire Oncology Medical Group, Rancho Cucamonga; University of California Los Angeles Community Oncology Research Network, Monterey Park; Fullerton Internal Medicine Clinic, Fullerton; Amgen Inc, Thousand Oaks, CA; M.D. Anderson Cancer Center, Houston, TX; and the Center for Cancer and Blood Disorders, Bethesda, MD Address reprint requests to John Glaspy, MD, MPH, Department of Medicine-Hematology and Oncology, University of California, Los Angeles School of Medicine, Box 956996, Suite 550, 100 Medical Plaza, Los Angeles, CA 90095; e-mail: jglaspy{at}mednet.ucla.edu
PURPOSE: Chemotherapy-induced anemia is widely treated in the United States with darbepoetin alfa (DA) or epoetin alfa (EA). This noninferiority study systematically compares efficacy and safety of DA and EA using common doses and schedules used in clinical practice.
METHODS: Patients had a diagnosis of nonmyeloid malignancy with
RESULTS: Of 1,220 patients randomly assigned, 1,209 received CONCLUSION: This large, phase III study demonstrates comparable efficacy of DA Q2W and EA QW. Less frequent dosing offers potential benefits for patients, caregivers and health care providers.
Anemia is common in patients receiving multicycle chemotherapy and may adversely affect health-related quality of life (HRQOL).1-3 Chemotherapy-induced anemia is commonly treated using the erythropoiesis-stimulating agents, darbepoetin alfa (DA; Aranesp; Amgen Inc, Thousand Oaks, CA) and epoetin alfa (EA; Procrit; Amgen, Inc), both proven to achieve significant reductions in RBC transfusion requirements and clinically relevant improvements in fatigue and other patient-reported outcomes.4-12 For the treatment of chemotherapy-induced anemia, the most common initial dosage is 200 µg every 2 weeks (Q2W) for DA and 40,000 units (U) every week (QW) for EA.13,14 At these dosages, the two agents have similar clinical effectiveness based on results from randomized, controlled trials,15-17 community-based studies,8,18 and large observational studies of clinical practice.13,14,19,20 Nonetheless, there was a clear demand for a formal, sufficiently powered, noninferiority study to allow for the rigorous comparison of these two therapies with respect to clinical outcomes. Questions regarding the comparability of clinical outcomes of these two agents and appropriate reimbursement have been raised by the US Centers for Medicare & Medicaid Services and the National Cancer Institute (Bethesda, MD), further emphasizing the importance of definitive data to define healthcare policy regarding erythropoietic agents (OPPS [Outpatient Prospective Payment System] rule 2003; NCI RFQ 72743). The large, phase III study reported here was designed to formally evaluate noninferiority of 200 µg Q2W DA with 40,000 U QW EA in cancer patients with anemia receiving multicycle chemotherapy. The primary hypothesis tested was that the incidence of RBC transfusion from week 5 to the end of treatment phase (EOTP) in patients receiving Q2W DA is comparable (defined as not inferior) with that of patients receiving QW EA. This is the standard transfusion end point used for the registration of erythropoietic therapies in oncology.4,6,21-23 Secondary objectives included comparison of HRQOL and hemoglobin surrogate end points, as well as the evaluation of safety.
Study Design This was a randomized, open-label, active-controlled, multicenter study of DA at a starting dose of 200 µg Q2W administered over a 16-week period for the treatment of anemia in patients with nonmyeloid malignancies receiving multicycle chemotherapy. The active control arm received EA at a starting dose of 40,000 U QW. For both treatment arms, a 50% dose escalation was permitted at week 5 if the hemoglobin increase was < 1 g/dL. Study drug was withheld if a patient's hemoglobin concentration exceeded 13 g/dL at any time, and was reinstated at 75% of the previously administered dose after the hemoglobin concentration decreased to  12 g/dL. After the 16-week treatment period, patients were monitored for 2 weeks for adverse events, concomitant medications, and transfusions received. The initial planned treatment period was 12 weeks. After the first 680 patients were randomly assigned, the study protocol was amended to be more representative of current clinical practice. The treatment period was extended from 12 weeks to 16 weeks, and the dose escalation rules were changed from a mandatory requirement to physician discretion. The sample size was increased to 1,200 patients, ensuring that the distribution of patients accrued under the original and amended protocols were similar. At the time of the amendment, patients who had already enrolled in the study reconsented and were treated under the amended protocol. Patients included in the amended protocol are referred to as the 16-week cohort and comprise a homogenous patient population with respect to dose escalation criteria and duration of therapy.
