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Bone Marrow Toxicity: Red Blood Cells

  • Pere Gascon
Chapter

Abstract

Anemia is a common manifestation in patients with cancer. Its cause can be multifactorial: the cancer itself, chemotherapy treatments, infiltration of bone marrow by cancer cells, hemolysis, nutritional deficiencies, blood loss, inflammation, and so forth. A major consequence of anemia is fatigue, a symptom that impacts the quality of life of cancer patients, and it can also compromise patients’ compliance with their treatments. A new generation of anticancer agents, antitargeted therapies, is widely used in oncology. Some of these new agents are associated with anemia, although their mechanism is not yet understood.

We now have different options to correct chemotherapy- or cancer treatment-induced anemia: red blood cell (RBC) transfusions, iron, and erythropoiesis-stimulating agents (ESAs). Their safety profile is good if we know when and how to administer them.

Red blood cell transfusions are reserved for critical situations, when the patient presents with symptomatic severe anemia. In addition to the possibility that the RBCs carry viruses and other pathogens, some new alarm signals associated with their use have been raised over the last few years and are currently being investigated. Of particular concern are RBCs that have been stored for more than 2 weeks in the blood banks. Apparently, they lose some of their oxygen-carrying capacity and their ability to cross the capillaries.

Iron has long been an agent used to correct the anemia of blood loss. Recently, however, the administration of intravenous iron has become more popular, because the new preparations do not provoke the allergic and anaphylactic reactions seen with the old preparations. Intravenous iron is now being used in combination with ESAs to produce faster and more robust corrections of anemia in the so-called functional iron deficiency, a type of anemia associated with chronic diseases and inflammation. In this condition there is a need for soluble iron, because one of the factors released during inflammation is hepcidin, a peptide that blocks the absorption of oral iron in the duodenum.

Finally, oncologists can utilize ESAs (recombinant human erythropoietin) for chemotherapy-induced anemia. Although they have been used for more than 20 years, over the last 8 years, several alarm signals have been associated with them. Their safety has been questioned after few clinical trial publications reported a poor outcome in patients receiving these agents in comparison to the control arm without ESAs. Many hypotheses have been suggested: ESAs would promote tumor growth via the presence of EPO receptors in cancer cells, a fact seriously questioned by recent publications; ESAs induce thromboembolic events; and so on. Another adverse event associated with the use of ESAs is pure red cell aplasia, in which the ESA molecule undergoes some structural changes due to physical or chemical conditions, causing the development of anti-EPO antibodies. This situation has been described only in patients with chronic renal failure receiving ESAs. The latest meta-analysis on ESAs regarding adverse events concludes that as long as ESAs are being used according to registry specifications in the setting of chemotherapy-induced anemia and the level of hemoglobin does not go beyond 12 g/dL, their use is safe.

Keywords

Anemia Red blood cell transfusions Iron Erythropoiesis-stimulating agents Adverse events Pure red cell aplasia Erythropoietin Thromboembolic events 

References

  1. 1.
    Ludwig H, Van Belle S, Barrett-Lee P, Birgegård G, Bokemeyer C, Gascón P, et al. The European Cancer Anaemia Survey (ECAS): a large, multinational, prospective survey defining the prevalence, incidence and treatment of anaemia in cancer patients. Eur J Cancer. 2004;40(15):2293–307.CrossRefPubMedGoogle Scholar
  2. 2.
    Ludwig H, Strasser K. Symptomatology of anemia. Semin Oncol. 2001;28(Suppl 8):7–14.CrossRefPubMedGoogle Scholar
  3. 3.
    Littlewood TJ, Bajetta E, Nortier JW, Vercammen E, Rapoport B, Epoetin Alfa Study Group. 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. 2001;19:2865–74.CrossRefPubMedGoogle Scholar
  4. 4.
    Glaser CM, Millesi W, Kornek GV, Lang S, Schüll B, Watzinger F, et al. Impact of hemoglobin level and use of recombinant erythropoietin on efficacy of preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx. Int J Radiat Oncol Biol Phys. 2001;50:705–15.CrossRefPubMedGoogle Scholar
  5. 5.
