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Update on Erythropoiesis-Stimulating Agents and Clinical Trials in Oncology

^aMultidisciplinary Oncology Institute, Genolier, Switzerland; ^bJohns Hopkins University, School of Medicine, Baltimore, Maryland, USA

Key Words. Anemia • Erythropoiesis-stimulating agents • Guidelines

Correspondence: Matti S. Aapro, M.D., IMO Clinique de Genolier, 1 Route du Muids, 1272 Genolier, Switzerland. Telephone: 41223669106; Fax: 41223669131; e-mail: maapro{at}genolier.net

Received February 23, 2009; accepted for publication June 24, 2009.

Disclosures: Matti Aapro: Consultant/advisory role: ESMO, SIOG, ESO, EuroCancer, EORTC, IUCC; Honoraria: Amgen, Johnson & Johnson, Roche, Sanofi-Aventis, Bayer Schering, Merck-Serono, Merck, Helsinn, Novartis, Pfizer, Pierre Fabre; Research funding/contracted research: Amgen, Roche, Sanofi-Aventis, Merck-Serono, Merck, Helsinn, Cephalon, Pierre Fabre; Jerry L. Spivak: Consultant/advisory role: Amgen, Ortho Biotech, Roche.

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers.

	ABSTRACT

Top Abstract Introduction Overview of the Current... Update of Recent Breast... Conclusions Author Contributions References

 
Anemia commonly occurs among cancer patients receiving chemotherapy. In these patients, erythropoiesis-stimulating agents (ESAs) are effective in managing anemia but there is an increased risk for thrombovascular events. In more recent randomized clinical trials, there have been differing results regarding the impact of ESAs on overall survival and mortality. The balance between studies that show higher ESA-associated mortality and those that don't show ESA-associated mortality is examined in this review. This review discusses where we stand today on anemia management in cancer patients. Preliminary results from a recent independent patient data meta-analysis for on-study deaths and overall survival in patients receiving chemotherapy (the only oncology population for which ESA treatment is currently indicated) showed no statistically significant difference between the ESA and control groups (on-study deaths hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.98–1.24; overall survival HR, 1.04; 95% CI, 0.97–1.11, compared with controls). Possible factors that could influence study results are discussed in this review. There are no convincing data to support ESA-induced tumor stimulation in patients. ESAs decrease RBC transfusion needs and sustain targeted hemoglobin levels, and this ESA response does not significantly impact overall survival or mortality when ESAs are used within guidelines and labeling. However, based on the currently available data and meta-analysis, the use of ESAs has to be carefully balanced against any possible risk for higher mortality.

	INTRODUCTION

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Anemia in patients with cancer is multifactorial and frequent amongst cancer patients receiving chemotherapy [1]. Use of erythropoiesis-stimulating agents (ESAs) decreases the proportion of chemotherapy patients requiring RBC transfusions [2–4]. However, ESAs increase the risk for thrombovascular events in chemotherapy-induced anemia (CIA), chronic renal failure, and surgery.

Data from >12,000 patients in controlled studies are available to provide information on the benefit–risk ratio. Outside the approved indication for the use of ESAs (i.e., ESAs are indicated only for the treatment of anemia resulting from concomitant myelosuppressive chemotherapy, ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure, and ESAs must be discontinued following the completion of a chemotherapy course), there is a higher risk for mortality; however, this is not the case if used within indication. The most rigorous study to date (20010145-small cell lung cancer [SCLC]), which was conducted to the most exacting standards, did not demonstrate greater mortality or tumor progression [5]. Furthermore, a relationship between epoetin receptor expression and tumor proliferation is unclear [6–9].

The need to assess the risks and benefits of ESAs has led to the convening of numerous regulatory meetings, including the Oncology Drug Advisory Committee (ODAC) of the U.S. Food and Drug Administration (FDA) 2004 and 2007 Advisory Board meetings, the 2007 American Society of Hematology/American Society of Clinical Oncology and European Organization for Research and Treatment of Cancer (EORTC) guideline update, the 2007 October Committee for Medicinal Products for Human Use (CHMP) safety committee, the 2008 CHMP and European Medicines Agency (EMEA): ESA label changes and harmonization, the 2008 March ODAC Advisory Board meeting, the 2008 May 15 Scientific Advisory Groups/EMEA hearing, and the Summer 2008 regulatory decisions. Based on the updated data, the regulatory authorities have narrowed the indications for the use of ESAs to improve benefits and minimize risks.

