Download PDF
Semin Thromb Hemost 2014; 40(03): 306-312
DOI: 10.1055/s-0034-1370768
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Current Status of Use of Erythropoietic Agents in Cancer Patients

John Glaspy
1   Department of Medicine, UCLA School of Medicine, Los Angeles, California
› Author Affiliations
Further Information

Publication History

Publication Date:
27 March 2014 (online)

    Permissions and Reprints

Abstract

Anemia is frequently observed in cancer patients and can cause symptoms and result in red cell transfusions. The erythropoiesis stimulating agents (ESAs) have been shown to increase hemoglobin levels and reduce transfusion requirements in anemic subjects with cancer who are receiving chemotherapy. Initially, these benefits motivated broad use of the ESAs in oncology. Over the past 10 years, recognition of the adverse events that can be associated with ESA use in these patients, particularly venous thrombosis, has resulted in a rethinking of the issue of who are the correct candidates for treatment. Different health care systems have come to different conclusions based upon the available data and additional data are still being generated. This article will review the data concerning the safety of ESAs in cancer patients, including the results of additional trials published in the past 2 years. This will include a discussion of the potential of ESAs to impact tumor progression or survival. Thrombosis remains the most important and best documented adverse event associated with ESA therapy in oncology. The mechanism(s) through which ESAs alter thrombosis risk are still very poorly understood.

Keywords

erythropoietin - epoetin - darbepoetin - anemia - erythropoietin receptor - chemotherapy
 