    Glaspy F, Bukowski R, Steinberg D, Taylor C, Tchekmedyian S, Vadhan-Raj S, for the Procrit Study Group. Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. J Clin Oncol. 1997;15:1218–34.CrossRefPubMedGoogle Scholar
  6. 6.
    Demetri GD, Kris M, Wade J, Degos L, Cella D. Quality-of-life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: results from a prospective community oncology study. J Clin Oncol. 1998;16:3412–25.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Gabrilove JL, Cleeland CS, Livingston RB, Sarokhan B, Winer E, Einhorn LH. Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin Oncol. 2001;19:2875–82.CrossRefPubMedGoogle Scholar
  8. 8.
    Miller CB, Jones RJ, Piantadosi S, Abeloff MD, Spivak JL. Decreased erythropoietin response in patients with the anemia of cancer. N Engl J Med. 1990;322(24):1689–92.CrossRefPubMedGoogle Scholar
  9. 9.
    Glaspy J. Erythropoietin in cancer patients. Annu Rev Med. 2009;60:181–92.CrossRefPubMedGoogle Scholar
  10. 10.
    Haurani FI. Hepcidin and the anemia of chronic disease. Ann Clin Lab Sci. 2006;36(1):3–6.PubMedGoogle Scholar
  11. 11.
    Nemeth E, Ganz T. The role of hepcidin in iron metabolism. Acta Haematol. 2009;122(2–3):78–86.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Rivera S, Liu L, Nemeth F, Gabayan V, Sorensen OE, Ganz T. Hepcidin excess induces the sequestration of iron and exacerbates tumor-associated anemia. Blood. 2005;105:1797–802.CrossRefPubMedGoogle Scholar
  13. 13.
    Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004;22(11):2184–91.CrossRefPubMedGoogle Scholar
  14. 14.
    Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol. 2005;23(4):792–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Sher AF. Effect of bevacizumab on the risk of chemotherapy-associated anemia in cancer patients. A meta-analysis. J Clin Oncol. 2010;28(Suppl):15a. abstract 9136.Google Scholar
  16. 16.
    Eisen T, Sternberg CN, Robert C, Mulders P, Pyle L, Zbinden S, et al. Targeted therapies for renal cell carcinoma: review of adverse event management strategies. J Natl Cancer Inst. 2012;104(2):93–113.CrossRefPubMedGoogle Scholar
  17. 17.
    Keefe DM, Bateman EH. Tumor control versus adverse events with targeted anticancer therapies. Nat Rev Clin Oncol. 2011;9(2):98–109.CrossRefPubMedGoogle Scholar
  18. 18.
    Henry D. The evolving role of epoetin alfa in cancer therapy. Oncologist. 2004;9:97–107.CrossRefPubMedGoogle Scholar
  19. 19.
    Blohmer JU, Paepke S, Sehouli J, Boehmer D, Kolben M, Würschmidt F, et al. Randomized phase III trial of sequential adjuvant chemoradiotherapy with or without erythropoietin Alfa in patients with high-risk cervical cancer: results of the NOGGO-AGO intergroup study. J Clin Oncol. 2011;29(28):3791–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Wauters I, Vansteenkiste J. Darbepoetin alfa in the treatment of chemotherapy-induced anaemia. Expert Opin Biol Ther. 2009;9(2):221–30.CrossRefPubMedGoogle Scholar
  21. 21.
    Crawford J, Cella D, Cleeland CS, Cremieux PY, Demetri GD, Sarokhan BJ, et al. Relationship between changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients receiving epoetin alfa therapy. Cancer. 2002;95:888–95.CrossRefPubMedGoogle Scholar
  22. 22.
    Rizzo JD, Somerfield MR, Hagerty KL, Seidenfeld J, Bohlius J, Bennett CL, et al. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update. J Clin Oncol. 2008;26(1):132–49.CrossRefPubMedGoogle Scholar
  23. 23.
