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Originally published as JCO Early Release 10.1200/JCO.2007.14.2885 on January 28 2008 © 2008 American Society of Clinical Oncology. Darbepoetin Alfa for the Treatment of Anemia in Patients With Active Cancer Not Receiving Chemotherapy or Radiotherapy: Results of a Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study
From the South Carolina Oncology Associates, Columbia, SC; Amgen Inc, Thousand Oaks; University of California, Los Angeles, School of Medicine, Los Angeles, CA; Clinique de Genolier, Genolier, Switzerland; Wilhelminenspital, 1.Medizinische Abteilung mit Onkologie, Vienna, Austria; Petz Aladar County Teaching Hospital, Gyor, Hungary; Ustav Onkologie a Pneumologie Na Plesi, Onkologicke oddeleni, Plesi, Czech Republic; and Institutul Oncologic "Ion Chiricuta," Cluj-Napoca, Romania Corresponding author: John Glaspy, MD, MPH, Division of Hematology-Oncology, Department of Medicine, University of California, Los Angeles, School of Medicine, 100 UCLA Medical Plaza, Suite 550, Los Angeles, CA 90095-6956; e-mail: jglaspy{at}mednet.ucla.edu
Purpose The efficacy and safety of darbepoetin alfa (DA) for treating patients with active cancer and anemia not receiving or planning to receive cytotoxic chemotherapy or myelosuppressive radiotherapy was evaluated. Patients and Methods Patients with active cancer and anemia not receiving or planning to receive chemotherapy or radiotherapy were enrolled onto a phase III, multicenter, randomized, placebo-controlled study and administered placebo or DA 6.75 µg/kg every 4 weeks (Q4W) for up to 16 weeks with a 2-year follow-up for survival. Patients who completed 16 weeks of treatment could receive the same treatment as randomized Q4W for an additional 16 weeks. The primary end point was all occurrences of transfusions from weeks 5 through 17; safety end points included incidence of adverse events and survival. Results The incidence of transfusions between weeks 5 and 17 was lower in the DA group but was not statistically significantly different from that of placebo. DA was associated with an increased incidence of cardiovascular and thromboembolic events and more deaths during the initial 16-week treatment period. Long-term survival data demonstrated statistically significantly poorer survival in patients treated with DA versus placebo (P = .022). This effect varied by baseline covariates including, sex, tumor type, and geographic region; statistical significance diminished (P = .12) when the analysis was adjusted for baseline imbalances or known prognostic factors. Conclusion DA was not associated with a statistically significant reduction in transfusions. Shorter survival was observed in the DA arm; thus, this study does not support the use of erythropoiesis-stimulating agents in this subset of patients with anemia of cancer.
Anemia is common in patients with cancer and may be caused by the treatment or the disease itself.1-4 The pathogenesis of anemia of cancer (AoC) in patients not receiving cancer therapy is poorly defined and may be due to various factors, including inflammatory cytokines, marrow infiltration, and residual marrow impairment from treatment.2,5-7 Anemia is associated with a number of debilitating symptoms that may negatively impact patients’ quality of life8,9 and may also be an independent prognostic factor for survival.10 Current therapies for AoC include RBC transfusions and erythropoiesis-stimulating agents (ESAs). Transfusions are associated with risks, including immunosuppression, hemolytic reactions, iron overload, and disease transmission.5,11-13 A limited number of clinical trials have evaluated the efficacy and safety of ESAs in patients with AoC and demonstrated increased hemoglobin levels, reduced transfusion incidence, and improved quality of life.14-22 Although ESAs are approved by the United States Food and Drug Administration and/or the European Agency for the Evaluation of Medicinal Products for the treatment of patients with chemotherapy-induced anemia,23-25 none are approved for use in patients with AoC. A previous dose- and schedule-finding study suggested that the ESA darbepoetin alfa (DA) was well tolerated and effective in patients with AoC and that less-frequent (every 4 weeks; Q4W) DA may benefit patients not receiving cancer treatment.21 Here we present results from a large, phase III, multicenter, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of DA administered 6.75 µg/kg Q4W for treating the subset of patients with active cancer and anemia who are not receiving or planning to receive cytotoxic chemotherapy or myelosuppressive radiotherapy.
