- Email: [email protected]
Safety and efficacy outcomes with erythropoiesis-stimulating agents in patients with breast cancer: a meta-analysis
1
Safety and efficacy outcomes with erythropoiesis-stimulating agents in patients with breast cancer: a meta-analysis M. Aapro1, V. Moebus2, U. Nitz3, J. O’Shaughnessy4, P. Pronzato5, M. Untch6, D. Tomita7, C. Bohac7, B. Leyland-Jones8 1
Multidisciplinary Oncology Institute, Clinique de Genolier, Genolier, Switzerland
2
Department of Gynecology and Obstetrics. Höchst Frankfurt Clinic, Academic Hospital of the Goethe University, Frankfurt, Germany 3
Geriatric Breast Center, Evangelina Bethesda Hospital for Breast Diseases, Nordrhein-Westfalen, Germany 4
Texas Oncology Baylor Sammons Cancer Center, US Oncology, Dallas, Texas, USA
Department of Medical Oncology, IRCCS University Hospital San Martino – IST, National Institute for Cancer Research, Genova, Italy 5
6
Department of Obstetrics and Gynecology, Helios Clinic Berlin-Buch, Berlin, Germany
7
Amgen Inc., Thousand Oaks, California, USA
8
Edith Sanford Breast Cancer Research, Sioux Falls, South Dakota, USA
Corresponding Author: Prof. Matti Aapro, Multidisciplinary Oncology Institute, Clinique de Genolier, 3 route du Muids, 1272 Genolier, Switzerland, Telephone +41223669136, Fax +41223669207, Email: [email protected]
Key Message: "A meta-analysis of trials of ESA use in patients with breast cancer receiving chemotherapy was conducted. Nine studies were analyzed (N=4713; ESA n=2346, control n=2367). The overall stratified random-effects odds ratio (95% CI) was 1.17 (0.99-1.39) for death and 1.01 (0.87-1.16) for disease progression-related endpoints. Odds ratios for overall survival and disease-related endpoints remain consistent with prior data after including recent results."
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
2 SUMMARY Background New data on erythropoiesis-stimulating agents (ESAs) regarding overall survival and disease progression-related outcomes in patients with breast cancer receiving chemotherapy are presented in a meta-analysis of controlled trials of ESA use (epoetin alfa, epoetin beta, darbepoetin alfa, biosimilars). Patients and Methods A literature search identified reports from January 1997 through March 2014. We used company databases for Amgen Inc. or Janssen studies and published data for other studies. Random-effects odds ratios (OR) were calculated to compare results for patients randomized to ESA with those randomized to control. Results Deaths were reported for 571 of 2346 patients (24%) in the ESA groups and 523 of 2367 patients (22%) in the control groups (OR, 1.20; 95% CI 1.03–1.40). Sensitivity analyses were conducted to explore the effects of individual studies and exclusion of one study (BEST) resulted in an OR for death of 1.12 (95% CI 0.94–1.34). In seven studies reporting progression-related endpoints (N= 4197; ESA n=2088; control n=2109), the OR was 1.01 (95% CI 0.87–1.16) for ESA compared to control. Conclusions After incorporating recent results of ESA use in patients with breast cancer, risks of survival and progression-free survival remain consistent with previously published data.
Keywords: Breast cancer, erythropoiesis stimulating agents, darbepoetin alfa, epoetin alfa, chemotherapy induced anemia, meta-analysis
3
Introduction Anemia, a common consequence of chemotherapy, can cause debilitating fatigue, dyspnea, reduced functional status [1, 2], and increased costs of care [3]. In patients receiving chemotherapy for breast cancer, the estimated incidence of anemia ranges from 50% to 86%, increasing over the course of treatment [1, 2]. The two primary treatments for chemotherapyinduced anemia are red blood cell (RBC) transfusions and erythropoiesis-stimulating agents (ESAs). RBC transfusions reverse anemia quickly, but expose patients to potential risks [4] including thrombosis, immunologic complications, exposure to infectious agents, transfusionrelated acute lung injury, iron overload, non-immunogenic hemolytic reactions, and hypothermia. ESAs, which stimulate the production of endogenous RBCs, decrease the requirement for transfusions, reduce fatigue, and improve quality of life [1, 2, 5, 6]. ESA use in patients with cancer has been reported to be associated with reduced survival and reduced time to disease progression [7, 8], and with a well-characterized risk for an increased incidence of thromboembolic events [9, 10]. However, results from controlled trials in various cancer types regarding the effects of ESAs on disease progression and mortality in cancer have been inconsistent [6], due in part to methodology differences in the trials (eg, different target hemoglobin levels). Eight trials in solid tumors and hematologic malignancies with or without chemotherapy showing increases in disease progression or mortality in various cancers are now included in the current U.S. prescribing information for darbepoetin alfa and epoetin alfa [9, 10]. No data are yet available from trials that reflect implementation of the new prescribing information. Several meta-analyses have examined the effects of ESAs on overall survival (OS) in patients with various tumor types. In patients receiving chemotherapy (the current approved indication), analyses have reported no significant effect of ESA use on OS [8, 11, 12]. Analyses that included patients receiving radiotherapy only or no cancer therapy (anemia of cancer) reported higher mortality risks [8, 11, 12].
4 The Glaspy 2010 meta-analysis also examined progression-related outcomes, including disease progression, recurrence, and relapse-free or progression-free survival (PFS). For the 21 studies that measured disease progression in patients receiving chemotherapy, the effect of ESA use on disease progression was not significant. While studies of multiple tumor types are useful, clinicians treating patients with breast cancer may benefit from tumor-specific data. The 2009 Cochrane review included a subset analysis of seven controlled studies of ESA use in 4,038 patients with breast cancer receiving chemotherapy, reporting a hazard ratio (HR) of 1.15 (95% CI 1.01–1.30) for overall mortality [13]. The 2012 Cochrane review did not specifically analyze breast cancer outcomes, and new data have recently become available [14-17], with longer-term follow-up than had been previously available. We conducted a meta-analysis of all currently available data from randomized, controlled trials to evaluate mortality, disease progression, transfusions, health related quality of life (HRQOL), and thromboembolic/cardiovascular events of ESA therapy for patients with breast cancer receiving chemotherapy.