	OVERVIEW OF THE CURRENT STATUS OF ESA CLINICAL ONCOLOGY STUDIES

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Meta-analyses are helpful to detect a signal of a rare event, and although they are not a substitute for properly conducted prospective studies, they have allowed progress in various areas of oncology. They can help in assessing data and indicate areas for further study of ESA treatment of anemic cancer patients on chemotherapy.

Survival and Safety
An overview of the ESA meta-analyses and their effects on survival showed the hazard ratio (HR) to be 1.08 in the Cochrane meta-analysis (n = 8,167 patients) and 1.03 in the updated Cochrane meta-analysis (n = 9,652 patients), 1.17 for the CIA extended analysis set (n = 4,536 patients), and 1.17 for "Cochrane-like" epoetin alfa only studies (n = 6,918 patients) [10]. For the latter two meta-analyses, the HR decreased to 1.04 and 0.97, respectively, in analyses with long-term follow-up [10]. An HR of 1.00 shows no negative impact of the ESA on survival and an HR < 1.00 favors the ESA [10].

In the meta-analysis of 12 randomized, double-blinded, placebo-controlled studies of both on-label and off-label epoetin alfa, no specific signals for survival outside the off-label use studies were observed [3, 10–12]. In this meta-analysis, only one study (the Breast Cancer Erythropoietin Survival Trial [BEST]) produced an HR that significantly favored placebo. In these 12 studies of anemia, the HR for on-study mortality was 1.13 (95% confidence interval [CI], 0.95–1.34), but this included studies in patients not receiving chemotherapy (Study H87-032, H87-014, and H87-015) and in which treatment went beyond the correction of anemia (BEST, N93-004).

In the initial independent analysis published by Bohlius et al. [3], overall, the HR in 42 trials and 8,167 patients was 1.08 (95% CI, 0.99–1.18) in disfavor of ESA treatment use. However, this included cancer patients with or without concurrent chemotherapy [3].

In a further analysis presented by Amgen to the U.S. FDA, divided by on-label and off-label use, the trend is toward favoring the control for the off-label use whereas the on-label use favors the ESA [11, 13]. The fixed effects and random effects models in this particular meta-analysis gave a Peto odds ratio of 1.03 (95% CI, 0.93–1.15) [11, 13]. This meta-analysis involved 59 controlled ESA studies, with 15,249 patients, and divided the patients into three groups: anemia of cancer, radiation therapy setting (RTx), and CIA [11, 13]. In the RTx setting, there was a negative signal related to the head and neck (H&N) setting in studies of mainly nonanemic patients using radiation therapy without chemotherapy [Erythropoietin in Head and Neck Cancer Study (ENHANCE) and Danish Head and Neck Cancer Group Study (DAHANCA)] [11, 13]. These concerns are now well known and have led radiation oncologists to avoid epoetin use in the setting of standard radiation therapy without chemotherapy.

In the CIA data, the most recent studies regarded by authorities as favoring the control are the Gynecologic Oncology Group (GOG)-0191 study in cervical cancer and the PREPARE study in neoadjuvant breast cancer [14, 15]. GOG-0191 and PREPARE explored ESA use in nonanemic patients and/or a high hemoglobin (Hb) target (>13 g/dl), and in our opinion cannot be viewed as valid arguments against the use of ESAs. The GOG-0191 study aimed at maintaining an Hb level 13g/dl in cervical cancer patients treated with chemoradiation [14]. The GOG-0191 study was a truncated study and the log-rank test for a negative effect of epoetin on overall survival compared with a control (with no epoetin) produced a p-value of 0.44, which was not statistically significant (HR, 1.28; 95% CI, 0.68–2.42) [14]. In the PREPARE study, in neoadjuvant breast cancer patients who were not anemic, an interim analysis that was not initially designed to look at survival was conducted [15]. In an updated interim assessment, there was no significant difference in overall survival (p = .16) between the epoetin group and the control group (patients not receiving epoetin) (HR, 1.34; 95% CI, 0.89–2.00) [15].