Patient Population Study protocols were approved by the institutional review board at each study site, and written informed consent was obtained before study-related procedures were begun.
Patients eligible for the initial 16 weeks of treatment were Patients were eligible to receive a further 16 weeks of treatment if they completed 16 weeks of treatment and met certain eligibility criteria (Fig 1).
Study Design This study was conducted in Europe, North America, and Australia. Patients received up to 16 weeks of treatment followed by an end-of-study visit at week 19 and 2 years of follow-up for survival. Patients who completed 16 weeks of treatment could receive the same blinded treatment Q4W for a further 16 weeks with an end-of-study visit at week 35.
Patients were randomly allocated 1:1 in the initial protocol to receive either DA 6.75 µg/kg or placebo subcutaneously Q4W until 145 patients had received one or more transfusions between weeks 5 and 17. Additional patients were randomly assigned 9:1 (DA:placebo) until 500 patients were enrolled onto the DA group (for safety evaluation). Randomization was stratified by geographic region (Europe v rest of world), baseline hemoglobin (< 10 v Treatment was withheld when hemoglobin was greater than 13 g/dL and reinstated with a 25% reduction when hemoglobin reached 12 g/dL. Treatment was reduced by 25% if hemoglobin was greater than 12 g/dL or increased greater than 1 g/dL in 14 days. Patients could receive noncytotoxic antineoplastic therapy or nonmyelosuppressive radiation at the discretion of the investigator.
Study End Points Safety end points included adverse events, serious adverse events, and deaths (during the treatment phase and 2-year follow-up period). Adverse events were assigned a preferred term using the Medical Dictionary for Regulatory Activities (version 9.0) and grouped by system organ class. The presence of neutralizing antibodies to DA was assessed at baseline and end of treatment.
Statistical Analysis Continuous end points were summarized as mean and standard deviation (SD), discrete data as frequency and percent.
All occurrences of transfusions between weeks 5 and 17 (primary end point) were determined in patients who were randomly assigned 1:1, received one or more dose of study drug, and completed
The Kaplan-Meier method was used to estimate the incidences of first transfusion, first transfusion or hemoglobin An analysis of covariance model was used to compare the adjusted means of the treatment groups for changes in hemoglobin concentration and FACT-Fatigue scores from baseline to end of treatment period. Missing hemoglobin values at the end of treatment were imputed using the last postbaseline hemoglobin measurement not within 28 days after a transfusion; missing FACT-Fatigue scores at the end of treatment were imputed using the last observation carried forward. All analyses were stratified or adjusted for stratification variables at randomization (hemoglobin at screening, region, prior transfusion, tumor type/treatment, and ECOG status). Kaplan-Meier survival curves were plotted for time to all deaths, including those from the long-term follow-up period. Cox proportional hazards models were fit: (1) adjusted for stratification factors at randomization; (2) adjusted for stratification factors at randomization and enrollment status (as a time-dependent covariate indicating use of DA or placebo for up to 32 weeks); and (3) adjusted for stratification factors at randomization, enrollment status, and prognostic factors at baseline (sex, baseline disease stage, prior cytotoxic chemotherapy, and prior radiotherapy). Time to death was also summarized by tumor type, sex, geographic region, screening hemoglobin, prior transfusions, and ECOG status. P values for tests of homogeneity of treatment differences for each subgroup are provided. Cox regression analyses, adjusted for baseline covariates, evaluated the association between survival during the initial 16-week treatment period and three time-dependent covariates: achieving hemoglobin greater than 12 g/dL, having a more than 1-g/dL increase in hemoglobin in 14 days, or having a transfusion.
