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Review |

Venous Thromboembolism and Mortality Associated With Recombinant Erythropoietin and Darbepoetin Administration for the Treatment of Cancer-Associated Anemia FREE

Charles L. Bennett, MD, PhD; Samuel M. Silver, MD, PhD; Benjamin Djulbegovic, MD, PhD; Athena T. Samaras, BA; C. Anthony Blau, MD; Kara J. Gleason, BS; Sara E. Barnato, MD; Kathleen M. Elverman; D. Mark Courtney, MD; June M. McKoy, MD, MPH, JD; Beatrice J. Edwards, MD; Cara C. Tigue, BA; Dennis W. Raisch, PhD; Paul R. Yarnold, PhD; David A. Dorr, MD, MS; Timothy M. Kuzel, MD; Martin S. Tallman, MD; Steven M. Trifilio, RPh; Dennis P. West, PhD; Stephen Y. Lai, MD, PhD; Michael Henke, MD
[+] Author Affiliations

Author Affiliations: VA Chicago Healthcare System, Departments of Medicine, Dermatology, and Emergency Medicine, Northwestern University Feinberg School of Medicine, and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois (Drs Bennett, Barnato, Courtney, McKoy, Edwards, Yarnold, Kuzel, Tallman, and West, and Mss Samaras, Gleason, Elverman, and Tigue); University of Michigan Health System, Ann Arbor (Dr Silver); Interdisciplinary Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa (Dr Djulbegovic); Department of Medicine/Hematology and the Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle (Dr Blau); University of New Mexico, VA Cooperative Studies Program Clinical Research Pharmacy, Albuquerque (Dr Raisch); Department of Medical Informatics and Clinical Epidemology, Oregon Health and Science University, Portland (Dr Dorr); Department of Pharmacy, Northwestern Memorial Hospital, Chicago, Illinois (Mr Trifilio); Departments of Otolaryngology and Pharmacology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania (Dr Lai); and University Hospital of Freiberg, Freiburg, Germany (Dr Henke).


JAMA. 2008;299(8):914-924. doi:10.1001/jama.299.8.914.
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Context The erythropoiesis-stimulating agents (ESAs) erythropoietin and darbepoetin are licensed to treat chemotherapy-associated anemia in patients with nonmyeloid malignancies. Although systematic overviews of trials have identified venous thromboembolism (VTE) risks, none have identified mortality risks with ESAs.

Objective To evaluate VTE and mortality rates associated with ESA administration for the treatment of anemia among patients with cancer.

Data Sources A published overview from the Cochrane Collaboration (search dates: January 1, 1985-April 1, 2005) and MEDLINE and EMBASE databases (key words: clinical trial, erythropoietin, darbepoetin, and oncology), the public Web site of the US Food and Drug Administration and ESA manufacturers, and safety advisories (search dates: April 1, 2005-January 17, 2008).

Study Selection Phase 3 trials comparing ESAs with placebo or standard of care for the treatment of anemia among patients with cancer.

Data Extraction Mortality rates, VTE rates, and 95% confidence intervals (CIs) were extracted by 3 reviewers from 51 clinical trials with 13 611 patients that included survival information and 38 clinical trials with 8172 patients that included information on VTE.

Data Synthesis Patients with cancer who received ESAs had increased VTE risks (334 VTE events among 4610 patients treated with ESA vs 173 VTE events among 3562 control patients; 7.5% vs 4.9%; relative risk, 1.57; 95% CI, 1.31-1.87) and increased mortality risks (hazard ratio, 1.10; 95% CI, 1.01-1.20).

Conclusions Erythropoiesis-stimulating agent administration to patients with cancer is associated with increased risks of VTE and mortality. Our findings, in conjunction with basic science studies on erythropoietin and erythropoietin receptors in solid cancers, raise concern about the safety of ESA administration to patients with cancer.

Figures in this Article

The erythropoiesis-stimulating agents (ESAs), erythropoietin and darbepoetin, are widely used to treat anemia in patients with cancer.1 These drugs received approval from the US Food and Drug Administration (FDA) for cancer indications in 1993 and 2002, respectively, based on transfusion benefits among patients with nonmyeloid malignancies who developed anemia associated with chemotherapy.2,3 When erythropoietin received its approval, concerns over venous thromboembolism (VTE) and tumor progression were raised.4 Early trials evaluated serum hemoglobin levels and red blood cell transfusions when ESAs were administered to patients for treating chemotherapy-associated anemia. Two trials5,6 reported in 2003 evaluated the potential for ESAs to improve overall or progression-free survival. In these trials, poorer survival was identified for patients with breast cancer who were treated with ESA and chemotherapy, as well as patients with head and neck cancer who received radiotherapy. Published overviews from the Cochrane Collaboration, the National Institutes for Clinical Excellence, and the Blue Cross/Blue Shield Technology Evaluation Center of clinical trials published before mid-2005 included safety information for ESAs in the oncology setting.710 Two overviews found increased VTE risks associated with ESAs, but none identified mortality risks.810 The FDA has indicated that it will hold a meeting of its Oncologic Drug Advisory Committee (ODAC) in March 2008 to review safety concerns with ESAs that had been previously reported at ODAC meetings in 2004 and 2007.11,12 In this article, we review information for phase 3 trials that assessed ESA administration for treatment of anemia among patients with cancer. The primary data source, the 2006 Cochrane overview, was supplemented by reports for phase 3 trials reported more recently.9,10,1224

Analyzed Studies

We reviewed results of trials evaluating ESAs for the treatment of anemia in the oncology setting (Figure 1). Data sources included reports of outcomes for phase 3 trials published between January 1, 1985, and April 1, 2005, as described previously,7,8 augmented by review of phase 3 trials identified in MEDLINE or EMBASE for ESA studies in the oncology setting published or presented between April 2005 and January 17, 2008 (key words: clinical trial, erythropoietin, darbepoetin, and oncology); presentations at the 2007 ODAC meeting on ESAs12; or phase 3 clinical trial summaries reported by health authorities, ESA manufacturers, or clinical investigators at national conferences.1113,16,19,25 Our review includes both independent and industry-sponsored studies.

Place holder to copy figure label and caption
Figure 1. Search Strategy and Selection of Phase 3 Trials That Reported Survival and Venous Thromboembolism Outcomes
Graphic Jump Location

FDA indicates US Food and Drug Administration; ODAC, Oncologic Drug Advisory Committee.

aOf the 13 studies added for this meta-analysis for survival, 12 studies were reported between April 2005 and January 17, 2008. A 13th study was not included in the 2006 Cochrane Review,24 because it was published only as an abstract.

Main Outcome Measures

Information on VTE and mortality rates was abstracted by independent researchers (A.T.S., K.J.G., and S.E.B.) and compared. Where disagreements were identified, the first author of the article resolved these differences. There was 100% agreement on abstracted results in the final data set.

Statistical Analysis

The meta-analyses evaluated VTE rates and survival rates for all studies as well as according to prospective inclusion of survival as primary or secondary outcome measures. To test for differences of treatment, the test of interaction was used.26 Effect estimates for relative risks (RRs), hazard ratios (HRs), and 95% confidence intervals (CIs) were derived from Stata version 9.1 (Stata Inc, College Station, Texas), calculated with random-effects models, and pooled by use of the Dersimonian and Laird method.27 When mortality events were not available, HRs were calculated by using the inverse variance method to pool HRs. When VTE events were not available, a correction factor (0.5) was used to compute the RRs. All statistical tests were 2-sided. Effect estimates were deemed statistically significant when P ≤ .05.

