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Venous Thromboembolism and Mortality Associated With Recombinant Erythropoietin and Darbepoetin Administration for the Treatment of Cancer-Associated Anemia
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
JAMA. 2008;299(8):914-924.
ABSTRACT
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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.
INTRODUCTION
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.7-10 Two overviews found increased VTE risks associated with ESAs, but none identified mortality risks.8-10 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.9-10,12-24
METHODS
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.11-13,16, 19, 25 Our review includes both independent and industry-sponsored studies.
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Figure 1. Search Strategy and Selection of Phase 3 Trials That Reported Survival and Venous Thromboembolism Outcomes
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.
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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.
RESULTS
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).12-24 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, 11-24,28-61 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).
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Table 1. Characteristics of the 51 Phase 3 Trials (13 611 Patients) Included in the Survival Meta-analysis and Analyses for Both Survival and VTE
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Table 2. Characteristics of the Phase 3 Trials Included Only in Venous Thromboembolism Analysis
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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.
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Table 3. Summary of 8 Trials That Individually Demonstrate Increased Mortality and/or Tumor Progression Among Patients Treated With ESAa
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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  2 = 1.99; I2 = 21.1%; P = .16).
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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
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.
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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.
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Figure 3. Meta-analysis of VTE Rates in Phase 3 Trials of ESAs vs Placebo or Control
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.
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COMMENT
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).7-11,62-64 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
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Table 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
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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.69-72 Erythropoietin-mediated functions may result from autocrine/paracrine signaling or recruitment of both endogenous and exogenous erythropoietin by the tumor.73-75 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.7-9 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, 78-82 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.
AUTHOR INFORMATION
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{at}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.
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).
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