    National Comprehensive Cancer Network. Practice guidelines in oncology. Cancer and treatment-related anemia. vol. 1. Fort Washington: National Comprehensive Cancer Network, Inc; 2008. www.nccn.org.
  24. 24.
    Aapro MS, Link H. September 2007 update on EORTC guidelines and anemia management with erythropoiesis-stimulating agents. Oncologist. 2008;13(Suppl 3):33–6.CrossRefPubMedGoogle Scholar
  25. 25.
    Schrijvers D, De Samblanx H, Roila F, ESMO Guidelines Working Group. Erythropoiesis-stimulating agents in the treatment of anaemia in cancer patients: ESMO Clinical Practice Guidelines for use. Ann Oncol. 2010;21(Suppl 5):v244–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy MO, Spivak JL, et al. American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. Blood. 2010;116(20):4045–59. Epub 2010 Oct 25.CrossRefPubMedGoogle Scholar
  27. 27.
    NCCN Clinical Practice Guidelines in Oncology 2012. http://www.nccn.org.
  28. 28.
    Lichtin AE. Clinical practice guidelines for the use of erythroid-stimulating agents: ASCO, EORTC, NCCN. Cancer Treat Res. 2011;157:239–48.CrossRefPubMedGoogle Scholar
  29. 29.
    Kamioner D. Erythropoietin biosimilars currently available in hematology-oncology. Target Oncol. 2012;7(Suppl 1):25–8. Epub 2012 Jan 18.CrossRefGoogle Scholar
  30. 30.
    Bohlius J, Weingart O, Trelle S, Engert A. Cancer-related anemia and recombinant human erythropoietin – an updated overview. Nat Clin Pract Oncol. 2006;3:152–64.CrossRefPubMedGoogle Scholar
  31. 31.
    Goodnough LT. Erythropoietin and iron-restricted erythropoiesis. Exp Hematol. 2007;35:167–72.CrossRefPubMedGoogle Scholar
  32. 32.
    Auerbach M, Ballard H, Trout JR, McIlwain M, Ackerman A, Bahrain H, et al. Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multicenter, open-label, randomized trial. J Clin Oncol. 2004;22(7):1301.CrossRefPubMedGoogle Scholar
  33. 33.
    Henry DH, Dahl NV, Auerbach M, Tchekmedyian S, Laufman LR. Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy. Oncologist. 2007;12:231–42.CrossRefPubMedGoogle Scholar
  34. 34.
    Hedenus M, Birgegard G, Nasman P, Ahlberg L, Karlsson T, Lauri B, et al. Addition of intravenous iron to epoetin beta increases hemoglobin response and decreases epoetin dose requirement in anemic patients with lymphoproliferative malignancies: a randomized multicenter study. Leukemia. 2007;21:627–32.CrossRefPubMedGoogle Scholar
  35. 35.
    Bastit L, Vandebroek A, Altintas S, Gaede B, Pintér T, Suto TS, et al. Randomized, multicenter, controlled trial comparing the efficacy and safety of darbepoetin alfa administered every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. J Clin Oncol. 2008;26:1611–8.CrossRefPubMedGoogle Scholar
  36. 36.
    Pedrazzoli P, Farris A, Del PS, Del Gaizo F, Ferrari D, Bianchessi C, et al. Randomized trial of intravenous iron supplementation in patients with chemotherapy-related anemia without iron deficiency treated with darbepoetin alfa. J Clin Oncol. 2008;26:1619–25.CrossRefPubMedGoogle Scholar
  37. 37.
    Auerbach M, Silberstein PT, Webb RT, Averyanova S, Ciuleanu TE, Shao J, et al. Darbepoetin alfa 300 or 500 μg once every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. Am J Hematol. 2010;85(9):655–93.CrossRefPubMedGoogle Scholar
  38. 38.
    F P, Borgonovo K, Cabiddu M, Lonati V, Barni S. Addition of iron to erythropoiesis-stimulating agents in cancer patients: a meta-analysis of randomized trials. J Cancer Res Clin Oncol. 2012 Feb;138(2):179–87.CrossRefGoogle Scholar
  39. 39.