Patient Characteristics Patients were enrolled between April 15, 2004, and May 23, 2006, at 144 sites in Europe, Australia, and North America; most patients (75%) were from Europe. A total of 1,473 patients were screened, 989 were randomly assigned to receive either placebo (n = 472) or DA (n = 517). Two patients per group never received investigational drug. The randomization of the last 64 patients 9:1 (darbepoetin:placebo) resulted in more patients in the DA group. Approximately 52% (n = 517) completed the 16-week treatment period. Of these, 371 opted to continue in the study for a further 16 weeks: 173 patients receiving placebo and 198 patients receiving DA; 66% (n = 245) completed the additional 16-week treatment period (Consort diagram; Fig 1). Patient demographics were broadly similar between the groups (Table 1). However, the DA group had more men (55.3%, DA; 46.8%, placebo), more patients with stage IV disease, more who had received prior chemotherapy, and a shorter time from prior chemotherapy to first dose of study drug. Most cancers were solid tumors; the most frequent were non–small-cell lung, breast, prostate, colorectal, and kidney. The most common hematologic malignancies were multiple myeloma and non-Hodgkin's lymphoma; a higher proportion of patients in the DA group had aggressive non-Hodgkin's lymphoma and stage III multiple myeloma. On-study antineoplastic therapies were well balanced between the treatment groups (Table A1, online only).
Transfusions All occurrences of transfusions between weeks 5 and 17 were lower in the DA group but were not significantly different from placebo (Table 2). However, the incidence of transfusions and the incidence of transfusions or hemoglobin  8 g/dL were statistically significant, favoring DA (P = .046 and P = .009, respectively; Table 2). The incidence of transfusions among the European study sites was lower than that of the rest of the world (Table 2); among the 75 patients (42 patients receiving placebo; 33 patients receiving DA) whose hemoglobin decreased 8 g/dL but were not transfused, 71 patients (95%) were from Eastern Europe.
Hemoglobin End Points Mean change in hemoglobin from baseline, hemoglobin response, hemoglobin correction, and hematopoietic response were all statistically significantly higher for the DA group than for the placebo group (Fig 2; Table 2).
Patient-Reported Quality of Life No significant improvement or worsening of FACT-Fatigue scores was observed in the DA and placebo groups (Table A2, online only).
Exposure to Study Drug
Safety
During treatment, 113 patients (21.9%) receiving DA compared with 35 patients (7.4%) receiving placebo exceeded a hemoglobin of 13 g/dL, and 217 patients (42.1%) receiving DA compared with 126 patients (26.8%) receiving placebo had a greater than 1-g/dL increase in hemoglobin in 14 days (all unrelated to transfusions). Cardiovascular and thromboembolic events did not seem to occur more frequently in patients exceeding hemoglobin 13 g/dL compared with those who did not (hazard ratio [HR] = 0.43; 95% CI, 0.13 to 1.41) nor with those with a greater than 1-g/dL increase in hemoglobin in 14 days compared with those who did not (HR = 0.81; 95% CI, 0.45 to 1.44). No neutralizing antibodies to DA were detected. Survival. A total of 234 patients died while enrolled in the study (either during treatment or within 6 weeks after the last dose of study drug); 138 patients (26.8%) in the DA group died versus 96 patients (20.4%) in the placebo group. More deaths in the DA group were attributed by the investigators to cancer (Table 3). Including patients who opted to continue participating in the study for a further 16 weeks, deaths while enrolled in the study were 165 patients (32.0%) for DA and 117 patients (24.9%) for placebo. Significantly more patients receiving DA versus placebo died during treatment and long-term follow-up. The median time to death was estimated at 37 weeks versus 47 weeks, respectively, with median follow-up times of 25.9 and 29.4 weeks. There was a significant difference in survival between the two groups that favored placebo (HR = 1.22; 95% CI, 1.03 to 1.45; P = .022); however, the HRs and statistical significance diminished when posthoc analyses were further adjusted for baseline imbalances or known prognostic factors (Fig 3).
The observed effect of treatment on overall survival during treatment and follow-up varied by tumor type. When treated with DA, patients with kidney, non–small-cell lung, prostate, or stomach cancers, non-Hodgkin's lymphoma, or multiple myeloma seemed to have worse survival outcomes (although this only seemed significant in patients with multiple myeloma); the opposite was observed for patients with breast, colon, ovarian, or cervical cancer (Fig 4A). Men, patients from Western Europe, or those with screening hemoglobin  10 g/dL also seemed to have worse survival outcomes when treated with DA (Fig 4A). However, none of the P values for testing of homogeneity of treatment differences among subgroups was less than .05.
