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Symptom Management and Supportive Care |
aCancer Care Centers of South Texas and the U.S. Oncology Research Network, San Antonio, Texas, USA; bColumbia University Medical Center, New York, New York, USA; cDepartment of Internal Medicine, Cache Valley Cancer Treatment and Research Clinic Inc., Logan, Utah, USA; dAmgen Inc., Thousand Oaks, CA, USA; eCancer Center, St. Agnes Hospital, Baltimore, Maryland, USA
Key Words. Anemia of cancer • Darbepoetin alfa • Transfusions • Erythropoiesis-stimulating agent • Hemoglobin
Correspondence: David H. Gordon, M.D., Cancer Care Centers of South Texas, 540 Madison Oak Drive, Suite 200, San Antonio, Texas 78258, USA. Telephone: 210-545-6972; Fax: 210-545-1016; e-mail: David.Gordon{at}usoncology.com
Received December 10, 2007; accepted for publication May 5, 2008.
Disclosure: The article discusses darbepoetin alfa (Amgen). D.G., D.T. (employee), and T.L. (employee) own stock in Amgen. G.N. became an employee of Hoffmann-La Roche after this study was conducted. C.M. has acted as a consultant to Amgen (darbepoetin alfa). This study (20030204) was supported by research funding from Amgen Inc. No other potential conflicts of interest were reported by the authors.
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ABSTRACT |
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INTRODUCTION |
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Patients with AoC are often treated with RBC transfusions [3]. However, RBC transfusions can pose risks for the patient, including iron overload and disease transmission [7, 8, 11].
Erythropoiesis-stimulating agents (ESAs), such as epoetin alfa and darbepoetin alfa, are approved in the U.S. and Europe for the treatment of chemotherapy-induced anemia (CIA) [12, 13]. Previous studies suggested that both agents can also effectively treat patients with AoC. For example, epoetin alfa, administered at either 40,000 U weekly (QW) or 150 U/kg three times a week to patients with AoC increased hemoglobin levels [14–16] and improved patient-reported quality-of-life scores [16]. Also, in a dose- and schedule-finding study in patients with AoC, darbepoetin alfa, administered once per week or at extended-dosing intervals (every three weeks [Q3W] and every 4 weeks [Q4W]), increased hemoglobin levels without any apparent safety concerns [17].
The goal of this phase II, randomized, double-blind, placebo-controlled study was to evaluate the efficacy and safety of darbepoetin alfa administered Q4W for treating anemia in patients with AoC (administering darbepoetin alfa at extended dosing intervals may be advantageous for patients with AoC who may not visit a clinic frequently because they are not receiving chemotherapy or radiotherapy). The primary endpoint was the effect of darbepoetin alfa treatment on the percentage of patients achieving a hematopoietic response (
2-g/dl rise in hemoglobin from baseline or achievement of a hemoglobin level 12 g/dl without RBC transfusions during the prior 28 days). Secondary endpoints included the impact of darbepoetin alfa treatment on hemoglobin levels, transfusion incidence, patient-reported fatigue, and safety parameters.
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METHODS |
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Eligible patients were 18 years old with a nonmyeloid malignancy, anemia (hemoglobin 
11 g/dl), an Eastern Cooperative Oncology Group (ECOG) performance status score 2, and adequate renal and liver function. Patients were excluded from the study if they had received, or planned to receive, cytotoxic chemotherapy or myelosuppressive radiotherapy during the study or within 30 days before screening, had anemia related to nutritional deficiencies or to diseases other than the nonmyeloid malignancy, and had a history of pure RBC aplasia. Patients were also excluded if they had uncontrolled hypertension, a cardiac condition (uncontrolled angina, congestive heart failure, or uncontrolled cardiac arrhythmia), iron deficiency, a positive HIV test, a known positive antibody response to any erythropoietic agent, and had received epoetin alfa or darbepoetin alfa within 30 days prior to screening. Patients who were pregnant, breast-feeding, or hypersensitive to mammalian-derived products were also excluded.
