REVIEW

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
HE 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
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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.
JAMA. 2008;299(8):914-924 www.jama.com

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 pa-

tients with breast cancer who were treated with ESA and chemotherapy, as well as patients with head and neck cancer who received radiotherapy. PubAuthor Affiliations are listed at the end of this article. 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).

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VENOUS THROMBOEMBOLISM AND MORTALITY FOR CANCER-ASSOCIATED ANEMIA

lished 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

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 industrysponsored studies.
Main Outcome Measures

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

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

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

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,

Figure 1. Search Strategy and Selection of Phase 3 Trials That Reported Survival and Venous Thromboembolism Outcomes
Survival Outcomes 42 Potentially relevant trials published between January 1985 and April 2005, identified in a Cochrane review 9, 10 4 Excluded 1 Included patients with myelodysplastic syndrome 3 Mortality not reported 13 Trials not included in the Cochrane review identifieda Venous Thromboembolism Outcomes 35 Potentially relevant trials published between January 1985 and April 2005, identified in a Cochrane review 9, 10 5 Trials reported between May 2005 and January 17, 2008, identified

2 Excluded (included patients with myelodysplastic syndrome)

51 Trials (13 611 patients) included in analysis 31 Published trials 12 Abstracts 8 FDA/ODAC trials

38 Trials (8172 patients) included in analysis 23 Published trials 8 Abstracts 7 FDA/ODAC trials

FDA indicates US Food and Drug Administration; ODAC, Oncologic Drug Advisory Committee. a Of 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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VENOUS THROMBOEMBOLISM AND MORTALITY FOR CANCER-ASSOCIATED ANEMIA

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
Total No. of Randomized Patients (Treated With ESA Control) 413 (213 200)

Source Abels,28 1993 a

Study Drug Epoetin alfa

Duration of Treatment 8 wk

Concomitant Treatment None

Cancer Types Included Any excluding primary myeloid malignancy or acute leukemia Ovarian, NSCLC, SCLC, other Cervical cancer Various solid and nonmyeloid tumors MM, NHL Nonmeyeloid malignancies Various solid tumors and lymphomas SCLC Nonmyeloid malignancies MM Breast cancer Head and neck, NSCLC Limited disease SCLC Stages I-IV breast cancer Head and neck, stage IV NSCLC Nonmyeloid malignancy Cervix carcinoma

Bamias et al,29 2003 a Blohmer et al,24 2003 (AGO/NOGG) Case et al,30 1993 a Cazzola et al,31 1995 Charu et al,15 2007 a Coiffier et al,32 2001 Amgen DA 145,13 2007 a Taylor et al,21 2005 (DA 232) Dammacco et al,33 2001 a Del Mastro et al,34 1997 Dunphy et al, 1999 EPO-CAN-15,11 2004 a EPO-CAN-17,12 2007 a EPO-GBR-7,12 2007 a Debus et al,16 2007 (EPO-GER-22) a Glaspy et al,19 2007 (Amgen 103) Thomas et al,36 2007 (GOG-191) a
35

Epoetin alfa Epoetin alfa Epoetin alfa Epoetin beta Darbepoetin Epoetin beta Darbepoetin Darbepoetin Epoetin alfa Epoetin b Epoetin b Epoetin alfa Epoetin alfa Epoetin alfa Epoetin alfa Darbepoetin Epoetin alfa

144 (72 256 157 (81 146 (117 285 (226 262 (133 583 391 145 (69 62 (31 30 (15 106 (53 354 300 (151 389 985 113 (58

72)

12 wk 8 wk

Chemotherapy Chemoradiotherapy Chemotherapy Chemotherapy None Chemotherapy Chemotherapy Chemotherapy Previous chemotherapy Chemotherapy Chemotherapy Chemoradiotherapy Chemotherapy Radiation therapy Chemoradiotherapy None Chemoradiotherapy

76) 29) 59) 129) 12 wk

12 wk 8 wk 9 optional wk 12 wk 24 wk 15 wk

76) 31) 15) 53) 149)

12 wk 14 wk 6 wk 12-24 wk 28 wk max Terminated early for poor accrual Terminated early for poor accrual 16 wk

55)

Not reported, closed early because of concerns with VTE 17 wk 12 wk 7-9 wk 12 wk

Gordon et al,17 2006 a Hedenus et al,37 2003 Henke et al,5 2003 a Henry and Abels,38 1994 a