Methods Literature Search A study-level meta-analysis of controlled ESA trials conducted in the setting of chemotherapy for breast cancer was performed. The 2006 Cochrane Collaborative report (Analysis 05.05) [18] was used as the starting point. A literature search using the Ovid system searched the BIOSIS Previews, Current Contents/All Editions, EMBASE, Ovid Medline, and Ovid MEDLINE InProcess & Other Non-Indexed Citations databases to identify controlled ESA studies in the breast cancer setting published since the Cochrane report from April 2005 through March 2014 (see Supplemental Methods). Studies included are randomized, controlled trials of patients with breast cancer receiving chemotherapy who were treated with the ESAs epoetin alfa, epoetin beta, or darbepoetin alfa or
5 biosimilars plus transfusions compared with control patients who received either placebo or best standard of care for prophylaxis or treatment of anemia (eg, transfusions without ESAs). Eligible studies reported on death or percent death in each treatment group or collected mortality data that were available for analysis. Interim analyses of ESA trials were included. Studies were excluded if English-language abstracts were not available, if the articles were editorials, letters, clinical guidelines, or case studies, or if they allowed ESAs to be administered to the control arm as part of standard medical care (Supplemental Figure 1).
Statistical Methods Endpoints analyzed included reported deaths and progression-related endpoints (relapsefree survival, event-free survival, recurrence-free survival, or PFS, analyzed collectively). Transfusion incidence in each study was also analyzed, from either week 1 or week 5 (as reported in individual studies) to the end of the study. Analysis of embolic and thrombotic events and patient-reported outcomes was considered, but was not feasible because of inconsistent and incomplete data; these data are reported descriptively (see Supplemental Methods).
Results The literature search identified nine randomized controlled studies that compared the use of ESAs versus control (no ESAs) in patients with breast cancer receiving chemotherapy [5, 14, 15, 19-25]. Some of these studies [5, 19-25] were included in the 2012 Cochrane review [8] but two others were not [15, 16], and 10-year data have become available from another study [14]. Key characteristics are listed in Table 1. The study by Del Mastro included patients with early-stage breast cancer [20]; Leyland-Jones and Aapro studied patients with metastatic breast cancer [5, 21], and the remaining studies included patients with breast cancer of various disease and treatment stages (metastatic, neoadjuvant and adjuvant, or mixed) [5, 14-16, 19, 22-25]. In six of the studies, patients received epoetin alfa [14, 19-24]; in one, they received epoetin beta [5]; and
6 in two studies, darbepoetin alfa [15, 25]. Target hemoglobin levels in the studies ranged from 12 g/dL to 15 g/dL.
Mortality Deaths were reported for 571 of 2346 patients (24%) in the ESA groups and 523 of 2367 patients (22%) in the control groups (ESA compared to control, OR, 1.20; 95% CI 1.03–1.40 for both random effects and fixed effects models; I2 = 0%) (Figure 1). Sensitivity analyses were conducted to explore the effects of individual studies on the overall result (Supplemental Figure 2). The study with the largest impact was the BEST study [21] with its exclusion resulting in an OR for death of 1.12 (95% CI 0.94–1.34). Overall mortality was also examined for subgroups based on disease status and treatment stage. When studies were stratified by metastatic stage, mixed stage, or adjuvant/neoadjuvant treatment, the OR for death in the overall study was 1.17 (95% CI 0.99–1.39; I2 = 0%). In the stratified analyses using the random effects model, among the subgroup of patients receiving adjuvant or neoadjuvant chemotherapy, the OR for death was 1.17 (95% CI 0.93–1.46; I2 = 0%) for ESA groups compared to control groups; for studies of patients with metastatic disease, the OR for death was 1.24 (95% CI 0.90–1.72; I2 = 42.6%) for ESA compared to control. In the two studies of mixed populations, the OR for death was 1.07 (95% CI 0.69–1.66; I2 = 0%) for ESA compared with control. In stratified analyses using the fixed effects model, the OR for death was 1.20 (95% CI 1.03–1.39) and for studies of patients with metastatic disease, the OR for death was 1.27 (95% CI 1.01–1.61). Results for the remaining strata were identical to the random effects model.
Progression-related endpoints Data on relapse-free survival, recurrence-free survival, or PFS were available in seven studies of 4197 patients (ESA n=2088; control n=2109). In these studies, the OR for progression was 1.01 (95% CI 0.87-1.16; I2 = 0%) for ESA compared to control (Figure 2). Among the subgroup
7 of patients with metastatic disease, the OR for progression was 0.84 (95% CI 0.66-1.08; I2 = 0%) in the ESA groups compared to the control groups. The OR for relapse, recurrence, or progression among patients receiving adjuvant or neoadjuvant chemotherapy was 1.13 (95% CI 0.93-1.36; I2 = 0%) for ESA compared to control.
Transfusions Of the nine studies analyzed for mortality, eight included data on the proportion of patients who received transfusions (Figure 3). The proportion of patients receiving transfusions in the ESA groups ranged from 0% to 14%, compared with 0% to 28% in the control groups.
Patient-reported outcomes data HRQOL was evaluated in six of the nine studies using the FACT-An, FACT-AN Fatigue, Cancer Linear Analog Scale, or Linear-analog scale assessment tools. The Chang [19], O’Shaughnessy [23], and Pronzato [24] studies found differences favoring the ESA groups compared to control groups in FACT-An scores at three or six months; these changes were statistically significant in the Chang and Pronzato studies. No statistically significant difference between the ESA and control groups was observed in the Leyland-Jones [21], Aapro [5], or Nitz studies [16].