Study Design
This was a multicenter, randomized, double-blind, placebo-controlled, phase II study of darbepoetin alfa compared with placebo for treating AoC. All screening tests and procedures were performed within a maximum of 7 days before randomization. Patients were randomly allocated in a 3:1 ratio to receive darbepoetin alfa or placebo, respectively. Treatment-group assignment was obtained by calling into an interactive voice-response system. Randomization was stratified by screening hemoglobin categories of <10 g/dl and 10 g/dl. A patient's treatment assignment was unblinded only when knowledge of the treatment was essential for further management of the patient's care. Study visits occurred every 2 weeks, and darbepoetin alfa (6.75 µg/kg) and placebo were administered s.c. Q4W for 13 weeks (four doses). All patients had an end-of-study visit at week 17 (or 4 weeks after the last dose of study product).
If, after 8 weeks (two doses), the hemoglobin concentration was <10 g/dl or had declined below the baseline value, darbepoetin alfa could be escalated at the investigator's discretion to 10 µg/kg Q4W. If the hemoglobin increased by >1 g/dl in a 2-week period, then the darbepoetin alfa dose was reduced by 25%, and if the hemoglobin exceeded 13 g/dl, darbepoetin alfa was withheld until it fell to 12 g/dl. Darbepoetin alfa was then reinstated at a dose 25% below the previous dose.
Study Drug, Concomitant Medications, and Study Assessments
Darbepoetin alfa was supplied as a clear, sterile protein solution of 500 µg/ml in 1-ml vials with a polysorbate-containing solution as the vehicle. Placebo was supplied in containers identical to those for darbepoetin alfa.
Investigators could prescribe concomitant medications or treatments necessary to provide adequate supportive care. Nonmyelosuppressive radiation for local palliation was permitted. Patients could not receive investigational agents, erythropoietic agents (other than darbepoetin alfa as defined in the protocol), cytotoxic chemotherapy, or myelosuppressive radiotherapy. Iron status was evaluated Q4W, and iron supplementation was recommended in patients with serum iron <50 µg/dl, ferritin <100 ng/dl, transferrin saturation <20%, or laboratory-defined iron deficiency. The dose, frequency, and route of administration of iron supplementation were at the discretion of the investigator.
Hemoglobin was measured Q2W. RBC transfusions were recommended, but not required, for patients with a hemoglobin concentration 8 g/dl or for patients with a hemoglobin concentration >8 g/dl who displayed symptoms of anemia. Functional Assessment of Cancer Therapy–Fatigue (FACT-F) questionnaires were completed at week 1 and weeks 5, 9, 13, and 17.
Study Endpoints
The primary endpoint was the percentage of patients who achieved a hematopoietic response by week 17 (after 13 weeks of treatment). Secondary endpoints included the change in hemoglobin concentration from baseline to week 17, incidence of RBC transfusions from week 5 to week 17, and change in FACT-F scores from baseline to week 17. Safety endpoints included the incidence and severity of adverse events (including those associated with hypothetical or known safety concerns regarding the use of ESAs) and the incidence of formation of neutralizing antibodies against darbepoetin alfa.
Because this study was among the first double-blind, randomized, controlled trials of darbepoetin alfa in the AoC setting, additional exploratory endpoints were identified as clinical experience expanded. These endpoints included the incidence of transfusions from week 1 to week 17, the percentage of patients achieving the hemoglobin target (11 g/dl), and the mean hemoglobin concentration maintained after the target hemoglobin was reached (maintaining hemoglobin in the range of 11–13 g/dl is in accordance with evidence-based guidelines that were in effect at the time of the study [18–20]).
Statistical Analysis
This study was designed to demonstrate benefit with respect to hematopoietic response in patients receiving darbepoetin alfa 6.75 µg/kg Q4W compared with placebo Q4W. The assumptions used to determine the sample size for this study were 20% and 45% hematopoietic response rates for the placebo and darbepoetin alfa groups, respectively. To have 90% power to detect the difference between an underlying placebo proportion of 20% and a treated proportion of 45% (using a 
2 test with a 0.05 two-sided significance level), the estimated sample size was 220 patients (darbepoetin alfa, 165; placebo, 55).
Efficacy and safety analyses were performed on randomized patients who received at least one dose of study product. Quality-of-life analyses were performed on randomized patients who received at least one dose of study product and who completed both the baseline and at least one subsequent FACT-F questionnaire. For efficacy analyses, patients were analyzed as randomized; for safety analyses, patients were analyzed by treatment received.
Statistical analyses were performed using SAS software (version 8.2; SAS Institute Inc., Cary, NC). Results were stratified by screening hemoglobin concentration category (<10 g/dl and 10 g/dl). Categorical variables were summarized using frequency and percent, and continuous variables were summarized by the mean, standard deviation (SD), and 95% confidence intervals (CIs). For time-to-event endpoints, the median and CI were calculated.
The percentages of patients who achieved a hematopoietic response, who achieved the target hemoglobin level, or who received a transfusion were estimated using the Kaplan–Meier (KM) method with the 95% CI. For the KM method, the 95% CI was based on the normal approximation with the variance estimated using Greenwood's formula. The KM graph of the time to hematopoietic response was generated.
Differences between the treatment groups for each endpoint were calculated. Based on the sample size, the weighted mean of the difference between the two treatment groups was assumed to follow a normal distribution, and a test of whether the difference between the two treatment groups was significantly different from zero was performed at the 
= 0.05 level of significance.
Hemoglobin data collected within 28 days after an RBC transfusion were excluded from the analysis of hemoglobin endpoints. Hemoglobin values were analyzed using two methods: in the last-value-carried-forward (LVCF) approach, missing hemoglobin values were imputed using the preceding hemoglobin value; in the available data approach, missing values were not imputed. Available data were used for FACT-F scores and were not adjusted for RBC transfusions.
All adverse events were summarized by system organ class and preferred term within system organ class using the MedDRA dictionary, version 9.0 (PSI International Inc., Fairfax, VA).
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RESULTS |
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In general, patients in both treatment groups had similar baseline characteristics (Table 1). The majority of patients were women, white, and 65 years of age. The most common primary tumor type was breast cancer. Similar percentages of patients in both groups had a screening hemoglobin level <10 g/dl (darbepoetin alfa, 35%; placebo, 34%). The darbepoetin alfa group had a higher mean baseline level of endogenous erythropoietin than the placebo group; however, the median endogenous erythropoietin levels were similar. The darbepoetin alfa group had a significantly higher (p = .03) baseline FACT-F score than the placebo group, and a higher percentage of patients in the darbepoetin alfa group received prior chemotherapy. Other cancer treatments (nonmyelosuppressive) were received by 34% and 46% of patients in the darbepoetin alfa group and placebo group, respectively. The most common on-study cancer treatments were hormonal therapy and monoclonal antibodies.
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10-g/dl hemoglobin stratum had a hematopoietic response than in the <10-g/dl stratum (Fig. 2A). The median time to a hematopoietic response was 7 weeks (95% CI, 7–11) in the darbepoetin alfa group but could not be estimated in the placebo group (Fig. 2B).
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10-g/dl hemoglobin stratum than in the <10-g/dl hemoglobin stratum in both treatment groups (Table 2). The median time to reach the target hemoglobin was 5 weeks (95% CI, 3–7) in the darbepoetin alfa group but could not be estimated in the placebo group. Once the target hemoglobin concentration of 11 g/dl was achieved, the majority of patients treated with darbepoetin alfa in both screening-hemoglobin strata then maintained hemoglobin concentrations within the recommended range of 11–13 g/dl (Table 2) [18–20]. The mean (SD) change in hemoglobin from baseline to week 17 was 1.3 (1.4) g/dl in the darbepoetin alfa group and 0.2 (1.0) g/dl in the placebo group; this was consistent in both screening-hemoglobin strata (LVCF approach) (Fig. 3). Analyses using available data indicated that the mean (SD) change in hemoglobin from baseline to week 17 was 1.4 (1.3) g/dl in the darbepoetin alfa group and 0.4 (1.0) g/dl in the placebo group.
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10 g/dl received transfusions (Fig. 4).
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10 g/dl (darbepoetin, 6.6; placebo, 6.8) (online supplementary Figure 1).
Safety Endpoints
The mean (SD) weeks of dosing was 11.7 (3.1) weeks in the darbepoetin alfa group and 11.5 (3.4) weeks in the placebo group, and the mean (SD) weekly dose of darbepoetin alfa was 116.2 (48.0) µg/week. The percentages of patients who had one or more doses withheld because the hemoglobin threshold (>13 g/dl) was reached were 30% in the darbepoetin alfa group (n = 50) and 4% in the placebo group (n = 2). The percentages of patients who had a dose increase were 28% and 57% in the darbepoetin alfa and placebo groups, respectively.
