Intervention Review

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

  1. Julia Bohlius1,*,
  2. Kurt Schmidlin1,
  3. Corinne Brillant2,
  4. Guido Schwarzer3,
  5. Sven Trelle1,
  6. Jerome Seidenfeld4,
  7. Marcel Zwahlen1,
  8. Mike J Clarke5,
  9. Olaf Weingart2,
  10. Sabine Kluge2,
  11. Margaret Piper6,
  12. Maryann Napoli7,
  13. Dirk Rades8,
  14. David Steensma9,
  15. Benjamin Djulbegovic10,
  16. Martin F Fey11,
  17. Isabelle Ray-Coquard12,
  18. Volker Moebus13,
  19. Gillian Thomas14,
  20. Michael Untch15,
  21. Martin Schumacher16,
  22. Matthias Egger17,
  23. Andreas Engert2

Editorial Group: Cochrane Haematological Malignancies Group

Published Online: 8 JUL 2009

Assessed as up-to-date: 11 MAY 2009

DOI: 10.1002/14651858.CD007303.pub2

Database Title

Additional Information

How to Cite

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.

Author Information

  1. 1

    University of Bern, Institute of Social and Preventive Medicine, Bern, Switzerland

  2. 2

    University Hospital of Cologne, Cochrane Haematological Malignancies Group, Department I of Internal Medicine, Cologne, Germany

  3. 3

    Insitute of Medical Biometry and Medical Informatics, German Cochrane Centre, Freiburg, Germany

  4. 4

    American Society of Clinical Oncology, Department of Cancer Policy and Clinical Affairs, Alexandria, VA, USA

  5. 5

    UK Cochrane Centre, Oxford, UK

  6. 6

    Blue Cross and Blue Shield Association, Technology Evaluation Center, Chicago, IL, USA

  7. 7

    Center for Medical Consumers, New York, USA

  8. 8

    University Hospital, Department of Radiation Oncology, Lübeck, Germany

  9. 9

    Mayo Clinic, Rochester, MN, USA

  10. 10

    Center for Evidence Based Medicine and Health Outcomes Research, University of South Florida, Professor of Medicine and Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida, USA

  11. 11

    University and Inselspital Bern, Department of Medical Oncology, Bern, Switzerland

  12. 12

    Centre Léon Bérard, Lyon, France

  13. 13

    Academic Hospital Frankfurt am Main Höchst, Department of Gynecology, Frankfurt a.M., Germany

  14. 14

    University of Toronto, Odette Sunnybrook Cancer Centre, Toronto, Ontario, Canada

  15. 15

    Helios Hospital Berlin-Buch, Clinic for Gynaecology, Berlin, Germany

  16. 16

    Institute of Medical Biometry and Medical Informatics, University Medical Center Freiburg, German Cochrane Center, Freiburg, Germany

  17. 17

    Institute of Social and Preventive Medicine, Institute of Social Medicine, Bern, Switzerland

*Julia Bohlius, Institute of Social and Preventive Medicine, University of Bern, Bern, 3012, Switzerland. jbohlius@ispm.unibe.ch. jbohlius@ispm.unibe.ch.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 8 JUL 2009

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Abstract

  1. Top of page
  2. Abstract
  3. Plain language summary
  4. 摘要

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 efficacy outcomes in cancer patients.

Search methods

We searched the Cochrane Library, Medline, Embase and conference proceedings for eligible trials. Manufacturers of ESAs were contacted to identify additional trials.

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 fixed-effects and random-effects 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-specified 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

  1. Top of page
  2. Abstract
  3. Plain language summary
  4. 摘要

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 red-blood 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.

 

摘要

  1. Top of page
  2. Abstract
  3. Plain language summary
  4. 摘要

背景

促紅血球生成素(Erythropoietin)或達貝泊汀(Darbepoetin)使用於癌症病人利用統合分析法研究個別病人資料

促紅血球生成刺激劑(ESAs)能減少癌症患者的貧血且可能改善生活品質,但亦有人擔心促紅血球生成刺激劑可能會增加死亡率.

目標

我們的目標是研究促紅血球生成刺激劑的影響, 及確定促紅血球生成刺激劑在癌症病人上對其總生存率, 無進展生存率, 血栓栓塞及心血管事件以及是否需要輸血和其他重要安全性和結果有效性的影響因素.

搜尋策略

我們檢索了Cochrane Library, Medline, Embase和會議記錄的合格試驗. 也和促紅血球生成刺激劑的製造商進行聯繫以確定更多的研究.