Darbepoetin Darbepoetin Epoetin beta Epoetin alfa

220 349 (176 351 (180 132 (67 173) 171) 65)

None Chemotherapy Radiation therapy Chemotherapy

Nonmyeloid malignancies Lymphoma, HD, NHL, MM Advanced (stage III, IV) head and neck cancer Any excluding primary myeloid malignancy or acute leukemia Ovarian Mixed Breast, gynecologic, gastrointestinal, lung, other Metastatic breast cancer Various solid and nonmyeloid hematologic tumors Head and neck nonmetastatic, not resected

INT-1,11 2004 a INT-3,11 2004 a Kotasek et al,39 2003

Epoetin alfa Epoetin alfa Darbepoetin

244 (164 200 (135 259 (208

80) 65) 51)

1 mo after chemotherapy 12 wk 12 wk

Not reported Not reported Chemotherapy

Leyland-Jones et al,40 2005 (INT-76) a Littlewood et al,41 2001 a Machtay et al,42 2007 (RTOG 99-03) a

Epoetin alfa Epoetin alfa Epoetin alfa

939 (469 375 (251 148 (74

470) 124) 74)

52 wk 28 wk 9-10 wk

Chemotherapy Chemotherapy Radiation therapy, advanced stages received chemoradiotherapy Chemotherapy None Chemotherapy

Moebus et al,18 2007 Mystakidou et al,22 2005 Grote et al,43 2005 (N93-004) a

Epoetin alfa Epoetin alfa Epoetin alfa

658 100 224 (109 115)

24 wk 24 wk Not reported, terminated early, assumed to be 12 wk 12 wk

Adjuvant breast cancer Solid malignancies SCLC, limited and extended disease

Oberhoff et al,44 1998

Epoetin beta

227 (117

110)

Chemotherapy

Various solid based tumors

(continued)

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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 (cont)
Total No. of Randomized Patients (Treated With ESA Control) 100 (51 49) 121 (82 39) 349 522

Source OShaughnessy et al,45 2005 Osterborg et al,46 1996 a Osterborg et al,47 2005 a Overgaard et al,14 2007 (DAHANCA 10) P-174,11 2004 a PREPARE,12,48 2008 Razzouk et al,49 2004 a Rose et al,50 1994 a Savonije et al,51 2004 a Smith et al,52 2003 a

Study Drug Epoetin alfa Epoetin beta Epoeitn beta Darbepoetin

Epoetin alfa Darbepoetin Epoetin alfa Epoetin alfa Epoetin alfa Darbepoetin

45 (33 12) 733 (377 356) 224 (113 111) 221 (142 79) 315 (211 104) 86 (64 22)

Duration of Treatment 12 wk 24 wk 16 wk Terminated early, due to futility of interim analysis 12 wk Not reported 16 wk 12 wk 14 wk 12 wk

Concomitant Treatment Chemotherapy Chemotherapy Chemotherapy Radiation therapy

Cancer Types Included Breast cancer, stages I-IIIB MM, NHL NHL, CLL, MM Head and neck squamous cell carcinoma CLL Breast cancer Solid tumors, HD, NHL, all CLL Solid tumors Genitourinary, breast, gastrointestinal, lymphoma, myeloma, chronic lymphocytic lymphoma, NHL Advanced cervical cancer Ovarian carcinoma SCLC SCLC Cervix and bladder carcinoma Gastric or rectal cancer combined SCLC and NSCLC Ovarian cancer Lung, breast, other

Not reported Chemotherapy Chemotherapy None Chemotherapy None

Strauss et al,23 2007 ten Bokkel Huinink et al,53 1998 a Thatcher et al,54 1999 a Thatcher et al,54 1999 a Throuvalas et al,55 2000 a Vadhan-Raj et al,56 2004 a

Epoetin beta Epoetin beta Epoetin alfa Epoetin alfa Epoetin b Epoetin alfa

74 (34 122 (88 64 (42 66 (44 55 (28 60 (29

40) 34) 22) 22) 27) 31)

12 wk 24 wk 26 wk 26 wk 6 wk 16 wk, early termination due to increased TEE 12 wk 28 wk 16 wk

Chemoradiotherapy Chemotherapy Chemotherapy Chemotherapy Chemoradiotherapy Chemoradiotherapy

Vansteenkiste et al,2 2002 a Wilkinson et al,20 2006 a Witzig et al,57 2005 a

Darbepoetin Epoetin alfa Epoetin alfa

320 173 (114 344 (174

59) 170)

