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a The West Clinic, Memphis, Tennessee, USA; b Northwest Medical Specialties, Tacoma, Washington, USA; c Pacific Cancer Medical Center, Anaheim, California, USA; d Amgen, Thousand Oaks, California, USA
Correspondence: Lee S. Schwartzberg, M.D., F.A.C.P., The West Clinic, 100 North Humphreys Boulevard, Memphis, Tennessee 38120, USA. Telephone: 901-683-0055; Fax: 901-685-9718; e-mail: lschwartzberg{at}westclinic.com
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ABSTRACT |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionConclusionReferencesAdditional Reading |
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Key Words. Chemotherapy-induced anemia • Darbepoetin alfa • Epoetin alfa • Head-to-head • Quality of life
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INTRODUCTION |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionReferencesAdditional Reading |
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The current usage patterns and the relative efficacies of darbepoetin alfa and epoetin alfa are of interest to clinicians and reimbursement authorities (e.g., The Centers for Medicare and Medicaid Services) [8]. Multicenter retrospective chart analyses conducted in the U.S. have shown that darbepoetin alfa at a dose of 200 µg Q2W and epoetin alfa at a dose of 40,000 U QW are the most commonly used dosages of these drugs and result in similar hematologic and clinical outcomes [9–11]. However, while these studies have a high degree of external validity and generalizability, retrospective observational studies are subject to potential systematic, nonsystematic, and inferential biases [12].
To date, the only published randomized comparison of Q2W darbepoetin alfa and QW epoetin alfa is a small, active-controlled dose-finding study of darbepoetin alfa [3]. Comparable efficacies were observed in patients treated with 3 µg/kg Q2W darbepoetin alfa and those treated with 40,000 U QW epoetin alfa. However, due to the small sample size and differences in dose modification rules in the study, definitive conclusions on the relative efficacies of the two agents could not be drawn [3].
A report of a single-arm community study provided additional clinical trial evidence of the effectiveness of this darbepoetin alfa dose and schedule in a substantially larger (n 
1,500) broad cancer population (patients with nonmyeloid malignancies) [4]. The magnitude of response was notably impacted by both tumor type and baseline hemoglobin concentration. This highlights the importance of clinical trial designs to consider disease characteristics, trial conduct, and baseline covariates of response. Currently, as no comparison of darbepoetin alfa and epoetin alfa has been published without confounding factors or substantial limitations, a randomized, formal, prospective comparison of these two agents is necessary to evaluate their relative efficacy.
We conducted a randomized comparison of darbepoetin alfa (200 µg Q2W) and epoetin alfa (40,000 U QW) in patients with breast cancer, non-small cell lung cancer (NSCLC), or gynecologic cancer receiving concurrent chemotherapy. For logistical and administrative reasons, three identical but separate protocols were used, one for each tumor type, with a combined analysis of all data from each trial prespecified in each protocol. The trials were designed to validate the Patient Satistaction Questionnaire for Anemia (PSQ-An) tool; however, due to the technical nature of the validation, the detailed summary of these findings will be presented in a separate report. Herein, we report results of the utility of the PSQ-An and of the secondary endpoints of relative clinical efficacy and safety of darbepoetin alfa and epoetin alfa. Results from both the individual analyses and the combined analysis of all three trials are provided.
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PATIENTS AND METHODS |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionReferencesAdditional Reading |
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18 years old, anemic (hemoglobin 
11 g/dl at screening), planned concurrent chemotherapy for at least 8 additional weeks, Karnofsky performance status (KPS) score 50%, adequate renal function (serum creatinine concentration 2.0 mg/dl), adequate liver function (aspartate aminotransferase or alanine aminotransferase 2 times the upper limit of the normal range or serum bilirubin 1.5 times the upper limit of the normal range), and the ability to complete questionnaires. Patients were excluded from the trials if they had received an RBC transfusion within 4 weeks of screening or erythropoietic therapy within 2 weeks of randomization, had inadequate iron stores (transferrin saturation <15% and ferritin <10 ng/ml), a known positive antibody response to any erythropoietic agent, or a known history of any of the following: pure red cell aplasia, uncontrolled hypertension, or anemia due to a hematologic disorder other than chemotherapy-induced anemia.
