Article

Venous Thromboembolism and Mortality Associated With Recombinant Erythropoietin and Darbepoetin Administration for the Treatment of Cancer-Associated Anemia

VA Chicago Healthcare System, Department of Medicine, Northwestern University Feinberg School of Medicine, and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 30.39). 03/2008; 299(8):914-24. DOI: 10.1001/jama.299.8.914
Source: PubMed

ABSTRACT The erythropoiesis-stimulating agents (ESAs) erythropoietin and darbepoetin are licensed to treat chemotherapy-associated anemia in patients with nonmyeloid malignancies. Although systematic overviews of trials have identified venous thromboembolism (VTE) risks, none have identified mortality risks with ESAs.
To evaluate VTE and mortality rates associated with ESA administration for the treatment of anemia among patients with cancer.
A published overview from the Cochrane Collaboration (search dates: January 1, 1985-April 1, 2005) and MEDLINE and EMBASE databases (key words: clinical trial, erythropoietin, darbepoetin, and oncology), the public Web site of the US Food and Drug Administration and ESA manufacturers, and safety advisories (search dates: April 1, 2005-January 17, 2008).
Phase 3 trials comparing ESAs with placebo or standard of care for the treatment of anemia among patients with cancer.
Mortality rates, VTE rates, and 95% confidence intervals (CIs) were extracted by 3 reviewers from 51 clinical trials with 13 611 patients that included survival information and 38 clinical trials with 8172 patients that included information on VTE.
Patients with cancer who received ESAs had increased VTE risks (334 VTE events among 4610 patients treated with ESA vs 173 VTE events among 3562 control patients; 7.5% vs 4.9%; relative risk, 1.57; 95% CI, 1.31-1.87) and increased mortality risks (hazard ratio, 1.10; 95% CI, 1.01-1.20).
Erythropoiesis-stimulating agent administration to patients with cancer is associated with increased risks of VTE and mortality. Our findings, in conjunction with basic science studies on erythropoietin and erythropoietin receptors in solid cancers, raise concern about the safety of ESA administration to patients with cancer.

Download full-text

Full-text

Available from: Benjamin Djulbegovic, Dec 19, 2013
2 Followers
 · 
139 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Fatal adverse events (FAEs) have been reported with sorafenib, a vascular endothelial growth factor receptor kinase inhibitor (VEGFR TKI). We here performed an up-to-date and detailed meta-analysis to determine the overall risk of FAEs associated with sorafenib. Methods: Databases, including PubMed, Embase and Web of Science, and abstracts presented at the American Society of Clinical Oncology annual meetings were searched to identify relevant studies. Eligible studies included randomized controlled trials evaluating sorafenib effects in patients with all malignancies. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated for FAEs. In addition, subgroup analyses were performed according to tumor type and therapy regimen. Results: 13 trials recruiting 5,546 patients were included in our analysis. The overall incidence of FAEs with sorafenib was 1.99% (95%CI, 0.98-4.02%). Patients treated with sorafenib had a significantly increased risk of FAEs compared with patients treated with control medication, with an RR of 1.77 (95%CI 1.25-2.52, P=0.001). Risk varied with tumour type, but appeared independent of therapy regimen. A significantly increased risk of FAEs was observed in patients with lung cancer (RR 2.26; 95% CI 1.03-4.99; P= 0.043) and renal cancer (RR 1.84; 95% CI 1.15-2.94; P= 0.011). The most common causes of FAEs were hemorrhage (8.6%) and thrombus or embolism (4.9%). Conclusions: It is important for health care practitioners to be aware of the risks of FAEs associated with sorafenib, especially in patients with renal and lung cancer.
    Asian Pacific journal of cancer prevention: APJCP 11/2013; 14(11):6681-6. DOI:10.7314/APJCP.2013.14.11.6681 · 2.51 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: PURPOSE: Anemia in cancer patients can be a result of the underlying cancer or related to treatment. Erythropoiesis-stimulating agents (ESAs) are an important option for many patients with chemotherapy-induced anemia, but are immersed in controversy. This article aims to reconcile conflicting opinions and provide expert guidance for appropriate ESA use. METHODS: Teleconference, email, and a face-to-face meeting were used to assess ESA therapy "interpretive" data, which included two current meta-analyses, expert guidelines, and regulatory approved indications from Canada, Europe, and the USA. RESULTS: Risks and benefits are associated with both red blood cell transfusions and ESA therapy, including improvements in hemoglobin levels and quality of life. ESAs have been associated with concerns regarding survival and progression of cancer, particularly when used in patients with cancer-related anemia. CONCLUSION: Although safety concerns do exist, ESA therapy can be considered for use in patients with chemotherapy-induced anemia in accordance with Health Canada labeling.
    Critical reviews in oncology/hematology 01/2013; 87(2). DOI:10.1016/j.critrevonc.2012.12.010 · 4.05 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Erythropoietin-stimulating agents (ESAs) effectively decrease the transfusion requirements of patients with chemotherapy-induced anaemia (CIA). Recent studies indicate that ESAs increase mortality and accelerate tumour progression. The studies also identify a 1.6-fold increased risk of venous thromboembolism. The ESA labelling was thus revised in Europe and the United States in 2008. This is the first randomised, phase III trial evaluating the efficacy and safety of epoetin-β (EPO), an ESA, dosed in accordance with the revised labelling, which specifies that ESAs should be administered to CIA patients with a haemoglobin level of ≤ 10 g dl⁻¹ and that a sustained haemoglobin level of > 12 g dl⁻¹ should be avoided. A total of 186 CIA patients (8.0 g dl⁻¹ ≤ haemoglobin ≤ 10.0 g dl⁻¹) with lung or gynaecological cancer were randomised to receive EPO 36,000 IU or placebo weekly for 12 weeks.Results:The proportion of patients receiving transfusions or with haemoglobin < 8.0 g dl⁻¹ between week 5 and the end of the treatment period as the primary end point was significantly lower in the EPO group (n=89) than in the placebo group (n=92; 10.0% vs 56.4%, P < 0.001). The proportion receiving transfusions was significantly lower in the EPO group (4.5% vs 19.6%, P=0.002). Changes in quality of life were not different. No significant differences in adverse events - for example, the incidence of thromboembolic events was 1.1% for each group - or the 1-year overall survival were observed between groups. Weekly EPO administered according to the revised labelling approved by the European Medicines Agency is effective and well tolerated for CIA treatment. Further investigations are needed on the effect of ESAs on mortality.
    British Journal of Cancer 09/2011; 105(9):1267-72. DOI:10.1038/bjc.2011.395 · 4.82 Impact Factor