In the 2006 Cochrane overview, 42 trials with 8167 patients were evaluated for overall survival. We excluded 4 trials that were included in the Cochrane overview because 1 study evaluated patients with myelodysplastic syndrome rather than cancer and 3 studies had HRs that were not estimable. We added 13 new trials (5369 patients).1224 In total, survival was evaluated for 13 611 patients with cancer who were treated in 51 phase 3 trials and VTE was evaluated for 8172 patients with cancer who were treated in 38 phase 3 trials (Figure 1). Trials differed with respect to study drug, patient numbers, treatment duration, concomitant treatments, and cancer diagnoses (Table 1 and Table 2).2,5,1124,2861 For the mortality analysis, a median of 223 patients were included in the individual trials (range, 30-985). Epoetin alfa or epoetin beta were evaluated in 40 trials with 8878 patients and darbepoetin in 11 trials with 4733 patients. Twenty-six trials included 7384 patients with a single cancer diagnosis (lung cancer [7 trials], breast cancer [6 trials], head and neck cancer [4 trials], cervical cancer [3 trials], ovarian cancer [3 trials], lymphoma [2 trials], and multiple myeloma [1 trial]). Duration of ESA treatment ranged from 6 to 52 weeks and duration of follow-up ranged from 11 to 62 months. Treatment-related anemia was evaluated in 45 trials with 11 522 patients, and cancer-related anemia was evaluated in 6 trials with 2089 patients. Concomitant treatment varied between trials as follows: chemotherapy (28 trials), radiotherapy (3 trials), chemoradiotherapy (7 trials), mixed treatment (2 trials), palliative radiotherapy (1 trial), no treatment (7 trials), and treatment not reported (3 trials).

Table Graphic Jump LocationTable 1. Characteristics of the 51 Phase 3 Trials (13 611 Patients) Included in the Survival Meta-analysis and Analyses for Both Survival and VTE
Table Graphic Jump LocationTable 2. Characteristics of the Phase 3 Trials Included Only in Venous Thromboembolism Analysis

Eight trials (4062 patients), recently identified in 2 FDA safety advisories,25,62 individually demonstrate significantly increased mortality risks and faster tumor growth among patients treated with ESA (Table 3).5,12,14,19,36,37,40,48,58 These trials included patients with anemia and breast cancer (2 studies),12,40,48 non–small cell lung cancer (1 study),58 head and neck cancer (2 studies),5,14 nonmyeloid cancers (1 study),19 lymphoma (1 study),37 and cervical cancer (1 study).36,36 Among these trials, sample sizes ranged from 70 to 985 patients, with a median of 533 patients. Five trials14,19,36,37,48 administered the drug darbepoetin alfa, 2 trials40,58 evaluated epoetin alfa, and 1 trial5 evaluated epoetin beta. Furthermore, in 3 trials,37,40,48 patients received concomitant chemotherapy; 2 trials5,14 included patients who received concomitant radiotherapy; in 1 trial,19 no concomitant treatment was used; in 1 trial,36 concomitant chemoradiotherapy was used; and in 1 trial,58 palliative radiotherapy was administered to some patients.

Table Graphic Jump LocationTable 3. Summary of 8 Trials That Individually Demonstrate Increased Mortality and/or Tumor Progression Among Patients Treated With ESAa

Survival was evaluated for 13 611 patients with cancer who were treated in 51 phase 3 trials (Figure 1). For survival, the HR for mortality was significantly higher for patients with cancer who were treated with ESA vs the control (placebo) group (HR, 1.10; 95% CI, 1.01-1.20; P = .03) (Figure 2). This association was not dominated by a small number of trials, with the largest 8 trials each contributing between 5% and 9% of the total number of clinical trial patients. Subgroup analyses evaluated mortality risks with ESA administration to patients with anemia and cancer for 6 trials with 2089 patients who were not receiving chemotherapy or radiation therapy (anemia of cancer) and 45 trials with 11 522 patients that evaluated patients with anemia and cancer with chemotherapy or radiation therapy–associated anemia (treatment-related anemia). Patients in the ESA group had nonsignificantly increased mortality risks in the anemia of cancer studies (HR, 1.29; 95% CI, 1.00-1.67; P = .05) and a nonsignificant increase in mortality risk in the treatment-related anemia studies (HR, 1.09; 95% CI, 0.99-1.19). There was no significant heterogeneity when evaluating all 51 trials as well as between trials evaluating anemia of cancer vs treatment-related anemia (heterogeneity χ2 = 1.99; I2 = 21.1%; P = .16).

Place holder to copy figure label and caption
Figure 2. Meta-analysis of Overall Mortality Rates for Phase 3 Oncology Trials With ESAs vs Placebo or Control, Comparing Anemia of Cancer and Treatment-Related Anemia Trials
Graphic Jump Location

ESAs indicate erythropoiesis-stimulating agents; CI, confidence interval; NR, not reported. Weights are from random-effects analysis. P = .11 for overall is the P value for the test for I2 (the variation in ESA attributable to heterogeneity). ESA-associated mortality (treatment effect on outcomes), P = .03.

Venous thromboembolism was evaluated for 38 trials that included 8172 patients (Figure 1). These trials identified a significantly increased risk of VTE among patients treated with ESA (334 events among 4610 patients treated with ESA vs 173 events among 3562 control patients; RR, 1.57; 95% CI, 1.31-1.87) (Figure 3). This association also was not dominated by a small number of trials.

Place holder to copy figure label and caption
Figure 3. Meta-analysis of VTE Rates in Phase 3 Trials of ESAs vs Placebo or Control
Graphic Jump Location

VTE indicates venous thromboembolism; ESA, erythropoiesis-stimulating agent; CI, confidence interval. Weights are from random-effects analysis. Some trials are represented more than once due to having more than 1 group within the trial. Each ESA-containing group in these trials evaluated different doses of ESAs in comparison with controls. The point estimates and CIs for the bottom 3 trials could not be calculated because no events were reported in these studies.

We found a 1.57-fold increased VTE risk and a 1.10-fold increased mortality risk when ESAs were administered to patients with anemia and cancer. These risks are important given the prevalence of ESA use as a supportive care drug among patients with cancer as well as the dissemination of a series of safety advisories by the FDA and ESA manufacturers.

Our mortality results differ from those reported in published overviews based on trials reported before mid-2005 (Table 4).711,6264 Only 23.8% of trials included in the 2006 Cochrane Review prospectively evaluated survival as a primary or secondary outcome. However, 8 recently reported trials with 4062 patients have individually identified increased rates of tumor progression or mortality with ESA use; all of these trials prospectively evaluated survival as a primary or secondary outcome (Table 3).5,14,19,36,37,40,48,58 Although the mechanism by which ESAs may affect survival of patients with cancer is not completely understood, concern exists over the potential for ESAs to directly affect tumors.65

Table Graphic Jump LocationTable 4. Systematic Reviews Evaluating VTE and Mortality Rates with Epoetin Alfa, Epoetin Beta, or Darbepoetin vs Placebo/Standard of Care for Treatment for Anemia in Patients With Cancer

Expression of erythropoietin and erythropoietin receptors has been demonstrated in a variety of human cancers.66 Erythropoieitn stimulation of cancer cells in vitro activates signal transduction pathways, including phosphatidylinositol 3-kinase-Akt and JAK-STAT (Janus kinase-Signal Transducer and Activator of Transcription).67,68 Depending on the type of cancer, activation of the erythropoietin/erythropoietin receptor signaling axis results in measurable cellular effects, including proliferation, antiapoptosis, and invasion.6972 Erythropoietin-mediated functions may result from autocrine/paracrine signaling or recruitment of both endogenous and exogenous erythropoietin by the tumor.7375 Clearly, many issues remain to be clarified regarding the specific actions of ESAs in human cancer cells.

Our estimate of a 1.57-fold increased VTE risk with ESA administration to patients with cancer mirror findings reported in published overviews and by the ESA manufacturers at ODAC meetings.79 Increased risks of thrombovascular complications with ESAs have been noted in other clinical settings. The Normal Hematocrit Study76 of patients with kidney and heart disease identified a 1- to 5-fold increased risk of myocardial infarctions and vascular access thrombosis when ESAs were administered with target hemoglobin levels of 14 g/dL. Similarly, the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) study77 of patients with chronic kidney disease identified increased risks of mortality and congestive heart failure among patients who received ESAs targeted to hemoglobin levels of 13.5 g/dL vs 11.3 g/dL. In these settings, no relationship was identified between hemoglobin levels and increased VTE risks.