Thromboembolic or cardiovascular events Thromboembolic or cardiovascular events were not included in the meta-analysis because of differences in reporting. Table 2 summarizes the events reported. No thromboembolic or cardiovascular events were reported in the Del Mastro study. Higher rates of thromboembolic events were reported for the ESA groups than for controls in the Leyland-Jones (16% vs 14%) and Aapro studies (13% vs 6%) of patients with metastatic cancer. Thromboembolic events were fatal for six patients in the ESA group and two in the control group in the Leyland-Jones study, and for
8 four patients in each group in the Aapro study. Thromboembolic events were also more frequent in the ESA group compared with controls in the Untch, Pronzato, Moebus, and Nitz studies (Table 2).
Discussion This study-level meta-analysis examined the effects of ESA use on survival and PFS, transfusions, patient-reported outcomes, and thromboembolic events in nine controlled trials in patients with breast cancer receiving chemotherapy. Analyses incorporating the most recent data, using both random-effects and fixed effects models, yielded OS results consistent with those previously reported for patients with breast cancer treated with ESAs [13]. These effects are not statistically significant when analyses were stratified by treatment or disease status (adjuvant/neoadjuvant, metastatic, or mixed). Similarly, newly analyzed studies did not show an increased risk for disease progression or recurrence, consistent with previously reported data. The higher mortality risks seen in the Leyland-Jones and Untch studies [21, 25] have been known for several years and are included in the current US prescribing information for ESAs. It is possible that differences in patient populations, tumor characteristics, target hemoglobin levels, and/or study design contribute to the increased risk.
Transfusions, HRQOL, and safety ESA use reduced the incidence of transfusions in all the breast cancer studies for which randomized data were available on ESA use. Improvements in patient-reported outcomes were associated with ESA use in three studies, while three other studies found no effects. These varied results could be attributed to the different methodologies used to assess HRQOL. Additional studies using validated instruments to measure patient reported outcomes are needed to better understand the effects of ESA use on fatigue-related quality of life. In some studies, the use of ESAs was found to be associated with an increased number of thromboembolic events. This finding is consistent with those reported in a retrospective US study
9 of 2266 patients over 66 years of age with stage IV breast cancer [26]. This risk needs to be considered in the context of patients’ individual risk factors when evaluating the use of ESAs for each patient.
Methodology considerations This study has limitations. The studies analyzed were conducted over a period of three decades, during which practices changed for the treatment of breast cancer and for the use of ESAs. The overall meta-analysis result continues to be influenced by the relative weight of a single published study (BEST) [21]. The studies were a heterogeneous mix of adjuvant, neoadjuvant, metastatic and mixed treatment stages; however, the use of a random effects model accounts for these differences and the stratified analyses may help to identify relevant data for particular patients. Various hemoglobin targets were also used in different studies; eg, for the BRAVE study [5], the hemoglobin target was 13 g/dL to 14 g/dL versus 12 g/dL to 14 g/dL in BEST [21] and 12.5 g/dL to 13 g/dL in PREPARE [25]. Currently, the US prescribing information for ESAs set a hemoglobin threshold of 11 g/dL; 12 g/dL is considered an appropriate target in Europe based on EORTC guidelines [27]. An additional limitation of this study is that inconsistent reporting of data about thromboembolic events does not allow a pooled analysis.
Additional studies and future directions In 2012, results for NSABP-38, a randomized adjuvant trial comparing three chemotherapy regimens, were presented [28]. Because ESA use was not randomly assigned, this study was not included in the current meta-analysis, but the results are consistent. In this trial, ESAs were used at investigators’ discretion; data were recorded on ESA use and survival outcomes for the treatment arms. After a median follow-up of 5.3 years, no statistically significant effect of ESAs on OS or disease-free survival were reported. Looking ahead, the Epo-ANE 3010 study (ClinicalTrials.gov NCT00338286) evaluates the use of epoetin alfa vs standard supportive care (RBC transfusions)
10 for patients with metastatic breast cancer receiving standard chemotherapy and may provide further guidance for the treatment of this population. This meta-analysis provides the most recent and relevant information specifically related to the use of ESAs in breast cancer, providing information on both OS and disease-free survival. No new risks were identified. Additional details from these analyses based on disease and treatment stratification may help clinicians to evaluate the use of ESAs, adding to the body of data available to clinicians as they evaluate options within the context of the current label guidelines for the management of anemia in patients receiving chemotherapy for breast cancer.
Acknowledgements The authors acknowledge the assistance of Janine Pitt (Amgen Inc.) for assistance with the literature search. They also acknowledge medical writing assistance from Shawn Lee (Amgen Inc.) and Sue Hudson, whose services were funded by Amgen Inc.
Funding This work was supported by Amgen Inc. No grants were used in the funding of this study.
Disclosure The authors declare the following potential conflicts of interest: M. Aapro has served as a consultant or advisory board member to Sandoz and Amgen Inc. He has received research funding from Sandoz and Viforpharma and honoraria and other remuneration from Amgen Inc., Johnson & Johnson, Hospira, and Roche. B. Leyland-Jones served as an advisory board member to Amgen Inc. and Johnson & Johnson but has not received renumeration in the past 3 years. V. Moebus has received honoraria from Amgen Inc., GSK, Pfizer, and Roche. He has received research funding from Amgen Inc., Novartis, Roche, and Johnson & Johnson. U.
11 Nitz has received honoraria from Sanofi-Aventis and Amgen Inc. J. O’Shaughnessy has received honoraria from Amgen Inc. for serving on a speaker’s bureau. P. Pronzato has received honoraria from Janssen, Cilag, and Amgen Inc. M. Untch declares no potential conflicts of interest. D. Tomita and C. Bohac are employees of Amgen Inc. and have received Amgen stock/stock options.
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Figure Legends Figure 1. Study-level meta-analysis of mortality in randomized controlled trials of patients with breast cancer receiving chemotherapy. Patients received erythropoiesis-stimulating agents or controls, including odds ratio for death using a random-effects model. A) Overall analysis; B) Analysis stratified by adjuvant/neoadjuvant chemotherapy, mixed tumors, or metastatic tumors.