A similar proportion of patients in both treatment groups experienced adverse events and serious adverse events (Table 3). The most common serious adverse events were: disease progression (darbepoetin alfa, 4%; placebo, 7%), pneumonia (darbepoetin alfa, 3%; placebo, 2%), dehydration (darbepoetin alfa, 3%; placebo, 2%), and anemia (darbepoetin alfa, 2%; placebo, 4%). Treatment-related adverse events were reported by five patients in the darbepoetin alfa group (myalgia, n = 1; rash, n = 1, pruritic rash, n = 1; deep vein thrombosis, n = 2) and one patient in the placebo group (fatigue). There were no serious treatment-related adverse events reported in the placebo group. However, serious treatment-related adverse events (deep vein thrombosis) were reported in two patients from the darbepoetin alfa group.
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Nineteen patients died during the study or within 30 days following the end-of-study visit: 13 (8.0%) in the darbepoetin alfa group (nine because of cancer, one as a result of sepsis, one as a result of respiratory failure/septic shock, one as a result of pleural effusion, and one of unknown cause) and six (11%) in the placebo group (five because of cancer, and one of unknown cause).
During this study, none of the patients developed neutralizing antibodies to darbepoetin alfa.
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DISCUSSION |
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Previous studies have yielded conflicting results on the effectiveness of ESAs in reducing transfusion requirements in patients with AoC. For example, in three open-label studies, ESAs reduced transfusion requirements [15, 16, 21]; however, in three placebo-controlled trials, only trends toward a lower transfusion incidence in the ESA-treated group than in the placebo group were observed [14, 17, 22]. Likewise, in the present study, although darbepoetin alfa increased hemoglobin levels above those attained with placebo, there was no significant difference in the incidence of transfusions between the two treatment groups. In contrast, studies in cancer patients with CIA have consistently shown that treatment with darbepoetin alfa results in a significantly lower incidence of transfusions than with placebo [23, 24]. The discrepancy between the AoC and CIA patient populations may be related to differences in baseline transfusion requirements. For example, patients with AoC have lower baseline transfusion rates than patients with CIA [15, 16]. It is of interest to note, however, that in the present AoC study, patients with a screening hemoglobin level <10 g/dl had a lower incidence of transfusions if they received darbepoetin alfa than if they received placebo. In addition, patients in both treatment groups who had a screening hemoglobin level 10 g/dl had a lower incidence of transfusions than those with a screening hemoglobin level <10 g/dl.
There are also conflicting data on the effect of ESAs on the quality of life of patients with AoC. In a number of studies, quality-of-life measures were improved after treatment with ESAs [15, 17, 21, 25]; however, in a recently completed large, placebo-controlled study of darbepoetin alfa in patients with AoC, darbepoetin alfa did not improve FACT-F scores above those observed with placebo [26]. In the present study, both treatment groups had a clinically meaningful rise (three or more points) [27] in FACT-F score from baseline, but darbepoetin alfa did not improve FACT-F scores above those observed with placebo. Given that the darbepoetin alfa group had a significantly higher mean baseline FACT-F score than the placebo group, this observation is difficult to interpret. In patients with screening hemoglobin <10 g/dl, darbepoetin alfa did, however, improve the mean FACT-F scores.
In the present study, both treatment groups had a similar incidence of adverse events, suggesting that darbepoetin alfa was well tolerated in these study patients. In addition, the incidence of thromboembolic events in patients who received darbepoetin alfa (4%) was similar to that reported in a comprehensive meta-analysis of the effects of ESAs in patients with cancer [7]. This is a recognized risk associated with ESA use that has remained consistent over time and is documented in the original product labeling.
Since the completion of this trial, safety results from a phase III randomized, placebo-controlled, double-blind trial of darbepoetin alfa in the AoC setting (using the same dosing regimen as the present study) were reported [22]. That trial failed to meet its primary endpoint of reducing all occurrences of RBC transfusions, although when 75 patients who were not transfused according to the protocol guidelines were included in the analysis, significant benefit was observed. Significant improvement in hemoglobin endpoints was also observed. An unexpected safety finding was that more deaths occurred in the darbepoetin alfa group (26.8%, 138/515) than in the placebo group (20.4%, 96/470) during the 16-week treatment period, and overall survival was worse in the darbepoetin alfa group (hazard ratio [HR], 1.29; 95% CI, 1.08–1.55). It is noteworthy that the phase III trial was not designed to measure survival and that imbalances in baseline prognostic factors may have influenced survival outcomes; the HR was 1.17 (95% CI, 0.97–1.42) after adjusting for prognostic factors including baseline hemoglobin level, FACT-F score, ECOG performance status score, stage, and tumor type. These survival results are inconsistent with those seen in the present study and previous studies in similar populations. It is possible that differences in the patient populations contributed to these disparate outcomes: 82% of patients in the phase III trial had stage III/IV disease and all had active disease, whereas 57% of patients in the present study had stage III/IV disease and 20% were in complete remission.