Additional research on ESA safety is clearly needed. At the prior ODAC meetings in 2004 and 2007, FDA reviewers indicated that they would monitor survival and tumor progression rates for patients with cancer participating in ongoing phase 3 trials.11,12 Data for 8 trials that have completed patient accrual since that meeting are currently being evaluated.25,62 Four completed trials evaluated chemotherapy-associated anemia settings in which ESAs were withheld when hemoglobin levels reached 13 g/dL. Six studies, with 3000 patients, continue to evaluate the potential for ESAs to affect locoregional disease responses or survival among patients with cancer.14,62 At a December 2007 workshop on ESAs and tumor growth convened by the National Cancer Institute, clinical and basic science researchers agreed that continued preclinical work is necessary to evaluate the precise role of erythropoietin and erythropoietin-receptor expression in human cancers, and future clinical trials should include the collection of tissue specimens to directly assess ESA effects in tumor cells.

Our analysis had some study limitations. We did not have access to original source data and therefore evaluated trial summaries reported in overviews, published literature, and FDA briefing materials. Although additional trials might exist, it is unlikely that neither the FDA nor the manufacturers would be aware of such studies. We pooled results of individual trials, most of which had limited ability to evaluate survival or tumor progression. The VTE definitions varied across trials and VTE rate was not a predefined primary outcome measure in any trial. Finally, we did not report separately on epoetin vs darbepoetin, because the American Society of Clinical Oncology/American Society of Hematology guidelines and the National Comprehensive Cancer Network guidelines, the FDA, and the ODAC considered the products as belonging to a single class.78

In conclusion, we found that ESA administration to patients with cancer is associated with increased VTE and mortality risks. Safety concerns account in large part for changes observed in patterns of use, reimbursement policies, clinical guidelines, and FDA-approved package inserts pertaining to ESAs in the oncology setting.25,7882 Our findings, in conjunction with basic science reports on erythropoietin and erythropoietin receptors in solid cancers, raise concern about ESA safety for patients with cancer.

Corresponding Author: Charles L. Bennett, MD, PhD, VA Center for the Management of Complex Chronic Care, VA Chicago Healthcare System, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, 303 E Chicago Ave, Olson Pavilion Ste 8250, Chicago, IL 60611 (cbenne@northwestern.edu).

Author Contributions: Dr Bennett had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Bennett, Gleason, Courtney, McKoy, West, Henke.

Acquisition of data: Bennett, Samaras, Gleason, Barnato, Elverman, Edwards.

Analysis and interpretation of data: Bennett, Silver, Djulbegovic, Blau, Gleason, Barnato, Courtney, McKoy, Edwards, Tigue, Raisch, Yarnold, Dorr, Kuzel, Tallman, Trifilio, West, Lai.

Drafting of the manuscript: Bennett, Samaras, Gleason, Barnato, Courtney, Trifilio, West, Henke.

Critical revision of the manuscript for important intellectual content: Bennett, Silver, Djulbegovic, Blau, Gleason, Elverman, Courtney, McKoy, Edwards, Tigue, Raisch, Yarnold, Dorr, Kuzel, Tallman, West, Lai, Henke.

Statistical analysis: Bennett, Djulbegovic, Barnato, Courtney, Yarnold.

Obtained funding: Bennett.

Administrative, technical, or material support: Bennett, Samaras, Gleason, Elverman, McKoy, Tigue, Dorr, West, Henke.

Study supervision: Bennett, Edwards, Kuzel, Tallman, Trifilio, West.

Financial Disclosures: Dr Blau reported that he was named as an inventor on patent applications related to the regulation of blood cell production and is a cofounder of CellNexus LLC, which aims to develop this technology for the treatment of anemia. Drs Bennett and Djulbegovic reported serving as consultants to AMGEN and Dr Bennett reported that he has received grant support from AMGEN previously. Dr Silver reported that he is a consultant for Bear Stearns, Maverick Capital, and The Marwood Group. No other authors reported financial disclosures.

Funding/Support: This work (Research on Adverse Drug Events and Reports [RADAR]) was supported by grants 1R01CA 102713-01, 1R-1 CA125077-01A1, and P 30 CA60553 from the National Cancer Institute and grant 5K23HL077404-04 from the National Heart, Lung, and Blood Institute. The RADAR project does not accept funds from medical schools, hospitals, pharmaceutical organizations, or philanthropic donations. Dr Lai received support from the Young Clinical Scientist Award from the Flight Attendant Medical Research Institute and a National Institutes of Health Mentored Career Development Award (K08 DE018061).

Role of the Sponsor: The sponsors of this study had no role in the design and conduct of the study, in the collection, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.

Previous Presentations: This work has been presented in part at the plenary session for the Society of Clinical Trialists; May 23, 2007; Montreal, Canada, and at a poster session for the American Society of Clinical Oncology; June 5, 2007; Chicago, Illinois.

Additional Contributions: Simone N. Boyle, BA, Divisions of Hematology/Oncology, Northwestern University Feinberg School of Medicine, provided assistance with searching for studies included in the meta-analysis. Ms Boyle was supported by grant 1R-1 CA125077-01A1 from the National Cancer Institute.