Wright et al,58 2007 (EPO-CAN-20) a

Epoetin alfa

70 (33

37)

12 wk

Chemotherapy Chemotherapy Chemotherapy, some radiation therapy Palliative radiotherapy

NSCLC

Abbreviations: CLL, chronic lymphocytic lymphoma; ESA, erythropoiesis-stimulating agent; HD, Hodgkin disease; MM, multiple myeloma; NHL, non-Hodgkin lymphoma; NSCLC, non small cell lung cancer; SCLC, small cell lung cancer; TEE, thromboembolic event; VTE, venous thromboembolism. a Included in both mortality and VTE analyses. b Studies did not specify whether epoetin alfa or epoetin beta were administered.

(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 pa-

tients. 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). 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 nonsmall 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).36,48 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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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 can-

cer 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 therapyassociated anemia (treatmentrelated 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, 0.991.19). There was no significant hetero-

geneity 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). 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. 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.

Table 2. Characteristics of the Phase 3 Trials Included Only in Venous Thromboembolism Analysis
Total No. of Randomized Patients Duration of (Treated With Treatment, Concomitant Cancer Types Study Drug ESA Control) wk Treatment Included Epoetin alfa 100 9 Chemotherapy Various solid tumors Epoetin alfa 25 (19 6) 12 Chemotherapy Metastatic breast cancer Epoetin alfa 30 24 Chemotherapy Ovarian carcinoma

Source Cascinu et al,59 1994 Rosenzweig et al,60 2004 Welch et al,61 1995

Abbreviation: ESA, erythropoiesis-stimulating agent.

Table 3. Summary of 8 Trials That Individually Demonstrate Increased Mortality and/or Tumor Progression Among Patients Treated With ESA a
Concomitant Treatment Radiotherapy No. of Patients Randomized ESA Treatment 351 Epoetin beta (300 IU/kg 3/wk) 349 939 Darbepoetin alfa (2.25 g/kg/wk) Epoetin alfa (40 000 U/wk) Epoetin alfa (40 000 U/wk) Darbepoetin alfa (150 g/wk) Hemoglobin Stopping Value, g/dL Adverse Outcome 14 (women) Locoregional progression (HR, 15 (men) 1.69; P = .007); HR for death, 1.39; P = .02 14 (women) Shortened overall survival; HR for 15 (men) death, 1.37; P = .04 14 Survival at 12 mo ESA vs placebo, 70% vs 76% (P = .01) 14 Overall survival vs placebo, 63 vs 129 d; HR for death, 1.84; P = .04 15.5 Increased risk in local-regional failure (RR, 1.44; P = .03); trend toward shorter survival (RR, 1.28; P = .08) 13 Shorter overall survival; HR for death, 1.30; P = .008

Source Henke et al,5 2003

Hedenus et al,37 2003 Leyland-Jones et al,40 2005 (INT-76) Metastatic nonsmall cell Wright et al,58 2007 lung cancer (EPO-CAN-20) Locally advanced head Overgaard et al,14 2007 and neck cancer (DAHANCA 10) Glaspy et al,19 2007 (Amgen 103)

Cancer Type Advanced (stage III, IV) head and neck cancer Lympho-proliferative cancers Metastatic breast cancer

Chemotherapy Chemotherapy

Palliative radiotherapy Radiotherapy

70

522

PREPARE,12,48 2008 Thomas et al,36,48 2007 (GOG-191)

Nonmyeloid cancers in None patients not receiving chemotherapy or myelosuppressive radiation therapy Breast cancer Chemotherapy

985

Darbepoetin alfa (6.75 g/kg/wk)

733

Cervix carcinoma

Chemoradiotherapy

113

Darbepoetin alfa (4.5 g/kg/2 wk) Darbepoetin alfa (40 000 U/wk)

13

14

Shortened survival overall (14% death ESA vs 9% death placebo); faster tumor growth Shortened survival overall and faster tumor growth (42% death and free of cancer growth ESA vs 34% placebo)

Abbreviations: ESA, erythropoiesis-stimulating agent; HR, hazard ratio; RR, relative risk. a These trials were recently identified by 2 US Food and Drug Administration safety advisories.25,62