Interestingly, during the initial 16-week treatment period, survival outcomes seemed to be better after achieving hemoglobin greater than 12 g/dL and were neutral after having a more than 1-g/dL increase in hemoglobin in 14 days (Fig 4B). Survival outcomes seemed to be worse after having a transfusion for patients receiving either DA or placebo (HR = 2.55; Fig 4C).
This is the largest randomized trial to date in which an ESA was used to treat anemia in the subset of patients with active cancer not receiving or planning to receive cytotoxic chemotherapy or myelosuppressive radiotherapy. Results of previous trials suggested that treatment with ESAs in this setting reduced transfusion risk; however, in two published placebo-controlled studies, this difference was not statistically significant.15,21 Likewise, our trial did not demonstrate a statistically significant reduction in all occurrences of transfusions with DA treatment, although therapy was associated with increased hemoglobin concentration. Our failure to demonstrate a statistically significant reduction in occurrences of transfusions may be attributed to insufficient power resulting from a lower-than-predicted transfusion rate (including the failure to administer transfusion for 75 patients at recommended hemoglobin levels) and a greater-than-expected mean hemoglobin increase in the placebo group (0.5 g/dL); DA was associated with a significant reduction in transfusion incidence when the analysis included patients who should have undergone transfusion. Our data did not show improved quality of life associated with DA therapy, possibly owing to the high proportion of patients with advanced disease receiving palliative care. The safety of DA in this subset of patients with AoC is an important issue. Although the incidence of serious adverse events was greater in patients receiving DA, the incidence of serious adverse events attributed to DA was not higher in these patients. Only cardiovascular and thromboembolic events were observed with a higher frequency in patients receiving DA; this is reflected in the product label, and recent meta-analyses of published trials have documented similar or greater incidences of thromboembolic events associated with ESA treatment versus controls in patients with chemotherapy-induced anemia.13,27,28 Previous controlled trials of DA in the AoC setting did not demonstrate a detrimental effect on survival.21,22 Also, published meta-analyses demonstrated no reduced survival outcomes in patients with chemotherapy-induced anemia treated with ESAs.13,27,28 Thus the significantly higher proportion of deaths in the DA group in the present trial was unexpected. It is important to note that survival was not an end point of this trial, and appropriate stratification factors were not used to ensure balance in baseline-prognostic factors for survival between the two treatment groups. Posthoc analyses accounting for these factors reduced the observed survival difference and diminished statistical significance. Although the test for interaction failed to reach significance at a P = .066, it is noteworthy that the HR was 0.95 for female patients compared with 1.32 for male patients, a somewhat surprising difference with no clear explanation. Although more deaths on study were attributed to the underlying malignancy in the DA arm, interpretation of this observation is difficult because assessment of tumor progression was not performed, and cause of death was not reported. Several hypotheses have been proposed to account for adverse outcomes observed in other studies with ESAs in oncology populations.29,30 These include the effects of high-target hemoglobin levels on cardiovascular and thromboembolic events (for which oncology patients are at increased risk), a putative role for the erythropoietin receptor (EpoR) in tumor progression (however, the anti-EpoR antibodies used to identify EpoR in tissue samples are nonspecific31,32), and direct effects of ESAs on either promoting tumor vascularization or increasing risk for cardiovascular and thromboembolic events. Although a higher incidence of cardiovascular and thromboembolic events was observed in the DA group, deaths attributed to these events were balanced between the two groups. Cause of death was not adjudicated in this study; thus deaths from cardiovascular and thromboembolic disease may have been under reported. Interestingly, although this study did not target high hemoglobin levels, neither a greater than 1 g-dL increase in hemoglobin in 14 days nor an increase to more than 12 g/dL seemed to be associated with decreased survival, arguing against a detrimental effect of either higher or rapidly achieved hemoglobin levels. In contrast, transfusion, a potential marker of lack of response to therapy and poorer health, seemed to be associated with worse survival outcomes. No formal data on disease progression were collected, thus no conclusions on an effect of ESA on tumor progression can be made. Importantly, breast cancer patients did not experience an adverse outcome with respect to mortality, and this result is in contrast to a previous study of anemia prevention in breast cancer patients with chemotherapy-induced anemia.29 Therefore, the data from the present study do not allow an explanation for the observed adverse mortality outcome: there is no support for either increased thrombotic risk or effects of high hemoglobin levels as possible explanations. In conclusion, in this trial of DA to treat anemia in patients with active cancer not receiving or planning to receive cytotoxic chemotherapy or myelosuppressive radiotherapy, we did not observe a statistically significant reduction in transfusions and cannot exclude a negative impact on survival. Thus this study does not support the use of ESAs in these patients. It is unknown whether these findings can be generalized to the broader AoC population.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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.
