Safety Update on Erythropoiesis-Stimulating Agents: Trials Within and Outside the Accepted Indications

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1 Safety Update on Erythropoiesis-Stimulating Agents: Trials Within and Outside the Accepted Indications Pere Gascón Medical Oncology, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain Key Words. Erythropoiesis-stimulating agents ESAs Anemia Safety Survival Disclosure: The author has received honoraria for lecturing from Roche Pharma, Amgen, and Janssen-Cilag, manufacturers of epoetin beta, darbepoetin alfa, and epoetin alfa, respectively. No other potential conflicts of interest were reported by the author, planners, reviewers, or staff managers of this article. Introduction Cancer patients undergoing chemotherapy frequently experience anemia [1]. In the era before the development of erythropoiesis-stimulating agents (ESAs), RBC transfusion was the main management option. Erythropoietic agents currently used for the treatment of chemotherapy-induced anemia include: epoetin alfa (Eprex /Epypo, Ortho Biotech/Janssen-Cilag, High Wycombe, United Kingdom; Procrit, Ortho Biotech Products, L.P., Bridgewater, NJ), epoetin beta (NeoRecormon, Hoffmann-La Roche, Basel, Switzerland), and darbepoetin alfa (Aranesp, Amgen Inc., Thousand Oaks, CA). Since the introduction of ESAs, many patients have benefited from their ability to reliably raise hemoglobin (Hb) levels without the need for transfusion, and to improve quality of life [2 4]. Recently, however, there has been concern that the use of ESAs might actually be reducing overall survival in cancer patients (Table 1) [3, 5 11]. This has prompted regulatory authorities such as the Oncology Drug Advisory Committee of the U.S. Food and Correspondence: Pere Gascón, M.D., Ph.D., Hospital Clinic, Division of Medical Oncology, IDIBAPS, Institut Clinic Malalties Hemato- Oncològiques (ICMHO), University of Barcelona, Barcelona, Spain. Telephone: ; Fax: ; gascon@clinic.ub.es Received November 16, 2007; accepted for publication January 7, AlphaMed Press /2008/$30.00/0 doi: /theoncologist.13-S3-4 The Oncologist 2008;13(suppl 3): Abstract Certain studies in which erythropoiesis-stimulating agents (ESAs) have been given not with the aim of correcting anemia but to achieve higher target levels of hemoglobin have shown significantly poorer survival among treated patients. However, studies in which ESAs were administered with the aim of reducing the need for RBC transfusions in patients with chemotherapyassociated anemia demonstrate that the use of these agents is not associated with any adverse effect on survival when compared with placebo controls. We can therefore be reassured that using ESAs within the labeled indications will not adversely affect patient outcome. The Oncologist 2008;13(suppl 3):4 10 Drug Administration and the European Medicines Evaluation Agency urgently to review the available data [12]. In doing so, one important distinction that must be made is between studies that have administered ESAs within their currently accepted indications and those that have investigated the potential risks and benefits of extending their use to wider patient groups. Use according to the label means essentially confining eligibility to patients with chemotherapy-induced anemia, starting treatment only if the baseline Hb level is <11 g/dl, and discontinuing treatment when the Hb level rises to >12 g/dl in the U.S. and keeping Hb levels in the range of g/dl in Europe. Overview of Epoetin Studies Figure 1 shows the hazard ratio (HR) for survival in 12 randomized, double-blinded, placebo-controlled studies of epoetin alfa [2, 3, 7, 12 21]. Values to the left of the central line favor the ESA, values to the right favor placebo. The width of the horizontal bars, on either side of the HR, indicates the 95% confidence interval (CI) around the esti-