Random Assignment
Eligibility Criteria
Efficacy Evaluations
Efficacy was assessed using secondary hemoglobin-based end points, including the proportion of patients achieving a hemoglobin HRQOL changes were compared using standard instruments (Functional Assessment of Cancer Therapy-Fatigue [FACT-Fatigue], FACT-Anemia, Energy, Daily Activity, Overall Health, and Patient Satisfaction Questionnaire for Anemia Treatment questionnaires)27 administered to patients at baseline, weeks 5, 9, and 17.
Safety Evaluation
Statistical Considerations The sample size specified in the original protocol had approximately 90% power to conclude noninferiority. Power calculations were based on unstratified analysis and confirmed using a Bayesian two-stage resampling technique applied to data from previous studies; with 1,200 patients, there is approximately 99% power to conclude noninferiority.
It is critical that results from noninferiority studies are shown to be robust with respect to the method of analysis used or analysis set (population effect). Accordingly, preplanned sensitivity analyses were performed with respect to transfusion end points. The population effect was examined using different patient cohorts; the 16-week cohort and a predefined per-protocol analysis set. The per-protocol subset comprised randomly assigned patients who received Statistical analyses were performed by the sponsor using SAS statistical software version 8.2 (SAS Institute, Cary, NC); study investigators reviewed these results. Descriptive statistics included frequencies and means (with 95% CIs or standard deviation [SD]) for categoric and continuous variables, respectively. Changes in hemoglobin levels, total number of RBC units, total number of days transfused, and patient-reported outcomes for each patient were analyzed using the analysis of covariance (ANCOVA) model, which included the stratification factors. Analysis of patient-reported outcomes was also adjusted for the baseline score (as a continuous or dichotomous variable). Two analytic approaches were used to account for missing hemoglobin data: imputation (last-value-carried forward) and available data. Hemoglobin values within 28 days after a transfusion were considered to be missing; using the last-value-carried forward method, the pretransfusion hemoglobin value was used to impute all weekly hemoglobin values during the 28 days following a transfusion. Change in hemoglobin was evaluated using both methods; achieving target hemoglobin was calculated only using the last-value-carried forward method. Hemoglobin end points were adjusted by the same stratification factors as the transfusion end points. Adverse events were defined using the Medical Dictionary for Regulatory Activities (MedDRA MSSO, Reston, VA) terms. The number and percentage of patients reporting adverse events (all, serious, related, and serious related) were tabulated by the actual treatment received (safety analysis set).
Patient Characteristics A total of 177 US centers enrolled 1,220 patients (Table 1). All patients were randomly assigned and 1,209 received  one dose of study drug (primary analysis set; Fig 1). During the final analysis, one patient was identified who was randomly assigned to receive DA but who received only EA (eight doses). Efficacy analyses were performed as planned using an intent-to-treat approach, for example, analyzing this patient as randomized (ie, in the DA group), rather than as treated. Patient demographic and baseline disease characteristics are summarized in Table 2.
Efficacy Evaluations RBC transfusions. The adjusted Kaplan-Meier percentages of patients who received an RBC transfusion between week 5 and EOTP were 21% (95% CI, 17% to 24%) for the DA 200 µg Q2W group and 16% (95% CI, 12% to 19%) for the EA 40,000 U QW group. These are KM estimates adjusted for stratification factors; crude rates are suboptimal in the study of erythropoietic agents because they cannot account for response to therapy and time at risk when patients discontinue early. Noninferiority was demonstrated because the upper limit of the 95% CI of the difference between groups (10.8%) was below the prespecified noninferiority margin of 11.5%. When the first 4 weeks were included in the analysis, the proportions of patients receiving one transfusion were 27% (95% CI, 24% to 31%) for the DA group and 22% (95% CI, 19% to 26%) for the EA group. Comparison of transfusion results with the expected rates observed in placebo-controlled trials provides a good measure of external validity (Fig 2A).
The robustness of the noninferiority conclusion was evaluated in a series of sensitivity analyses of the primary (week 5 to EOTP) and secondary (week 1 to EOTP) transfusion end points (Fig 2B). Results were consistent with the primary analysis; the upper 95% CI limit of the difference between the two treatment groups excluded 11.5%. Additionally, inclusion of the patient randomly assigned to DA but who received EA only as treated (rather than as randomly assigned) in the analysis of the primary end point did not alter the noninferiority conclusion.