  • References

  • 1 Groopman JE, Itri LM. Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst 1999; 91 (19) 1616-1634
    CrossrefPubMedGoogle Scholar
  • 2 Ludwig H, Van Belle S, Barrett-Lee 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) 2293-2306
    CrossrefPubMedGoogle Scholar
  • 3 Glaspy J, Vadhan-Raj S, Patel R , et al; 20030125 Study Group Trial. Randomized comparison of every-2-week darbepoetin alfa and weekly epoetin alfa for the treatment of chemotherapy-induced anemia: the 20030125 Study Group Trial. J Clin Oncol 2006; 24 (15) 2290-2297
    CrossrefPubMedGoogle Scholar
  • 4 Besarab A, Bolton WK, Browne JK , 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 (9) 584-590
    CrossrefPubMedGoogle Scholar
  • 5 Drüeke TB, Locatelli F, Clyne N , et al; CREATE Investigators. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006; 355 (20) 2071-2084
    CrossrefPubMedGoogle Scholar
  • 6 Solomon SD, Uno H, Lewis EF et al; Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) Investigators. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N Engl J Med 2010; 363 (12) 1146-1155
    CrossrefPubMedGoogle Scholar
  • 7 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) 1689-1692
    CrossrefPubMedGoogle Scholar
  • 8 Vansteenkiste J, Pirker R, Massuti B , et al; Aranesp 980297 Study Group. Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst 2002; 94 (16) 1211-1220
    CrossrefPubMedGoogle Scholar
  • 9 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 nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol 2001; 19 (11) 2865-2874
    CrossrefPubMedGoogle Scholar
  • 10 Fallowfield L, Gagnon D, Zagari M , et al; Epoetin Alfa Study Group. Multivariate regression analyses of data from a randomised, double-blind, placebo-controlled study confirm quality of life benefit of epoetin alfa in patients receiving non-platinum chemotherapy. Br J Cancer 2002; 87 (12) 1341-1353
    CrossrefPubMedGoogle Scholar
  • 11 Casadevall N, Nataf J, Viron B , et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 2002; 346 (7) 469-475
    CrossrefPubMedGoogle Scholar
  • 12 Bohlius J, Langensiepen S, Schwarzer G , et al. Recombinant human erythropoietin and overall survival in cancer patients: results of a comprehensive meta-analysis. J Natl Cancer Inst 2005; 97 (7) 489-498
    CrossrefPubMedGoogle Scholar
  • 13 Bohlius J, Wilson J, Seidenfeld J , et al. Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst 2006; 98 (10) 708-714
    CrossrefPubMedGoogle Scholar
  • 14 Bohlius J, Schmidlin K, Brillant C , et al. Erythropoietin or Darbepoetin for patients with cancer—meta-analysis based on individual patient data. Cochrane Database Syst Rev 2009; (3) CD007303
    PubMedGoogle Scholar
  • 15 Glaspy JA. Cancer patient survival and erythropoietin. J Natl Compr Canc Netw 2005; 3 (6) 796-804
    PubMedGoogle Scholar
  • 16 Glaspy J. Update on safety of ESAs in cancer-induced anemia. J Natl Compr Canc Netw 2012; 10 (5) 659-666
    PubMedGoogle Scholar
  • 17 Ludwig H, Crawford J, Osterborg 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) 2838-2847
    CrossrefPubMedGoogle Scholar
  • 18 Glaspy J. Erythropoietin in cancer patients. Ann Rev Med. 2009; 60: 181-192
    CrossrefPubMedGoogle Scholar
  • 19 Auerbach M, Ballard H, Trout JR , 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) 1301-1307
    CrossrefPubMedGoogle Scholar
  • 20 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 (2) 231-242
    CrossrefPubMedGoogle Scholar
  • 21 Hedenus M, Birgegård G, Näsman P , 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 (4) 627-632
    PubMedGoogle Scholar
  • 22 Pedrazzoli P, Farris A, Del Prete S , et al. Randomized trial of intravenous iron supplementation in patients with chemotherapy-related anemia without iron deficiency treated with darbepoetin alpha. J Clin Oncol 2008; 26 (10) 1619-1625
    CrossrefPubMedGoogle Scholar
  • 23 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) 308-310
    CrossrefPubMedGoogle Scholar
  • 24 Tonia T, Mettler A, Robert N , et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev 2012; 12: CD003407
    PubMedGoogle Scholar
  • 25 Smith Jr RE, Aapro MS, Ludwig H , et al. Darbepoetin alpha 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) 1040-1050
    CrossrefPubMedGoogle Scholar
  • 26 Curt GA, Breitbart W, Cella D , et al. Impact of cancer-related fatigue on the lives of patients: new findings from the Fatigue Coalition. Oncologist 2000; 5 (5) 353-360