Figure 2: Study-level meta-analysis of disease progression in patients with breast cancer receiving chemotherapy. Patients received erythropoiesis-stimulating agents or controls; odds ratio for disease progression using a random-effects model. *Denotes studies where disease progression was evaluated only as part of tumor assessment.
Figure 3: Proportion of patients who received transfusions in studies of patients with breast cancer receiving chemotherapy. Patients received erythropoiesis-stimulating agents or controls in randomized controlled trials. ESA, erythropoiesis-stimulating agent
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17
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Table 1. Studies included in meta-analysis Study Publication
Study Number or Alias
Sample size ESA
Disease stage
Control
Cancer Treatment Stage
Anemia Treatments
Baseline Hb, Mean (standard deviation) ESA
Target Hb
Followup
Control
Study Endpoints Included Mortality
Adjuvant/Neoadjuvant Chemotherapy Del Mastro L, et al. 1997 [20]
31
31
II
Accelerated adjuvant chemotherapy
Epoetin alfa 150 U/kg 3 times weekly or no additional treatment
13.0 g/dL (0.7)
13.1 g/dL (0.6)
13–15 g/dL
None
No
O’Shaughnessy J, et al. 2002 and 2005 [23, 29]
51
49
I-III
Adjuvant or neoadjuvant chemotherapy
Epoetin alfa 40,000 U once weekly or placebo
12.8 g/dL (1.0)
13.0 g/dL (1.0)
12–14 g/dL
None
No
Nitz U et al. 2008, 2011, and 2013 [15, 16, 30]
ARAPLUS
615
619
Nodepositive nonmetastatic
Adjuvant chemotherapy
Darbepoetin alfa 500 µg Q3W or control
12.95 g/dL
12.87 g/dL
13–14 g/dL
40 months
Yes
Untch M, et al. 2011 [25, 31]
PREPARE
356
377
II-III
Neoadjuvant or adjuvant chemotherapy for primary breast cancer
Darbepoetin alfa 4.5 µg/kg body weight or control
13.6 g/dL
13.6 g/dL
12.5–13.0 g/dL
Approximately 3 years
Yes
Moebus V, et al. 2012 and 2013 [14, 17 ]
AGO-ETC
324
317
III
Adjuvant chemotherapy
Epoetin alfa 150 IU/kg 3 times weekly or control during chemotherapy administration
Median: 12.4 g/dL
Median: 12.8 g/dL
12.5–13.0 g/dL
5 and 10 years
Yes
Mixed Therapy Stages
Chang J, et al. 2005 [19]
EPOCAN-17
Pronzato P, et al. EPO2010 [24] INT-47
176
178
I-IV
Mixed adjuvant/ neoadjuvant or metastatic disease
Epoetin alfa 40,000 U QW or standard of care
11.3 g/dL (0.9)
11.2 g/dL (0.8)
12–14 g/dL
2 years
No
110
113
I-IV
Mixed adjuvant/ neoadjuvant or metastatic disease
Epoetin alfa 10,000 IU 3 times weekly or standard of care
10.7 g/dL
10.8 g/dL
12.5–14.0 g/dL
1 year
Yes
231
232
IV
Chemotherapy for metastatic disease
Epoetin beta 30,000 U subcutaneous QW or control
11.5 g/dL (1.1)
11.2 g/dL (1.2)
13–15 g/dL
24 to 43 months
Yes
469
470
IV
First-line chemotherapy for metastatic disease
Epoetin alfa 40,000 U once weekly or placebo
12.5 g/dL (1.8)
12.5 g/dL (1.7)
12–14 g/dL
1 year
Yes
Metastatic Disease Aapro M, et al. 2008 [5]
BRAVE
Leyland-Jones B, BEST et al. 2005 [21]
ESA, erythropoiesis-stimulating agent; Hb, hemoglobin; IU, international units; Q3W, every 3 weeks; SD, standard deviation
Table 2. Thromboembolic or cardiovascular events reported in studies included in meta-analysis of patients with breast cancer (patient incidence)*
Study
Myocardial infarction/coronary artery disorder ESA Control
Other/Notes Cerebrovascular accident ESA Control
Thrombovascular/ thromboembolic events (TEE) ESA Control No events reported
Del Mastro L, et al. 1997 [20] 19 (10.8%)
14 (7.9%)
Moderate to severe thrombovascular events
16% 5 fatal events
14% 1 fatal events
Pulmonary embolism: ESA, N = 5 Control, N = 1
Aapro M, et al. 2008 [5]
29 (13%)
13 (6%)
Serious TEEs: ESA, N = 10 (4%) Control, N = 8 (3%) Fatal TEEs: ESA, N = 4 Control, N = 4
Moebus V, et al. 2013 [17]
22 (7%)
10 (3%)
Chang J, et al. 2005 [19]
Leyland-Jones B, et al. 2005 [21]
N=1
N=1
N=1 (fatal)
O’Shaughnessy J, et al. 2005 [23]
Clinically relevant thrombotic vascular events Untch M, et al. 2011 [25, 31]
0 (0.0%)
5 (1.3%)
1 (0.3%)
0 (0.0%)
18 (5.7%)
12 (3.0%)
Cardiovascular and thromboembolic events: ESA, N = 20 (6.3%) Control, N = 17 (4.3%) Arrhythmias: ESA, N = 1 (0.3%) Control, N = 2 (0.6%)
Study
Myocardial infarction/coronary artery disorder ESA Control
Pronzato P, et al. 2010 [24]
Nitz U, et al. 2008, 2011, and 2013 [15, 16, 30]
* Empty cells indicate no events reported ESA, erythropoiesis-stimulating agent
Other/Notes Cerebrovascular accident ESA Control
Thrombovascular/ thromboembolic events (TEE) ESA Control 8 (7.3%) 7 (6.4%)
Serious thrombovascular events: ESA, N = 4 Control, N = 1 Cardiovascular and thromboembolic events: ESA, N = 24 Control, N = 13 Thrombosis: ESA, N = 17 Control , N = 6 OR, 3.1; 95% CI 1.1‒8.8 Pulmonary embolism ESA, N = 2 Control, N = 2
Safety and efficacy outcomes with erythropoiesis-stimulating agents in patients with breast cancer: a meta-analysis M. Aapro1, V. Moebus2, U. Nitz3, J. O’Shaughnessy4, P. Pronzato5, M. Untch6, D. Tomita7, C. Bohac7, B. Leyland-Jones8 1
Multidisciplinary Oncology Institute, Clinique de Genolier, Genolier, Switzerland
2
Department of Gynecology and Obstetrics. Höchst Frankfurt Clinic, Academic Hospital of the Goethe University, Frankfurt, Germany 3
Geriatric Breast Center, Evangelina Bethesda Hospital for Breast Diseases, Nordrhein-Westfalen, Germany 4
Texas Oncology Baylor Sammons Cancer Center, US Oncology, Dallas, Texas, USA
Department of Medical Oncology, IRCCS University Hospital San Martino – IST, National Institute for Cancer Research, Genova, Italy 5
6
Department of Obstetrics and Gynecology, Helios Clinic Berlin-Buch, Berlin, Germany
7
Amgen Inc., Thousand Oaks, California, USA
8
Edith Sanford Breast Cancer Research, Sioux Falls, South Dakota, USA