The average hemoglobin at the time of transfusion was 9.05 g/dL for the DA group and 9.06 g/dL for the EA group, indicating that there was no suggestion of bias in the decision to transfuse. Exploratory analyses were also performed to evaluate transfusion intensity among patients who received Hemoglobin end points. In both groups, the mean hemoglobin concentrations improved from approximately 10.2 g/dL at baseline to 11.8 g/dL by the EOTP, with no meaningful differences in mean hemoglobin change observed at week 9 or EOTP (Fig 3). Using the last-value-carried forward approach, mean hemoglobin levels at EOTP were 11.6 g/dL for DA and 11.8 g/dL for EA.
More than three quarters of patients in each group achieved the target hemoglobin range of 11 g/dL to 13 g/dL. The median time to achieve target hemoglobin was 6 weeks for the DA group and 5 weeks for the EA group (Fig 4). The majority of these patients maintained hemoglobin levels in this range for the remainder of the treatment period (Table 3). Due to the dose titration rules employed in the study, the mean hemoglobin after achievement of the target stabilized at approximately 12 g/dL in both groups.
Patient-reported outcomes. The improvements in FACT-Fatigue subscale scores from baseline between the two treatment groups were similar and no differences were observed between the two groups for any of the other HRQOL assessment (Figs 5 and 6).
Safety In order to minimize hyporesponse or hyper-response to therapy, rules regarding dose titration were included in this trial. Dose was modified at least once for more than 80% of patients in both groups, with a mean actual dose per patient delivered for DA of 229 µg Q2W compared with 42,714 U QW for EA (Table 4).
The safety profiles of DA and EA were consistent with existing clinical experience for adverse events in anemic cancer patients receiving cytotoxic chemotherapy with no differences observed between groups. Safety was evaluated for patients who received one or more study drug; patients who were randomly assigned to the EA treatment group who received one or more dose of DA were analyzed as EA for safety. Six percent of DA patients and 7% of EA patients reported cardiovascular/thromboembolic events. No antibodies to erythropoietic compounds were detected, and no clinical sequelae suggestive of neutralizing antibody formation were observed. The rates of death on study were 11% for DA and 14% for EA (safety analysis set).
In this noninferiority study, DA 200 µg Q2W was shown to be as effective as EA 40,000 U QW with respect to transfusion requirements, with multiple sensitivity analyses providing internal validity and supporting the noninferiority conclusion. Despite the open-label design, no differences were observed between groups in the decision to transfuse patients. The validity of this outcome was further supported by results of the secondary end points in the trial (eg, improvement in HRQOL, increase in hemoglobin concentration, and safety); these findings are consistent with previously reported observational studies13,14,19,20 and phase II trials.15,17 Transfusion rates observed in the control group of this trial were comparable with pooled rates from large, phase III, placebo-controlled EA trials,4,21,22,28 and provided confirmation of external validity. The intent-to-treat approach, commonly used in conventional clinical trials where the objective is to demonstrate that one treatment is superior to another (ie, a null hypothesis that treatments are equivalent), represents a conservative approach and minimizes any observed differences from sources other than true differences related to the treatment effect. However, in noninferiority trials where the aim is to demonstrate equivalence (ie, a null hypothesis that one treatment is superior), the intent-to-treat approach may be anticonservative for the reason that it minimizes differences between groups. To assess this potential for bias towards equivalency, preplanned sensitivity analyses of the transfusion end points used two alternate cohorts: per-protocol analysis set, which examined the impact of patient attrition and protocol deviations, and 16-week cohort, which examined the impact of the extended treatment period resulting from the study amendment. The results of these analyses did not demonstrate differences between groups and confirmed the conclusion of noninferiority. Indeed, point estimates of the difference between treatments trended further toward 0 for patients who were compliant with the protocol. A number of questions have been raised regarding relative rapidity of response for DA 200 µg Q2W compared with EA 40,000 U QW.29 Given these concerns, a potential criticism of this study may be the choice of primary end point, which excludes the first month of therapy. Selection of this end point was necessary, as most placebo-controlled trials of erythropoiesis-stimulating agents have reported transfusion incidence from week 5 to EOTP, and thus the evidence base on which to derive a noninferiority margin was limited to this timeframe. To address this limitation, an analysis of the transfusion requirements over the entire treatment period was prespecified as a key secondary end point. Results from these analyses confirm