2 Gascón 5 Table 1. Overview of meta-analyses of erythropoiesis-stimulating agents (ESAs): Survival Description (No. studies and patients) CT-induced anemia extended analysis set (22; 4,536 patients) 'Cochrane-like' (epoetin alfa only) (35; 6,918 patients) Cochrane (42; 8,167 patients) Updated Cochrane (48; 9,652 patients) Definition of study set used All randomized, controlled, company studies All epoetin alfa studies All ESAs randomized, controlled All ESAs, randomized, controlled + 6 HR (95% CI) on study data 1.17 ( ) 1.17 ( ) 1.08 ( ) 1.03 ( ) HR (95% CI) inc. long-term FU data 1.04 ( ) 0.97 ( ) Abbreviations: CI, confidence interval; CT, chemotherapy; FU, follow-up; HR, hazard ratio; NA, not available. NA NA Figure 1. Meta-analysis on randomized, double-blinded, placebo-controlled studies that were conducted with epoetin alfa: epoetin alfa survival [2, 3, 12 21]. Adapted from Bohlius J, Wilson J, Seidenfeld J et al. Recombinant human erythropoietins and cancer patients: Updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst 2006;98: , with permission. Abbreviations: BEST, Breast Cancer Erythropoietin Survival Trial; CI, confidence interval; ESA, erythropoiesis-stimulating agent; HR, hazard ratio.

3 6 Safety Update on ESAs mate. Ideally an HR of 1.00 shows no negative impact of ESAs on survival. The figure distinguishes between trials in which the use of epoetin alfa can be considered on-label and studies in which the agent was used for patients outside the accepted indications. The only trial that produced an HR that significantly favors placebo (HR, 1.36; 95% CI, ) is the Breast Cancer Erythropoietin Survival Trial (BEST) study [7, 21]. In that trial, the death rate at 1 year among placebo patients was 23.9% and that among patients receiving epoetin alfa was 30.6%. This excess mortality seemed attributable in part to a higher rate of venous thromboembolic events. Those entered into the study had metastatic breast cancer and were receiving first-line chemotherapy. The aim of the trial was to assess the effect on survival and quality of life of maintaining Hb in the range of g/dl. Patients could enter the study if their Hb level was 13 g/dl at baseline or during treatment, and the majority of the 939 women enrolled were nonanemic (the median Hb was 12.8 g/dl). Clearly, this study used epoetin alfa off-label. The HR for on-study mortality from these 12 studies of anemia was 1.13 (95% CI, ). However, this included one study conducted in patients not receiving chemotherapy (Study H87-032, H87-014, H87-015) and two studies (BEST, N93-004) in which treatment went beyond the correction of anemia. Restricting consideration to the nine studies that used epoetin alfa in the chemotherapy setting, and excluding the BEST data because of its off-label use, gives an HR for survival of 1.00 (95% CI, ). Hence, the effect of using this epoetin alfa for its licensed indication of treating chemotherapyinduced anemia appears to be entirely neutral with regard to mortality. Meta-Analyses of Mortality in Studies Using ESAs Figure 2 presents a similar plot, showing the odds ratio (OR) of death and the 95% CI for 36 individual randomized, controlled studies in which ESAs were administered to 9,652 patients [2, 3, 12 19, 21 46]. The figure again makes a distinction between the majority of studies, in which ESAs were used for on-label indications, and the minority (lower third of the list), in which the use was off-label. Meta-analysis of these data using either a fixed effects or a random effects model produces the same conclusion: the overall mortality risk associated with the ESAs is 1.03 (95% CI, ). These data therefore again support the view that the use of ESAs in general has no adverse effect on the risk for death. A previous Cochrane review reported an overall HR of 1.08 (95% CI, ) (Table 1) [3]. The HR for studies limiting entry to patients with an Hb level <10 g/dl was 1.01, and it was 0.98 for patients with an entry Hb of g/dl. The HR significantly favors placebo over ESA only in those studies having an eligibility criterion of >12 g/dl Hb at the start of therapy. In this setting, the HR of treatment is 1.27 (95% CI, ). Two previous meta-analyses, an extended analysis of trials of ESAs in chemotherapy-induced anemia and a Cochrane-like analysis including only epoetin trials, both arrived at an HR of 1.17 (Table 1). In both cases, the confidence interval spanned 1.00, and in both studies the inclusion of longer-term follow-up data suggested a lower HR. Off-Label Use of ESAs Recent attention has been focused particularly on five trials that have investigated the possible role of ESAs outside their labeled indications (Table 2) [5 7, 10, 21, 39, 47]. Of these trials, that of Aapro et al. [39], in metastatic breast cancer patients who were treated with no limit on Hb, reported an HR for epoetin versus placebo of 1.07 [39]. However, as already noted, the HR for mortality of 1.37 found by Leyland-Jones et al. [7], again in metastatic breast cancer, was statistically significant. Importantly, the majority of women in that trial did not meet a conventional definition of anemia. That was true also of the Erythropoietin in Head and Neck Cancer (ENHANCE) study, in which Henke et al. [5] randomized head and neck cancer patients undergoing radiation therapy to an ESA, in the hope of achieving radiosensitization. In that study, the relative risk for death was It was even higher (1.84) in Wright et al. s [48] smaller study of patients with small-cell lung cancer. However, in that trial as well, the Hb value set for inclusion ( 14.5 g/dl) was again set high. In the Amgen study, reporting an HR of 1.22, darbepoetin was given in the nonchemotherapy (non- CT) setting of palliation in progressive disease. The Kaplan Meier survival curves for the BEST, ENHANCE, Amgen non-ct, and Breast Cancer Anemia and the Value of Erythropoietin (BRAVE) studies are shown in Figure 3 [5 7, 10, 21, 39, 47]. In the BEST and ENHANCE studies, the survival rates were lower for patients receiving epoetin than for those receiving placebo. In the BEST, ENHANCE, and BRAVE studies, patients were treated with epoetin beyond the approved Hb target levels [5 7, 21, 39]. The Oncologist Conclusions Overall, therefore, the impression given by these data is reassuring. The use of ESAs in off-label indications cannot be encouraged, and they should be used only within the context of a clinical trial. However, patients with chemo-