Littlewood TJ, Cella D, Nortier JW. Erythropoietin improves quality of life.  Lancet Oncol. 2002;3(8):459-460
PubMed   |  Link to Article
Vansteenkiste J, Pirker R, Massuti B,  et al.  Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy.  J Natl Cancer Inst. 2002;94(16):1211-1220
PubMed   |  Link to Article
Henry DH, Brooks BJ Jr, Case DC Jr,  et al.  Recombinant human erythropoietin therapy for anemic cancer patients receiving cisplatin chemotherapy.  Cancer J Sci Am. 1995;1(4):252-260
PubMed
Steinbrook R. Erythropoietin, the FDA, and oncology.  N Engl J Med. 2007;356(24):2448-2451
PubMed   |  Link to Article
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. 2003;362(9392):1255-1260
PubMed   |  Link to Article
Leyland-Jones B. Breast cancer trial with erythropoietin terminated unexpectedly.  Lancet Oncol. 2003;4(8):459-460
PubMed   |  Link to Article
Wilson J, Yao G, Raftery J,  et al.  A systematic review and economic evaluation of epoetin alfa, epoetin beta and darbepoetin alfa in anaemia associated with cancer, especially that attributable to cancer treatment.  Health Technol Assess. 2007;11(13):1-220
PubMed
Seidenfeld JPM, Bohlius J, Weingart O,  et al.  Comparative effectiveness of epoetin and darbepoetin for managing anemia in patients undergoing cancer treatment. Rockville, MD: Agency for Healthcare Research and Quality; 2006. Comparative Effectiveness Review No 3. http://www.effectivehealthcare.ahrq.gov/reports/final.cfm. Accessed January 11, 2008
Bohlius JWJ, Seidenfeld J, Piper M,  et al.  Erythropoietin or darbepoetin for patients with cancer.  Cochrane Database of Syst Rev. 2006;(3):CD003407doi:10.1002/14651858.CD003407.pub4
Bohlius J, Langensiepen S, Schwarzer G,  et al.  Recombinant human erythropoietin and overall survival in cancer patients: results of a comprehensive meta-analysis.  J Natl Cancer Inst. 2005;97(7):489-498
Link to Article
 FDA Briefing Document: Safety Concerns Associated with Aranesp (darbepoetin alfa) Amgen, Inc. and Procrit (epoetin alfa) Ortho Biotech, L.P., for the Treatment of Anemia Associated with Cancer Chemotherapy: Hearings Before the SubCommittee on Oncologic Drugs Advisory Committee, Center for Drug Evaluation and Research. http://www.fda.gov/ohrms/dockets/ac/04/briefing/4037B2_04_FDA-Aranesp-Procrit.htm#_ednref45. Accessed January 10, 2008
 FDA Briefing Document. May 10, 2007: Oncologic Drugs Advisory Committee. Continuting reassessment of the risks of erythropoiesis-stimulating agents (ESAs) administered for the treatment of anemia associated with cancer chemotherapy. http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4301b2-02-FDA.pdf. Accessed January 11, 2008
 Amgen DA 145 Study. April 19, 2007. http://wwwext.amgen.com/media/media_pr_detail.jsp?year=2007&releaseID=987476. Accessed January 9, 2008
Overgaard J, Hoff C, Sand Hansen H,  et al.  Randomized study of the importance of novel erythropoiesis stimulating protein (Aranesp) for the effect of radiotherapy in patients with primary squamous cell carcinoma of the head and neck (HNSCC): the Danish Head and Neck Cancer Group DAHANCA 10 rand [abstract].  Eur J Cancer Suppl. 2007;5(6):7
Link to Article
Charu V, Belani CP, 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 II trial.  Oncologist. 2007;12(6):727-737
PubMed   |  Link to Article
Debus JHS, Morr H, Mezger J, Sebastian M, Angermund R, Drings P. Epoetin alfa (EPO) and survival in patients with non-resectable NSCLC: interim results. German Medical Sciencehttp://www.egms.de/en/meetings/dkk2006/06dkk257.shtml. Accessed December 17, 2007
Gordon DH, Nichols G, Ben-Jacob A,  et al.  Treating anemia of cancer with darbepoetin alfa administration every 4 weeks: final results from a phase 2, randomized, double-blind, placebo-controlled study in cancer patients not receiving chemotherapy and/or radiotherapy. Presented at: American Society of Hematology; December 9, 2006; Orlando, FL. Abstract 1304
Moebus VLH, Thomssen C, Harbeck N,  et al.  The impact of epoetin-alpha on anemia, red blood cell (RBC) transfusions, and survival in breast cancer patients (pts) treated with dose-dense sequential chemotherapy: mature results of an AGO phase III study (ETC study).  J Clin Oncol. 2007;25(18S):(suppl)  5692007 ASCO Annual Meeting Proceedings Part I
Glaspy J, Smith R, Aapro M,  et al.  Results from a phase III, randomized, double-blind, placebo-controlled study of darbepoetin alfa for the treatment of anemia in patients not receiving chemotherapy or radiotherapy. Paper presented at: Proceedings from the American Association for Cancer Research Annual Meeting; April 14-28, 2007; Los Angeles, CA
Wilkinson PM, Antonopoulos M, Lahousen M, Lind M, Kosmidis P. Epoetin alfa in platinum-treated ovarian cancer patients: results of a multinational, multicentre, randomised trial.  Br J Cancer. 2006;94(7):947-954
PubMed   |  Link to Article
Taylor KB, Ganly P, Charu V,  et al.  Randomized, double-blind, placebo-controlled study of darbepoetin alfa every 3 weeks for the treatment of chemotherapy-induced anemia. Abstract presented at: Blood (ASH Annual Abstract Meeting); December 12, 2005; Atlanta, GA. Abstract 3556
Mystakidou K, Kalaidopoulou O, Katsouda E,  et al.  Evaluation of epoetin supplemented with oral iron in patients with solid malignancies and chronic anemia not receiving anticancer treatment.  Anticancer Res. 2005;25(5):3495-3500
PubMed
Strauss HG, Haensgen G, Dunst J,  et al.  Effects of anemia correction with epoetin beta in patients receiving radiochemotherapy for advanced cervical cancer [published online ahead of print July 21, 2007].  Int J Gynecol Cancer
PubMed
Blohmer J-U, Wurschmidt F, Petry U,  et al.  Results with sequential adjuvant chemo-radiotherapy with vs without epoetin alfa for patients with high-risk cervical cancer: results of a prospective, randomized, open and controlled AGO and NOGGO-intergroup study. Paper presented at: European Cancer Conference; September 21-25, 2003; Copenhagen, Denmark. Abstract 477PD
US Food and Drug Administration.  FDA alert: information on erythropoesis-stimulating agents. http://www.fda.gov/cder/drug/infopage/RHE/default.htm. Accessed January 11, 2008
Altman DG, Bland JM. Interaction revisisted: the difference between two estimates.  BMJ. 2003;326(7382):219
PubMed   |  Link to Article
DerSimonian R, Laird N. Meta-analysis in clinical trials.  Control Clin Trials. 1986;7(3):177-188
PubMed   |  Link to Article
Abels R. Erythropoietin for anaemia in cancer patients.  Eur J Cancer. 1993;29A:(suppl 2)  S2-S8
PubMed   |  Link to Article
Bamias A, Aravantinos G, Kalofonos C,  et al.  Prevention of anemia in patients with solid tumors receiving platinum-based chemotherapy by recombinant human erythropoietin (rHuEpo): a prospective, open label, randomized trial by the Hellenic Cooperative Oncology Group.  Oncology. 2003;64(2):102-110
PubMed   |  Link to Article
Case DC Jr, Bukowski RM, Carey RW,  et al.  Recombinant human erythropoietin therapy for anemic cancer patients on combination chemotherapy.  J Natl Cancer Inst. 1993;85(10):801-806
PubMed   |  Link to Article
Cazzola M, Messinger D, Battistel V,  et al.  Recombinant human erythropoietin in the anemia associated with multiple myeloma or non-Hodgkin's lymphoma: dose finding and identification of predictors of response.  Blood. 1995;86(12):4446-4453
PubMed
Coiffier B, Boogaerts M, Kainz C. Impact of epoetin beta versus standard care on quality of life in patients with malignant disease. Paper presented at: 6th Congress of the European Haematology Association; June 21-24, 2001; Frankfurt, Germany. Abstract 194
Dammacco F, Castoldi G, Rodjer S. Efficacy of epoetin alfa in the treatment of anaemia of multiple myeloma.  Br J Haematol. 2001;113(1):172-179
PubMed   |  Link to Article
Del Mastro L, Venturini M, Lionetto R,  et al.  Randomized phase III trial evaluating the role of erythropoietin in the prevention of chemotherapy-induced anemia.  J Clin Oncol. 1997;15(7):2715-2721
PubMed
Dunphy FR, Harrison BR, Dunleavy TL, Rodriguez JJ, Hilton JG, Boyd JH. Erythropoietin reduces anemia and transfusions: a randomized trial with or without erythropoietin during chemotherapy.  Cancer. 1999;86(7):1362-1367
PubMed   |  Link to Article
Thomas G, Ali S, Hoebers FJ,  et al.  Phase III trial to evaluate the efficacy of maintaining hemoglobin levels above 12.0 g/dL with erythropoietin vs above 10.0 g/dL without erythropoietin in anemic patients receiving concurrent radiation and cisplatin for cervical cancer [published online ahead of print November 26, 2007].  Gynecol Oncol
PubMed
Hedenus M, Adriansson M, San Miguel J,  et al.  Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study.  Br J Haematol. 2003;122(3):394-403
PubMed   |  Link to Article
Henry DH, Abels RI. Recombinant human erythropoietin in the treatment of cancer and chemotherapy-induced anemia: results of double-blind and open-label follow-up studies.  Semin Oncol. 1994;21(2):(suppl 3)  21-28
PubMed
Kotasek D, Steger G, Faught W,  et al.  Darbepoetin alfa administered every 3 weeks alleviates anaemia in patients with solid tumours receiving chemotherapy: results of a double-blind, placebo-controlled, randomised study.  Eur J Cancer. 2003;39(14):2026-2034
PubMed   |  Link to Article