Study Design
A randomized, open-label, multicenter design was used in all trials. Each protocol prespecified both an individual analysis and a patient-level combined analysis of all three trials. A total sample size of 300 patients was prospectively planned, with an anticipated sample size of 100 patients per individual tumor type; however, due to slow accrual in the gynecologic tumor trial, additional patients were enrolled into the breast cancer study to meet the overall planned sample size. Patients in each trial were randomized 1:1 centrally to receive either darbepoetin alfa at a dose of 200 µg Q2W or epoetin alfa at a dose of 40,000 U QW s.c. for up to 16 weeks (Fig. 1
). All dosing procedures were performed at the study sites. Randomization was stratified by screening hemoglobin category (<10 g/dl and 10 g/dl). After 4 weeks (study week 5), if hemoglobin levels did not increase by 1 g/dl from baseline (study week 1), doses were increased to 300 µg Q2W for darbepoetin alfa or 60,000 U QW for epoetin alfa. Doses for either drug were withheld if hemoglobin levels were >13 g/dl and were restarted at the previous dose once hemoglobin levels were 13 g/dl.
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Study Drugs
Darbepoetin alfa was supplied as a clear, colorless, sterile protein solution containing 200 µg or 325 µg of darbepoetin alfa per ml. Commercially available epoetin alfa was obtained by the clinical sites.
Study Objectives and Endpoints
The primary objective of each trial was the validation of the PSQ-An. The PSQ-An contains two parts: the descriptive part, which consists of 11 descriptive short-answer and check-box questions that assess the impact of receiving anemia treatment to the patient and their caregivers, and the proposed scale part, which consists of 10 questions that assess the same impact on a 5-point Likert scale (see Appendix). Endpoints included demonstration of validity, the percentage of patients who completed the PSQ-An (feasibility), and the degree to which items within a single scale were associated with one another (internal consistency).
Secondary objectives evaluated the efficacy and safety of the two agents. Secondary endpoints were standard hemoglobin and transfusion-based efficacy endpoints for each trial as well as for the prespecified combined analysis. Additional analyses of prespecified endpoints stratified by baseline hemoglobin category (<10 g/dl or 10 g/dl) were conducted using the combined dataset.
Safety was assessed by summarizing the incidence of adverse events by treatment group. All adverse events were summarized by the system organ class affected based on the Medical Dictionary for Regulatory Activities (MedDRA) adverse event preferred term dictionary. MedDRA is the international medical terminology developed by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use [13].
Antibody formation was assessed at baseline and at the end of study (2 weeks after the last dose of study drug).
Statistical Analysis
Statistical analyses were conducted using the primary analysis set (all patients who were randomized and received at least one dose of study drug). To test the validity of the PSQ-An, a sample size of 300 patients was selected. In order to have a clinically useful tool to assess satisfaction, at least 70% of patients needed to consistently complete the tool (i.e., completion rate of 70%). For an estimated 70% completion rate, the width of the 95% confidence interval (CI) is ±9%. For example, if the completion rate of the PSQ-An of the sample is 70%, then 95% of the time, the population completion rate will fall between 61% and 79%. PSQ-An outcomes were descriptive and were evaluated for the total patient sample. The feasibility of the PSQ-An was summarized as the mean patient completion rate throughout treatment and 95% CI; the 95% CI was calculated using Greenwood’s estimate of variance [14]. The internal consistency of the proposed scale was analyzed by calculating Cronbach’s 
coefficients [15]. All other analyses were conducted by treatment group for either the individual trials or the combined analysis.
Baseline demographics, clinical characteristics, and outcomes of the descriptive part of the PSQ-An were summarized as the mean and standard deviation (SD), for continuous measures, and as the number and percentage, for categorical measures.
Change in hemoglobin level from baseline to the end of treatment was summarized as the mean and 95% CI. To handle missing hemoglobin data, two statistical approaches were used. The first was an imputation-based method that ensures that all patients who were randomized and received study drug were included in the analysis. Using this method, missing hemoglobin values were imputed using the last available hemoglobin value (termed the last value carried forward [LVCF] analytical approach). Similarly, hemoglobin values in the 28 days following an RBC transfusion were excluded from the analyses and replaced with the last pretransfusion hemoglobin value. An alternative method (available data approach) was also used as a sensitivity analysis, where missing hemoglobin values and values in the 28 days following an RBC transfusion were excluded but not imputed. Crude proportions were calculated for the overall and monthly incidences of transfusion and for the hematopoietic response (2-g/dl-increase in hemoglobin from baseline or hemoglobin level 12 g/dl). The median time to response was estimated using Kaplan-Meier methodology. Time to response in the two groups were compared using the Wilcoxon test; however, this result should be considered descriptive rather than a definitive inferential finding.
