Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials

doi:10.1016/S0140-6736(09)60502-X

The Lancet

Volume 373, Issue 9674, 2–8 May 2009, Pages 1532-1542

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https://doi.org/10.1016/S0140-6736(09)60502-X Get rights and content

Summary

Background

Erythropoiesis-stimulating agents reduce anaemia in patients with cancer and could improve their quality of life, but these drugs might increase mortality. We therefore did a meta-analysis of randomised controlled trials in which these drugs plus red blood cell transfusions were compared with transfusion alone for prophylaxis or treatment of anaemia in patients with cancer.

Methods

Data for patients treated with epoetin alfa, epoetin beta, or darbepoetin alfa were obtained and analysed by independent statisticians using fixed-effects and random-effects meta-analysis. Analyses were by intention to treat. Primary endpoints were mortality during the active study period and overall survival during the longest available follow-up, irrespective of anticancer treatment, and in patients given chemotherapy. Tests for interactions were used to identify differences in effects of erythropoiesis-stimulating agents on mortality across prespecified subgroups.

Findings

Data from a total of 13 933 patients with cancer in 53 trials were analysed. 1530 patients died during the active study period and 4993 overall. Erythropoiesis-stimulating agents increased mortality during the active study period (combined hazard ratio [cHR] 1·17, 95% CI 1·06–1·30) and worsened overall survival (1·06, 1·00–1·12), with little heterogeneity between trials (I² 0%, p=0·87 for mortality during the active study period, and I² 7·1%, p=0·33 for overall survival). 10 441 patients on chemotherapy were enrolled in 38 trials. The cHR for mortality during the active study period was 1·10 (0·98–1·24), and 1·04 (0·97–1·11) for overall survival. There was little evidence for a difference between trials of patients given different anticancer treatments (p for interaction=0·42).

Interpretation

Treatment with erythropoiesis-stimulating agents in patients with cancer increased mortality during active study periods and worsened overall survival. The increased risk of death associated with treatment with these drugs should be balanced against their benefits.

Funding

German Federal Ministry of Education and Research, Medical Faculty of University of Cologne, and Oncosuisse (Switzerland).

Introduction

Erythropoiesis-stimulating agents increase haemoglobin concentrations, reduce the need for red blood cell transfusions, and could improve quality of life in patients with cancer.1, 2, 3 However, they have been reported to increase the risk of thromboembolic events2, 4 and might stimulate tumour growth.⁵ Uncertainty remains about whether and how these drugs affect survival; their safety has been discussed repeatedly at hearings of the US Food and Drug Administration and the European Medicines Agency.4, 6, 7, 8, 9, 10, 11, 12

Previous studies addressing this issue were literature-based meta-analyses of aggregated results that combined heterogeneous mortality endpoints and could not examine whether effects differed across subgroups—eg, patients with different haemoglobin concentrations at baseline.2, 3, 4 These limitations can be overcome in meta-analyses that are based on individual patient data, but up till now such meta-analyses have been small (2301¹³ and 2112¹⁴ patients), focused on epoetin beta or darbepoetin alfa, and were sponsored by the manufacturers.13, 14 Since erythropoiesis-stimulating drugs are widely used in patients with cancer, more definitive analyses of mortality in individuals randomly assigned to receive or not to receive these drugs are needed.

We therefore did a comprehensive meta-analysis that was based on the individual patient data from randomised controlled trials, including trials done by manufacturers of erythropoiesis-stimulating agents and independent investigators. Our objectives were to examine the effects of these drugs on the survival of patients with cancer and to identify factors that might modify such effects.

Section snippets

Patients and study selection

Main analyses were defined in a peer-reviewed protocol¹⁵ and a statistical analysis plan, and main analyses were done independently in two academic departments. A steering committee consisting of clinicians and methodologists reviewed results and agreed on their interpretation.