選擇標準

我們包括隨機對照試驗比較紅血球生成素或達貝泊汀(若必要時)加紅血球輸注, 與(若必要時)單純紅血球輸注, 以預防或治療貧血在成人或兒童癌症患者, 不論其有或無合併抗腫瘤治療.

資料收集與分析

我們進行了一項統合分析, 以隨機對照試驗比較紅血球生成素α (Epoetin alpha), 紅血球生成素β(Epoetin beta)或達貝泊汀α (darbepoetin alpha) 加上紅血球輸注與單純紅血球輸注, 用於預防或治療在接受抗癌治療期間或之後的貧血. 我們取得病人數據並以兩個獨立的學術部門統計分析, 利用固定效應(fixedeffects)和隨機效應統合分析(randomeffects metaanalysis). 分析是根據治療意向分析法為原則. 主要研究終點是不管患者接受抗癌治療或化學治療在可獲得的最長時間追蹤的死亡率和總生存期. 交互作用的檢測用來辨別促紅血球生成刺激劑在預先指定的次族群死亡率影響的差異

主要結論

來自53個試驗的總共13933位癌症病人被分析. 1530位病人在研究過程中死亡而全部共有4993位死亡. 促紅血球生成刺激劑增加了研究中的死亡率(合併危險比[cHR] 1.17; 95％CI為1.06至1.30)且惡化了整體存活期(cHR 1.06; 95％CI為1.00 – 1.12), 試驗間的異質性很少(各為I2 0％, p = 0.87和I2 7.1％, p = 0.33). 38個試驗中收集10441個接受化療的患者. 在研究中死亡率的cHR為1.10(95％CI為0.98 – 1.24)和整體存活率的cHR為1.04(95％CI為0.97 – 1.11). 只有很少的證據顯示在病人接受癌症不同治療的試驗上有差異(P for interaction = 0.42).

作者結論

促紅血球生成刺激劑在癌症病人的治療上增加了研究中的死亡率及惡化存活率. 接受化療期間,病人使用促紅血球生成刺激劑的增加不太明顯, 但其不良的影響不能排除.

翻譯人

本摘要由慈濟醫院吳懿峰翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

癌症病人可能發展出稱之為貧血的血液相關的問題,其可來自於治療或疾病本身.他們有低於水平的健康紅血球, 進而造成更多的健康問題. 多年來, 醫生們以促紅血球生成刺激劑試圖預防或治療貧血, 為了免去癌症病人因紅血球輸注造成的許多嚴重危害(如肝炎, 輸血相關急性肺損傷, 感染). 在早期文獻回顧的研究中顯示促紅血球生成刺激劑的治療能減少輸血的需要, 但近幾年,很多研究顯示促紅血球生成刺激劑本身亦會造成損害. 例如，這種藥物可能會刺激腫瘤的生長, 並造成致命血栓. 2007年, 新的研究報告顯示, 促紅血球生成刺激劑縮短了乳癌、非小細胞肺癌、頭頸部、淋巴和子宮頸癌病人的生存期.一個新的系統性的回顧被需要去進行以同時評估舊的和新的證據, 來確定促紅血球生成刺激劑對癌症患者存活期的影響, 看看是否有哪群患者可增加或減少風險. 要做到這一點, 這個統合分析的作者從全球53個試驗共有近14,000位病人中進行了深入評估個別病人的數據. 每個患者的數據主要由三家製造促紅血球生成刺激劑的公司提供: Amgen, Johnson & Johnson, 和Roche, 以及一些獨立研究人員. (然而, 藥廠沒有參與統合分析的執行)這些試驗研究兩種類型的促紅血球生成刺激劑, 紅血球生成素或達貝泊汀, 並比較了使用其中一種藥物加上紅血球輸注(如需要), 與單純紅血球輸注(如需要). 大多數患者在接受抗癌治療(化學治療和/或 放射線治療)時給予治療, 但一部份人在完成其抗癌療法後才接受促紅血球生成刺激劑或輸血治療. 有些患者已經有了貧血, 有些則是為了預防貧血. 病人有許多不同形式的癌症和許多不同的抗癌治療. 這一新的統合分析作者的結論是，促紅血球生成刺激劑會縮短存活期. 他們無法確切確定任何次群體病人在使用促紅血球生成刺激劑會增加或減少死亡風險. 在醫生幫助下, 癌症病人應該考慮的使用促紅血球生成刺激劑及輸血治療的風險. 請注意, 其重要性仍然存在有不確定性.

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