Corresponding Author: Prof. Matti Aapro, Multidisciplinary Oncology Institute, Clinique de Genolier, 3 route du Muids, 1272 Genolier, Switzerland, Telephone +41223669136, Fax +41223669207, Email: [email protected]
Key Message: "A meta-analysis of trials of ESA use in patients with breast cancer receiving chemotherapy was conducted. Nine studies were analyzed (N=4713; ESA n=2346, control n=2367). The overall stratified random-effects odds ratio (95% CI) was 1.17 (0.99-1.39) for death and 1.01 (0.87-1.16) for disease progression-related endpoints. Odds ratios for overall survival and disease-related endpoints remain consistent with prior data after including recent results."
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
2 SUMMARY Background New data on erythropoiesis-stimulating agents (ESAs) regarding overall survival and disease progression-related outcomes in patients with breast cancer receiving chemotherapy are presented in a meta-analysis of controlled trials of ESA use (epoetin alfa, epoetin beta, darbepoetin alfa, biosimilars). Patients and Methods A literature search identified reports from January 1997 through March 2014. We used company databases for Amgen Inc. or Janssen studies and published data for other studies. Random-effects odds ratios (OR) were calculated to compare results for patients randomized to ESA with those randomized to control. Results Deaths were reported for 571 of 2346 patients (24%) in the ESA groups and 523 of 2367 patients (22%) in the control groups (OR, 1.20; 95% CI 1.03–1.40). Sensitivity analyses were conducted to explore the effects of individual studies and exclusion of one study (BEST) resulted in an OR for death of 1.12 (95% CI 0.94–1.34). In seven studies reporting progression-related endpoints (N= 4197; ESA n=2088; control n=2109), the OR was 1.01 (95% CI 0.87–1.16) for ESA compared to control. Conclusions After incorporating recent results of ESA use in patients with breast cancer, risks of survival and progression-free survival remain consistent with previously published data.
Keywords: Breast cancer, erythropoiesis stimulating agents, darbepoetin alfa, epoetin alfa, chemotherapy induced anemia, meta-analysis
3
Introduction Anemia, a common consequence of chemotherapy, can cause debilitating fatigue, dyspnea, reduced functional status [1, 2], and increased costs of care [3]. In patients receiving chemotherapy for breast cancer, the estimated incidence of anemia ranges from 50% to 86%, increasing over the course of treatment [1, 2]. The two primary treatments for chemotherapyinduced anemia are red blood cell (RBC) transfusions and erythropoiesis-stimulating agents (ESAs). RBC transfusions reverse anemia quickly, but expose patients to potential risks [4] including thrombosis, immunologic complications, exposure to infectious agents, transfusionrelated acute lung injury, iron overload, non-immunogenic hemolytic reactions, and hypothermia. ESAs, which stimulate the production of endogenous RBCs, decrease the requirement for transfusions, reduce fatigue, and improve quality of life [1, 2, 5, 6]. ESA use in patients with cancer has been reported to be associated with reduced survival and reduced time to disease progression [7, 8], and with a well-characterized risk for an increased incidence of thromboembolic events [9, 10]. However, results from controlled trials in various cancer types regarding the effects of ESAs on disease progression and mortality in cancer have been inconsistent [6], due in part to methodology differences in the trials (eg, different target hemoglobin levels). Eight trials in solid tumors and hematologic malignancies with or without chemotherapy showing increases in disease progression or mortality in various cancers are now included in the current U.S. prescribing information for darbepoetin alfa and epoetin alfa [9, 10]. No data are yet available from trials that reflect implementation of the new prescribing information. Several meta-analyses have examined the effects of ESAs on overall survival (OS) in patients with various tumor types. In patients receiving chemotherapy (the current approved indication), analyses have reported no significant effect of ESA use on OS [8, 11, 12]. Analyses that included patients receiving radiotherapy only or no cancer therapy (anemia of cancer) reported higher mortality risks [8, 11, 12].
4 The Glaspy 2010 meta-analysis also examined progression-related outcomes, including disease progression, recurrence, and relapse-free or progression-free survival (PFS). For the 21 studies that measured disease progression in patients receiving chemotherapy, the effect of ESA use on disease progression was not significant. While studies of multiple tumor types are useful, clinicians treating patients with breast cancer may benefit from tumor-specific data. The 2009 Cochrane review included a subset analysis of seven controlled studies of ESA use in 4,038 patients with breast cancer receiving chemotherapy, reporting a hazard ratio (HR) of 1.15 (95% CI 1.01–1.30) for overall mortality [13]. The 2012 Cochrane review did not specifically analyze breast cancer outcomes, and new data have recently become available [14-17], with longer-term follow-up than had been previously available. We conducted a meta-analysis of all currently available data from randomized, controlled trials to evaluate mortality, disease progression, transfusions, health related quality of life (HRQOL), and thromboembolic/cardiovascular events of ESA therapy for patients with breast cancer receiving chemotherapy.