In eligible studies, epoetin or darbepoetin plus red blood cell transfusions (as necessary) were compared with red blood cell transfusions (as necessary) alone to prevent or treat anaemia in adult or paediatric patients

Results

We identified 63 eligible studies and 53 (84%) contributed individual patient data (figure 1). Three manufacturers of erythropoiesis-stimulating agents (Amgen, Johnson & Johnson, and Hoffmann-La Roche) and five independent investigators provided individual patient data.9, 22, 23, 24, 25 14 206 patients were included in the dataset; 273 (2%) were excluded for the following reasons: no study arm was allocated (n=164), they had leukaemia and were included in a separate stratum (n=98),²⁶ or date of

Discussion

Erythropoiesis-stimulating agents caused an estimated 17% increase in mortality relative to control during the active study periods in all patients with cancer and a 10% increase in relation to control in those undergoing chemotherapy. There was little evidence for differences in effects across different patient groups and trials. In particular, although mortality during the active study periods was less markedly increased in patients given chemotherapy than those given other treatments, this

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ArticlesRecombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Patients and study selection

Results

Discussion

Lancet

Gynecol Oncol

Int J Radiat Oncol Biol Phys

Eur J Cancer

Lung Cancer

Lancet Oncol

Blood

Blood

Ann Oncol

Eur J Cancer

Lung Cancer

J Pain Symptom Manage

Eur J Cancer

Lancet

Am J Kidney Dis

Blood

Epoetin treatment of anemia associated with cancer therapy: a systematic review and meta-analysis of controlled clinical trials

J Natl Cancer Inst

Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients

J Natl Cancer Inst

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

Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia

JAMA

Do erythropoietin receptors on cancer cells explain unexpected clinical findings?

J Clin Oncol

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

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 randomized trial

Eur J Cancer

Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia

J Clin Oncol

Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study

Br J Haematol

ESAs further restricted, but debate continues

J Natl Cancer Inst

Effect of treatment with epoetin-beta on survival, tumour progression and thromboembolic events in patients with cancer: an updated meta-analysis of 12 randomised controlled studies including 2301 patients

Br J Cancer

Evaluation of the association between hemoglobin (Hb) events and safety outcomes in cancer patients (pts) with chemotherapy-induced anemia (CIA): an integrated analysis of patient-level data from 6 randomized, placebo-controlled trials (RCTs) of darbepoetin alpha (DA)

Eur J Cancer

Erythropoietin or darbepoetin for patients with cancer—meta-analysis based on individual patient data (Protocol)

Cochrane Database Syst Rev

Meta-analysis of individual patient data from randomized trials: a review of methods used in practice

Clin Trials

Bias in meta-analysis detected by a simple, graphical test

BMJ

Rationale, potentials, and promise of systematic reviews

Estimating treatment effects from randomized clinical trials with noncompliance and loss to follow-up: the role of instrumental variable methods

Stat Methods Med Res

Calculating the number needed to treat for trials where the outcome is time to an event

BMJ

R: a language for data analysis and graphics

J Comput Graph Stat

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 trial)

J Clin Oncol

J Clin Oncol

ELYPSE 4: a prospective randomized trial comparing Epo A in primary prophylaxis of severe anemia requiring red cells transfusion in high risk patients

Ann Oncol

Double-blind, placebo-controlled study of quality of life, hematologic end points, and safety of weekly epoetin alfa in children with cancer receiving myelosuppressive chemotherapy

J Clin Oncol

Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy

J Natl Cancer Inst

Safety and efficacy of darbepoetin alpha in previously untreated extensive-stage small-cell lung cancer treated with platinum plus etoposide

J Clin Oncol

Randomized, double-blind, placebo-controlled study of darbepoetin alfa every 3 weeks for the treatment of chemotherapy-induced anemia

Blood

Randomized, double-blind, placebo-controlled, dose-finding study of darbepoetin alfa administered once every 3 (Q3W) or 4 (Q4W) weeks in patients with solid tumors

Proc Am Soc Clin Oncol

Articles
Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials