Darbepoetin alfa administered every 3 weeks alleviates anaemia in patients with solid tumours receiving chemotherapy; results of a double-blind, placebo-controlled, randomised study

doi:10.1016/S0959-8049(03)00456-8

European Journal of Cancer

Volume 39, Issue 14, September 2003, Pages 2026-2034

https://doi.org/10.1016/S0959-8049(03)00456-8 Get rights and content

Abstract

This dose-finding, placebo-controlled study evaluated the safety and efficacy of darbepoetin alfa administered every 3 weeks (Q3W) to anaemic patients receiving chemotherapy. In part A, patients (haemoglobin ⩽110 g/l) were randomised in a 1:4 ratio to receive 1 of 6 doses of darbepoetin alfa (4.5, 6.75, 9.0, 12.0, 13.5 and 15.0 μg/kg) or placebo Q3W for 12 weeks. In part B, patients received open-label darbepoetin alfa. Patients (n=249) were evaluated for safety, haemoglobin endpoints and red blood cell (RBC) transfusions. Darbepoetin alfa given at doses ranging from 4.5 to 15.0 μg/kg Q3W was well tolerated and comparable to placebo in terms of safety. No neutralising antibodies were detected. All doses (from 4.5 to 15 μg/kg) reduced transfusions compared with placebo, and resulted in >50% of patients achieving a haematopoietic response. Administration of darbepoetin alfa Q3W has a tolerable safety profile and effectively ameliorates anaemia due to chemotherapy.

Introduction

Anaemia is a common side-effect in many patients with cancer receiving chemotherapy and contributes to the fatigue experienced by these patients 1, 2, 3, 4. Recombinant human erythropoietin is effective in relieving anaemia in this setting 2, 3, 4, 5, 6, 7. Approximately 40–60% of patients in these studies achieved a haemoglobin increase of at least 20 g/l, and improvements in clinical outcomes (transfusion requirements and quality-of-life measures) were demonstrated.

Despite the rationale for the use of erythropoietic therapy for cancer-related anaemia, anaemic patients frequently do not receive this treatment until their haemoglobin level has dropped as low as 90 g/l [8]. Factors that may contribute to the current low rate of treatment include the cost of therapy, the lack of perception of the importance of anaemia by treating physicians, the indicated administration schedule of 3 times per week (TIW), and the relatively high degree of non response to therapy.

A recent study demonstrated the effectiveness of once-weekly (QW) dosing of recombinant human erythropoietin, although at this schedule a 33% increase in dose was required compared with the registered dosing recommendations of TIW administration [4]. These results have led to the adoption of a QW schedule in many community practices in the United States. Further reductions in dosing frequency would be desirable, particularly if an erythropoietic agent could be administered at the same schedule as many common chemotherapy regimens (e.g., Q3W).

Darbepoetin alfa stimulates erythropoiesis by the same mechanism as endogenous erythropoietin and recombinant human erythropoietin through binding to the erythropoietin receptor [9]. However, darbepoetin alfa has 2 additional carbohydrate side chains, which result in an extended residence time and a consequential increase in potency compared with recombinant human erythropoietin [9].

We report the results of a large, international, randomised, double-blind, placebo-controlled, dose-finding study of darbepoetin alfa given subcutaneously (s.c.) Q3W to patients with cancer receiving chemotherapy. The purpose of the study was to assess the safety of darbepoetin alfa in patients receiving chemotherapy, to assess the feasibility of administering darbepoetin alfa Q3W, and to characterise the dose–response relationships for darbepoetin alfa when given Q3W.

Section snippets

Study population

The independent ethics committee or central ethics committee for each of the 26 participating centres in Australia, Canada, Costa Rica, and Europe approved the protocol and all patients gave written informed consent before any study-specific procedures were done. Patients who were ⩾18 years of age with solid tumours and were receiving cyclic chemotherapy were eligible for this study if they had a ⩾6-month life expectancy, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2,

Patient demographics and disposition

A total of 249 patients received at least one dose of study drug (198 darbepoetin alfa and 51 placebo). In general, baseline demographic and clinical characteristics of patients were well balanced between the darbepoetin alfa and placebo groups (Table 1). A slightly higher proportion of patients in the 12.0-μg/kg group had breast cancer (61%) compared with the other groups, which ranged from 15 to 38%. The 12.0-μg/kg group also had a slightly higher mean baseline haemoglobin concentration (104

Discussion

The prolonged half-life of darbepoetin alfa compared with recombinant human erythropoietin suggested that it might be possible to administer darbepoetin alfa Q3W, coinciding with the schedule of administration for many of the common chemotherapy regimens. The present study was undertaken to assess the feasibility of Q3W dosing with darbepoetin alfa in anaemic patients undergoing chemotherapy for solid tumours. To better characterise the relationship of dose to the safety and efficacy of

Acknowledgements

The authors thank the study coordinators and patients at each of the participating centres. Joan O'Byrne, Claire Dewey, and James Robinson assisted with the statistical analysis. Russell Berg managed the study. Kathleen Jelaca-Maxwell, RN, assisted with the safety analysis. Ngum-Aza Teh coordinated the data management. Christine Dale, MS, and MaryAnn Foote, PhD, assisted in the writing of the manuscript. This study was supported by Amgen Inc., Thousand Oaks, CA, USA.

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Cited by (132)

Effectiveness of Darbepoetin Alfa for Chemotherapy-induced Anemia When Initiated at Hemoglobin ≤10 g/dL
2016, Clinical Therapeutics
Citation Excerpt :
More patients with a baseline Hb <9 g/dL needed transfusions than patients with a baseline Hb 9 to ≤10 g/dL in both the DA and placebo arms (Table IV). The sensitivity analysis included 2 additional randomized, placebo-controlled, dose-finding studies,19,20 providing an overall total of 598 patients (DA, n = 313; placebo, n = 285). Inclusion of these 2 studies did not change the interpretation of the efficacy findings from the main comparative analysis.
Limited data are available to describe the effectiveness of darbepoetin alfa (DA) in terms of hemoglobin (Hb) and transfusion outcomes when initiated at Hb ≤10 g/dL (the threshold specified in the summary of prescribing characteristics). We assessed DA, initiated according to current labeling (Hb ≤10 g/dL), in chemotherapy-induced anemia (CIA).
Data for patients with cancer and CIA who initiated DA at Hb ≤10 g/dL were extracted from a database of Amgen-sponsored trials. A comparative analysis was limited to randomized, controlled trials in patients treated with DA or control (placebo/best supportive care). Data for the DA arm(s) of randomized, multiple-arm, or prospective, single-arm trials were also extracted (DA-only analysis; non–front-loaded studies only). Outcomes included Hb increase ≥1 g/dL or ≥2 g/dL during the first 12 weeks of treatment. Crude and Kaplan–Meier proportions of patients who experienced each outcome and time (days) to each outcome were summarized by treatment arm. Meta-analysis (fixed-effects inverse-variance method) was performed to compare outcomes for DA with control.
The comparative analysis included 4 studies (2 in lung cancer, 1 in lymphoproliferative disease, and 1 in non-myeloid malignancy: DA, n = 261; control, n = 273). The DA-only analysis included 15 studies (n = 3768). In comparative analyses, more patients who received DA than placebo achieved Hb increase of ≥1 g/dL (fixed-effects hazard ratio [HR] = 2.07; 95% CI, 1.62–2.63) or ≥2 g/dL (HR = 2.91; 95% CI, 2.09–4.06). Median times to ≥1 g/dL or ≥2 g/dL increase were 43 or 78 days for DA (not evaluable for placebo). Transfusions were less common in patients who received DA (HR = 0.58; 95% CI, 0.44–0.77). Addition of 2 dose-finding studies did not change the findings of the main comparative analysis. Results were similar in the DA-only analyses.
This is the first patient-level meta-analysis, to our knowledge, to evaluate the efficacy in terms of Hb response of DA treatment when initiated according to current product labeling in patients with CIA. Limitations include the small number of studies and patients eligible for inclusion in the comparative analyses and the absence of non-Amgen trials of DA. The results of the comparative analysis confirm that DA is more effective than placebo at increasing serum Hb levels and at reducing the need for transfusion in patients with CIA when treatment is initiated at Hb ≤10 g/dL, as per current product labeling.
Use of erythropoiesis stimulating agents
2014, Revue des Maladies Respiratoires
L’anémie est très fréquente dans les cancers bronchiques et sa prise en charge influence la qualité de vie et le pronostic des patients. Souvent multifactorielle, le traitement de l’anémie repose d’abord sur la correction de ses différentes causes (carentielle avec en particulier la correction d’une carence martiale, inflammatoire et liées à la maladie ou au traitement). Les agents stimulant l’érythropoïèse et surtout l’érythropoïétine recombinante, permettent d’augmenter le taux d’hémoglobine et ainsi de diminuer les besoins transfusionnels et d’améliorer la qualité de vie des patients. Cependant, ces traitements exposent également à un risque thromboembolique plus élevé et leur effet sur la survie globale reste discuté. Leur prescription est donc soumise à des recommandations strictes : ils sont indiqués chez les patients en phase palliative uniquement, recevant un traitement par chimiothérapie mais pas de radiothérapie, avec un taux d’hémoglobine initial inférieur à 100 g/L et le taux d’hémoglobine cible ne doit pas dépasser 120 g/L.
Anemia is fairly common in lung neoplasms and adequate management can influence both the prognosis and the quality of life of patients. Anemia can stem from diverse mechanisms, and its management must include the search for correctable causes (iron deficiency, inflammation, disease- or treatment-related), and their subsequent treatment. Use of erythropoiesis stimulating agents, namely recombinant erythropoietin, results in hemoglobin increase, fewer blood transfusions, and better quality of life. However, there is also a significant increase in thromboembolic risk associated with this treatment, and their effect on overall survival is still debated. Thus, their use must be restricted to patients treated with palliative intent, receiving chemotherapy but no radiotherapy, with a baseline hemoglobin level under 100 g/L, and target hemoglobin level must not exceed 120 g/L.
Benefits and risks of using erythropoiesis-stimulating agents (ESAs) in lung cancer patients: Study-level and patient-level meta-analyses
2012, Lung Cancer
Citation Excerpt :
All endpoints were reported by randomized treatment groups. In the Kotasek study [43], the different DA dose groups were analyzed as a single DA group; because patients randomly assigned to placebo could cross over to DA after 12 weeks, data were truncated at the end of the double-blind treatment period. Hazard ratios (HRs) were generated to summarize the effect of DA relative to placebo for time-to-event endpoints (overall survival and progression-free survival) using Cox proportional hazards models stratified by study.
In anemic patients receiving myelosuppressive chemotherapy, erythropoiesis-stimulating agents (ESAs) raise hemoglobin levels and reduce transfusion requirements, but ESA-related safety concerns exist. To evaluate ESA benefits and risks in lung cancer, we conducted meta-analyses of data from controlled ESA trials conducted in lung cancer patients. Study-level analyses included controlled ESA trials reporting lung cancer mortality, identified from the 2006 Cochrane ESA report and from a systematic search for studies published through December 2010. Patient-level analyses included data from lung cancer patients receiving chemotherapy in Amgen studies evaluating darbepoetin alfa (DA) vs placebo. Study-level and patient-level analyses examined deaths, progression, and transfusion incidence. Patient-level analyses also examined adverse events (AEs) and fatigue.
In a study-level meta-analysis of nine ESA studies of 2342 patients receiving chemotherapy, the ESA odds ratio (OR) was 0.87 (95% confidence interval [CI] 0.69–1.09) for mortality; the overall random-effects risk difference (95% CI) for mortality was −0.02 (−0.06, 0.02). The ESA OR (95% CI) for disease progression in five chemotherapy studies reporting progression was 0.84 (0.65–1.09). The ESA odds ratio (95% CI) was 0.34 (0.28–0.41) for transfusion incidence.
In a patient-level meta-analysis of four studies evaluating 1009 patients through follow-up, the median survival time was 41 weeks with DA and 38 weeks with placebo. During the combined study and follow-up periods, 80% of placebo-group patients and 74% of DA patients died (mortality hazard ratio [HR] 0.90 [95% CI, 0.78–1.03] for DA); results were similar for small cell lung cancer and non-small cell lung cancer. Overall, 87% of placebo patients and 84% of DA patients progressed or died. Fewer DA patients had transfusions (week 5 through end-of-study, DA 19%, placebo 43%). AEs included thrombotic/embolic events (DA 10.5%, placebo 7.2%), cerebrovascular disorders (DA 3.7%, placebo 4.2%), pulmonary edema (DA 0.4%, placebo 1.0%) and pulmonary embolism (DA 1.8%, placebo 0.6%).
These meta-analyses suggest that ESAs reduce transfusions without increasing mortality or disease progression in lung cancer patients undergoing chemotherapy.
Addition of darbepoetin alfa to dose-dense chemotherapy: Results from a randomized phase II trial in small-cell lung cancer patients receiving carboplatin plus etoposide
2011, Clinical Lung Cancer
Citation Excerpt :
The efficacy endpoints used in these studies were the hemoglobin response (ie, an absolute hemoglobin concentration ≥ 12 g/dL or an increase from baseline ≥ 2 g/dL) and/or the incidence of RBC transfusions. Enrolled subjects were clinically ill cancer patients receiving darbepoetin alfa (vs. placebo) to alleviate their chemotherapy-induced anemia21–25 or their anemia of cancer occurring in the absence of concomitant (or recent) chemotherapy.21,26–29 In 2002, the positive efficacy and safety results in the earliest of the above studies led to approval by the Food and Drug Association (FDA) of darbepoetin alfa in the oncology setting with a label of “treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy.”
Darbepoetin alfa, an erythropoiesis-stimulating agent (ESA), is used in cancer patients as a supportive care for anemia. For small-cell lung cancer (SCLC), several studies have shown that the administration of ESAs does not affect survival but decreases the need for blood transfusions and improves the quality of life (QOL) of patients receiving chemotherapy. The present randomized phase II study assessed the feasibility, efficacy, and safety of the administration of darbepoetin alfa to patients with SCLC receiving dose-dense (every 2 weeks) standard chemotherapy consisting of carboplatin plus etoposide, pegfilgrastim prophylactically. Seventy-four chemotherapy-naive patients with limited or extensive SCLC received combination chemotherapy for 6 cycles, and half of the patients additionally received darbepoetin to achieve a target hemoglobin concentration of 12-13 g/dL. The primary study outcome, progression-free survival, showed no difference between the 2 arms of the study. Among the secondary endpoints, objective response was similar in the presence and absence of darbepoetin (best response rates = 75.0% vs. 77.8%). Likewise, 1-year survival rates were not different between the 2 treatment arms (40.1% vs. 45.9%). There were no significant differences in grade 3/4 toxicities. As expected, the need for blood transfusions differed significantly: 19.4% of patients in the darbepoetin arm received transfusions versus 38.9% in the control arm. Analysis of European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ-C30) scales at different time points showed that the darbepoetin group’s QOL was significantly better for certain readouts and never significantly worse than that of the control group. Thus, the combination of darbepoetin alfa with dose-dense carboplatin plus etoposide was feasible and well tolerated. Addition of darbepoetin alfa to chemotherapy lowered the need for blood transfusions and did not affect measures of survival and objective response.
Use of latent growth curve models for assessing the effects of darbepoetin alfa on hemoglobin and fatigue
2010, Contemporary Clinical Trials
Citation Excerpt :
The findings of these analyses are consistent with clinician observations and previous research on ESAs in cancer populations. Previous clinical trials have demonstrated that darbepoetin alfa and the other ESAs reduce transfusion rates and improve hemoglobin levels in oncology patients with anemia who are undergoing chemotherapy [10–12,14–16]. Several studies have demonstrated that improvements in hemoglobin levels have concomitant effects on reducing patient reported fatigue [4,10,17,31–33].
The relationship between darbepoetin alfa and fatigue in chemotherapy-induced anemia (CIA) patients is complex because of patients receiving transfusions and the mediating effect of hemoglobin. Latent growth models (LGMs) were used to examine simultaneously relationships among drug exposure, fatigue outcomes, covariates, and mediating factors.
Data from four CIA studies (AMG 20010145: small cell lung cancer, n = 547; AMG 980297: lung cancer, n = 288; AMG 20000161: lymphoproliferative malignancies, n = 339; AMG 20030232: non-myeloid malignancies, n = 320) were analyzed separately. Patients reported fatigue using the FACT-Fatigue. The effect of darbepoetin alfa on FACT-F changes mediated through hemoglobin changes was examined with LGMs controlling for transfusions, age, sex, baseline ECOG performance status, and health status (EQ-5D VAS). Model fit was assessed using multiple indices including the comparative fit index (CFI).
Darbepoetin alfa increased hemoglobin levels which were associated with decreases in fatigue. Increases in hemoglobin were statistically significantly (p < 0.05) related to decreases in fatigue in the studies (AMG 20030145: β̂ = 0.28; AMG 980297: β̂ = 0.46; AMG 20000161: β̂ = 0.59; and AMG 20030232: β̂ = 0.39). Darbepoetin alfa statistically significantly increased hemoglobin (AMG 20010145:β̂ = 0.50, AMG 980297:β̂ = 0.53, AMG 20000161:β̂ = 0.47, and AMG 20030232:β̂ = 0.30) while controlling for covariates. Model fit was acceptable (CFI ≥ 0.89) in all studies.
Results indicate LGMs may be a valuable statistical method for modeling complex relationships among clinical and patient reported outcomes. A statistically significant effect of darbepoetin alfa on fatigue change through hemoglobin change occurred across four studies, after modeling the effects of transfusions, age, sex, EQ-5D VAS and ECOG.
Intravenous iron versus oral iron versus no iron with or without erythropoiesis- stimulating agents (ESA) for cancer patients with anaemia: a systematic review and network meta-analysis
2022, Cochrane Database of Systematic Reviews

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Darbepoetin alfa administered every 3 weeks alleviates anaemia in patients with solid tumours receiving chemotherapy; results of a double-blind, placebo-controlled, randomised study

Abstract

Introduction

Section snippets

Study population

Patient demographics and disposition

Discussion

Acknowledgements

Patient, caregiver, and oncologist perceptions of cancer-related fatigueresults of a tripart assessment survey

Semin. Hematol.

Quality-of-life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor typeresults from a prospective community oncology study

J. Clin. Oncol.

Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Procrit Study Group

J. Clin. Oncol.

Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patientsimprovements in hemoglobin and quality of life are similar to three-times-weekly dosing

J. Clin. Oncol.

Anemia in cancer patients

Semin. Oncol.

Efficacy of epoetin alfa in the treatment of anaemia of multiple myeloma

Br. J. Haematol.