Overall data from eight of the 59 controlled phase III studies in oncology raised concern about the use of ESAs in cancer patients (Fig. 1) [11, 13, 14–17]. The 59 studies are divided as follows: (a) 46 of these studies included cancer patients receiving chemotherapy, (b) nine of these studies included cancer patients with CIA, and (c) four studies included cancer patients receiving radiotherapy.

View larger version (38K): [in this window] [in a new window]   Figure 1. Summary of eight of the 59 controlled phase III studies in oncology that raised concerns regarding the use of ESAs in cancer patients [11, 13, 14–17]. Nineteen of the 46 studies (which included patients receiving chemotherapy) had long-term follow-up. Of these, four studies raised concern (i.e., BEST, PREPARE, GOG-0191, and AMG-20000161). Two of the nine "anemia of cancer " studies caused concern, namely, AMG-20010103 and EPO-CAN-20. Of the four "radiotherapy" studies, two caused concern (i.e., ENHANCE and DAHANCA). Abbreviations: BEST, Breast Cancer Erythropoietin Survival Trial; DAHANCA, Danish Head and Neck Cancer Group; ENHANCE, Erythropoietin in Head and Neck Cancer Study; ESA, erythropoiesis-stimulating agent; GOG, Gynecologic Oncology Group; PREPARE, Preoperative Epirubicin Paclitaxel Aranesp Study. From the Oncology Drug Advisory Committee 2008 [16, 17].

The signals in the GOG-0191 and PREPARE studies are inconclusive and not confirmed by well-controlled studies in similar settings (Table 1) [14, 15, 18, 19]. The other large cervical cancer study, conducted by Blohmer et al. [18], involving 250 patients, did not give a negative signal. In fact, in the Blohmer et al. [18] study, the relapse rate was in favor of the ESA group, although the difference was not statistically significant [18]. In the breast cancer setting, Möbus et al. [19] studied the effect of ESAs in the adjuvant setting and this study gave no negative signal whatsoever. Regarding these studies, we need to try to understand what went wrong, what went right, and why. These studies are discussed in more detail further on in this article.

A second meta-analysis on epoetin beta including recent studies that had not been included in the initial meta-analysis was recently published [22]. The newer studies included MF4449 (Henke et al. [23]), MO16375 (Management of Anemia Under RadioChemotherapy), and BA16756 (Breast Cancer-Anemia and the Value of Erythropoietin [BRAVE]) [22–24]. This second meta-analysis of epoetin beta included a total of 12 randomized, controlled studies and 2,297 patients (epoetin beta, n = 1,244; control, n = 1,053) [22]. This analysis evaluated the impact of epoetin beta on overall survival, tumor progression, and thromboembolic events, and a prespecified subgroup analysis also assessed effects in patients with a baseline Hb level 11 g/dl, in accordance with current EORTC guidelines (Table 2) [22]. No negative signal was observed for overall survival or disease progression and the HR for transfusion-free survival was 0.74 (95% CI, 0.65–0.86) [22].

	UPDATE OF RECENT BREAST AND CERVICAL CANCER CLINICAL STUDIES

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The data shown in Table 1 from the PREPARE and Möbus et al. [19] studies are the latest data as of November 2008. These studies showed that there was no statistically significant difference in overall survival and progression-free survival when the Hb level was targeted at 12.5–13 g/dl [16, 17, 19]. These findings are in agreement with the Del Mastro et al. [30] study, which stressed the importance of preventing anemia and controlling Hb levels with epoetin in dose-dense CIA patients.