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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
No. of Deaths/Total No. (%) Source Anemia of Cancer Mystakidou et al,22 2005 Gordon et al,17 2006 Abels,28 1993 Charu et al,15 2007 Glaspy et al,19 2007 Smith et al,52 2003 Subtotal I 2 = 0%; P = .54 Treatment NR NR 13/65 (20) 16/226 (7) 136/515 (26) 3/64 (5) Control NR NR 13/59 (22) 3/59 (5) 94/470 (20) 0/22 (0) Weight, % 0.14 0.60 1.13 0.54 5.19 0.11 7.72 Hazard Ratio (95% CI) 0.50 (0.05-4.99) 0.67 (0.23-2.00) 0.89 (0.41-1.93) 1.38 (0.44-4.33) 1.43 (1.06-1.92) 3.96 (0.29-54.12) 1.29 (1.00-1.67) Favors Treatment Favors Control

Treatment-Related Anemia Throuvalas et al,55 2000 Dunphy et al,35 1999 Vadhan-Raj et al,56 2004 Dammacco et al,33 2001 Del Mastro et al,34 1997 Cazzola et al,31 1995 P-174,11 2004 Thatcher et al,54 1999 Kotasek et al,39 2003 Oberhoff et al,44 1998 Blohmer et al,24 2003 (AGO/NOGG) Henry and Abels,38 1994 Vansteenkiste et al,2 2002 Littlewood et al,41 2001 Taylor et al,21 2005 (DA 232) EPO-CAN-17,12 2007 Amgen DA 145,13 2007 Razzouk et al,49 2004 Savonije et al,51 2004 ten Bokkel Huinink et al,53 1998 Osterborg et al,46 1996 Coiffier et al,32 2001 Debus et al,16 2007 (EPO-GER-22) Osterborg et al,47 2005 EPO-GBR-7,12 2007 Case et al,30 1993 Witzig et al,57 2005 Moebus et al,18 2007 Strauss et al,23 2007 Thomas et al,36 2007 (GOG-191) Thatcher et al,54 1999 Overgaard et al,14 2007 (DAHANCA 10) Hedenus et al,37 2003 Leyland-Jones et al,40 2005 (INT-76) Henke et al,5 2003 Machtay et al,42 2007 (RTOG 99-03) PREPARE,48 2007 Grote et al,43 2005 (N93-004) INT-3,11 2004 INT-1,11 2004 Rose et al,50 1994 Bamias et al,29 2003 Wright et al,58 2007 (EPO-CAN-20) EPO-CAN-15,11 2004 Wilkinson et al,20 2006 OShaughnessy et al,45 2005 Subtotal I 2 = 21.1%; P = .11 Heterogeneity between groups P = .13 Overall I 2 = 19.5%; P = .11

0/28 (0) 0/15 (0) 0/28 (0) 3/69 (4) 1/31 (3) 2/117 (2) 1/33 (3) 1/42 (2) 7/198 (4) 4/114 (4) 16/33 (48) 8/67 (12) 100/155 (65) 155/251 (62) NR 24/176 (14) NR 2/112 (2) 12/211 (6) 4/87 (5) 15/47 (32) 8/133 (6) NR 110/170 (65) 52/151 (34) 10/81 (12) 105/166 (63) NR NR 8/58 (14) 5/44 (11) NR 74/175 (42) 148/469 (32) 109/180 (61) 27/71 (38) 50/356 (14) 100/109 (92) 9/135 (7) 6/164 (4) 16/142 (11) 7/72 (10) 32/33 (97) 21/53 (40) NR 1/47 (2)

1/27 (4) 1/15 (7) 1/31 (3) 11/76 (14) 3/31 (10) 1/29 (3) 1/12 (8) 1/22 (5) 3/51 (6) 12/104 (12) 23/116 (20) 10/65 (15) 119/159 (75) 82/124 (66) NR 27/178 (15) NR 2/110 (2) 6/104 (6) 2/33 (6) 12/49 (24) 8/129 (6) NR 119/173 (69) 50/149 (34) 9/76 (12) 103/164 (63) NR NR 9/55 (16) 2/22 (9) NR 61/169 (36) 115/470 (24) 89/171 (52) 21/70 (30) 37/377 (10) 101/115 (88) 3/65 (5) 2/80 (3) 6/79 (8) 4/72 (6) 34/37 (92) 10/53 (19) NR 0/47 (0)

0.01 0.05 0.01 0.59 0.19 0.22 0.11 0.09 0.29 0.80 1.43 0.72 6.01 5.82 1.64 1.85 10.44 0.19 0.70 0.26 1.38 0.73 2.17 5.91 3.67 0.86 5.74 3.50 2.28 1.54 0.27 5.59 4.54 6.39 5.53 1.97 2.92 0.94 0.42 0.28 0.80 0.48 1.79 0.99 0.13 0.05 92.28