4 Gascón 7 Figure 2. Meta-analysis of death for erythropoiesis-stimulating agent (ESA) studies: 39 studies, 9,652 patients; OR, 1.03; 95% CI, [2, 3, 12 19, 21 46]. Meta-analysis using log OR, I 2 = 0. Sensitivity analysis excluding Razzouk, O Shaughnessy, Wilkinson, and INT-47 has a random effects model OR of 1.02 (95% CI, ). Three studies did not report any deaths (Hedenus et al. [30], Cascinu et al. [49], Kurz et al. [50]) but were randomized cancer-induced anemia studies. Adapted from Bohlius J, Wilson J, Seidenfeld J et al. Recombinant human erythropoietins and cancer patients: Updated metaanalysis of 57 studies including 9353 patients. J Natl Cancer Inst 2006;98: , with permission of Oxford University Press. Abbreviations: CI, confidence interval; HR, hazard ratio; OR, odds ratio. Table 2. Off-label erythropoiesis-stimulating agent (ESA) studies [5 7, 10, 21, 39,47] Study (author) BEST (Leyland-Jones) ENHANCE (Henke) EPO-CAN-15 (Wright) Amgen non-ct 103/149 No. patients (ESA/PBO) How outside label Stage 3+4 (E/P; %) 448/456 No Hb limit All metastatic 121/121 High Hb goal RT (non-ct) Tumor type Breast 96% / 99% Head & neck Survival and outcome reasons HR: 1.37 (12 mo) HR: 1.00 (ext) VTEs RR: 1.39 Over-treatment Imbalance in risk factors 52/52 No Hb limit SCLC HR: /444 Non-CT 82.5% / 80.6% BRAVE (Aapro) 231/232 No Hb limit All metastatic Mixed HR: 1.22 Progressive, palliative patients Breast HR: 1.07 Abbreviations: BEST, Breast Cancer Erythropoietin Survival Trial; BRAVE, Breast Cancer Anemia and the Value of Erythropoietin; CT, chemotherapy; E/P, epoietin/placebo; ENHANCE, Erythropoietin in Head and Neck Cancer; EPO-CAN-15, Epoietin-Canadian study-15; Hb, hemoglobin; HR, hazard ratio; PBO, placebo; RR, relative risk; RT, radiotherapy; SCLC, small cell lung cancer; VTE, venous thromboembolism.

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