    CrossrefPubMedGoogle Scholar
  • 27 Cella D, Zagari MJ, Vandoros C, Gagnon DD, Hurtz HJ, Nortier JW. Epoetin alfa treatment results in clinically significant improvements in quality of life in anemic cancer patients when referenced to the general population. J Clin Oncol 2003; 21 (2) 366-373
    CrossrefPubMedGoogle Scholar
  • 28 Ross SD, Fahrbach K, Frame D, Scheye R, Connelly JE, Glaspy J. The effect of anemia treatment on selected health-related quality-of-life domains: a systematic review. Clin Ther 2003; 25 (6) 1786-1805
    CrossrefPubMedGoogle Scholar
  • 29 Berndt E, Kallich J, McDermott A, Xu X, Lee H, Glaspy J. Reductions in anaemia and fatigue are associated with improvements in productivity in cancer patients receiving chemotherapy. Pharmacoeconomics 2005; 23 (5) 505-514
    CrossrefPubMedGoogle Scholar
  • 30 Cella D, Kallich J, McDermott A, Xu X. The longitudinal relationship of hemoglobin, fatigue and quality of life in anemic cancer patients: results from five randomized clinical trials. Ann Oncol 2004; 15 (6) 979-986
    CrossrefPubMedGoogle Scholar
  • 31 Chavez-MacGregor M, Zhao H, Fang S, Srokowski TP, Hortobagyi GN, Giordano SH. Complications associated with erythropoietin-stimulating agents in patients with metastatic breast cancer: a Surveillance, Epidemiology, and End Results-Medicare study. Cancer 2011; 117 (16) 3641-3649
    CrossrefPubMedGoogle Scholar
  • 32 Vallés J, Santos MT, Aznar J , et al. Platelet-erythrocyte interactions enhance alpha(IIb)beta(3) integrin receptor activation and P-selectin expression during platelet recruitment: down-regulation by aspirin ex vivo. Blood 2002; 99 (11) 3978-3984
    CrossrefPubMedGoogle Scholar
  • 33 Wun T, Paglieroni T, Hammond WP, Kaushansky K, Foster DC. Thrombopoietin is synergistic with other hematopoietic growth factors and physiologic platelet agonists for platelet activation in vitro. Am J Hematol 1997; 54 (3) 225-232
    CrossrefPubMedGoogle Scholar
  • 34 Stohlawetz PJ, Dzirlo L, Hergovich N , et al. Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans. Blood 2000; 95 (9) 2983-2989
    PubMedGoogle Scholar
  • 35 Lin A, Ryu J, Harvey D, Sieracki B, Scudder S, Wun T. Low-dose warfarin does not decrease the rate of thrombosis in patients with cervix and vulvo-vaginal cancer treated with chemotherapy, radiation, and erythropoeitin. Gynecol Oncol 2006; 102 (1) 98-102
    CrossrefPubMedGoogle Scholar
  • 36 Akl EA, van Doormaal FF, Barba M , et al. Parenteral anticoagulation for prolonging survival in patients with cancer who have no other indication for anticoagulation. Cochrane Database Syst Rev 2007; (3) CD006652
    PubMedGoogle Scholar
  • 37 Kasthuri RS, Taubman MB, Mackman N. Role of tissue factor in cancer. J Clin Oncol 2009; 27 (29) 4834-4838
    CrossrefPubMedGoogle Scholar
  • 38 Lyman GH, Khorana AA, Kuderer NM , et al. Cancer, clots and consensus: new understanding of an old problem. J Clin Oncol 2009; 27 (29) 4821-4826
    CrossrefPubMedGoogle Scholar
  • 39 Semenza GL. Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit Rev Biochem Mol Biol 2000; 35 (2) 71-103
    CrossrefPubMedGoogle Scholar
  • 40 Spivak JL. The anaemia of cancer: death by a thousand cuts. Nat Rev Cancer 2005; 5 (7) 543-555
    CrossrefPubMedGoogle Scholar
  • 41 Van Belle SJ, Cocquyt V. Impact of haemoglobin levels on the outcome of cancers treated with chemotherapy. Crit Rev Oncol Hematol 2003; 47 (1) 1-11
    CrossrefPubMedGoogle Scholar
  • 42 Thews O, Kelleher DK, Vaupel P. Erythropoietin restores the anemia-induced reduction in cyclophosphamide cytotoxicity in rat tumors. Cancer Res 2001; 61 (4) 1358-1361
    PubMedGoogle Scholar
  • 43 Höckel M, Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 2001; 93 (4) 266-276
    CrossrefPubMedGoogle Scholar
  • 44 Henke M, Laszig R, Rübe C , et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 2003; 362 (9392) 1255-1260
    CrossrefPubMedGoogle Scholar
  • 45 Leyland-Jones B ; BEST Investigators and Study Group. Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol 2003; 4 (8) 459-460
    CrossrefPubMedGoogle Scholar
  • 46 Leyland-Jones B, Semiglazov V, Pawlicki M , et al. 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 (25) 5960-5972
    CrossrefPubMedGoogle Scholar
  • 47 Glaspy JA. Erythropoiesis-stimulating agents in oncology. J Natl Compr Canc Netw 2008; 6 (6) 565-575
    PubMedGoogle Scholar
  • 48 Glaspy J. Hematology: ESAs to treat anemia—balancing the risks and benefits. Nat Rev Clin Oncol 2009; 6 (9) 500-502