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. 2005;23(25):5960-5972
PubMed   |  Link to Article
Littlewood TJ, Bajetta E, Nortier JW, Vercammen E, Rapoport B. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial.  J Clin Oncol. 2001;19(11):2865-2874
PubMed
Machtay M, Pajak TF, Suntharalingam M,  et al; Radiation Therapy Oncology Group.  Radiotherapy with or without erythropoietin for anemic patients with head and neck cancer: a randomized trial of the radiation therapy oncology group (RTOG 99-03).  Int J Radiat Oncol Biol Phys. 2007;69(4):1008-1017
PubMed   |  Link to Article
Grote T, Yeilding AL, Castillo R,  et al.  Efficacy and safety analysis of epoetin alfa in patients with small-cell lung cancer: a randomized, double-blind, placebo-controlled trial.  J Clin Oncol. 2005;23(36):9377-9386
PubMed   |  Link to Article
Oberhoff C, Neri B, Amadori D,  et al.  Recombinant human erythropoietin in the treatment of chemotherapy-induced anemia and prevention of transfusion requirement associated with solid tumors: a randomized, controlled study.  Ann Oncol. 1998;9(3):255-260
PubMed   |  Link to Article
O'Shaughnessy JA, Vukelja SJ, Holmes FA,  et al.  Feasibility of quantifying the effects of epoetin alfa therapy on cognitive function in women with breast cancer undergoing adjuvant or neoadjuvant chemotherapy.  Clin Breast Cancer. 2005;5(6):439-446
PubMed   |  Link to Article
Osterborg A, Boogaerts MA, Cimino R,  et al.  Recombinant human erythropoietin in transfusion-dependent anemic patients with multiple myeloma and non-Hodgkin's lymphoma: a randomized multicenter study. The European Study Group of Erythropoietin (Epoetin Beta) Treatment in Multiple Myeloma and Non-Hodgkin's Lymphoma.  Blood. 1996;87(7):2675-2682
PubMed
Osterborg A, Brandberg Y, Hedenus M. Impact of epoetin-beta on survival of patients with lymphoproliferative malignancies: long-term follow up of a large randomized study.  Br J Haematol. 2005;129(2):206-209
PubMed   |  Link to Article
US Food and Drug Administration.  Press release: FDA receives new data on risks of anemia drugs consistent with previous data on tumor growth and death. http://www.fda.gov/bbs/topics/NEWS/2008/NEW01769.html. Accessed January 4, 2008
Razzouk BIHM, Hinds PS, Rackoff W, Hord JD. A double-blind, placebo-controlled study of once-weekly epoetin alfa in children with cancer undergoing myelosuppressive chemotherapy. J Clin Oncol. 22:14S. June 5, 2004. Presented at: 40th Annual Meeting of the American Society of Clinical Oncology; June 5-8, 2004; New Orleans, LA. Abstract 8527
Rose ERK, Revicki D, Brown R, Reblando J. Clinical and health status assessments in anemic chronic lymphocytic leukemia (CLL) patients treated with epoetin alfa (EPO).  Blood. 1994;4(10):(suppl 1)  526a
 Savonije J VGC, Van Bochove A, Pinedo H, Giaccone G. Early intervention with epoetin-alfa during platinum-based chemotherapy. J Clin Oncol. 22:14S. June 5, 2004. Presented at: 40th Annual Meeting of the American Society of Clinical Oncology; June 5-8, 2004; New Orleans, LA. Abstract 8111
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. 2003;88(12):1851-1858
PubMed   |  Link to Article
ten Bokkel Huinink WW, de Swart CA, van Toorn DW,  et al.  Controlled multicentre study of the influence of subcutaneous recombinant human erythropoietin on anaemia and transfusion dependency in patients with ovarian carcinoma treated with platinum-based chemotherapy.  Med Oncol. 1998;15(3):174-182
PubMed   |  Link to Article
Thatcher N, De Campos ES, Bell DR,  et al.  Epoetin alpha prevents anaemia and reduces transfusion requirements in patients undergoing primarily platinum-based chemotherapy for small cell lung cancer.  Br J Cancer. 1999;80(3-4):396-402
PubMed   |  Link to Article
Throuvalas N, Antonadou D, Boufi M, Lavey R. Erythropoietin decreases transfusion requirements during radiochemotherapy. Paper presented at: 36th Annual Meeting of the American Society of Clincial Oncology; May 20-24, 2000; New Orleans, LA. Abstract 1558
Vadhan-Raj SSJ, Crane C, Buesos-Ramos CE,  et al.  Randomized, double-blind, placebo-controlled trial of epoetin alfa (Procrit) in patients with rectal and gastric cancer undergoing chemo-radiotherapy (CT/RT) followed by surgery: early termination of the trial due to increased incidence of thrombo-embolic events (TEE). Blood. 104:797a. Presented at: 46th Annual Meeting of the American Sociey of Hematology; December 4-7, 2004; San Diego, CA. Abstract 2915
Witzig TE, Silberstein PT, Loprinzi CL,  et al.  Phase III, randomized, double-blind study of epoetin alfa compared with placebo in anemic patients receiving chemotherapy.  J Clin Oncol. 2005;23(12):2606-2617
PubMed   |  Link to Article
Wright JR, Ung YC, Julian JA,  et al.  Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia.  J Clin Oncol. 2007;25(9):1027-1032
PubMed   |  Link to Article
Cascinu S, Fedeli A, Del Ferro E, Luzi Fedeli S, Catalano G. Recombinant human erythropoietin treatment in cisplatin-associated anemia: a randomized, double-blind trial with placebo.  J Clin Oncol. 1994;12(5):1058-1062
PubMed
Rosenzweig MQ, Bender CM, Lucke JP, Yasko JM, Brufsky AM. The decision to prematurely terminate a trial of R-HuEPO due to thrombotic events.  J Pain Symptom Manage. 2004;27(2):185-190
Link to Article
Welch RS, James RD, Wilkinson PM, Belli F, Cowan RA. Recombinant human erythropoietin and platinum-based chemotherapy in advanced ovarian cancer.  Cancer J Sci Am. 1995;1(4):261-266
US Food and Drug Administration.  Safety of erythropoietin-stimulating agents (ESAs) in oncology. http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4301b2-01-01-Amgen.pdf. Accessed January 11, 2008
 Briefing package for FDA Oncologic Drugs Advisory Committee Meeting: (epotein beta). http://www.fda.gov/ohrms/dockets/ac/04/briefing/4037B2_03_Hoffman-LaRoche-NeoRecorman.pdf. Accessed January 11, 2008
US Food and Drug Administration.  Safety of erythropoietin receptor agonists (ERAs) in patients with cancer. http://www.fda.gov/OHRMS/DOCKETS/AC/04/briefing/4037B2_02_JohnsonJohnson-Procrit.pdf. Accessed January 11, 2008
Henke M, Mattern D, Pepe M,  et al.  Do erythropoietin receptors on cancer cells explain unexpected clinical findings?  J Clin Oncol. 2006;24(29):4708-4713
PubMed   |  Link to Article
Hardee ME, Arcasoy MO, Blackwell KL, Kirkpatrick JP, Dewhirst MW. Erythropoietin biology in cancer.  Clin Cancer Res. 2006;12(2):332-339
PubMed   |  Link to Article
Hardee ME, Rabbani ZN, Arcasoy MO,  et al.  Erythropoietin inhibits apoptosis in breast cancer cells via an Akt-dependent pathway without modulating in vivo chemosensitivity.  Mol Cancer Ther. 2006;5(2):356-361
PubMed   |  Link to Article
Sytkowski AJ. Does erythropoietin have a dark side? epo signaling and cancer cells.  Sci STKE. 2007;2007(395):pe38
PubMed   |  Link to Article
Acs G, Acs P, Beckwith SM,  et al.  Erythropoietin and erythropoietin receptor expression in human cancer.  Cancer Res. 2001;61(9):3561-3565
PubMed
Mohyeldin A, Lu H, Dalgard C,  et al.  Erythropoietin signaling promotes invasiveness of human head and neck squamous cell carcinoma.  Neoplasia. 2005;7(5):537-543
PubMed   |  Link to Article
Lai SY, Childs EE, Xi S,  et al.  Erythropoietin-mediated activation of JAK-STAT signaling contributes to cellular invasion in head and neck squamous cell carcinoma.  Oncogene. 2005;24(27):4442-4449
PubMed   |  Link to Article
Kumar SM, Yu H, Fong D, Acs G, Xu X. Erythropoietin activates the phosphoinositide 3-kinase/Akt pathway in human melanoma cells.  Melanoma Res. 2006;16(4):275-283
PubMed   |  Link to Article
Acs G, Chen M, Xu X, Acs P, Verma A, Koch CJ. Autocrine erythropoietin signaling inhibits hypoxia-induced apoptosis in human breast carcinoma cells.  Cancer Lett. 2004;214(2):243-251
PubMed   |  Link to Article
Kumar SM, Acs G, Fang D, Herlyn M, Elder DE, Xu X. Functional erythropoietin autocrine loop in melanoma.  Am J Pathol. 2005;166(3):823-830
PubMed   |  Link to Article
Lai SY, Grandis JR. Understanding the presence and function of erythropoietin receptors on cancer cells.  J Clin Oncol. 2006;24(29):4675-4676
PubMed   |  Link to Article
Besarab A, Bolton WK, Browne JK,  et al.  The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin.  N Engl J Med. 1998;339(9):584-590
PubMed   |  Link to Article
Singh AK, Szczech L, Tang KL,  et al.  Correction of anemia with epoetin alfa in chronic kidney disease.  N Engl J Med. 2006;355(20):2085-2098
PubMed   |  Link to Article
Rizzo JD, Somerfield MR, Hagerty KL,  et al.  Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update.  J Clin Oncol. 2008;26(1):132-149
PubMed   |  Link to Article
 Aranesp [package insert]. Thousand Oaks, CA: Amgen Inc; 2007. http://www.aranesp.com/pdf/aranesp_PI.pdf. Accessed January 11, 2008
 Epogen [package insert]. Thousand Oaks, CA: Amgen Inc; 2007. http://www.epogen.com/pdf/epogen_pi.pdf. Accessed January 11, 2008
US Centers for Medicare & Medicaid Services.  Coverage decision memorandum for the use of erythropoiesis stimulating agents in cancer and related neoplastic conditions. July 30, 2007. http://www.cms.hhs.gov/scripts/ctredirector.dll/.pdf?@_CPR0a0a043a07d1.YE_Qa3N_cvb. Accessed September 7, 2007
Pollack A. Amgen finds anemia drug holds risks in cancer use. New York Times. January 26, 2007; Business section