The mean weekly dose of study drug was calculated as the cumulative dose divided by the weeks of exposure. The weeks of exposure was the number of weeks between the last dose (including withheld doses) and the first dose, adding 1 week for epoetin alfa and 2 weeks for darbepoetin alfa.
The most frequent serious and treatment-related serious adverse events were summarized as the number and percentage of patients with either event.
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RESULTS |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionReferencesAdditional Reading |
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). Of these, 312 were randomized and received at least one dose of study drug (Table 1): 141 (72 darbepoetin alfa; 69 epoetin alfa) in the breast cancer trial, 102 (51 in each treatment group) in the NSCLC trial, and 69 (34 darbepoetin alfa; 35 epoetin alfa) in the gynecologic cancer trial (primary analysis set for each trial; Fig. 2). A higher attrition rate (approximately 60%) was observed in the NSCLC trial than in the breast or gynecological cancer trials (approximately 20% and 25%, respectively; Fig. 2). In the combined analysis, 47 (30%) patients randomized to and treated with darbepoetin alfa and 58 (37%) patients randomized to and treated with epoetin alfa withdrew from the trials. Reasons for withdrawals were similar in the two treatment groups within each trial, with the main reason being informed consent withdrawal. In the stage IIIb/IV NSCLC trial, death was cited as the reason for trial withdrawal in 14% of patients in both treatment groups and was higher than that in other tumor types (0%–6% for breast and gynecologic malignancies).
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). As expected, more platinum-containing therapy was given to patients with lung (59% darbepoetin alfa; 67% epoetin alfa) and gynecologic malignancies (71% darbepoetin alfa; 66% epoetin alfa) than to patients with breast cancer (13% darbepoetin alfa; 12% epoetin alfa).
PSQ-An Results
The PSQ-An instrument was feasible, reliable, and valid. PSQ-An completion rates were similar among the three trials, with slightly lower rates in the NSCLC trial than in the gynecologic or breast cancer trials (Table 2). Completion rates were greater than 70% at each time point in each tumor type (74%–98%), except at week 17 in the NSCLC trial, which was 60%. Factor analysis identified two distinct subscales measuring treatment burden and overall satisfaction. Test-retest reliability was examined using intraclass correlation coefficients (ICC: 0.45–0.67), and both subscales were internally consistent (Cronbach’s coefficient = 0.83). Both subscales exhibited convergent and divergent validity with independent measures of health. Further details of the PSQ-An validation will be published in a separate report.
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). Over all time points, at least 42% of patients were driven to the clinic by someone else, and the majority would have preferred to have spent time with family or friends instead of going to the clinic to receive anemia treatment (Table 4).
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RBC Transfusions
No evidence suggesting a greater incidence of RBC transfusions in the darbepoetin-alfa-treated patients was observed for any of the individual tumor types (Fig. 3A). In the combined analysis, the incidence of transfusions were similar in the two treatment groups, at 16% for darbepoetin alfa and 17% for epoetin alfa (Fig. 3B).
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Hematologic Outcomes
Using either of the prespecified analytical methods to account for missing or excluded hemoglobin values, mean hemoglobin levels increased by the end of treatment in patients with each of the three tumor types (Fig. 4A). In the breast and gynecologic tumor types, the mean change in hemoglobin from baseline was similar for patients given darbepoetin alfa and those given epoetin alfa regardless of analytical approach (Fig. 4A). In the stage IIIb/IV NSCLC trial, using the LVCF approach, a nonsignificant difference in the mean change in hemoglobin between darbepoetin alfa and epoetin alfa was observed; however, this was not confirmed in the sensitivity analysis using the available data approach (no imputation of missing values), which indicated similar increases in hemoglobin (1.8 g/dl for darbepoetin alfa versus 1.6 g/dl for epoetin alfa).
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For the combined analysis, the mean changes in hemoglobin level from baseline to end of treatment were similar for both treatment groups regardless of analytical method (Fig. 4B). No major differences between treatment groups were observed when analyzed by baseline hemoglobin strata (Fig. 4B).