    CrossrefPubMedGoogle Scholar
  • 49 Vaupel P, Thews O, Mayer A, Höckel S, Höckel M. Oxygenation status of gynecologic tumors: what is the optimal hemoglobin level?. Strahlenther Onkol 2002; 178 (12) 727-731
    CrossrefPubMedGoogle Scholar
  • 50 Vaupel P, Dunst J, Engert A , et al. Effects of recombinant human erythropoietin (rHuEPO) on tumor control in patients with cancer-induced anemia. Onkologie 2005; 28 (4) 216-221
    CrossrefPubMedGoogle Scholar
  • 51 Arcasoy MO, Amin K, Chou SC, Haroon ZA, Varia M, Raleigh JA. Erythropoietin and erythropoietin receptor expression in head and neck cancer: relationship to tumor hypoxia. Clin Cancer Res 2005; 11 (1) 20-27
    PubMedGoogle Scholar
  • 52 Acs G, Acs P, Beckwith SM , et al. Erythropoietin and erythropoietin receptor expression in human cancer. Cancer Res 2001; 61 (9) 3561-3565
    PubMedGoogle Scholar
  • 53 Lopez TV, Lappin TR, Maxwell P , et al. Autocrine/paracrine erythropoietin signalling promotes JAK/STAT-dependent proliferation of human cervical cancer cells. Int J Cancer 2011; 129 (11) 2566-2576
    CrossrefPubMedGoogle Scholar
  • 54 Rades D, Setter C, Dahl O, Schild SE, Noack F. Prognostic impact of erythropoietin expression and erythropoietin receptor expression on locoregional control and survival of patients irradiated for stage II/III non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2011; 80 (2) 499-505
    CrossrefPubMedGoogle Scholar
  • 55 Elliott S, Busse L, Bass MB , et al. Anti-Epo receptor antibodies do not predict Epo receptor expression. Blood 2006; 107 (5) 1892-1895
    CrossrefPubMedGoogle Scholar
  • 56 Sinclair AM, Rogers N, Busse L , et al. Erythropoietin receptor transcription is neither elevated nor predictive of surface expression in human tumour cells. Br J Cancer 2008; 98 (6) 1059-1067
    CrossrefPubMedGoogle Scholar
  • 57 Brown WM, Maxwell P, Graham AN , et al. Erythropoietin receptor expression in non-small cell lung carcinoma: a question of antibody specificity. Stem Cells 2007; 25 (3) 718-722
    PubMedGoogle Scholar
  • 58 Aapro M, Jelkmann W, Constantinescu SN, Leyland-Jones B. Effects of erythropoietin receptors and erythropoiesis-stimulating agents on disease progression in cancer. Br J Cancer 2012; 106 (7) 1249-1258
    CrossrefPubMedGoogle Scholar
  • 59 Moebus V, Jackisch C, Schneeweiss A , et al; AGO Breast Study Group. Adding epoetin alfa to intense dose-dense adjuvant chemotherapy for breast cancer: randomized clinical trial. J Natl Cancer Inst 2013; 105 (14) 1018-1026
    CrossrefPubMedGoogle Scholar
  • 60 Szkandera J, Absenger G, Stotz M , et al. The functional polymorphism of erythropoietin gene rs1617640 G>T is not associated with susceptibility and clinical outcome of early-stage breast cancer. Anticancer Res 2012; 32 (8) 3473-3478
    PubMedGoogle Scholar
  • 61 Engert A, Josting A, Haverkamp H , et al. Epoetin alfa in patients with advanced-stage Hodgkin's lymphoma: results of the randomized placebo-controlled GHSG HD15EPO trial. J Clin Oncol 2010; 28 (13) 2239-2245
    CrossrefPubMedGoogle Scholar
  • 62 Delarue R, Haioun C, Coiffier B, Fornecker L, Fournier M, Mounier N , et al. Survival impact of darbepoetin alfa in patients with diffuse large B-cell lymphoma (DLBCL) treated with immunochemotherapy: The LNH03-6B study. Journal of Clinical Oncology, ASCO abstracts 2011. 2011;
    PubMedGoogle Scholar
  • 63 Cabanillas ME, Kantarjian H, Thomas DA , et al. Epoetin alpha decreases the number of erythrocyte transfusions in patients with acute lymphoblastic leukemia, lymphoblastic lymphoma, and Burkitt leukemia/lymphoma: results of a randomized clinical trial. Cancer 2012; 118 (3) 848-855
    CrossrefPubMedGoogle Scholar
  • 64 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) 1220-1226
    CrossrefPubMedGoogle Scholar
  • 65 Bohlius J, Schmidlin K, Brillant C , et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet 2009; 373 (9674) 1532-1542
    CrossrefPubMedGoogle Scholar
  • 66 Bokemeyer C, Aapro MS, Courdi A , et al. EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. Eur J Cancer 2004; 40 (15) 2201-2216
    CrossrefPubMedGoogle Scholar
  • 67 Bokemeyer C, Aapro MS, Courdi A , et al; European Organisation for Research and Treatment of Cancer (EORTC) Taskforce for the Elderly. EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer: 2006 update. Eur J Cancer 2007; 43 (2) 258-270
    CrossrefPubMedGoogle Scholar