Figures

Place holder to copy figure label and caption
Figure 1. Search Strategy and Selection of Phase 3 Trials That Reported Survival and Venous Thromboembolism Outcomes
Graphic Jump Location

FDA indicates US Food and Drug Administration; ODAC, Oncologic Drug Advisory Committee.

aOf the 13 studies added for this meta-analysis for survival, 12 studies were reported between April 2005 and January 17, 2008. A 13th study was not included in the 2006 Cochrane Review,24 because it was published only as an abstract.

Place holder to copy figure label and caption
Figure 2. Meta-analysis of Overall Mortality Rates for Phase 3 Oncology Trials With ESAs vs Placebo or Control, Comparing Anemia of Cancer and Treatment-Related Anemia Trials
Graphic Jump Location

ESAs indicate erythropoiesis-stimulating agents; CI, confidence interval; NR, not reported. Weights are from random-effects analysis. P = .11 for overall is the P value for the test for I2 (the variation in ESA attributable to heterogeneity). ESA-associated mortality (treatment effect on outcomes), P = .03.

Place holder to copy figure label and caption
Figure 3. Meta-analysis of VTE Rates in Phase 3 Trials of ESAs vs Placebo or Control
Graphic Jump Location

VTE indicates venous thromboembolism; ESA, erythropoiesis-stimulating agent; CI, confidence interval. Weights are from random-effects analysis. Some trials are represented more than once due to having more than 1 group within the trial. Each ESA-containing group in these trials evaluated different doses of ESAs in comparison with controls. The point estimates and CIs for the bottom 3 trials could not be calculated because no events were reported in these studies.

Tables

Table Graphic Jump LocationTable 1. Characteristics of the 51 Phase 3 Trials (13 611 Patients) Included in the Survival Meta-analysis and Analyses for Both Survival and VTE
Table Graphic Jump LocationTable 2. Characteristics of the Phase 3 Trials Included Only in Venous Thromboembolism Analysis
Table Graphic Jump LocationTable 3. Summary of 8 Trials That Individually Demonstrate Increased Mortality and/or Tumor Progression Among Patients Treated With ESAa
Table Graphic Jump LocationTable 4. Systematic Reviews Evaluating VTE and Mortality Rates with Epoetin Alfa, Epoetin Beta, or Darbepoetin vs Placebo/Standard of Care for Treatment for Anemia in Patients With Cancer

