Supportive Care in Cancer

, Volume 21, Issue 8, pp 2359–2369 | Cite as

Prognostic impact of the combination of erythropoiesis-stimulating agents to cancer treatment: literature review

  • L. Boulaamane
  • A. Goncalves
  • S. Boutayeb
  • P. Viens
  • H. M’rabti
  • F. Bertucci
  • H. Errihani
Review Article


Cancer patients commonly develop anaemia. Erythropoiesis-stimulating agents (ESAs) are frequently used in cancer treatment. Numerous controlled studies indicate that ESAs can raise haemoglobin levels, reduce transfusion requirements and improve quality of life in anaemic cancer patients receiving chemotherapy. They were previously used to enhance response to radiation therapy, via increasing tumour cell oxygenation. Since the 2002 guideline, there has been increasing attention to the safety of ESA treatment in patients with cancer. Two placebo-controlled phase III randomised clinical trials published in 2003 showed evidence of harmful effects of ESAs on survival and/or tumour outcomes. Subsequently, recent trials and several large meta-analyses have confirmed negative impact on survival and/or disease progression. To comprehensively examine whether ESA use affects safety outcomes in cancer patients in different settings (chemotherapy, radiotherapy and targeted therapies), we conducted a literature review of all clinical trials, small and large meta-analyses from 1990 to 2012.


Epoetin Darbepoetin Erythropoiesis-stimulating agents Survival Progression-free survival Meta-analysis 


  1. 1.
    Groopman JE, Itri LM (1999) Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst 91:1616–1634PubMedCrossRefGoogle Scholar
  2. 2.
    Egrie JC, Strickland TW, Lane J, Aoki K, Cohen AM, Smalling R, Trail G, Lin FK, Browne JK, Hines DK (1986) Characterization and biological effects of recombinant human erythropoietin. Immunobiology 172:213–224PubMedCrossRefGoogle Scholar
  3. 3.
    Klein HG, Spahn DR, Carson JL (2007) Red blood cell transfusion in clinical practice. Lancet 370:415–426PubMedCrossRefGoogle Scholar
  4. 4.
    Littlewood TJ, Bajetta E, Nortier JW, Vercammen E, Rapoport B (2001) Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving non platinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol 19:2865–2874PubMedGoogle Scholar
  5. 5.
    Vansteenkiste J, Pirker R, Massuti B, Barata F, Font A, Fiegl M, Siena S, Gateley J, Tomita D, Colowick AB, Musil J, Aranesp 980297 Study Group (2002) Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst 94:1211–1220PubMedCrossRefGoogle Scholar
  6. 6.
    Ross SD, Allen IE, Henry DH, Seaman C, Sercus B, Goodnough LT (2006) Clinical benefits and risks associated with epoetin and darbepoetin in patients with chemotherapy-induced anemia: a systematic review of the literature. Clin Ther 28:801–831PubMedCrossRefGoogle Scholar
  7. 7.
    Bokemeyer C, Aapro MS, Courdi A, Foubert J, Link H, Osterborg A, Repetto L, Soubeyran P (2007) EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer: 2006 update. Eur J Cancer 43:258–270PubMedCrossRefGoogle Scholar
  8. 8.
    Amgen. Aranesps(Darbepoetin alfa) (2011) Package Insert. Amgen Inc, Thousand OaksGoogle Scholar
  9. 9.
    eMC (2011) Electronic Medicines Compendium (eMC) website Available from
  10. 10.
    EMEA (2011) European public assessment reports for authorised medicinal products for human use. European Medicines Agency website Available from
  11. 11.
    Bohlius JF, Langensiepen S, Engert A, Schwarzer G, Bennett CL (2005) Effectiveness of erythropoietin in the treatment of patients with malignancies: methods and preliminary results of a Cochrane review. Best Practice & Research. Clin Haematol 18(3):449–454Google Scholar
  12. 12.
    Bennett CL, Silver SM, Djulbegovic B, Samaras AT, Blau CA, Gleason KJ, Barnato SE, Elverman KM, Courtney DM, McKoy JM, Edwards BJ, Tigue CC, Raisch DW, Yarnold PR, Dorr DA, Kuzel TM, Tallman MS, Trifilio SM, West DP, Lai SY, Henke M (2008) Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 299:914–924PubMedCrossRefGoogle Scholar
  13. 13.
    Glaspy J, Crawford J, Vansteenkiste J, Henry D, Rao S, Bowers P, Berlin JA, Tomita D, Bridges K, Ludwig H (2010) Erythropoiesis-stimulating agents in oncology: a study-level meta-analysis of survival and other safety outcomes. Br J Cancer 102:301–315PubMedCrossRefGoogle Scholar
  14. 14.
    Henke M, Laszig R, Rube C, Schafer U, Haase KD, Schilcher B, Mose S, Beer KT, Burger U, Dougherty C, Frommhold H (2003) Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 362:1255–1260PubMedCrossRefGoogle Scholar
  15. 15.
    Overgaard J, Hoff C, Sand Hansen H, Specht L, Overgaard M, Grau C, Andersen E, Johansen J, Andersen L, Evensen J (2007) Randomized study of the importance of novel erythropoiesis stimulating protein (Aranesps) 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 4:7, Abstract 628Google Scholar
  16. 16.
    Wright JR, Ung YC, Julian JA, Pritchard KI, Whelan TJ, Smith C, Szechtman B, Roa W, Mulroy L, Rudinskas L, Gagnon B, Okawara GS, Levine MN (2007) Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol 25:1027–1032PubMedCrossRefGoogle Scholar
  17. 17.
    Smith RE Jr, Aapro MS, Ludwig H, Pinter T, Smakal M, Ciuleanu TE, Chen L, Lillie T, Glaspy JA (2008) Darbepoetin alfa for the treatment of anemia in patients with active cancer not receiving chemotherapy or radiotherapy: results of a phase III, multicenter, randomized, double-blind, placebo-controlled study. J Clin Oncol 26:1040–1050PubMedCrossRefGoogle Scholar
  18. 18.
    Hedenus M, Adriansson M, San Miguel J, Kramer MH, Schipperus MR, Juvonen E, Taylor K, Belch A, Altes A, Martinelli G, Watson D, Matcham J, Rossi G, Littlewood TJ (2003) Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study. Br J Haematol 122:394–403PubMedCrossRefGoogle Scholar
  19. 19.
    Leyland-Jones B, Semiglazov V, Pawlicki M, Pienkowski T, Tjulandin S, Manikhas G, Makhson A, Roth A, Dodwell D, Baselga J, Biakhov M, Valuckas K, Voznyi E, Liu X, Vercammen E (2005) 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 23:5960–5972PubMedCrossRefGoogle Scholar
  20. 20.
    Amgen (2007) Amgen announces interim results of Aranesps ‘PREPARE’ study in breast cancer patients (Amgen press release). Nov 30, 2007; Available from: [Accessed February 29, 2008]
  21. 21.
    ODAC (2008) Amgen Inc. in collaboration with Johnson & Johnson Pharmaceutical Research and Development, L.L.C. Background Information. For The Oncologic Drugs Advisory Comittee (ODAC) Meeting 13 March 2008. Available from: [Accessed March 21, 2008]
  22. 22.
    EMEA (2008) European public assessment reports for authorised medicinal products for human use. European Medicines Agency website. Available from: [Accessed October 29, 2008]
  23. 23.
    eMC (2008) electronic Medicines Compendium (eMC) website. Available from: [Accessed October 29, 2008]
  24. 24.
    Amgen (2009) Aranesps (Darbepoetin alfa) Package Insert. Amgen Inc, Thousand OaksGoogle Scholar
  25. 25.
    Ortho (2009) Procrits (Epoetin alfa) Package Insert. Centocor Ortho Biotech Inc, RaritanGoogle Scholar
  26. 26.
    Overgaard J, Hoff C, Hansen HS, Specht L, Overgaard M, Grau C, Andersen E, Johansen J, Andersen LJ, Evensen JF (2010) Randomized study of Aranesp as modifier of radiotherapy in patients with primary squamous cell carcinoma of the head and neck (HNSCC)—final outcome of the DAHANCA 10 trial. Radiother Oncol 96(Suppl 15): abstract 197Google Scholar
  27. 27.
    Thomas G, Ali S, Hoebers FJ, Darcy KM, Rodgers WH, Patel M, Abulafia O, Lucci JA 3rd, Begg AC (2008) Phase III trial to evaluate the efficacy of maintaining hemoglobin levels above 12.0 g/dl with erythropoietin vs above 10.0 g/dl without erythropoietin in anemic patients receiving concurrent radiation and cisplatin for cervical cancer. Gynecol Oncol 108:317–325PubMedCrossRefGoogle Scholar
  28. 28.
    Untch M, von Minckwitz G, Konecny GE, Conrad U, Fett W, Kurzeder C, Luck HJ, Stickeler E, Urbaczyk H, Liedtke B, Beckmann MW, Salat C, Harbeck N, Muller V, Schmidt M, Hasmuller S, Lenhard M, Nekljudova V, Loibl S, Fasching PA (2011) PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel, and CMF versus a standard dosed epirubicin-cyclophosphamide followed by paclitaxel with or without darbepoetin alfa in primary breast cancer—outcome on prognosis. Ann Oncol 22:1999–2006PubMedCrossRefGoogle Scholar
  29. 29.
    Henke M, Mattern D, Pepe M, Bezay C, Weissenberger C, Werner M, Pajonk F (2006) Do erythropoietin receptors on cancer cells explain unexpected clinical findings? J Clin Oncol 24:4708–4713PubMedCrossRefGoogle Scholar
  30. 30.
    Danish Head and Neck Cancer Group (DAHANCA) (2006) Study of the importance of Novel Erthropoiesis Stimulating Protein (Aranesp) for the effect of radiotherapy in patients with primary squamous cell carinoma of the head and neck.
  31. 31.
    Machtay M, Pajak TF, Suntharalingam M et al (2007) Radiation Therapy Oncology Group. Radiotherapy with or without erythropoietin for anemic patients with head and neck cancer: a randomized trial of the radiation therapy oncology group (RTOG 99–03). Int J Radiat Oncol Biol Phys 69(4):1008–1017PubMedCrossRefGoogle Scholar
  32. 32.
    Hoskin PJ, Robinson M, Slevin N, Morgan D, Harrington K, Gaffney C (2009) Effect of epoetin alfa on survival and cancer treatment-related anemia and fatigue in patients receiving radical radiotherapy with curative intent for head and neck cancer. J Clin Oncol 27:5751–5756PubMedCrossRefGoogle Scholar
  33. 33.
    Blohmer J-U, Wurschmidt F, Petry U et al (2003) Results with sequential adjuvant chemo-radiotherapy with vs without epoetin alfa for patients with high-risk cervical cancer: results of a prospective, randomized, open and controlled AGO and NOGGO-intergroup study. Paper presented at: European Cancer Conference; September 21–25, Copenhagen, Denmark. Abstract 477PDGoogle Scholar
  34. 34.
    Amgen (2008) Amgen Inc. in collaboration with Johnson & Johnson Pharmaceutical Research and Development, L.L.C. Background Information. For The Oncologic Drugs Advisory Comittee (ODAC) Meeting. 13 March 2008 available from
  35. 35.
    Untch M, Fasching PA, Konecny GE, von Koch F, Conrad U, Fett W, Kurzeder C, Luck HJ, Stickeler E, Urbaczyk H, Liedtke B, Salat C, Harbeck N, Muller V, Schmidt M, Hasmuller S, Lenhard M, Schuster T, Nekljudova V, Loibl S, von Minckwitz G (2011) PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose intensified chemotherapy with epirubicin, paclitaxel and CMF versus a standard-dosed epirubicin/cyclophosphamide followed by paclitaxel {+/−} darbepoetin alfa in primary breast cancer—results at the time of surge. Ann Oncol 22:1988–1998PubMedCrossRefGoogle Scholar
  36. 36.
    Roddy JV, Partridge SM, Rockey ML, Pruemer JM, Guo JJ, Desai SJ, Safa MM (2010) Thromboembolic events in patients with colorectal cancer receiving the combination of bevacizumab-based chemotherapy and erythropoietin stimulating agents. Am J Clin Oncol 33(1):36–42PubMedCrossRefGoogle Scholar
  37. 37.
    Moebus V, Jackisch C, Lueck HJ, du Bois A, Thomssen C, Kurbacher C, Kuhn W, Nitz U, Schneeweiss A, Huober J, Harbeck N, von Minckwitz G, Runnebaum IB, Hinke A, Kreienberg R, Konecny GE, Untch M (2010) Intense dose-dense sequential chemotherapy with epirubicin, paclitaxel, and cyclophosphamide compared with conventionally scheduled chemotherapy in high-risk primary breast cancer: mature results of an AGO phase III study. J Clin Oncol 28:2874–2880PubMedCrossRefGoogle Scholar
  38. 38.
    Nitz U, Gluz O, Oberhoff C, Reimer T, Schumacher C, Hackmann J, Warm M, Uleer C, Runde V, Kuemmel S, Zuna I, Harbeck N (2011) Adjuvant chemotherapy with or without darbepoetin alpha in node-positive breast cancer: survival and quality of life analysis from the prospective randomized WSG ARA Plus trial. Paper presented at The 34th San Antonio Breast Cancer Symposium; December 6–10, 2011; San Antonio, United StatesGoogle Scholar
  39. 39.
    Pirker R, Ramlau RA, Schuette W, Zatloukal P, Ferreira I, Lillie T, Vansteenkiste JF (2008) Safety and efficacy of darbepoetin alfa in previously untreated extensive-stage small-cell lung cancer treated with platinum plus etoposide. J Clin Oncol 26:2342–2349PubMedCrossRefGoogle Scholar
  40. 40.
    Engert A, Josting A, Haverkamp H, Villalobos M, Lohri A, Sokler M, Zijlstra J, Sturm I, Topp MS, Rank A, Zenz T, Vogelhuber M, Nogova L, Borchmann P, Fuchs M, Flechtner HH, Diehl V (2010) Epoetin alfa in patients with advanced-stage Hodgkin’s lymphoma: results of the randomized placebo-controlled GHSG HD15EPO trial. J Clin Oncol 28:2239–2245PubMedCrossRefGoogle Scholar
  41. 41.
    Delarue R, Haioun C, Coiffier B, Fornecker L, Fournier M, Mounier N, Molina TJ, Bologna S, Fruchart C, Picard S, Tilly H, Bosly A (2011) Survival effect of darbepoetin alfa in patients with diffuse large B-cell lymphoma (DLBCL) treated with immunochemotherapy: The LNH03-6B study. J Clin Oncol 29(Suppl 15): abstract 9048Google Scholar
  42. 42.
    Katodritou E, Verrou E, Hadjiaggelidou C, Gastari V, Laschos K, Kontovinis L, Kapetanos D, Constantinou N, Terpos E, Zervas K (2008) Erythropoiesis-stimulating agents are associated with reduced survival in patients with multiple myeloma. Am J Hematol 83:697–701PubMedCrossRefGoogle Scholar
  43. 43.
    Hershman DL, Buono DL, Malin J, McBride R, Tsai WY, Neugut AI (2009) Patterns of use and risks associated with erythropoiesis-stimulating agents among Medicare patients with cancer. J Natl Cancer Inst 101:1633–1641PubMedCrossRefGoogle Scholar
  44. 44.
    Wagner LM, Billups CA, Furman WL, Rao BN, Santana VM (2004) Combined use of erythropoietin and granulocyte colony-stimulating factor does not decrease blood transfusion requirements during induction therapy for high-risk neuroblastoma: a randomized controlled trial. J Clin Oncol 22:1886–1893PubMedCrossRefGoogle Scholar
  45. 45.
    Reed SD, Radeva JI, Daniel DB, Fastenau JM, Williams D, Schulman KA (2005) Early hemoglobin response and alternative metrics of efficacy with erythropoietic agents for chemotherapy-related anemia. Curr Med Res Opin 21:1527–1533PubMedCrossRefGoogle Scholar
  46. 46.
    Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, Zwahlen M, Clarke M, Weingart O, Kluge S, Piper M, Rades D, Steensma DP, Djulbegovic B, Fey MF, Ray-Coquard I, Machtay M, Moebus V, Thomas G, Untch M, Schumacher M, Egger M, Engert A (2009) Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet 373:1532–1542PubMedCrossRefGoogle Scholar
  47. 47.
    Gupta S, Singh PK, Bisth SS, Bhatt ML, Pant M, Gupta R, Singh S, Negi MP (2009) Role of recombinant human erythropoietin in patients of advanced cervical cancer treated ‘by chemoradiotherapy‘. Cancer Biol Ther 8:13–17PubMedCrossRefGoogle Scholar
  48. 48.
    Ludwig H, Crawford J, Osterborg A, Vansteenkiste J, Henry DH, Fleishman A, Bridges K, Glaspy JA (2009) Pooled analysis of individual patient-level data from all randomized, double-blind, placebo-controlled trials of darbepoetin alfa in the treatment of patients with chemotherapy-induced anemia. J Clin Oncol 27:2838–2847PubMedCrossRefGoogle Scholar
  49. 49.
    Nagel S, Kellner O, Engel-Riedel W, Guetz S, Schumann C, Gieseler F, Schuette W (2011) Addition of darbepoetin alfa to dose-dense chemotherapy: results from a randomized phase II trial in small-cell lung cancer patients receiving carboplatin plus etoposide. Clin Lung Cancer 12:62–69PubMedCrossRefGoogle Scholar
  50. 50.
    Food and Drug Administration Oncologic Drugs Advisory Committee Briefing Document (2007) Continuing Reassessment of the Risks of Erythropoiesis-Simulating Agents (ESAs) Administered for the Treatment of Anemia associated with Cancer Chemotherapy.
  51. 51.
    Bohlius J, Wilson J, Seidenfeld J, Piper M, Schwarzer G, Sandercock J, Trelle S, Weingart O, Bayliss S, Djulbegovic B, Bennett CL, Langensiepen S, Hyde C, Engert A (2006) Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst 98:708–714PubMedCrossRefGoogle Scholar
  52. 52.
    Tonelli M, Hemmelgarn B, Reiman T, Manns B, Reaume MN, Lloyd A, Wiebe N, Klarenbach S (2009) Benefits and harms of erythropoiesis stimulating agents for anemia related to cancer: a meta-analysis. CMAJ 180:62–71CrossRefGoogle Scholar
  53. 53.
    Lambin P, Ramaekers BLT, van Mastrigt GAPG, Van den Ende P, de Jong J, De Ruysscher DKM, Pijls-Johannesma M (2009) Erythropoietin as an adjuvant treatment with (chemo) radiation therapy for head and neck cancer (Review). Cochrane Database of Systematic Reviews 2009, Issue 3.Google Scholar
  54. 54.
    Hedenus M, Vansteenkiste J, Kotasek D, Austin M, Amado RG (2005) Darbepoetin alfa for the treatment of chemotherapy-induced anemia: disease progression and survival analysis from four randomized, double-blind, placebo-controlled trials. J Clin Oncol 23:6941–6948PubMedCrossRefGoogle Scholar
  55. 55.
    Boogaerts M, Oberhoff C, Ten Bokkel HW, Nowrousian MR, Hayward CR, Burger HU (2006) Epoetin beta (NeoRecormon) therapy in patients with solid tumours receiving platinum and non-platinum chemotherapy: a meta-analysis. Anticancer Res 26:479–484PubMedGoogle Scholar
  56. 56.
    Seidenfeld J, Piper M, Bohlius J, Weingart O, Trelle S, Engert A, Skoetz N, Schwarzer G, Wilson J, Brunskill S, Hyde C, Bonnell C, Ziegler KM, Aronson N (2006) Comparative effectiveness of epoetin and darbepoetin for managing anemia in patients undergoing cancer treatment comparative effectiveness Review no. 3. (Prepared by Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. 290-02-0026). Agency for Healthcare Research and Quality: Rockville, MD. May 2006 Available from
  57. 57.
    Aapro M, Osterwalder B, Scherhag A, Burger HU (2009) Epoetin-beta treatment in patients with cancer chemotherapy-induced anaemia: the impact of initial haemoglobin and target haemoglobin levels on survival, tumour progression and thromboembolic events. Br J Cancer 101:1961–1971PubMedCrossRefGoogle Scholar
  58. 58.
    Razzouk BI, Hord JD, Hockenberry M, Hinds PS, Feusner J, Williams D, Rackoff WR (2006) 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 24:3583–3589PubMedCrossRefGoogle Scholar
  59. 59.
    Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy M, Spivak J, Bennett C, Bohlius J, Evanchuk D, Goode M, Jakubowski A, Regan D, Somerfield M (2010) Use of epoetin and darbepoetin in adult patients with cancer. American Society of Clinical Oncology/American Society of Hematology Clinical Practice Guideline Update. J Clin Oncol 28:4996–5010PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • L. Boulaamane
    • 1
  • A. Goncalves
    • 2
  • S. Boutayeb
    • 1
  • P. Viens
    • 2
  • H. M’rabti
    • 1
  • F. Bertucci
    • 2
  • H. Errihani
    • 1
  1. 1.Department of Medical OncologyNational Institute of OncologyRabatMorocco
  2. 2.Department of Medical OncologyPaoli-Calmettes InstituteMarseilleFrance

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