0.13 (0-332.66) 0.14 (0-6.88) 0.15 (0-415.90) 0.32 (0.11-0.95) 0.36 (0.05-2.56) 0.37 (0.06-2.27) 0.41 (0.03-5.76) 0.49 (0.03-8.71) 0.55 (0.11-2.71) 0.61 (0.24-1.55) 0.67 (0.34-1.33) 0.75 (0.28-2.01) 0.78 (0.60-1.01) 0.81 (0.62-1.06) 0.85 (0.45-1.60) 0.88 (0.49-1.59) 0.93 (0.82-1.05) 0.98 (0.14-6.90) 0.98 (0.36-2.67) 1.01 (0.19-5.31) 1.02 (0.51-2.04) 1.02 (0.38-2.73) 1.02 (0.60-1.74) 1.04 (0.80-1.35) 1.07 (0.73-1.57) 1.08 (0.44-2.66) 1.09 (0.83-1.43) 1.14 (0.77-1.69) 1.16 (0.69-1.95) 1.25 (0.65-2.41) 1.26 (0.24-6.60) 1.28 (0.97-1.69) 1.36 (0.98-1.89) 1.37 (1.07-1.75) 1.39 (1.05-1.84) 1.41 (0.80-2.49) 1.50 (0.96-2.34) 1.53 (0.65-3.61) 1.56 (0.42-5.79) 1.58 (0.32-7.82) 1.68 (0.66-4.29) 1.80 (0.53-6.12) 1.84 (1.01-3.35) 2.70 (1.17-6.23) 4.54 (0.40-51.20) 7.39 (0.15-366.10) 1.09 (0.99-1.19)

100.00

1.10 (1.01-1.20) .01 .1 1.0 10 50

Hazard Ratio (95% CI)

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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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 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-kinaseAkt and JAK-STAT ( Janus kinaseSignal 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. 7 3 - 7 5 Clearly, many issues remain to be clarified regarding the specific actions of ESAs in human cancer cells.

Figure 3. Meta-analysis of VTE Rates in Phase 3 Trials of ESAs vs Placebo or Control