In the Möbus et al. [19] study, breast cancer patients received adjuvant treatment with either a standard regimen (four cycles of epirubicin and cyclophosphamide followed by four cycles of paclitaxel) or a dose-dense regimen consisting of three courses each of epirubicin (150 mg/m²), paclitaxel (225 mg/m²), and cyclophosphamide (2,500 mg/m²) at 2-week intervals (the ETC regimen) with growth factor support [19]. Patients in the dose-dense ETC arm then underwent a second randomization and received either epoetin alfa or transfusion support (Fig. 2). The target Hb level was 12.5–13 g/dl. In that study, 1,255 patients were evaluable and 658 patients were randomized in the dose-dense ETC arm (333 received epoetin alfa), with a median follow-up of 62 months [19]. The ESA arm maintained a higher Hb level and anemia occurred significantly more often in the ETC-alone arm than in the ETC–ESA arm (p < .0001) [19]. There were significantly more transfusions in the ETC-alone arm than in the ETC–ESA arm (28% versus 13%, respectively; p < .0001) [19]. There was no significant difference in the 5-year overall survival rate (83% for the observation arm versus 81% for the epoetin alfa arm; p = .89) and in the disease-free survival rate (71% in the observation arm versus 73% in the epoetin alfa arm; p = .86) between the ETC-alone arm and the ETC–ESA arm [19]. There was a higher incidence of thromboembolic events in the ETC–ESA arm (3.0% versus 1.7%).

View larger version (11K): [in this window] [in a new window]   Figure 2. Study design of the phase III Möbus et al. [19] study including epoetin alfa in the dose-dense adjuvant treatment arm of breast cancer patients. Abbreviations: DFS, disease-free survival; EC, epirubicin and cyclophosphamide standard arm; EFS, event-free survival; ESA, erythropoiesis-stimulating agent; ETC, epirubicin, cyclophosphamide, and paclitaxel dose-dense arm; Hb, hemoglobin; OS, overall survival; Q, every.

A phase III prospective randomized trial compared adjuvant chemotherapy (docetaxel, doxorubicin, and cyclophosphamide or 5-fluorouracil, epirubicin, and cyclophosphamide) plus darbepoetin (ARA⁺) with adjuvant chemotherapy without darbepoetin (ARA^–) in node-positive breast cancer patients and was recently reported in preliminary form [31]. In 1,234 patients, in total, 279 serious adverse events were reported: 150 in the ARA⁺ group versus 129 in the ARA^– group [31]. In the ARA⁺ group of patients there was a modestly higher rate of thrombosis and cardiovascular events (ARA⁺, 24; ARA^–, 13) [31]. There was significantly more anemia in ARA^– patients and their Hb levels decreased during therapy. In ARA⁺ patients, Hb levels were stable over the whole treatment period and overstimulation was rare. In that study, darbepoetin was initiated at an Hb level <13 g/dl (which was a later amendment to an Hb level <12g/dl) and was stopped at an Hb level of 14 g/dl [31]. The investigators found that the short-term toxicity and safety results were reassuring in this study [31].

Thus, contrary to the results of the BEST study, subsequent studies have not demonstrated shorter survival in breast cancer patients treated with recombinant erythropoietin.

Cervical Cancer Update
The Thomas et al. [14] study was closed prematurely, with 114 accrued patients (<25% of the planned accrual), because of potential concerns for thromboembolic events, although there was no statistical confirmation of this problem at the time the study was stopped. Of the 114 accrued patients, 109 patients were eligible, 52 received the control treatment (chemoradiotherapy), and 57 received epoetin alfa plus chemoradiotherapy [14]. The difference in the incidence of thromboembolic events between the two treatments was not statistically significant [14]. Furthermore, the mean Hb level over the treatment duration was <12.0 g/dl in 88.5% of patients in the control arm, versus 28.1% of patients in the epoetin alfa arm, and was 12.0 g/dl in 11.5% versus 71.9% of patients, respectively.