Employment or Leadership Position: Li Chen, Amgen (C); Tom Lillie, Amgen (C) Consultant or Advisory Role: Matti S. Aapro, Amgen (C); Heinz Ludwig, Amgen (C) Stock Ownership: Robert E. Smith Jr, Amgen; Li Chen, Amgen; Tom Lillie, Amgen Honoraria: Robert E. Smith Jr, Amgen; Matti S. Aapro, Amgen Research Funding: Robert E. Smith Jr, Amgen; Matti S. Aapro, Amgen; Heinz Ludwig, Amgen; Tamás Pintér, Amgen; Martin
Conception and design: Robert E. Smith Jr, Heinz Ludwig, Li Chen, Tom Lillie, John A. Glaspy Administrative support: Li Chen, Tom Lillie
Provision of study materials or patients: Robert E. Smith Jr, Matti S. Aapro, Heinz Ludwig, Tamás Pintér, Martin Collection and assembly of data: Li Chen, Tom Lillie, John A. Glaspy Data analysis and interpretation: Robert E. Smith Jr, Matti S. Aapro, Heinz Ludwig, Li Chen, Tom Lillie, John A. Glaspy
Manuscript writing: Robert E. Smith Jr, Matti S. Aapro, Heinz Ludwig, Tamás Pintér, Martin
Final approval of manuscript: Robert E. Smith Jr, Matti S. Aapro Jr, Heinz Ludwig, Tamás Pintér, Martin
We thank Bin Yao, MS, Yuriy Shamanov, MS, Julie Ma, PhD, Xuena Wang, PhD, Irene Ferreira, PhD, and Dianne Tomita, MPH, for their contributions to this study, and Kathryn Boorer, PhD, for assistance with writing this manuscript.
Supported by Amgen Inc (Amgen Study ID Nos. 20010103 and 20020149; ClinicalTrials.gov identifiers NCT00091858 [ClinicalTrials.gov] and NCT00115167 [ClinicalTrials.gov] ). Presented in part at the Annual Meeting of the American Association for Cancer Research, April 14-18, 2007, Los Angeles, CA; and at the 12th Congress of the European Hematology Association, June 7-10, 2007, Vienna, Austria. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. published online ahead of print at www.jco.org on January 28, 2008.