Concerns regarding a potential relationship between ESAs and an increased risk for mortality and/or tumor progression have also been raised in some clinical studies designed to explore the ability of higher hemoglobin targets to improve survival in patients with cancer receiving chemotherapy or radiotherapy. Overall, these signals have not been observed consistently across studies, and within the chemotherapy-treated population, study-level meta-analyses (including data on >8,000 patients) have not indicated a clear effect of ESAs on tumor progression or mortality. Given these inconsistent results, further research is required to directly assess the impact of ESAs on disease outcomes.
The 2007 update to the joint guidelines of the American Society of Clinical Oncology/American Society of Hematology does not recommend the use of darbepoetin alfa in patients with solid or nonmyeloid hematologic malignancies who are not receiving chemotherapy or radiation [28]. In 2008, the product labels for ESAs were updated with a boxed warning highlighting potential safety risks [12, 13]. The darbepoetin alfa label advises that the product should be used only for the treatment of anemia resulting from concomitant myelosuppressive chemotherapy (not AoC). The label also recommends that physicians should use the lowest dose of darbepoetin alfa needed to avoid RBC transfusions and discontinue darbepoetin alfa therapy following completion of a course of chemotherapy.
In conclusion, darbepoetin alfa administered Q4W significantly raised hemoglobin levels and appeared to be well tolerated in patients with AoC in this phase II trial. Although no differences in on-study survival were observed between the darbepoetin alfa and placebo groups in this study, the survival outcomes observed in the subsequent phase III trial suggest a potential safety concern regarding the use of darbepoetin alfa in the AoC setting. The explanation of such differences in survival outcome between studies is unclear and further research into the potential effects of ESAs on survival in oncology patients is ongoing, including patient-level pooled data analyses of existing studies and additional clinical studies.
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AUTHOR CONTRIBUTIONS |
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Administrative support: Carole Miller
Provision of study materials or patients: David Gordon, Gwen Nichols, Ali Ben-Jacob, Carole Miller
Collection/assembly of data: David Gordon, Ali Ben-Jacob, Carole Miller
Data analysis and interpretation: David Gordon, Ali Ben-Jacob, Dianne Tomita, Tom Lillie
Manuscript writing: David Gordon, Dianne Tomita, Tom Lillie
Final approval of manuscript: David Gordon, Gwen Nichols, Ali Ben-Jacob, Dianne Tomita, Tom Lillie, Carole Miller
The authors take full responsibility for the content of the paper, but thank Linda Runft, Ph.D., and Kathryn Boorer, Ph.D., employees of Amgen Inc., for their assistance in compiling the directives of the authors into drafts for review, collating the review comments of the authors into subsequent drafts, editing the drafts, and coordinating compliance of the authors with journal requirements.
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ACKNOWLEDGMENTS |
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The ClinicalTrials.gov identifier for this study is NCT00095277.
We wish to thank Hung Lam and Yong Mun, Ph.D., for their assistance with the statistical analyses.
In addition to the authors of the present paper, the following investigators participated in this study: Barry Berman, John Eckardt, Patrick Flynn, Gregory Guzley, David Smith, Clarence Vaughn, James Weick, Raymond Vivacqua, Marc Saltzman, Herbert Duvivier, Birbal Bhaskar, Veena Charu, Robert Moss, Julio Hajdenberg, Nilesh Mehta, Frank Slovick, Madhavan Pillai, Sunil Gandhi, Isaac Esseesse, Mukesh Bhatt, Vinay Raja, Rao Moravineni, Jorge Ayub, Niraj Gupta, Billy Clowney, Hema Rao, John Hankins, Sitki Ergul, Thomas Jones, Young Lee, James Cook, James Carinder, Rudolph Navari, Roberto Arevalo Araujo, Muhammad-Ali Zaydan Thomas Anderson, Patrick Elwood, Leo Orr, Michael Kosmo, Paul Richards, Donald Richards, Thomas Cartwright, David Dong, Larry Frase, Ira Felman, Carlos Rubin de Celis, David Schrier, and Mark Keaton.
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REFERENCES |
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