The design of the Blohmer et al. [14] study is shown in Figure 3. In that study, cervical cancer patients were randomized after surgery to either the epoetin arm (chemotherapy followed by radiotherapy with epoetin) or the control arm (chemotherapy followed by radiotherapy with transfusion support) [18]. The relapse rates, at a median of 105 weeks, were not statistically significantly different between the epoetin and control arms (17% versus 25%; p = .074), neither was the 2-year relapse-free survival rate (70% versus 81%; p = .058) [18]. The mean Hb level achieved in the epoetin arm was >12 g/dl, whereas that of the control arm was <12 g/dl. The investigators concluded that the addition of epoetin alfa to sequential chemoradiotherapy treatment resulted in a significantly lower incidence of grade 2 anemia (p = .0001) and significantly lower transfusion requirements (p = .0004) [18]. The mean Hb level was maintained at >12 g/dl throughout sequential chemoradiotherapy treatment in the epoetin alfa group, but not in the control group [18]. The addition of epoetin alfa treatment to sequential adjuvant chemoradiotherapy treatment resulted in a trend toward a lower rate of disease recurrences [18].

View larger version (10K): [in this window] [in a new window]   Figure 3. Study design of the phase III AGO/NOGGO Cervical CT/RT (randomized, open label) study [18]. Abbreviations: AGO/NOGGO, Arbeitsgemeinschaft Gynaekologische Onkologie/Nord-Ostdeutsche Gesellschaft für Gynaekologische Onkologie; Chemo, chemotherapy; CT/RT, chemotherapy/radiotherapy; Hb, hemoglobin; OS, overall survival; RFS, relapse-free survival; RT, radiotherapy; TTF, time to treatment failure.

Update in Lymphomas

The German Hodgkin's Study Group HD15-EPO Trial
Hodgkin's lymphoma is a highly curable disease in adults, with about two thirds of patients with advanced Hodgkin's disease being cured with current treatments [32]. Seven negative prognostic factors, present at diagnosis, assist in predicting the rate of freedom from progression of disease (Table 4) [32]. Included among these risk factors is an Hb level <10.5 g/dl at the time of diagnosis [32]. The Hb value is an even more striking risk factor at relapse. Of the three relevant risk factors (anemia, clinical stage, and time to relapse) at relapse, anemia is the strongest risk factor [33]. There is a statistically significant difference in the overall survival time between anemic (Hb value: females, <10.5 g/dl; males, <12 g/dl) and nonanemic (Hb value: females, >10.5 g/dl; males, >12 g/dl) Hodgkin's lymphoma patients (p < .0001) [33].

Cochrane Systematic Reviews on ESAs
A Cochrane independent patient data (IPD) meta-analysis was recently performed, based on the intent-to-treat principle, of cancer patients enrolled in randomized controlled trials comparing ESAs plus RBC transfusions (as needed) with transfusions alone, for prophylaxis or treatment of anemia while or after receiving anticancer therapy [35]. The IPD meta-analysis allows adjusting for prognostic factors, investigating subgroups, and assessing survival at prespecified time points. This approach was necessary in view of some of the questions raised above. Patient-level data were provided by companies and independent investigators. A peer-reviewed and statistical analysis plan was published on how the analysis would be done. An independent steering committee agreed on all analyses and interpretations. The data obtained were analyzed by independent statisticians. The primary endpoints were on-study mortality and overall mortality in cancer patients. On-study mortality was defined as death either during study treatment or within 28 days after the end of the active study phase. The decision to use this on-study mortality as an endpoint was to rule out deaths occurring a long time after the end of the active study phase that were a result of progression of metastatic cancers. There were also a number of secondary outcomes, and these included: on-study mortality in patients receiving radiotherapy, on-study mortality in patients not receiving anticancer treatment, and overall survival for patients receiving chemotherapy, for patients receiving radiotherapy, for patients receiving no anticancer treatment, and for all cancer patients. Data were available on 13,933 cancer patients (53 studies), which included 10,441 patients (38 trials) mainly receiving chemotherapy [35]. From the preliminary results in the chemotherapy population, there was no statistically significant signal for the on-study mortality HR, which was 1.10 (95% CI, 0.98–1.24), or overall survival HR, which was 1.04 (95% CI, 0.97–1.11) [35]. In all cancer patients, the on-study mortality was 17% greater (HR, 1.17; 95% CI, 1.06–1.30) and the overall survival was 6% lower (HR, 1.06; 95% CI, 1.00–1.12) [35]. The Cochrane IPD meta-analysis also looked for effect modification by prognostic factors, but found that adjusting for known prognostic factors had little effect on the overall estimates [35].