1. Moliterno AR, Spivak JL: Anemia of cancer. Hematol Oncol Clin North Am 10:345-363, 1996[CrossRef][Medline] 2. Birgegård G, Aapro MS, Bokemeyer C, et al: Cancer-related anemia: Pathogenesis, prevalence and treatment. Oncology 68:3-11, 2005 (suppl 1)[CrossRef][Medline] 3. Ludwig H, Van Belle S, Barrett-Lee P, et al: The European Cancer Anaemia Survey (ECAS): A large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients. Eur J Cancer 40:2293-2306, 2004[CrossRef][Medline] 4. Tchekmedyian NS: Anaemia in cancer patients: Significance, epidemiology, and current therapy. Oncology (Williston Park) 16:17-24, 2002 5. Mercadante S, Gebbia V, Marrazzo A, et al: Anemia in cancer: Pathophysiology and treatment. Cancer Treat Rev 26:303-311, 2000[CrossRef][Medline] 6. Pujade-Lauraine E, Gascon P: The burden of anemia in patients with cancer. Oncology 67:1-4, 2004 (suppl 1)[Medline] 7. 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Quirt I, Robeson C, Lau CY, et al: Epoetin alfa therapy increases hemoglobin levels and improves quality of life in patients with cancer-related anemia who are not receiving chemotherapy and patients with anemia who are receiving chemotherapy. J Clin Oncol 19:4126-4134, 2001 19. Johansson JE, Wersall P, Brandberg Y, et al: Efficacy of epoetin beta on hemoglobin, quality of life, and transfusion needs in patients with anemia due to hormone-refractory prostate cancer: A randomized study. Scand J Urol Nephrol 35:288-294, 2001[CrossRef][Medline] 20. Charu V, Belani C, Gill AN, et al: Efficacy and safety of every-2-week darbepoetin alfa in patients with anemia of cancer: A controlled, randomized, open-label phase 2 trial. The Oncologist 12:727-737, 2007 21. Smith RE Jr, Tchekmedyian NS, Chan D, et al: A dose- and schedule-finding study of darbepoetin alpha for the treatment of chronic anaemia of cancer. Br J Cancer 88:1851-1858, 2003[CrossRef][Medline] 22. Gordon DH, Nichols G, Ben-Jacob A, et al: Treating anemia of cancer with darbepoetin alfa administered every 4 weeks: Final results from a phase 2, randomized, double-blind, placebo-controlled study in cancer patients not receiving chemotherapy and/or radiotherapy. Blood 108:328a, 2006 (abstr 1304)[CrossRef] 23. Amgen Inc: Aranesp (Darbepoetin alfa) Package Insert. Thousand Oaks, CA, Amgen Inc, 2006 24. Ortho Biotech Products: L.P. Procrit (Epoetin alfa) Package Insert. Raritan, NJ, Ortho Biotech Products, 2005 25. Roche Registration Ltd: NeoRecormon (Epoetin beta) Package Insert. Hertfordshire, United Kingdom, Roche Registration Ltd, 2007 26. Anderson PK, Gill RD: Cox's regression model for counting processes: A large sample study. Ann Stat 10:1100-1120, 1982[CrossRef] 27. Seidenfeld J, Pipe M, Bohlius J, et al: Comparative effectiveness of epoetin and darbepoetin for managing anemia in patients undergoing cancer treatment: Comparative effectiveness review no. 3 (prepared by Blue Cross and Blue Shield Association Evaluation Center Evidence-based Practice Center under contract no. 290-02-0026). Rockville, MD, Agency for Healthcare Research and Quality, 2006. Available at: www.effectivehealthcare.arhq.gov/reports/final.cfm 28. Aapro M, Coiffier B, Dunst J, et al: Effect of treatment with epoetin beta on short-term tumour progression and survival in anaemic patients with cancer: A meta-analysis. Br J Cancer 95:1467-1473, 2006[CrossRef][Medline] 29. Leyland-Jones B, Semiglazov V, Pawlicki M, et al: Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: A survival study. J Clin Oncol 23:5960-5972, 2005 30. Henke M, Laszig R, Rube C, et al: Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: Randomised, double-blind, placebo-controlled trial. Lancet 362:1255-1260, 2003[CrossRef][Medline] 31. Elliott S, Busse L, Bass MB, et al: Anti-Epo receptor antibodies do not predict Epo receptor expression. Blood 107:1892-1895, 2006 32. Brown WM, Maxwell P, Graham AN, et al: Erythropoietin receptor expression in non-small cell lung carcinoma: A question of antibody specificity. Stem Cells 25:718-722, 2007[CrossRef][Medline] Submitted September 3, 2007; accepted December 3, 2007.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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makal
TOP
ABSTRACT
INTRODUCTION
Two patients in the darbepoetin alfa group received placebo but remained in the darbepoetin alfa group for survival analysis. 
One patient in the placebo group received one dose of darbepoetin alfa and was included in the darbepoetin alfa group for survival analysis.
makal, Amgen; Tudor E. Ciuleanu, Amgen; John A. Glaspy, Amgen Expert Testimony: None Other Remuneration: None 