References

Littlewood TJ, Cella D, Nortier JW. Erythropoietin improves quality of life.  Lancet Oncol. 2002;3(8):459-460
PubMed   |  Link to Article
Vansteenkiste J, Pirker R, Massuti B,  et al.  Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy.  J Natl Cancer Inst. 2002;94(16):1211-1220
PubMed   |  Link to Article
Henry DH, Brooks BJ Jr, Case DC Jr,  et al.  Recombinant human erythropoietin therapy for anemic cancer patients receiving cisplatin chemotherapy.  Cancer J Sci Am. 1995;1(4):252-260
PubMed
Steinbrook R. Erythropoietin, the FDA, and oncology.  N Engl J Med. 2007;356(24):2448-2451
PubMed   |  Link to Article
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. 2003;362(9392):1255-1260
PubMed   |  Link to Article
Leyland-Jones B. Breast cancer trial with erythropoietin terminated unexpectedly.  Lancet Oncol. 2003;4(8):459-460
PubMed   |  Link to Article
Wilson J, Yao G, Raftery J,  et al.  A systematic review and economic evaluation of epoetin alfa, epoetin beta and darbepoetin alfa in anaemia associated with cancer, especially that attributable to cancer treatment.  Health Technol Assess. 2007;11(13):1-220
PubMed
Seidenfeld JPM, Bohlius J, Weingart O,  et al.  Comparative effectiveness of epoetin and darbepoetin for managing anemia in patients undergoing cancer treatment. Rockville, MD: Agency for Healthcare Research and Quality; 2006. Comparative Effectiveness Review No 3. http://www.effectivehealthcare.ahrq.gov/reports/final.cfm. Accessed January 11, 2008
Bohlius JWJ, Seidenfeld J, Piper M,  et al.  Erythropoietin or darbepoetin for patients with cancer.  Cochrane Database of Syst Rev. 2006;(3):CD003407doi:10.1002/14651858.CD003407.pub4
Bohlius J, Langensiepen S, Schwarzer G,  et al.  Recombinant human erythropoietin and overall survival in cancer patients: results of a comprehensive meta-analysis.  J Natl Cancer Inst. 2005;97(7):489-498
Link to Article
 FDA Briefing Document: Safety Concerns Associated with Aranesp (darbepoetin alfa) Amgen, Inc. and Procrit (epoetin alfa) Ortho Biotech, L.P., for the Treatment of Anemia Associated with Cancer Chemotherapy: Hearings Before the SubCommittee on Oncologic Drugs Advisory Committee, Center for Drug Evaluation and Research. http://www.fda.gov/ohrms/dockets/ac/04/briefing/4037B2_04_FDA-Aranesp-Procrit.htm#_ednref45. Accessed January 10, 2008
 FDA Briefing Document. May 10, 2007: Oncologic Drugs Advisory Committee. Continuting reassessment of the risks of erythropoiesis-stimulating agents (ESAs) administered for the treatment of anemia associated with cancer chemotherapy. http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4301b2-02-FDA.pdf. Accessed January 11, 2008
 Amgen DA 145 Study. April 19, 2007. http://wwwext.amgen.com/media/media_pr_detail.jsp?year=2007&releaseID=987476. Accessed January 9, 2008
Overgaard J, Hoff C, Sand Hansen H,  et al.  Randomized study of the importance of novel erythropoiesis stimulating protein (Aranesp) for the effect of radiotherapy in patients with primary squamous cell carcinoma of the head and neck (HNSCC): the Danish Head and Neck Cancer Group DAHANCA 10 rand [abstract].  Eur J Cancer Suppl. 2007;5(6):7
Link to Article
Charu V, Belani CP, 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 II trial.  Oncologist. 2007;12(6):727-737
PubMed   |  Link to Article
Debus JHS, Morr H, Mezger J, Sebastian M, Angermund R, Drings P. Epoetin alfa (EPO) and survival in patients with non-resectable NSCLC: interim results. German Medical Sciencehttp://www.egms.de/en/meetings/dkk2006/06dkk257.shtml. Accessed December 17, 2007
Gordon DH, Nichols G, Ben-Jacob A,  et al.  Treating anemia of cancer with darbepoetin alfa administration every 4 weeks: final results from a phase 2, randomized, double-blind, placebo-controlled study in cancer patients not receiving chemotherapy and/or radiotherapy. Presented at: American Society of Hematology; December 9, 2006; Orlando, FL. Abstract 1304
Moebus VLH, Thomssen C, Harbeck N,  et al.  The impact of epoetin-alpha on anemia, red blood cell (RBC) transfusions, and survival in breast cancer patients (pts) treated with dose-dense sequential chemotherapy: mature results of an AGO phase III study (ETC study).  J Clin Oncol. 2007;25(18S):(suppl)  5692007 ASCO Annual Meeting Proceedings Part I
Glaspy J, Smith R, Aapro M,  et al.  Results from a phase III, randomized, double-blind, placebo-controlled study of darbepoetin alfa for the treatment of anemia in patients not receiving chemotherapy or radiotherapy. Paper presented at: Proceedings from the American Association for Cancer Research Annual Meeting; April 14-28, 2007; Los Angeles, CA
Wilkinson PM, Antonopoulos M, Lahousen M, Lind M, Kosmidis P. Epoetin alfa in platinum-treated ovarian cancer patients: results of a multinational, multicentre, randomised trial.  Br J Cancer. 2006;94(7):947-954
PubMed   |  Link to Article
Taylor KB, Ganly P, Charu V,  et al.  Randomized, double-blind, placebo-controlled study of darbepoetin alfa every 3 weeks for the treatment of chemotherapy-induced anemia. Abstract presented at: Blood (ASH Annual Abstract Meeting); December 12, 2005; Atlanta, GA. Abstract 3556
Mystakidou K, Kalaidopoulou O, Katsouda E,  et al.  Evaluation of epoetin supplemented with oral iron in patients with solid malignancies and chronic anemia not receiving anticancer treatment.  Anticancer Res. 2005;25(5):3495-3500
PubMed
Strauss HG, Haensgen G, Dunst J,  et al.  Effects of anemia correction with epoetin beta in patients receiving radiochemotherapy for advanced cervical cancer [published online ahead of print July 21, 2007].  Int J Gynecol Cancer
PubMed
Blohmer J-U, Wurschmidt F, Petry U,  et al.  Results with sequential adjuvant chemo-radiotherapy with vs without epoetin alfa for patients with high-risk cervical cancer: results of a prospective, randomized, open and controlled AGO and NOGGO-intergroup study. Paper presented at: European Cancer Conference; September 21-25, 2003; Copenhagen, Denmark. Abstract 477PD
US Food and Drug Administration.  FDA alert: information on erythropoesis-stimulating agents. http://www.fda.gov/cder/drug/infopage/RHE/default.htm. Accessed January 11, 2008
Altman DG, Bland JM. Interaction revisisted: the difference between two estimates.  BMJ. 2003;326(7382):219
PubMed   |  Link to Article
DerSimonian R, Laird N. Meta-analysis in clinical trials.  Control Clin Trials. 1986;7(3):177-188
PubMed   |  Link to Article
Abels R. Erythropoietin for anaemia in cancer patients.  Eur J Cancer. 1993;29A:(suppl 2)  S2-S8
PubMed   |  Link to Article
Bamias A, Aravantinos G, Kalofonos C,  et al.  Prevention of anemia in patients with solid tumors receiving platinum-based chemotherapy by recombinant human erythropoietin (rHuEpo): a prospective, open label, randomized trial by the Hellenic Cooperative Oncology Group.  Oncology. 2003;64(2):102-110
PubMed   |  Link to Article
Case DC Jr, Bukowski RM, Carey RW,  et al.  Recombinant human erythropoietin therapy for anemic cancer patients on combination chemotherapy.  J Natl Cancer Inst. 1993;85(10):801-806
PubMed   |  Link to Article
Cazzola M, Messinger D, Battistel V,  et al.  Recombinant human erythropoietin in the anemia associated with multiple myeloma or non-Hodgkin's lymphoma: dose finding and identification of predictors of response.  Blood. 1995;86(12):4446-4453
PubMed
Coiffier B, Boogaerts M, Kainz C. Impact of epoetin beta versus standard care on quality of life in patients with malignant disease. Paper presented at: 6th Congress of the European Haematology Association; June 21-24, 2001; Frankfurt, Germany. Abstract 194
Dammacco F, Castoldi G, Rodjer S. Efficacy of epoetin alfa in the treatment of anaemia of multiple myeloma.  Br J Haematol. 2001;113(1):172-179
PubMed   |  Link to Article
Del Mastro L, Venturini M, Lionetto R,  et al.  Randomized phase III trial evaluating the role of erythropoietin in the prevention of chemotherapy-induced anemia.  J Clin Oncol. 1997;15(7):2715-2721
PubMed
Dunphy FR, Harrison BR, Dunleavy TL, Rodriguez JJ, Hilton JG, Boyd JH. Erythropoietin reduces anemia and transfusions: a randomized trial with or without erythropoietin during chemotherapy.  Cancer. 1999;86(7):1362-1367
PubMed   |  Link to Article
Thomas G, Ali S, Hoebers FJ,  et al.  Phase III trial to evaluate the efficacy of maintaining hemoglobin levels above 12.0 g/dL with erythropoietin vs above 10.0 g/dL without erythropoietin in anemic patients receiving concurrent radiation and cisplatin for cervical cancer [published online ahead of print November 26, 2007].  Gynecol Oncol
PubMed
Hedenus M, Adriansson M, San Miguel J,  et al.  Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study.  Br J Haematol. 2003;122(3):394-403
PubMed   |  Link to Article
Henry DH, Abels RI. Recombinant human erythropoietin in the treatment of cancer and chemotherapy-induced anemia: results of double-blind and open-label follow-up studies.  Semin Oncol. 1994;21(2):(suppl 3)  21-28
PubMed
Kotasek D, Steger G, Faught W,  et al.  Darbepoetin alfa administered every 3 weeks alleviates anaemia in patients with solid tumours receiving chemotherapy: results of a double-blind, placebo-controlled, randomised study.  Eur J Cancer. 2003;39(14):2026-2034
PubMed   |  Link to Article
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. 2005;23(25):5960-5972