Similar proportions of patients achieving a hematopoietic response were observed in the darbepoetin alfa and epoetin alfa groups for all three tumor types (Fig. 5A). Similar to the mean change in hemoglobin results, the lowest proportion of patients achieving a hematopoietic response was observed in the stage IIIb/IV NSCLC group. In the combined analysis, the overall and baseline stratified hematopoietic response rates were similar in the two treatment groups (Fig. 5B).
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Exploratory Endpoints
Based on recommendations by the American Society of Hematology and the American Society of Clinical Oncology (ASH/ASCO) and National Comprehensive Cancer Network (NCCN) evidence-based guidelines and current U.S. package inserts for darbepoetin alfa and epoetin alfa [16–19], we explored the ability of both agents to achieve and maintain a clinically meaningful target hemoglobin of 11–13 g/dl (Table 5). Similar proportions of patients in both treatment groups achieved the target hemoglobin level (124 [82%] darbepoetin alfa; 128 [86%] epoetin alfa; Table 5). The Kaplan-Meier estimate of the median time to reach a hemoglobin level 11 g/dl was 5 weeks for darbepoetin alfa patients and 4 weeks for epoetin alfa patients, with no statistical difference observed between the two treatment groups in the time to achieve a hemoglobin level 11 g/dl (p = 0.3; Fig. 6). In the hemoglobin <10 g/dl stratum, the median times to target hemoglobin were 7 weeks for darbepoetin alfa and 8 weeks for epoetin alfa. In the hemoglobin 10 g/dl stratum, the median time to target was 3 weeks for both treatment groups.
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11 g/dl, the mean hemoglobin level was maintained at approximately 12 g/dl for the remainder of the trials in both treatment groups (Table 5). The mean duration of treatment after achieving the target hemoglobin threshold was approximately 9 weeks for darbepoetin alfa and approximately 10 weeks for epoetin alfa. Most patients in both groups who achieved the target hemoglobin threshold subsequently maintained a hemoglobin level within the target range of 11–13 g/dl (81% darbepoetin alfa; 75% epoetin alfa).
Drug Utilization
In the combined analysis, most patients (79% for darbepoetin alfa; 77% epoetin alfa) in both treatment groups had changes in dosing (dose increases, withholding, or decreases). The mean (SD) doses were 218.4 (57.0) µg Q2W (equivalent to 109 [29] µg QW) for darbepoetin alfa and 39,949 (12,503) U QW for epoetin alfa. The mean (SD) weeks of dosing for both agents were nearly identical, at 12.8 (4.4) weeks for darbepoetin alfa and 12.7 (5.0) weeks for epoetin alfa.
Safety Results
During the treatment period, one or more serious events were reported in 44 (28%) of the darbepoetin alfa patients and in 50 (32%) of the epoetin alfa patients (Table 6). Importantly, only three treatment-related serious adverse events were reported: one episode in each treatment group of deep venous thrombosis and one episode of pulmonary embolism in the epoetin alfa group.
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DISCUSSION |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionReferencesAdditional Reading |
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Validity, feasibility in completing the instrument, and internal consistency were shown for the PSQ-An, indicating that it is a valid tool for assessing the impact of anemia treatment. Due to the specific technical requirements regarding the validation of this instrument designed to assess patient reported outcomes, the detailed validation of the PSQ-An will be reported separately. From the PSQ-An, patients spent approximately 2 hours traveling to and from clinics for each injection, had considerable out-of-pocket expenses, and reported that they would have preferred to be doing other activities. Therefore, in treating patients with cancer, we must ensure not only that the therapies administered are safe and effective but also have the minimum impact of burden on the patients and their caregivers. The PSQ-An may be a useful instrument to explore and quantify these burdens in a larger, randomized trial.
Overall, darbepoetin alfa (200 µg Q2W) and epoetin alfa (40,000 U QW) were associated with comparable clinical and hematologic outcomes. In general, the findings of comparability of the two agents appeared robust across the three tumor types, across baseline hemoglobin levels (degree of anemia), and independent of analytical approach.
