Erythropoietin or Darbepoetin for patients with cancer meta-analysis based on individual patient data (Review)

Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, Zwahlen M, Clarke MJ, Weingart O, Kluge S, Piper M, Napoli M, Rades D, Steensma D, Djulbegovic B, Fey MF, Ray-Coquard I, Moebus V, Thomas G, Untch M, Schumacher M, Egger M, Engert A

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2010, Issue 11 http://www.thecochranelibrary.com

Erythropoietin or Darbepoetin for patients with cancer - meta-analysis based on individual patient data (Review) Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

[Intervention Review]

Erythropoietin or Darbepoetin for patients with cancer meta-analysis based on individual patient data
Julia Bohlius1 , Kurt Schmidlin1 , Corinne Brillant2 , Guido Schwarzer3 , Sven Trelle1 , Jerome Seidenfeld4 , Marcel Zwahlen1 , Mike J Clarke5 , Olaf Weingart2 , Sabine Kluge2 , Margaret Piper6 , Maryann Napoli7 , Dirk Rades8 , David Steensma9 , Benjamin Djulbegovic 10 , Martin F Fey11 , Isabelle Ray-Coquard12 , Volker Moebus13 , Gillian Thomas14 , Michael Untch15 , Martin Schumacher16 , Matthias Egger17 , Andreas Engert2 Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland. 2 Cochrane Haematological Malignancies Group, Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany. 3 German Cochrane Centre, Insitute of Medical Biometry and Medical Informatics, Freiburg, Germany. 4 Department of Cancer Policy and Clinical Affairs, American Society of Clinical Oncology, Alexandria, VA, USA. 5 UK Cochrane Centre, Oxford, UK. 6 Technology Evaluation Center, Blue Cross and Blue Shield Association, Chicago, IL, USA. 7 Center for Medical Consumers, New York, USA. 8 Department of Radiation Oncology, University Hospital, Lbeck, Germany. 9 Mayo Clinic, Rochester, MN, USA. 10 Professor of Medicine and Oncology, H. Lee Moftt Cancer Center, Center for Evidence Based Medicine and Health Outcomes Research, University of South Florida, Tampa, Florida, USA. 11 Department of Medical Oncology, University and Inselspital Bern, Bern, Switzerland. 12 Centre Lon Brard, Lyon, France. 13 Department of Gynecology, Academic Hospital Frankfurt am Main Hchst, Frankfurt a.M., Germany. 14 Odette Sunnybrook Cancer Centre, University of Toronto, Toronto, Canada. 15 Clinic for Gynaecology, Helios Hospital Berlin-Buch, Berlin, Germany. 16 German Cochrane Center, Institute of Medical Biometry and Medical Informatics, University Medical Center Freiburg, Freiburg, Germany. 17 Institute of Social Medicine, Institute of Social and Preventive Medicine, Bern, Switzerland Contact address: Julia Bohlius, Institute of Social and Preventive Medicine, University of Bern, Bern, 3012, Switzerland. jbohlius@ispm.unibe.ch. jbohlius@ispm.unibe.ch. Editorial group: Cochrane Haematological Malignancies Group. Publication status and date: Edited (no change to conclusions), published in Issue 11, 2010. Review content assessed as up-to-date: 11 May 2009. Citation: Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, Zwahlen M, Clarke MJ, Weingart O, Kluge S, Piper M, Napoli M, Rades D, Steensma D, Djulbegovic B, Fey MF, Ray-Coquard I, Moebus V, Thomas G, Untch M, Schumacher M, Egger M, Engert A. Erythropoietin or Darbepoetin for patients with cancer - meta-analysis based on individual patient data. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD007303. DOI: 10.1002/14651858.CD007303.pub2. Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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ABSTRACT Background Erythropoiesis-stimulating agents (ESAs) reduce anemia in cancer patients and may improve quality of life, but there are concerns that ESAs might increase mortality. Objectives Our objectives were to examine the effect of ESAs and identify factors that modify the effects of ESAs on overall survival, progression free survival, thromboembolic and cardiovascular events as well as need for transfusions and other important safety and efcacy outcomes in cancer patients. Search strategy We searched the Cochrane Library, Medline, Embase and conference proceedings for eligible trials. Manufacturers of ESAs were contacted to identify additional trials.
Erythropoietin or Darbepoetin for patients with cancer - meta-analysis based on individual patient data (Review) Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Selection criteria We included randomized controlled trials comparing epoetin or darbepoetin plus red blood cell transfusions (as necessary) versus red blood cell transfusions (as necessary) alone, to prevent or treat anemia in adult or pediatric cancer patients with or without concurrent antineoplastic therapy. Data collection and analysis We performed a meta-analysis of randomized controlled trials comparing epoetin alpha, epoetin beta or darbepoetin alpha plus red blood cell transfusions versus transfusion alone, for prophylaxis or therapy of anemia while or after receiving anti-cancer treatment. Patient-level data were obtained and analyzed by independent statisticians at two academic departments, using xed-effects and randomeffects meta-analysis. Analyses were according to the intention-to-treat principle. Primary endpoints were on study mortality and overall survival during the longest available follow-up, regardless of anticancer treatment, and in patients receiving chemotherapy. Tests for interactions were used to identify differences in effects of ESAs on mortality across pre-specied subgroups. The present review reports only the results for the primary endpoint. Main results A total of 13933 cancer patients from 53 trials were analyzed, 1530 patients died on-study and 4993 overall. ESAs increased on study mortality (combined hazard ratio [cHR] 1.17; 95% CI 1.06-1.30) and worsened overall survival (cHR 1.06; 95% CI 1.00-1.12), with little heterogeneity between trials (I2 0%, p=0.87 and I2 7.1%, p=0.33, respectively). Thirty-eight trials enrolled 10441 patients receiving chemotherapy. The cHR for on study mortality was 1.10 (95% CI 0.98-1.24) and 1.04; 95% CI 0.97-1.11) for overall survival. There was little evidence for a difference between trials of patients receiving different cancer treatments (P for interaction= 0.42). Authors conclusions ESA treatment in cancer patients increased on study mortality and worsened overall survival. For patients undergoing chemotherapy the increase was less pronounced, but an adverse effect could not be excluded.