No. of VTE Events/Total No. (%) Source Bamias et al,29 2003 Smith et al,52 2003 Case et al,30 1993 Henry and Abels,38 1994 Wright et al,58 2007 (EPO-CAN-20) Grote et al,43 2005 (N93-004) EPO-CAN-17,12 2007 Littlewood et al,41 2001 Vansteenkiste et al,2 2002 INT-1,11 2004 Leyland-Jones et al,40 2005 (INT-76) Witzig et al,57 2005 Osterborg et al,46 1996 Amgen DA 145,13 2007 Henke et al,5 2003 ten Bokkel Huinink et al,53 1998 Debus et al,16 2007 (EPO-GER-22) Charu et al,15 2007 Rose et al,50 1994 Thatcher et al,54 1999 Osterborg et al,46 1996 Abels,28 1993 Throuvalas et al,55 2000 GOG-191,11 2007 Razzouk et al,49 2004 Welch et al,61 1995 Osterborg et al,47 2005 Gordon et al,17 2006 ten Bokkel Huinink et al,53 1998 Vadhan-Raj et al,56 2004 INT-3,11 2004 Wilkinson et al,20 2006 Savonije et al,51 2004 Machtay et al,42 2007 (RTOG 99-03) EPO-GBR-7,12 2007 Dammacco et al,33 2001 EPO-CAN-15,11 2004 Rosenzweig et al,60 2004 Cascinu et al,59 1994 P-174,11 2004 Thatcher et al,54 1999 Overall I 2 = 0%; P = .88 Treatment 0/72 (0) 1/64 (2) 2/81 (2) 6/67 (9) 2/33 (6) 24/109 (22) 19/175 (11) 14/251 (6) 7/155 (2) 3/164 (2) 36/448 (8) 9/168 (5) 1/48 (2) 66/298 (22) 10/180 (6) 2/45 (4) 20/108 (19) 9/142 (6) 2/44 (5) 2/47 (4) 1/65 (2) 1/28 (4) 9/58 (16) 6/112 (5) 1/15 (7) 1/170 (1) 4/162 (16) 4/42 (10) 7/29 (24) 8/135 (6) 12/173 (7) 9/211 (4) 2/71 (3) 5/151 (3) 5/69 (7) 16/53 (30) 4/14 (29) 0/50 (0) 0/33 (0) 0/42 (0) Control 1/72 (1) 1/22 (5) 3/76 (4) 8/65 (12) 3/37 (20) 26/115 (23) 14/175 (8) 5/124 (4) 5/159 (3) 1/80 (1) 25/456 (5) 6/165 (4) 0/24 (0) 43/298 (14) 6/171 (4) 0/17 (0) 10/107 (9) 2/79 (3) 0/22 (0) 0/25 (0) 0/59 (0) 0/26 (0) 3/55 (5) 2/110 (2) 0/15 (0) 0/173 (0) 0/56 (5) 0/16 (0) 2/31 (6) 1/65 (2) 1/59 (2) 1/104 (1) 0/70 (0) 1/149 (1) 1/76 (1) 2/53 (4) 0/13 (0) 0/50 (0) 0/12 (0) 0/22 (0) Weight, % 0.31 0.42 1.02 3.14 1.06 13.20 7.29 3.17 2.49 0.62 12.97 3.09 0.32 25.92 3.22 0.35 6.25 0.37 1.39 0.35 0.35 0.31 0.32 2.01 1.27 0.32 0.31 0.37 0.38 1.43 0.75 0.77 0.75 0.35 0.69 0.70 1.57 0.39 0 0 0 100.00 Relative Risk (95% CI) 0.33 (0.01-8.05) 0.34 (0.02-5.27) 0.63 (0.11-3.64) 0.73 (0.27-1.98) 0.75 (0.13-4.20) 0.97 (0.60-1.59) 1.36 (0.70-2.62) 1.38 (0.51-3.75) 1.44 (0.47-4.43) 1.46 (0.15-13.85) 1.47 (0.89-2.40) 1.47 (0.54-4.05) 1.53 (0.06-36.23) 1.53 (1.08-2.18) 1.58 (0.59-4.26) 1.96 (0.10-38.79) 1.98 (0.97-4.03) 2.36 (0.13-43.20) 2.50 (0.55-11.30) 2.56 (0.13-51.05) 2.71 (0.14-54.32) 2.73 (0.11-65.68) 2.79 (0.12-65.66) 2.84 (0.81-9.96) 2.95 (0.61-14.28) 3.00 (0.13-68.26) 3.05 (0.13-74.41) 3.15 (0.17-57.55) 3.56 (0.20-62.58) 3.74 (0.85-16.56) 3.85 (0.49-30.15) 4.09 (0.54-30.80) 4.44 (0.57-34.55) 4.93 (0.24-100.89) 4.93 (0.58-41.73) 5.51 (0.66-45.98) 8.00 (1.93-33.09) 8.40 (0.50-142.27) Favors Treatment Favors Control

1.57 (1.31-1.87)

.01

.1

1.0

10

50

Relative Risk (95% CI)

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. 920 JAMA, February 27, 2008Vol 299, No. 8 (Reprinted)

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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.

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
RR of VTE (95% CI) 1.58 (0.94-2.66) HR for Mortality (95% CI) 0.81 (0.67-0.99)

Source Bohlius et al,9,10 2004 (Cochrane I) Bohlius et al,9,10 2006 (Cochrane II) Wilson et al,7 2007 (NICE)

Years Covered 1993-April 2002

Product

No. of Trials

No. of Patients 3287 Survival 1738 VTE 8167 Survival 6679 VTE

1993-April 2005

1993-September 4, 2004

Seidenfeld et al,8 2006 (BCBSA-TEC) All studies included in the current review

1993-March 2005

Trial-Level Systematic Reviews Epoetin alfa/beta for 27 Survival chemotherapy-related and 12 VTE cancer-related anemia Epoetin alfa/beta and 42 Survival darbepoetin for 35 VTE chemotherapy-related and cancer-related anemia Epoetin alfa/beta and 28 Survival darbepoetin for chemotherapy-related and cancer-related anemia Epoetin alfa/beta and 35 Survival darbepoetin for 30 VTE chemotherapy-related anemia Epoetin alfa/beta and darbepoetin for chemotherapy-related anemia and anemia of cancer 51 Survival 38 VTE

1.67 (1.35-2.06)

1.08 (0.99-1.18)

5308 Survival

NR

1.03 (0.92-1.16)

7891 Survival 6092 VTE

1.69 (1.36-2.10)

1.11 (0.99-1.23)

13 613 Survival 8172 VTE

1.57 (1.31-1.87)

1.10 (1.01-1.20)

Roche63 (2004 ODAC) Johnson & Johnson64 (2004 ODAC) AMGEN11 (2004 ODAC) AMGEN62 (2007 ODAC) Johnson & Johnson62 (2007 ODAC)

Patient-Level Overviews Presented at the 2004 and 2007 ODAC Meetings 1993-May 2004 Epoetin beta for 9 1409 1.78 (1.12-2.89) treatment-related anemia 1993-May 2004 Epoetin alfa for 10 1776 1.55 (0.96-2.50) treatment-related anemia 1993-May 2004 1993-May 2007 1993-May 2007 Darbepoetin for treatment-related anemia Darbepoetin for treatment-related anemia Epoetin alfa for treatment-related anemia 11 VTE 4 Survival 7 12 2251 VTE 1129 Survival 2112 3064 1.97 (1.15-3.39) 1.50 (0.97-2.33) a 1.44 (1.05-1.98) b

0.97 (0.69-1.36) 0.99 (0.76-1.28)

0.97 (0.79-1.18) 1.14 (0.76-1.74) NR

Abbreviations: BCBSA-TEC, Blue Cross/Blue Shield Associations Technology Evaluation Center; CI, confidence interval; HR, hazard ratio; NICE, National Institutes of Clinical Excellence; NR, not reported; ODAC, Oncologic Drug Advisory Committee; RR, relative risk; VTE, venous thromboembolism. a Indicates Peto odds ratio for thromboembolic and cardiovascular events. b Denotes HR rather than RR.

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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 FDAapproved 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 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 922

Cancer Institute, Pittsburgh, Pennsylvania (Dr Lai); and University Hospital of Freiberg, Freiburg, Germany (Dr Henke). 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 CA12507701A1, 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 metaanalysis. Ms Boyle was supported by grant 1R-1 CA125077-01A1 from the National Cancer Institute.

REFERENCES 1. Littlewood TJ, Cella D, Nortier JW. Erythropoietin improves quality of life. Lancet Oncol. 2002;3(8): 459-460. 2. Vansteenkiste J, Pirker R, Massuti B, et al. Doubleblind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving

chemotherapy. J Natl Cancer Inst. 2002;94(16):12111220. 3. 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. 4. Steinbrook R. Erythropoietin, the FDA, and oncology. N Engl J Med. 2007;356(24):2448-2451. 5. Henke M, Laszig R, Rube C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, doubleblind, placebo-controlled trial. Lancet. 2003;362 (9392):1255-1260. 6. Leyland-Jones B. Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol. 2003; 4(8):459-460. 7. 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):1220. 8. 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. 9. Bohlius J WJ, Seidenfeld J, Piper M, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database of Syst Rev. 2006;(3):CD003407. doi: 10.1002/14651858.CD003407.pub4. 10. 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):489498. 11. 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. 12. 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. 13. Amgen DA 145 Study. April 19, 2007. http: //wwwext.amgen.com/media/media_pr_detail.jsp ?year=2007&releaseID=987476. Accessed January 9, 2008. 14. 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. 15. 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, openlabel phase II trial. Oncologist. 2007;12(6):727-737. 16. 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 Science. http://www.egms.de /en/meetings/dkk2006/06dkk257.shtml. Accessed December 17, 2007. 17. Gordon DH, Nichols G, Ben-Jacob A, et al. Treat-

JAMA, February 27, 2008Vol 299, No. 8 (Reprinted)

2008 American Medical Association. All rights reserved.

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VENOUS THROMBOEMBOLISM AND MORTALITY FOR CANCER-ASSOCIATED ANEMIA

ing 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. 18. 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):569 2007 ASCO Annual Meeting Proceedings Part I. 19. Glaspy J, Smith R, Aapro M, et al. Results from a phase III, randomized, double-blind, placebocontrolled 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. 20. 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. 21. 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. 22. 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. 23. 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. . 24. 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. 25. 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. 26. Altman DG, Bland JM. Interaction revisisted: the difference between two estimates. BMJ. 2003;326 (7382):219. 27. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177-188. 28. Abels R. Erythropoietin for anaemia in cancer patients. Eur J Cancer. 1993;29A(suppl 2):S2-S8. 29. 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):102110. 30. 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. 31. Cazzola M, Messinger D, Battistel V, et al. Recombinant human erythropoietin in the anemia associated with multiple myeloma or non-Hodgkins lymphoma: dose finding and identification of predictors of response. Blood. 1995;86(12):4446-4453. 32. 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. 33. 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. 34. 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. 35. 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. 36. 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. . 37. 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. 38. Henry DH, Abels RI. Recombinant human erythropoietin in the treatment of cancer and chemotherapyinduced anemia: results of double-blind and openlabel follow-up studies. Semin Oncol. 1994;21(2) (suppl 3):21-28. 39. 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, placebocontrolled, randomised study. Eur J Cancer. 2003; 39(14):2026-2034. 40. 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. 41. 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. 42. 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):10081017. 43. Grote T, Yeilding AL, Castillo R, et al. Efficacy and safety analysis of epoetin alfa in patients with smallcell lung cancer: a randomized, double-blind, placebocontrolled trial. J Clin Oncol. 2005;23(36):93779386. 44. 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. 45. OShaughnessy 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):439446. 46. Osterborg A, Boogaerts MA, Cimino R, et al. Recombinant human erythropoietin in transfusiondependent anemic patients with multiple myeloma and non-Hodgkins lymphoma: a randomized multicenter study. The European Study Group of Erythropoietin (Epoetin Beta) Treatment in Multiple Myeloma and Non-Hodgkins Lymphoma. Blood. 1996; 87(7):2675-2682. 47. 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. 48. 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. 49. Razzouk BIHM, Hinds PS, Rackoff W, Hord JD. A double-blind, placebo-controlled study of onceweekly 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. 50. 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. 51. 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. 52. 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. 53. 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. 54. Thatcher N, De Campos ES, Bell DR, et al. Epoetin alpha prevents anaemia and reduces transfusion requirements in patients undergoing primarily platinumbased chemotherapy for small cell lung cancer. Br J Cancer. 1999;80(3-4):396-402. 55. 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. 56. 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. 57. 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):26062617. 58. Wright JR, Ung YC, Julian JA, et al. Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with diseaserelated anemia. J Clin Oncol. 2007;25(9):10271032. 59. 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. 923

2008 American Medical Association. All rights reserved.

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VENOUS THROMBOEMBOLISM AND MORTALITY FOR CANCER-ASSOCIATED ANEMIA

60. 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. 61. Welch RS, James RD, Wilkinson PM, Belli F, Cowan RA. Recombinant human erythropoietin and platinumbased chemotherapy in advanced ovarian cancer. Cancer J Sci Am. 1995;1(4):261-266. 62. 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. 63. 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. 64. 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. 65. 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. 66. Hardee ME, Arcasoy MO, Blackwell KL, Kirkpatrick JP, Dewhirst MW. Erythropoietin biology in cancer. Clin Cancer Res. 2006;12(2):332-339. 67. 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):356361. 68. Sytkowski AJ. Does erythropoietin have a dark side? epo signaling and cancer cells. Sci STKE. 2007; 2007(395):pe38. 69. Acs G, Acs P, Beckwith SM, et al. Erythropoietin and erythropoietin receptor expression in human cancer. Cancer Res. 2001;61(9):3561-3565. 70. 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. 71. Lai SY, Childs EE, Xi S, et al. Erythropoietinmediated activation of JAK-STAT signaling contributes to cellular invasion in head and neck squamous cell carcinoma. Oncogene. 2005;24(27):4442-4449. 72. 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. 73. Acs G, Chen M, Xu X, Acs P, Verma A, Koch CJ. Autocrine erythropoietin signaling inhibits hypoxiainduced apoptosis in human breast carcinoma cells. Cancer Lett. 2004;214(2):243-251. 74. Kumar SM, Acs G, Fang D, Herlyn M, Elder DE, Xu X. Functional erythropoietin autocrine loop in melanoma. Am J Pathol. 2005;166(3):823830. 75. Lai SY, Grandis JR. Understanding the presence and function of erythropoietin receptors on cancer cells. J Clin Oncol. 2006;24(29):4675-4676. 76. 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. 77. 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. 78. 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. 79. Aranesp [package insert]. Thousand Oaks, CA: Amgen Inc; 2007. http://www.aranesp.com/pdf /aranesp_PI.pdf. Accessed January 11, 2008. 80. Epogen [package insert]. Thousand Oaks, CA: Amgen Inc; 2007. http://www.epogen.com/pdf /epogen_pi.pdf. Accessed January 11, 2008. 81. 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. 82. Pollack A. Amgen finds anemia drug holds risks in cancer use. New York Times. January 26, 2007; Business section.

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