Interestingly, our findings support previously reported data on the importance of tumor type and baseline hemoglobin level as significant covariates of hematologic response [4]. In particular, the stage IIIb/IV NSCLC group had a lower incidence of hematological response and a higher incidence of transfusion. It is notable that, in these late-disease-stage patients, a higher attrition rate (60% versus 20%–25% for breast/gynecologic cancers) was observed, which included, as expected, a higher percentage of deaths (14% for NSCLC versus 0%–6% for breast/gynecologic cancers). With the high number of early withdrawals, NSCLC patients also had a shorter mean duration of therapy (10 weeks compared with 14 weeks for breast and gynecologic cancer patients). All these factors were likely to have contributed to poorer responses in the NSCLC patients. This may also explain the apparent differences in change in hemoglobin level in the NSCLC patients compared with other hematologic endpoints.
The degree of anemia at baseline is another covariate that appeared to affect the mean change in hemoglobin level and transfusion rate in the combined group of patients. As shown in the available data analyses, greater increases in hemoglobin (excluding the effect of transfusions) were observed in patients who initiated therapy at hemoglobin levels below 10 g/dl. However, lower transfusion requirements were observed in patients who initiated therapy at hemoglobin levels of 10–11 g/dl. Despite positive improvements in hemoglobin levels, our results suggest that waiting until more severe anemia develops to initiate anemia therapy may result in a greater risk of transfusion compared with earlier intervention.
The timeliness of response is an important characteristic of anemia therapy. To investigate this in a clinically meaningful way, we evaluated the achievement of a target hemoglobin threshold and subsequent maintenance of a hemoglobin range (11–13 g/dl) based on recommendations of the NCCN and ASH/ASCO evidence-based guidelines as well as on the approved label instructions for darbepoetin alfa and epoetin alfa [16–19]. In this trial, over 80% of all patients achieved this treatment target. No treatment differences were observed in either the proportion of patients achieving the target hemoglobin threshold of 11 g/dl or in the median time to achieve the target. After achievement of a hemoglobin level 11 g/dl, similar hemoglobin outcomes were observed for both treatment groups. Further, dose withholding at hemoglobin levels exceeding 13 g/dl allowed for the maintenance of hemoglobin levels within the target hemoglobin range. This approach of evaluating these endpoints incorporates the recommendations of the evidence-based clinical practice guidelines [16, 17], and these results address clinical outcomes of interest (transfusion reduction and symptom improvement).
No differences in safety between darbepoetin alfa and epoetin alfa were observed. Recent reports have suggested possible safety concerns with erythropoietic therapy, especially when administered in patients with high hemoglobin levels (i.e., >13 g/dl) [20, 21]. However, numerous commentaries have expressed difficulty in interpreting these data and their generalizability [22–26]. While no conclusions can be drawn on survival with erythropoietic therapy, no differences in thrombotic events occurred. Our data continue to support the safety of erythropoietic therapy, especially when administered according to guidelines or the package insert instructions.
We note the following important limitation of these trials. While the results indicate similar clinical outcomes across numerous endpoints and across all tumor types studied, the trials were not formally powered to test noninferiority. Future research that evaluates accepted measures of clinical efficacy (e.g., reductions in transfusions or quality of life assessments) [16, 17] with prospectively defined noninferiority/equivalence margins is required to definitively demonstrate noninferiority between these two regimens. Furthermore, regarding the primary endpoint, the study was designed to validate the PSQ-An, not to evaluate the differences in patient satisfaction between treatment groups. Consequently, we did not make these comparisons between treatment groups using the PSQ-An instrument nor did we address potential biases associated with differences in dosing schedules that may influence outcomes of the PSQ-An. Since these trials demonstrate internal consistency, we believe that this scale may be helpful in future studies of patient satisfaction. Despite these limitations, our findings in breast, lung, and gynecologic tumor types, which represent many chemotherapy-induced anemia populations, provide important data regarding the clinical comparability of these agents.
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CONCLUSION |
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ACKNOWLEDGMENT |
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We wish to acknowledge the study staffs of the physicians involved in these trials, Bin Yao, M.S., Joe Murray, M.S., Yating Wang, M.S., and Ben Frierson for statistical analysis and programming support, Elizabeth Mendes, M.P.H., and Dixon Terry, M.P.H., for managing the trials, and Mee Rhan Kim, Ph.D., for assistance with the writing of this manuscript.
The trials in this manuscript were presented previously by Schwartzberg et al. [27, 28].
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TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionReferencesAdditional Reading |
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ADDITIONAL READING |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionConclusionReferencesAdditional Reading |
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Gabrilove JL, Cleeland CS, Livingston RB et al. Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin Oncol
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Groopman JE, Itri LM. Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst
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