PubMed   |  Link to Article
Littlewood TJ, Bajetta E, Nortier JW, Vercammen E, Rapoport B. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial.  J Clin Oncol. 2001;19(11):2865-2874
PubMed
Machtay M, Pajak TF, Suntharalingam M,  et al; Radiation Therapy Oncology Group.  Radiotherapy with or without erythropoietin for anemic patients with head and neck cancer: a randomized trial of the radiation therapy oncology group (RTOG 99-03).  Int J Radiat Oncol Biol Phys. 2007;69(4):1008-1017
PubMed   |  Link to Article
Grote T, Yeilding AL, Castillo R,  et al.  Efficacy and safety analysis of epoetin alfa in patients with small-cell lung cancer: a randomized, double-blind, placebo-controlled trial.  J Clin Oncol. 2005;23(36):9377-9386
PubMed   |  Link to Article
Oberhoff C, Neri B, Amadori D,  et al.  Recombinant human erythropoietin in the treatment of chemotherapy-induced anemia and prevention of transfusion requirement associated with solid tumors: a randomized, controlled study.  Ann Oncol. 1998;9(3):255-260
PubMed   |  Link to Article
O'Shaughnessy JA, Vukelja SJ, Holmes FA,  et al.  Feasibility of quantifying the effects of epoetin alfa therapy on cognitive function in women with breast cancer undergoing adjuvant or neoadjuvant chemotherapy.  Clin Breast Cancer. 2005;5(6):439-446
PubMed   |  Link to Article
Osterborg A, Boogaerts MA, Cimino R,  et al.  Recombinant human erythropoietin in transfusion-dependent anemic patients with multiple myeloma and non-Hodgkin's lymphoma: a randomized multicenter study. The European Study Group of Erythropoietin (Epoetin Beta) Treatment in Multiple Myeloma and Non-Hodgkin's Lymphoma.  Blood. 1996;87(7):2675-2682
PubMed
Osterborg A, Brandberg Y, Hedenus M. Impact of epoetin-beta on survival of patients with lymphoproliferative malignancies: long-term follow up of a large randomized study.  Br J Haematol. 2005;129(2):206-209
PubMed   |  Link to Article
US Food and Drug Administration.  Press release: FDA receives new data on risks of anemia drugs consistent with previous data on tumor growth and death. http://www.fda.gov/bbs/topics/NEWS/2008/NEW01769.html. Accessed January 4, 2008
Razzouk BIHM, Hinds PS, Rackoff W, Hord JD. A double-blind, placebo-controlled study of once-weekly epoetin alfa in children with cancer undergoing myelosuppressive chemotherapy. J Clin Oncol. 22:14S. June 5, 2004. Presented at: 40th Annual Meeting of the American Society of Clinical Oncology; June 5-8, 2004; New Orleans, LA. Abstract 8527
Rose ERK, Revicki D, Brown R, Reblando J. Clinical and health status assessments in anemic chronic lymphocytic leukemia (CLL) patients treated with epoetin alfa (EPO).  Blood. 1994;4(10):(suppl 1)  526a
 Savonije J VGC, Van Bochove A, Pinedo H, Giaccone G. Early intervention with epoetin-alfa during platinum-based chemotherapy. J Clin Oncol. 22:14S. June 5, 2004. Presented at: 40th Annual Meeting of the American Society of Clinical Oncology; June 5-8, 2004; New Orleans, LA. Abstract 8111
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. 2003;88(12):1851-1858
PubMed   |  Link to Article
ten Bokkel Huinink WW, de Swart CA, van Toorn DW,  et al.  Controlled multicentre study of the influence of subcutaneous recombinant human erythropoietin on anaemia and transfusion dependency in patients with ovarian carcinoma treated with platinum-based chemotherapy.  Med Oncol. 1998;15(3):174-182
PubMed   |  Link to Article
Thatcher N, De Campos ES, Bell DR,  et al.  Epoetin alpha prevents anaemia and reduces transfusion requirements in patients undergoing primarily platinum-based chemotherapy for small cell lung cancer.  Br J Cancer. 1999;80(3-4):396-402
PubMed   |  Link to Article
Throuvalas N, Antonadou D, Boufi M, Lavey R. Erythropoietin decreases transfusion requirements during radiochemotherapy. Paper presented at: 36th Annual Meeting of the American Society of Clincial Oncology; May 20-24, 2000; New Orleans, LA. Abstract 1558
Vadhan-Raj SSJ, Crane C, Buesos-Ramos CE,  et al.  Randomized, double-blind, placebo-controlled trial of epoetin alfa (Procrit) in patients with rectal and gastric cancer undergoing chemo-radiotherapy (CT/RT) followed by surgery: early termination of the trial due to increased incidence of thrombo-embolic events (TEE). Blood. 104:797a. Presented at: 46th Annual Meeting of the American Sociey of Hematology; December 4-7, 2004; San Diego, CA. Abstract 2915
Witzig TE, Silberstein PT, Loprinzi CL,  et al.  Phase III, randomized, double-blind study of epoetin alfa compared with placebo in anemic patients receiving chemotherapy.  J Clin Oncol. 2005;23(12):2606-2617
PubMed   |  Link to Article
Wright JR, Ung YC, Julian JA,  et al.  Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia.  J Clin Oncol. 2007;25(9):1027-1032
PubMed   |  Link to Article
Cascinu S, Fedeli A, Del Ferro E, Luzi Fedeli S, Catalano G. Recombinant human erythropoietin treatment in cisplatin-associated anemia: a randomized, double-blind trial with placebo.  J Clin Oncol. 1994;12(5):1058-1062
PubMed
Rosenzweig MQ, Bender CM, Lucke JP, Yasko JM, Brufsky AM. The decision to prematurely terminate a trial of R-HuEPO due to thrombotic events.  J Pain Symptom Manage. 2004;27(2):185-190
Link to Article
Welch RS, James RD, Wilkinson PM, Belli F, Cowan RA. Recombinant human erythropoietin and platinum-based chemotherapy in advanced ovarian cancer.  Cancer J Sci Am. 1995;1(4):261-266
US Food and Drug Administration.  Safety of erythropoietin-stimulating agents (ESAs) in oncology. http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4301b2-01-01-Amgen.pdf. Accessed January 11, 2008
 Briefing package for FDA Oncologic Drugs Advisory Committee Meeting: (epotein beta). http://www.fda.gov/ohrms/dockets/ac/04/briefing/4037B2_03_Hoffman-LaRoche-NeoRecorman.pdf. Accessed January 11, 2008
US Food and Drug Administration.  Safety of erythropoietin receptor agonists (ERAs) in patients with cancer. http://www.fda.gov/OHRMS/DOCKETS/AC/04/briefing/4037B2_02_JohnsonJohnson-Procrit.pdf. Accessed January 11, 2008
Henke M, Mattern D, Pepe M,  et al.  Do erythropoietin receptors on cancer cells explain unexpected clinical findings?  J Clin Oncol. 2006;24(29):4708-4713
PubMed   |  Link to Article
Hardee ME, Arcasoy MO, Blackwell KL, Kirkpatrick JP, Dewhirst MW. Erythropoietin biology in cancer.  Clin Cancer Res. 2006;12(2):332-339
PubMed   |  Link to Article
Hardee ME, Rabbani ZN, Arcasoy MO,  et al.  Erythropoietin inhibits apoptosis in breast cancer cells via an Akt-dependent pathway without modulating in vivo chemosensitivity.  Mol Cancer Ther. 2006;5(2):356-361
PubMed   |  Link to Article
Sytkowski AJ. Does erythropoietin have a dark side? epo signaling and cancer cells.  Sci STKE. 2007;2007(395):pe38
PubMed   |  Link to Article
Acs G, Acs P, Beckwith SM,  et al.  Erythropoietin and erythropoietin receptor expression in human cancer.  Cancer Res. 2001;61(9):3561-3565
PubMed
Mohyeldin A, Lu H, Dalgard C,  et al.  Erythropoietin signaling promotes invasiveness of human head and neck squamous cell carcinoma.  Neoplasia. 2005;7(5):537-543
PubMed   |  Link to Article
Lai SY, Childs EE, Xi S,  et al.  Erythropoietin-mediated activation of JAK-STAT signaling contributes to cellular invasion in head and neck squamous cell carcinoma.  Oncogene. 2005;24(27):4442-4449
PubMed   |  Link to Article
Kumar SM, Yu H, Fong D, Acs G, Xu X. Erythropoietin activates the phosphoinositide 3-kinase/Akt pathway in human melanoma cells.  Melanoma Res. 2006;16(4):275-283
PubMed   |  Link to Article
Acs G, Chen M, Xu X, Acs P, Verma A, Koch CJ. Autocrine erythropoietin signaling inhibits hypoxia-induced apoptosis in human breast carcinoma cells.  Cancer Lett. 2004;214(2):243-251
PubMed   |  Link to Article
Kumar SM, Acs G, Fang D, Herlyn M, Elder DE, Xu X. Functional erythropoietin autocrine loop in melanoma.  Am J Pathol. 2005;166(3):823-830
PubMed   |  Link to Article
Lai SY, Grandis JR. Understanding the presence and function of erythropoietin receptors on cancer cells.  J Clin Oncol. 2006;24(29):4675-4676
PubMed   |  Link to Article
Besarab A, Bolton WK, Browne JK,  et al.  The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin.  N Engl J Med. 1998;339(9):584-590
PubMed   |  Link to Article
Singh AK, Szczech L, Tang KL,  et al.  Correction of anemia with epoetin alfa in chronic kidney disease.  N Engl J Med. 2006;355(20):2085-2098
PubMed   |  Link to Article
Rizzo JD, Somerfield MR, Hagerty KL,  et al.  Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update.  J Clin Oncol. 2008;26(1):132-149
PubMed   |  Link to Article
 Aranesp [package insert]. Thousand Oaks, CA: Amgen Inc; 2007. http://www.aranesp.com/pdf/aranesp_PI.pdf. Accessed January 11, 2008
 Epogen [package insert]. Thousand Oaks, CA: Amgen Inc; 2007. http://www.epogen.com/pdf/epogen_pi.pdf. Accessed January 11, 2008
US Centers for Medicare & Medicaid Services.  Coverage decision memorandum for the use of erythropoiesis stimulating agents in cancer and related neoplastic conditions. July 30, 2007. http://www.cms.hhs.gov/scripts/ctredirector.dll/.pdf?@_CPR0a0a043a07d1.YE_Qa3N_cvb. Accessed September 7, 2007
Pollack A. Amgen finds anemia drug holds risks in cancer use. New York Times. January 26, 2007; Business section
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