Methods Literature Search A study-level meta-analysis of controlled ESA trials conducted in the setting of chemotherapy for breast cancer was performed. The 2006 Cochrane Collaborative report (Analysis 05.05) [18] was used as the starting point. A literature search using the Ovid system searched the BIOSIS Previews, Current Contents/All Editions, EMBASE, Ovid Medline, and Ovid MEDLINE InProcess & Other Non-Indexed Citations databases to identify controlled ESA studies in the breast cancer setting published since the Cochrane report from April 2005 through March 2014 (see Supplemental Methods). Studies included are randomized, controlled trials of patients with breast cancer receiving chemotherapy who were treated with the ESAs epoetin alfa, epoetin beta, or darbepoetin alfa or
5 biosimilars plus transfusions compared with control patients who received either placebo or best standard of care for prophylaxis or treatment of anemia (eg, transfusions without ESAs). Eligible studies reported on death or percent death in each treatment group or collected mortality data that were available for analysis. Interim analyses of ESA trials were included. Studies were excluded if English-language abstracts were not available, if the articles were editorials, letters, clinical guidelines, or case studies, or if they allowed ESAs to be administered to the control arm as part of standard medical care (Supplemental Figure 1).
Statistical Methods Endpoints analyzed included reported deaths and progression-related endpoints (relapsefree survival, event-free survival, recurrence-free survival, or PFS, analyzed collectively). Transfusion incidence in each study was also analyzed, from either week 1 or week 5 (as reported in individual studies) to the end of the study. Analysis of embolic and thrombotic events and patient-reported outcomes was considered, but was not feasible because of inconsistent and incomplete data; these data are reported descriptively (see Supplemental Methods).
Results The literature search identified nine randomized controlled studies that compared the use of ESAs versus control (no ESAs) in patients with breast cancer receiving chemotherapy [5, 14, 15, 19-25]. Some of these studies [5, 19-25] were included in the 2012 Cochrane review [8] but two others were not [15, 16], and 10-year data have become available from another study [14]. Key characteristics are listed in Table 1. The study by Del Mastro included patients with early-stage breast cancer [20]; Leyland-Jones and Aapro studied patients with metastatic breast cancer [5, 21], and the remaining studies included patients with breast cancer of various disease and treatment stages (metastatic, neoadjuvant and adjuvant, or mixed) [5, 14-16, 19, 22-25]. In six of the studies, patients received epoetin alfa [14, 19-24]; in one, they received epoetin beta [5]; and
6 in two studies, darbepoetin alfa [15, 25]. Target hemoglobin levels in the studies ranged from 12 g/dL to 15 g/dL.
Mortality Deaths were reported for 571 of 2346 patients (24%) in the ESA groups and 523 of 2367 patients (22%) in the control groups (ESA compared to control, OR, 1.20; 95% CI 1.03–1.40 for both random effects and fixed effects models; I2 = 0%) (Figure 1). Sensitivity analyses were conducted to explore the effects of individual studies on the overall result (Supplemental Figure 2). The study with the largest impact was the BEST study [21] with its exclusion resulting in an OR for death of 1.12 (95% CI 0.94–1.34). Overall mortality was also examined for subgroups based on disease status and treatment stage. When studies were stratified by metastatic stage, mixed stage, or adjuvant/neoadjuvant treatment, the OR for death in the overall study was 1.17 (95% CI 0.99–1.39; I2 = 0%). In the stratified analyses using the random effects model, among the subgroup of patients receiving adjuvant or neoadjuvant chemotherapy, the OR for death was 1.17 (95% CI 0.93–1.46; I2 = 0%) for ESA groups compared to control groups; for studies of patients with metastatic disease, the OR for death was 1.24 (95% CI 0.90–1.72; I2 = 42.6%) for ESA compared to control. In the two studies of mixed populations, the OR for death was 1.07 (95% CI 0.69–1.66; I2 = 0%) for ESA compared with control. In stratified analyses using the fixed effects model, the OR for death was 1.20 (95% CI 1.03–1.39) and for studies of patients with metastatic disease, the OR for death was 1.27 (95% CI 1.01–1.61). Results for the remaining strata were identical to the random effects model.
Progression-related endpoints Data on relapse-free survival, recurrence-free survival, or PFS were available in seven studies of 4197 patients (ESA n=2088; control n=2109). In these studies, the OR for progression was 1.01 (95% CI 0.87-1.16; I2 = 0%) for ESA compared to control (Figure 2). Among the subgroup
7 of patients with metastatic disease, the OR for progression was 0.84 (95% CI 0.66-1.08; I2 = 0%) in the ESA groups compared to the control groups. The OR for relapse, recurrence, or progression among patients receiving adjuvant or neoadjuvant chemotherapy was 1.13 (95% CI 0.93-1.36; I2 = 0%) for ESA compared to control.
Transfusions Of the nine studies analyzed for mortality, eight included data on the proportion of patients who received transfusions (Figure 3). The proportion of patients receiving transfusions in the ESA groups ranged from 0% to 14%, compared with 0% to 28% in the control groups.
Patient-reported outcomes data HRQOL was evaluated in six of the nine studies using the FACT-An, FACT-AN Fatigue, Cancer Linear Analog Scale, or Linear-analog scale assessment tools. The Chang [19], O’Shaughnessy [23], and Pronzato [24] studies found differences favoring the ESA groups compared to control groups in FACT-An scores at three or six months; these changes were statistically significant in the Chang and Pronzato studies. No statistically significant difference between the ESA and control groups was observed in the Leyland-Jones [21], Aapro [5], or Nitz studies [16].