    Steensma DP, Sloan JA, Dakhil SR, Dalton R, Kahanic SP, Prager DJ, et al. Phase III, randomized study of the effects of parenteral iron, oral iron, or no iron supplementation on the erythropoietic response to darbepoetin alfa for patients with chemotherapy-associated anemia. J Clin Oncol. 2011;29:97–105.CrossRefPubMedGoogle Scholar
  40. 40.
    Beguin Y, Maertens J, De Prijck B, Schots R, Frere P, Bonnet C, et al. Darbepoetin-alfa and intravenous iron administration after autologous hematopoietic stem cell transplantation: a prospective multicenter randomized trial. Am J Hematol. 2013;88(12):990–6.CrossRefPubMedGoogle Scholar
  41. 41.
    Bellet RE, Ghazal H, Flam M, Drelichman A, Gabrail N, Woytowitz D, et al. A phase III randomized controlled study comparing iron sucrose intravenously (IV) to no iron treatment of anemia in cancer patients undergoing chemotherapy and erythropoietin stimulating agent (ESA) therapy. J Clin Oncol. 2007;25(18s.) Abstract 9109.Google Scholar
  42. 42.
    Auerbach M. Intravenous iron failed to improve erythropoietic response in patients with chemotherapy-induced anemia. 2010. http://www.hemonctoday.com/article.aspx?rid=78461.
  43. 43.
    Aapro M, Beguin Y, Birgegärd G, Gascón P, Hedenus M, Osterborg A. Too low iron doses and too many dropouts in negative iron trials? J Clin Oncol. 2011;29(17):e525–6.CrossRefPubMedGoogle Scholar
  44. 44.
    Gafter-Gvili A, Rozen-Zvi B, Vidal L, Gafter U, Vansteenkiste JF, Shpilberg O. Intravenous iron supplementation for the treatment of cancer-related anemia – systematic review and meta-analysis. Blood. 2010;116(21.) Abstract 4249.Google Scholar
  45. 45.
    Mhaskar R, Wao H, Kumar A, Miladinovic B, Djulbegovic B. Role of iron supplementation to erythropoiesis stimulating agents in the management of chemotherapy-induced anemia in cancer patients: a systematic review and meta-analysis. Blood. 2010;116(21.) Abstract 2055.Google Scholar
  46. 46.
    Steensma D, Dakhil SR, Novotny PJ, Kahanic SP, Kugler JW, Stella PJ, et al. A phase III, randomized study of the effects of parenteral iron, oral iron, or no iron supplementation on the erythropoietic response to darbepoetin alfa for patients with chemotherapy-associated anemia: a study of the Mayo Clinic Cancer Research Consortium (MCCRC). Blood. 2009;114:22. Abstract 3008.CrossRefGoogle Scholar
  47. 47.
    Dangsuwan P, Manchana T. Blood transfusion reduction with intravenous iron in gynecologic cancer patients receiving chemotherapy. Gynecol Oncol. 2010;116(3):522–5.CrossRefPubMedGoogle Scholar
  48. 48.
    Kim YT, Kim SW, Yoon BS, Cho HJ, Nahm EJ, Kim SH, et al. Effect of intravenously administered iron sucrose on the prevention of anemia in the cervical cancer patients treated with concurrent chemoradiotherapy. Gynecol Oncol. 2007;105(1):199–204.CrossRefPubMedGoogle Scholar
  49. 49.
    Steinmetz T, Tschechne B, Virgin G, et al. Ferric carboxymaltose for the correction of cancer- and chemotherapy-associated anemia in clinical practice. Eur J Cancer. 2011;47(S1):221–2. Abstract 3000.CrossRefGoogle Scholar
  50. 50.
    Hebert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med. 1999;340:409–17.CrossRefPubMedGoogle Scholar
  51. 51.
    Taylor RW, O’Brien J, Trottier SJ, Manganaro L, Cytron M, Lesko MF, et al. Red blood transfusions and nosocomial infections in critically ill patients. Crit Care Med. 2006;34:2302–8.CrossRefPubMedGoogle Scholar
  52. 52.
    Bernard AC, Davenport DL, Chang PK, Vaughan TB, Zwischenberger JB. Intraoperative transfusion of 1U to 2U packed red blood cells is associated with increased 30-day mortality, surgical-site infection, pneumonia and sepsis in general surgery patients. J Am Coll Surg. 2009;208:931–7.CrossRefPubMedGoogle Scholar
  53. 53.
    Gorman Koch C, Li L, Sessler DI, Figueroa P, Hoeltge GA, Mihaljevic T, et al. Duration of red-cell storage and complications after cardiac surgery. N Engl J Med. 2008;358:1229–39.CrossRefGoogle Scholar
  54. 54.
    Goodnough LT, Brecher ME, Kanter MH, AuBuchon JP. Transfusion medicine. N Engl J Med. 1999;340(6):438–47.CrossRefPubMedGoogle Scholar
  55. 55.
    Klein HG, Spahn DR, Carson JL. Red blood cell transfusion in clinical practice. Lancet. 2007;370(9585):415–26.CrossRefPubMedGoogle Scholar
  56. 56.
    Yazdanbakhsh K, Bao W, Zhong H. Immunomodulatory effects of stored red blood cells in transfusion medicine: adverse complications of stored blood. Hematology Am Soc Hematol Educ Program. 2011;2011:466–9.PubMedGoogle Scholar
  57. 57.
    Roback JD. Vascular effects of red blood cell storage lesion in transfusion medicine: adverse complications of stored blood. Hematology Am Soc Hematol Educ Program. 2011;2011:475–9.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Cascinu S, Fedeli A, Del Ferro E, Luzi Fedeli S, Catalano G. Recombinant human erythropoietin treatment in cisplatin-associated anemia: a randomized, double-blind trial with placebo. J Clin Oncol. 1994;12:1058–62.CrossRefPubMedGoogle Scholar
  59. 59.
    Cazzola M, Messinger D, Battistel V, Bron D, Cimino R, Enller-Ziegler L, et al. Recombinant human erythropoietin in the anemia associated with multiple myeloma or non-Hodgkin’s lymphoma: dose finding and identification of predictors of response. Blood. 1995;86(12):4446–53.PubMedGoogle Scholar
  60. 60.
    Witzig TE, Silberstein PT, Loprinzi CL, Sloan JA, Novotny PJ, Mailliard JA, et al. Phase III, randomized, double-blind study of epoetin alfa compared with placebo in anemic patients receiving chemotherapy. J Clin Oncol. 2005;23(12):2606–17.CrossRefPubMedGoogle Scholar
  61. 61.
    Vansteenkiste J, Pirker R, Massuti B, Barata F, Font A, Fiegl M, et al. Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst. 2002;94(16):1211–20.CrossRefPubMedGoogle Scholar
  62. 62.
    Hedenus M, Adriansson M, San Miguel J, Kramer MH, Schipperus MR, Juvonen E, et al. Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study. Br J Haematol. 2003;122(3):394–403.CrossRefPubMedGoogle Scholar
  63. 63.
    Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet. 2009;373(9674):1532–42.CrossRefPubMedGoogle Scholar
  64. 64.
    Glaspy J, Crawford J, Vansteenkiste J, Henry D, Rao S, Bowers P, et al. Erythropoiesis-stimulating agents in oncology: a study-level meta-analysis of survival and other safety outcomes. Br J Cancer. 2010;102(2):301–15.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Macdougall IC, Roger SD, de Francisco A, Goldsmith DJ, Schellekens H, Ebbers H, et al. Antibody-mediated pure red cell aplasia in chronic kidney disease patients receiving erythropoiesis-stimulating agents: new insights. Kidney Int. 2012;81(8):727–32.  https://doi.org/10.1038/ki.2011.500. Epub 2012 Feb 15.CrossRefPubMedGoogle Scholar
  66. 66.
    McKoy JM, Stonecash RE, Cournoyer D, Rossert J, Nissenson AR, Raisch DW, et al. Epoetin-associated pure red cell aplasia: past, present, and future considerations. Transfusion. 2008;48:1754–62.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Casadevall N, Nataf J, Viron B, Kolta A, Kiladjian JJ, Martin-Dupont P, et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med. 2002;346:469–75.CrossRefPubMedGoogle Scholar
  68. 68.
    Bohlius J, Langensiepen S, Schwarzer G, Seidenfeld J, Piper M, Bennett C, et al. Recombinant human erythropoietin and overall survival in cancer patients: results of a comprehensive meta-analysis. J Natl Cancer Inst. 2005;97:489–98.CrossRefPubMedGoogle Scholar
  69. 69.
    Bohlius J, Wilson J, Seidenfeld J, Piper M, Schwarzer G, Sandercock J, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev. 2006;3:CD003407.Google Scholar
  70. 70.
    Aapro M, Osterwalder B, Scherhag A, Burger HU. 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. 2009;101(12):1961–71.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Anderson FA, Spencer FA. Risk factors for venous thromboembolism. Circulation. 2003;107:I9–16.CrossRefPubMedGoogle Scholar
  72. 72.
    Khorana AA, Francis CW, Blumberg N, Culakova E, Refaai MA, Lyman GH, et al. Blood transfusions, thrombosis, and mortality in hospitalized patients with cancer. Arch Intern Med. 2008;168(21):2377–81.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Fujisaka Y, Sugiyama T, Saito H, Nagase S, Kudoh S, Endo M, et al. Randomised, phase III trial of epoetin-β to treat chemotherapy-induced anaemia according to the EU regulation. Br J Cancer. 2011;105(9):1267–72.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Henry DH, Dahl NV, Auerbach MA. Thrombocytosis and venous thromboembolism in cancer patients with chemotherapy induced anemia may be related to ESA induced iron restricted erythropoiesis and reversed by administration of IV iron. Am J Hematol. 2012;87(3):308–10.CrossRefPubMedGoogle Scholar
  75. 75.
    Khorana AA, Francis CW, Culakova E, Lyman GH. Risk factors for chemotherapy-associated venous thromboembolism in a prospective observational study. Cancer. 2005;104:2822–9.CrossRefPubMedGoogle Scholar
  76. 76.
    Henke M, Laszig R, Rube C, Schäfer U, Haase KD, Schilcher B, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled, trial. Lancet. 2003;362:1255–60.CrossRefPubMedGoogle Scholar
  77. 77.
    Leyland-Jones B, Semiglazov V, Pawlicki M. 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. 2005;23:5960–72.CrossRefPubMedGoogle Scholar
  78. 78.
    Leyland-Jones B, Mahmud S. Erythropoietin to treat anaemia in patients with head and neck cancer [letter]. Lancet. 2004;363:80.CrossRefPubMedGoogle Scholar
  79. 79.
    Vaupel P, Mayer A. Erythropoietin to treat anaemia in patients with head and neck cancer [letter]. Lancet. 2004;363:992.CrossRefPubMedGoogle Scholar
  80. 80.
    Overgaard J, Hoff C, Sand Hansen H, et al. 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. Eur J Cancer Suppl. 2007;5(6):7.CrossRefGoogle Scholar
  81. 81.
    Smith RE Jr, Aapro MS, Ludwig H, Pintér T, Smakal M, Ciuleanu TE, et al. 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. 2008;26(7):1040–50.CrossRefPubMedGoogle Scholar
  82. 82.
    Wright JR, Ung YC, Julian JA, Pritchard KI, Whelan TJ, Smith C, et al. Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol. 2007;25(9):1021–3.CrossRefGoogle Scholar
  83. 83.
    Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. 1998;339:584–90.CrossRefPubMedGoogle Scholar
  84. 84.
    Luksenburg H, Weir A, Wager R. FDA Briefing Document: Safety Concerns Associated with Aranesp (darbepoetin alfa) Amgen, Inc. and Procrit (epoetin alfa) Ortho Biotech, L.P., for the Treatment of Anemia Associated with Cancer Chemotherapy. 2004. http://www.fda.gov/ohrms/dockets/ac/cder04.html#oncologic.
  85. 85.
    Kelleher DK, Thews O, Vaupel P. Can erythropoietin improve tumor oxygenation? Strahlenther Onkol. 1998;174(Suppl IV):20–3.PubMedGoogle Scholar
  86. 86.
    Acs G, Acs P, Beckwith SM, Pitts RL, Clements E, Wong K, et al. Erythropoietin and erythropoietin receptor expression in human cancer. Cancer Res. 2001;61:3561–5.PubMedGoogle Scholar
  87. 87.
    Arcasoy MO, Amin K, Karayal AF, Chou SC, Raleigh JA, Varia MA, et al. Functional significance of erythropoietin receptor expression in breast cancer. Lab Investig. 2002;82(7):911–8.CrossRefPubMedGoogle Scholar
  88. 88.
    Yasuda Y, Fujita Y, Matsuo T, Koinuma S, Hara S, Tazaki A, et al. Erythropoietin regulates tumour growth of human malignancies. Carcinogenesis. 2003;24:1021–9.CrossRefPubMedGoogle Scholar
  89. 89.
    Elliott S, Busse L, Bass MB, Lu H, Sarosi I, Sinclair AM, et al. Anti-Epo receptor antibodies do not predict Epo receptor expression. Blood. 2006;107(5):1892–5.CrossRefPubMedGoogle Scholar
  90. 90.
    Elliott S, Busse L, McCaffery I, Rossi J, Sinclair A, Spahr C, et al. Identification of a sensitive anti-erythropoietin receptor monoclonal antibody allows detection of low levels of EpoR in cells. J Immunol Methods. 2010;352(1–2):126–39.CrossRefPubMedGoogle Scholar
  91. 91.
    Swift S, Ellison AR, Kassner P, McCaffery I, Rossi J, Sinclair AM, et al. Absence of functional EpoR expression in human tumor cell lines. Absence of functional EpoR expression in human tumor cell lines. Blood. 2010;115(21):4254–63.CrossRefPubMedGoogle Scholar
  92. 92.
    McCaffery I, Rossi J, Paweletz K, Tudor Y, Elliot S, Fitzpatrick VD, et al. Analysis of cell surface erythropoietin receptor (EpoR) expression and function in human epithelial tumor tissues reveals no detectable expression or function. J Clin Oncol. 2009;27(Suppl.):15s and poster. Abstract 11104.Google Scholar
  93. 93.
    Ross SD, Allen IE, Henry DH, Seaman C, Sercus B, Goodnough LT, et al. Clinical benefits and risks associated with epoetin and darbepoetin in patients with chemotherapy-induced anemia: a systematic review of the literature. Clin Ther. 2006;28(6):801–31.CrossRefPubMedGoogle Scholar
  94. 94.
    Aapro M, Coiffier B, Dunst J, Osterborg A, Burger HU, et al. Effect of treatment with epoetin beta on short-term tumour progression and survival in anaemic patients with cancer: a meta-analysis. Br J Cancer. 2006;95(11):1467–73.CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Ludwig H, Crawford J, Osterborg A, Vansteenkiste J, Henry DH, Fleishman A, et al. 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. 2009;27(17):2838–47.CrossRefPubMedGoogle Scholar
  96. 96.
    Aapro M, Scherhag A, Burger HU. Effect of treatment with epoetin beta on survival, tumour progression and thromboembolic events in patients with metastatic cancer: an updated meta-analysis of 12 randomized controlled studies including 2301 patients. Br J Cancer. 2008;99(1):14–22.CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Bennett CL, Silver SM, Djulbegovic B, Samaras AT, Blau CA, Gleason KJ, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA. 2008;299(8):914–24.CrossRefPubMedGoogle Scholar
  98. 98.
    Aapro M, Leonard RC, Barnadas A, Marangolo M, Untch M, Malamos N, et al. Effect of once weekly epoetin beta on survival in patients with metastatic breast cancer receiving anthracycline- and/or taxane-based chemotherapy – results of the BRAVE study. J Clin Oncol. 2008;26:592–8.CrossRefPubMedGoogle Scholar
  99. 99.
    Strauss HG, Haensgen G, Dunst J. Effects of anemia correction with epoetin beta in patients receiving radiochemotherapy for advanced cervical cancer. Int J Gynecol Cancer. 2008;18(3):515–24.CrossRefPubMedGoogle Scholar
  100. 100.
    Cantrell LA, Westin SN, Van Le L. The use of recombinant erythropoietin for the treatment of chemotherapy-induced anemia in patients with ovarian cancer does not affect progression-free or overall survival. Cancer. 2011;117(6):1220–6.CrossRefPubMedGoogle Scholar
  101. 101.
    Pronzato P, Cortesi E, van der Rijt CC, Bols A, Moreno-Nogueira JA, de Oliveira CF, et al. Epoetin alfa improves anemia and anemia-related, patient-reported outcomes in patients with breast cancer receiving myelotoxic chemotherapy: results of a European, multicenter, randomized, controlled trial. Oncologist. 2010;15(9):935–43. Epub 2010 Aug 26.CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Moebus V, Jackish C, Lueck H-J, du Bois A, Thomssen C, Kurbacher C, et al. Intense dose-dense sequential chemotherapy with epirubicin, paclitaxel, and cyclophosphamide compared with conventional scheduled chemotherapy in high-risk primary breast cancer: mature results of an AGO phase III study. J Clin Oncol. 2010;28(17):2874–80.CrossRefPubMedGoogle Scholar
  103. 103.
    Untch M, von Minckwitz G, Konecny G, Conrad U, Fett W, Kurzeder C, et al. 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 – long-term results. Ann Oncol. 2011;22:1999–2006.CrossRefPubMedGoogle Scholar
  104. 104.
    Nitz U, Gluz O, Oberhoff C, Reimer T, Schumacher C, Hackmann J, et al. Adjuvant chemotherapy with or without darbepoetin alfa in node-positive breast cancer: survival and quality of life analysis from the prospective randomized WSG ARA Plus trial. San Antonio Breast Cancer symposium. Cancer Res. 2011;71(s24):PD07-63s.Google Scholar
  105. 105.
    Delarue R. Survival effect of darbepoetin alfa in patients with diffuse large B-cell lymphoma (DLBCL) treated with immunochemotherapy. The LNH03-68 study. J Clin Oncol. 2011;29:561s. Abstract 9048.CrossRefGoogle Scholar
  106. 106.
    Bokemeyer C, Aapro MS, Courdi A, Foubert J, Link H, Osterborg A, et al. EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer: 2006 update. Eur J Cancer. 2007;43(2):258–70.CrossRefPubMedGoogle Scholar
  107. 107.
    Leyland-Jones B, Bondarenko I, Nemsadze G, Smirnov V, Litvin I, Kokhreidze I, et al. A randomized, open-label, multicenter, phase III study of Epoetin Alfa versus best standard of care in anemic patients with metastatic breast cancer receiving standard chemotherapy. J Clin Oncol. 2016;34(11):1197–207.CrossRefPubMedGoogle Scholar
  108. 108.
    Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmén J. Update on adverse drug events associated with parenteral iron. Nephrol Dial Transplant. 2006;21(2):378–82.CrossRefPubMedGoogle Scholar
  109. 109.
    Tarantino G, Brilli E, Zambito Y, Giordano G, Equitan F. Sucrosomial Iron® – a new highly bioavaible oral iron supplement. Blood. 2015;126(23):4561.Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Medical Oncology, Department of Hematology-OncologyInstitut Clinic de Malalties Hemato-Oncologiques, University of BarcelonaBarcelonaSpain

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