	CONCLUSIONS

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Once fully published, the IPD Cochrane meta-analysis will provide the most comprehensive and informative meta-analysis to date [35]. This IPD meta-analysis in cancer patients receiving chemotherapy, the cancer indication for which ESAs are approved, was based on 38 studies with 10,441 patients. Importantly, none of these studies used ESAs according to current label guidance (i.e., using the lowest ESA dose needed to avoid RBC transfusion, and using ESAs only for treatment of anemia resulting from concomitant myelosuppressive chemotherapy, etc.) [35, 36].

The question as to why a few of the more recent studies suggest that ESAs have a negative impact on overall survival in cancer patients remains open. A higher risk for thrombovascular events with ESAs is probably the most likely explanation. There are no convincing data to support epoetin alfa–induced tumor stimulation in patients. The complete IPD meta-analysis with nearly 14,000 patients might help to clarify this open question. In addition to off-label use, other possible reasons for the poorer results in some of the studies after 2002 may include: (A) changing to a more dose-dense ESA schedule in some clinical trials (i.e., the shifting of the ESA dose from three times per week to once weekly) and (B) moving the Hb target level from a correction of anemia to "beyond correcting" anemia. These two possible issues (ESA dosing schedule and Hb target level) are currently being addressed in oncology clinical trials.

The 2007/2008 position of the EORTC Working Party regarding ESAs has not changed since their first publication in 2004: Clinical trials have established that ESAs decrease transfusion needs and sustain Hb levels, without the need for intermittent transfusions; ESAs increase quality of life in symptomatic patients; and ESAs should be used within guidelines. The EORTC will wait for the updated data from the patient-level Cochrane meta-analysis before deciding if anything should be changed in these guidelines. This EORTC decision is expected in September 2009.

In conclusion, ESA therapy is effective in producing a hematopoietic response, and ESA response has been shown in a wide variety of tumor types, including solid and nonmyeloid hematologic malignancies. ESAs have a favorable risk–benefit ratio when used for labeled indications. This is further supported by the Paladini et al. [37] meta-analysis (17 studies with 3,788 patients), which assessed the safety of ESAs when used according to label indications, in patients with CIA (instead of cancer-induced anemia) with an Hb level <11g/dl. In that meta-analysis, there was no difference in the mortality rate associated with the use of ESAs (relative risk, 0.95; 95% CI, 0.88–1.03; p = .22), and the authors concluded that, when ESAs are used as indicated on the label, they are not associated with a higher mortality risk [37]. However, caution does need to be exercised with the use of ESAs, taking into account the patient's comorbidities and carefully balancing the benefits against any possible risk for higher mortality.

	AUTHOR CONTRIBUTIONS

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Conception/Design: Matti Aapro, Jerry L. Spivak

Collection/assembly of data: Matti Aapro, Jerry L. Spivak

Data analysis: Matti Aapro, Jerry L. Spivak

Manuscript writing: Matti Aapro, Jerry L. Spivak

Final approval of manuscript: Matti Aapro

The authors take full responsibility for the content of this article and thank Rob Stepney, medical writer, and Julia O'Regan, Bingham Mayne and Smith, Edinburgh, supported by an educational grant from Ortho Biotech, a division of Janssen-Cilag Europe, for their assistance in preparing a first draft of the manuscript based on an oral presentation at a meeting held on November 20, 2008 in Sitges, Spain, organized by a Scientific Committee of Matti Aapro, Mario Dicato, Pere Gascón, Francesco Locatelli, Jerry Spivak, and Jay Wish.

	ACKNOWLEDGMENTS

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The authors acknowledge and thank Andreas Engert (Cochrane Haematological Malignancies Group, Cologne, Germany) for his comments on this manuscript.

	REFERENCES

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