that the exclusion of the first month of therapy did not bias in favor of DA. Secondary HRQOL and hemoglobin surrogate end points also addressed the rapidity of response to therapy and evidence of differences between treatment groups. To further evaluate time to therapeutic effect, analysis of the proportion of patients who achieved a clinically relevant target hemoglobin concentration was performed. The difference between groups in mean time to this target hemoglobin range was 1 week (6 weeks for the DA group compared with 5 weeks for EA group), suggesting little difference in the ability to reach a therapeutic range. Moreover, as the intent of erythropoietic therapy is to decrease transfusion requirements and improve fatigue, any differences in hemoglobin change between treatment groups must be coupled with demonstrable differences in these outcomes. Our data show no significant differences between the two treatment groups regarding these clinical outcomes. Much of the debate regarding comparable efficacy of these two agents has been centered on relative cost and appropriate payment policy. Therefore, the dose requirements as well as the clinical efficacy were both important data to be derived from this trial. Given that this study demonstrated the noninferiority of DA with respect to clinical outcomes, no adjustment of effectiveness is required in the comparison of these agents (ie, a cost analysis rather than an incremental cost-effectiveness analysis suffices). For purposes of cost/benefit analysis, the costs for the mean weekly doses of the two agents can be compared without adjusting for significant differences in effectiveness. This head-to-head study demonstrated that DA 200 µg Q2W is as effective and safe as EA 40,000 U QW. Special considerations in design and statistical analysis were implemented to definitively evaluate the comparability of two commonly used erythropoietic agents. The ability to extend dosing intervals represents an important potential benefit for patients and their caregivers.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
We thank study investigators, coordinators, and participants from each institution, Alexander Liede for assistance in the writing of this report, Russell Berg for coordinating this study, and Yuriy Shamanov, Steven Pearce, and Matt Ness for statistical programming support. The sponsor of this study was Amgen Inc, Thousand Oaks, CA (NESP 20030125).
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Glaspy JA, Jadeja JS, Justice G, et al: Darbepoetin alfa given every 1 or 2 weeks alleviates anaemia associated with cancer chemotherapy. Br J Cancer 87:268-276, 2002[CrossRef][Medline] 16. Glaspy JA, Tchekmedyian NS: Darbepoetin alfa administered every 2 weeks alleviates anemia in cancer patients receiving chemotherapy. Oncology (Williston Park) 16:23-29, 2002 17. Schwartzberg LS, Yee LK, Senecal FM, et al: A randomized comparison of every-2-week darbepoetin alfa and weekly epoetin alfa for the treatment of chemotherapy-induced anemia in patients with breast, lung, or gynecologic cancer. Oncologist 9:696-707, 2004 18. Cleeland C, Crawford J, Lubeck D, et al: Using the MD Anderson Symptom Inventory (MDASI) to assess symptom burden and interference: Interim results of an open-label study of darbepoetin alfa 200 mcg every 2 weeks (Q2W) for the treatment of chemotherapy-induced anemia (CIA). J Clin Oncol 23:741, 2004 (abstr 8065) 19. 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Osterborg A, Brandberg Y, Molostova V, et al: Randomized, double-blind, placebo-controlled trial of recombinant human erythropoietin, epoetin Beta, in hematologic malignancies. J Clin Oncol 20:2486-2494, 2002 24. Rizzo JD, Lichtin AE, Woolf SH, et al: Use of epoetin in patients with cancer: Evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol 20:4083-4107, 2002 25. Rodgers GM: Guidelines for supportive care: Cancer and treatment-related anemia, Clin Pract Guide Oncol (ed v. 2.2004), National Comprehensive Cancer Network. http://www.nccn.org/physician_gls/index.html 26. Bokemeyer C, Aapro MS, Courdi A, et al: EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. Eur J Cancer 40:2201-2216, 2004[CrossRef][Medline] 27. Cella D: The Functional Assessment of Cancer Therapy-Anemia (FACT-An) scale: A new tool for the assessment of outcomes in cancer anemia and fatigue. Semin Hematol 34:13-19, 1997[Medline] 28. Dammacco F, Castoldi G, Rodjer S: Efficacy of epoetin alfa in the treatment of anaemia of multiple myeloma. Br J Haematol 113:172-179, 2001[CrossRef][Medline] 29. Waltzman R, Croot C, Williams D: Final hematologic results: Epoetin alfa 40,000 U QW vs darbepoetin alfa 200 mcg Q2W in anemic cancer patients receiving chemotherapy. J Clin Oncol 23:16S, 2005 (abstr 8030) 30. Moher D, Schulz KF, Altman D: The CONSORT statement: Revised recommendations for improving the quality of reports of parallel-group randomized trials. JAMA 285:1987-1991, 2001 31. Rizzo JD, Lichtin AE, Woolf SH, et al: Use of epoetin in patients with cancer: Evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. Blood 100:2303-2320, 2002 Submitted August 29, 2005; accepted January 25, 2006. Related Editorial
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ABSTRACT
INTRODUCTION