PLAIN LANGUAGE SUMMARY Anti-anemia drugs shorten survival for some cancer patients People with cancer may develop a blood problem called anemia, due to the treatment or from the disease itself. They will have very low levels of healthy red blood cells, causing additional health problems. For years, doctors have tried to prevent or treat anemia with injections of erythropoiesis stimulating agents (ESAs) in order to spare cancer patients the many serious harms associated with a redblood cell transfusion (such as hepatitis, transfusion-related acute lung injury, infection). Earlier reviews of the research showed that ESA treatment reduces the need for transfusion but, in recent years, several studies have shown that ESAs themselves cause harm. The drug may, for example, stimulate tumor growth and cause potentially fatal blood clots. In 2007, new studies reported that ESAs shortens survival in people with breast, non-small cell lung, head and neck, lymphoid and cervical cancers. A new systematic review was needed to evaluate the old and the new evidence together and determine the impact of ESAs on survival in cancer patients to see if there are groups of patients who are at increased or decreased risk compared to the average. To accomplish this the authors of this meta-analysis conducted an in-depth assessment of the individual patient data generated by the care of nearly 14,000 patients from 53 trials conducted worldwide. Data on each of these patients were provided by three companies that make ESAs: Amgen, Johnson & Johnson, and Roche, and by several independent researchers. (The drug companies, however, had no role in conducting the meta-analysis.) The trials investigated one of two types of ESAs, epoetin or darbepoetin, and compared the use of one of these drugs plus red blood cell transfusion (as needed), with red blood cell transfusion alone (as needed). Most patients were given their treatment while undergoing anti-cancer therapy (chemotherapy and/or radiotherapy); but others received the treatment after they had completed their anti-cancer therapy. Some patients already had anemia; others were treated in order to prevent it. The patients had many different forms of cancer and many different anti-cancer treatments. The authors of this new meta-analysis concluded that ESA treatment shortens survival. They could not identify with certainty any subgroup of patients at either increased or decreased risk of dying when taking ESAs. With their doctors help, cancer patients should consider the risks of taking ESA against the risks of a blood transfusion. Be aware, however, that uncertainties remain about the magnitude of each.
Erythropoietin or Darbepoetin for patients with cancer - meta-analysis based on individual patient data (Review) Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Erythropoietin or Darbepoetin for patients with cancer - meta-analysis based on individual patient data (Review) Copyright 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.