Thromboembolic or cardiovascular events Thromboembolic or cardiovascular events were not included in the meta-analysis because of differences in reporting. Table 2 summarizes the events reported. No thromboembolic or cardiovascular events were reported in the Del Mastro study. Higher rates of thromboembolic events were reported for the ESA groups than for controls in the Leyland-Jones (16% vs 14%) and Aapro studies (13% vs 6%) of patients with metastatic cancer. Thromboembolic events were fatal for six patients in the ESA group and two in the control group in the Leyland-Jones study, and for
8 four patients in each group in the Aapro study. Thromboembolic events were also more frequent in the ESA group compared with controls in the Untch, Pronzato, Moebus, and Nitz studies (Table 2).
Discussion This study-level meta-analysis examined the effects of ESA use on survival and PFS, transfusions, patient-reported outcomes, and thromboembolic events in nine controlled trials in patients with breast cancer receiving chemotherapy. Analyses incorporating the most recent data, using both random-effects and fixed effects models, yielded OS results consistent with those previously reported for patients with breast cancer treated with ESAs [13]. These effects are not statistically significant when analyses were stratified by treatment or disease status (adjuvant/neoadjuvant, metastatic, or mixed). Similarly, newly analyzed studies did not show an increased risk for disease progression or recurrence, consistent with previously reported data. The higher mortality risks seen in the Leyland-Jones and Untch studies [21, 25] have been known for several years and are included in the current US prescribing information for ESAs. It is possible that differences in patient populations, tumor characteristics, target hemoglobin levels, and/or study design contribute to the increased risk.
Transfusions, HRQOL, and safety ESA use reduced the incidence of transfusions in all the breast cancer studies for which randomized data were available on ESA use. Improvements in patient-reported outcomes were associated with ESA use in three studies, while three other studies found no effects. These varied results could be attributed to the different methodologies used to assess HRQOL. Additional studies using validated instruments to measure patient reported outcomes are needed to better understand the effects of ESA use on fatigue-related quality of life. In some studies, the use of ESAs was found to be associated with an increased number of thromboembolic events. This finding is consistent with those reported in a retrospective US study
9 of 2266 patients over 66 years of age with stage IV breast cancer [26]. This risk needs to be considered in the context of patients’ individual risk factors when evaluating the use of ESAs for each patient.
Methodology considerations This study has limitations. The studies analyzed were conducted over a period of three decades, during which practices changed for the treatment of breast cancer and for the use of ESAs. The overall meta-analysis result continues to be influenced by the relative weight of a single published study (BEST) [21]. The studies were a heterogeneous mix of adjuvant, neoadjuvant, metastatic and mixed treatment stages; however, the use of a random effects model accounts for these differences and the stratified analyses may help to identify relevant data for particular patients. Various hemoglobin targets were also used in different studies; eg, for the BRAVE study [5], the hemoglobin target was 13 g/dL to 14 g/dL versus 12 g/dL to 14 g/dL in BEST [21] and 12.5 g/dL to 13 g/dL in PREPARE [25]. Currently, the US prescribing information for ESAs set a hemoglobin threshold of 11 g/dL; 12 g/dL is considered an appropriate target in Europe based on EORTC guidelines [27]. An additional limitation of this study is that inconsistent reporting of data about thromboembolic events does not allow a pooled analysis.
Additional studies and future directions In 2012, results for NSABP-38, a randomized adjuvant trial comparing three chemotherapy regimens, were presented [28]. Because ESA use was not randomly assigned, this study was not included in the current meta-analysis, but the results are consistent. In this trial, ESAs were used at investigators’ discretion; data were recorded on ESA use and survival outcomes for the treatment arms. After a median follow-up of 5.3 years, no statistically significant effect of ESAs on OS or disease-free survival were reported. Looking ahead, the Epo-ANE 3010 study (ClinicalTrials.gov NCT00338286) evaluates the use of epoetin alfa vs standard supportive care (RBC transfusions)
10 for patients with metastatic breast cancer receiving standard chemotherapy and may provide further guidance for the treatment of this population. This meta-analysis provides the most recent and relevant information specifically related to the use of ESAs in breast cancer, providing information on both OS and disease-free survival. No new risks were identified. Additional details from these analyses based on disease and treatment stratification may help clinicians to evaluate the use of ESAs, adding to the body of data available to clinicians as they evaluate options within the context of the current label guidelines for the management of anemia in patients receiving chemotherapy for breast cancer.
Acknowledgements The authors acknowledge the assistance of Janine Pitt (Amgen Inc.) for assistance with the literature search. They also acknowledge medical writing assistance from Shawn Lee (Amgen Inc.) and Sue Hudson, whose services were funded by Amgen Inc.
Funding This work was supported by Amgen Inc. No grants were used in the funding of this study.
Disclosure The authors declare the following potential conflicts of interest: M. Aapro has served as a consultant or advisory board member to Sandoz and Amgen Inc. He has received research funding from Sandoz and Viforpharma and honoraria and other remuneration from Amgen Inc., Johnson & Johnson, Hospira, and Roche. B. Leyland-Jones served as an advisory board member to Amgen Inc. and Johnson & Johnson but has not received renumeration in the past 3 years. V. Moebus has received honoraria from Amgen Inc., GSK, Pfizer, and Roche. He has received research funding from Amgen Inc., Novartis, Roche, and Johnson & Johnson. U.
11 Nitz has received honoraria from Sanofi-Aventis and Amgen Inc. J. O’Shaughnessy has received honoraria from Amgen Inc. for serving on a speaker’s bureau. P. Pronzato has received honoraria from Janssen, Cilag, and Amgen Inc. M. Untch declares no potential conflicts of interest. D. Tomita and C. Bohac are employees of Amgen Inc. and have received Amgen stock/stock options.
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Figure Legends Figure 1. Study-level meta-analysis of mortality in randomized controlled trials of patients with breast cancer receiving chemotherapy. Patients received erythropoiesis-stimulating agents or controls, including odds ratio for death using a random-effects model. A) Overall analysis; B) Analysis stratified by adjuvant/neoadjuvant chemotherapy, mixed tumors, or metastatic tumors.
Figure 2: Study-level meta-analysis of disease progression in patients with breast cancer receiving chemotherapy. Patients received erythropoiesis-stimulating agents or controls; odds ratio for disease progression using a random-effects model. *Denotes studies where disease progression was evaluated only as part of tumor assessment.
Figure 3: Proportion of patients who received transfusions in studies of patients with breast cancer receiving chemotherapy. Patients received erythropoiesis-stimulating agents or controls in randomized controlled trials. ESA, erythropoiesis-stimulating agent
16
17
18
Table 1. Studies included in meta-analysis Study Publication
Study Number or Alias
Sample size ESA
Disease stage
Control
Cancer Treatment Stage
Anemia Treatments
Baseline Hb, Mean (standard deviation) ESA
Target Hb
Followup
Control
Study Endpoints Included Mortality
Adjuvant/Neoadjuvant Chemotherapy Del Mastro L, et al. 1997 [20]
31
31
II
Accelerated adjuvant chemotherapy
Epoetin alfa 150 U/kg 3 times weekly or no additional treatment
13.0 g/dL (0.7)
13.1 g/dL (0.6)
13–15 g/dL
None
No
O’Shaughnessy J, et al. 2002 and 2005 [23, 29]
51
49
I-III
Adjuvant or neoadjuvant chemotherapy
Epoetin alfa 40,000 U once weekly or placebo
12.8 g/dL (1.0)
13.0 g/dL (1.0)
12–14 g/dL
None
No
Nitz U et al. 2008, 2011, and 2013 [15, 16, 30]
ARAPLUS
615
619
Nodepositive nonmetastatic
Adjuvant chemotherapy
Darbepoetin alfa 500 µg Q3W or control
12.95 g/dL
12.87 g/dL
13–14 g/dL
40 months
Yes
Untch M, et al. 2011 [25, 31]
PREPARE
356
377
II-III
Neoadjuvant or adjuvant chemotherapy for primary breast cancer
Darbepoetin alfa 4.5 µg/kg body weight or control
13.6 g/dL
13.6 g/dL
12.5–13.0 g/dL
Approximately 3 years
Yes
Moebus V, et al. 2012 and 2013 [14, 17 ]
AGO-ETC
324
317
III
Adjuvant chemotherapy
Epoetin alfa 150 IU/kg 3 times weekly or control during chemotherapy administration
Median: 12.4 g/dL
Median: 12.8 g/dL
12.5–13.0 g/dL
5 and 10 years
Yes
Mixed Therapy Stages
Chang J, et al. 2005 [19]
EPOCAN-17
Pronzato P, et al. EPO2010 [24] INT-47
176
178
I-IV
Mixed adjuvant/ neoadjuvant or metastatic disease
Epoetin alfa 40,000 U QW or standard of care
11.3 g/dL (0.9)
11.2 g/dL (0.8)
12–14 g/dL
2 years
No
110
113
I-IV
Mixed adjuvant/ neoadjuvant or metastatic disease
Epoetin alfa 10,000 IU 3 times weekly or standard of care
10.7 g/dL
10.8 g/dL
12.5–14.0 g/dL
1 year
Yes
231
232
IV
Chemotherapy for metastatic disease
Epoetin beta 30,000 U subcutaneous QW or control
11.5 g/dL (1.1)
11.2 g/dL (1.2)
13–15 g/dL
24 to 43 months
Yes
469
470
IV
First-line chemotherapy for metastatic disease
Epoetin alfa 40,000 U once weekly or placebo
12.5 g/dL (1.8)
12.5 g/dL (1.7)
12–14 g/dL
1 year
Yes
Metastatic Disease Aapro M, et al. 2008 [5]
BRAVE
Leyland-Jones B, BEST et al. 2005 [21]
ESA, erythropoiesis-stimulating agent; Hb, hemoglobin; IU, international units; Q3W, every 3 weeks; SD, standard deviation
Table 2. Thromboembolic or cardiovascular events reported in studies included in meta-analysis of patients with breast cancer (patient incidence)*
Study
Myocardial infarction/coronary artery disorder ESA Control
Other/Notes Cerebrovascular accident ESA Control
Thrombovascular/ thromboembolic events (TEE) ESA Control No events reported
Del Mastro L, et al. 1997 [20] 19 (10.8%)
14 (7.9%)
Moderate to severe thrombovascular events
16% 5 fatal events
14% 1 fatal events
Pulmonary embolism: ESA, N = 5 Control, N = 1
Aapro M, et al. 2008 [5]
29 (13%)
13 (6%)
Serious TEEs: ESA, N = 10 (4%) Control, N = 8 (3%) Fatal TEEs: ESA, N = 4 Control, N = 4
Moebus V, et al. 2013 [17]
22 (7%)
10 (3%)
Chang J, et al. 2005 [19]
Leyland-Jones B, et al. 2005 [21]
N=1
N=1
N=1 (fatal)
O’Shaughnessy J, et al. 2005 [23]
Clinically relevant thrombotic vascular events Untch M, et al. 2011 [25, 31]
0 (0.0%)
5 (1.3%)
1 (0.3%)
0 (0.0%)
18 (5.7%)
12 (3.0%)
Cardiovascular and thromboembolic events: ESA, N = 20 (6.3%) Control, N = 17 (4.3%) Arrhythmias: ESA, N = 1 (0.3%) Control, N = 2 (0.6%)
Study
Myocardial infarction/coronary artery disorder ESA Control
Pronzato P, et al. 2010 [24]
Nitz U, et al. 2008, 2011, and 2013 [15, 16, 30]
* Empty cells indicate no events reported ESA, erythropoiesis-stimulating agent
Other/Notes Cerebrovascular accident ESA Control
Thrombovascular/ thromboembolic events (TEE) ESA Control 8 (7.3%) 7 (6.4%)
Serious thrombovascular events: ESA, N = 4 Control, N = 1 Cardiovascular and thromboembolic events: ESA, N = 24 Control, N = 13 Thrombosis: ESA, N = 17 Control , N = 6 OR, 3.1; 95% CI 1.1‒8.8 Pulmonary embolism ESA, N = 2 Control, N = 2