Cancer-related anemia and recombinant human erythropoietin—an updated overview

Abstract

For cancer patients, anemia can be a debilitating problem that negatively influences their overall quality of life and worsens their prognosis. The condition is caused either by the cancer itself or by cytotoxic treatment. Anemia is the primary indication for transfusion of red blood cells, but the development of recombinant human erythropoietins (epoetins) provides an alternative to red blood cell transfusions. Treatment with epoetins has been shown to reduce transfusion rates and increase hemoglobin response. There is some evidence that epoetins improve quality of life. It remains unclear, however, whether erythropoietin affects tumor growth and survival, and this area requires further investigation. Data from clinical trials suggest that erythropoietin increases the risk of thromboembolic complications. In the management of anemic patients, physicians should follow closely the dosing recommendations in products' package inserts or the ASCO/American Society of Hematology guidelines. Treatment of patients beyond the correction of anemia, however, has to be regarded as experimental and is potentially harmful, so should only be conducted in clinical trials.

Key Points

  • The pathophysiology of tumor anemia is multifactorial, and treatment with recombinant human erythropoietins has been shown to reduce transfusion rates and increase hemoglobin (Hb) response

  • For many cancers anemia is known to be a factor associated with a worse prognosis

  • In cancer patients, cytostatic therapy and radiation can aggravate anemia, and platinum-based chemotherapy regimens might diminish endogenous erythropoietin

  • Dose-intensified treatment regimens or shortened treatment intervals are associated with a higher degree of anemia

  • Systematic review analysis showed that patients receiving erythropoietin are three to four times more likely to achieve Hb response (Hb increase of 2 g/dl) than those not treated with this agent

  • Thromboembolic complications can be increased in patients receiving erythropoietin, and is not recommended in patients with Hb levels >12 g/dl

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Pathophysiology of anemia.
Figure 2: Meta-analysis of the relative risk to receive red blood cell transfusions for cancer patients receiving erythropoietin or standard care.

References

  1. 1

    Ludwig H et al. (2004) 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 40: 2293–2306

    PubMed  Article  Google Scholar 

  2. 2

    Knight K et al. (2004) Prevalence and outcomes of anemia in cancer: a systematic review of the literature. Am J Med 116 (Suppl 7A): S11–S26

    Article  Google Scholar 

  3. 3

    Groopman JE and Itri LM (1999) Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst 91: 1616–1634

    CAS  PubMed  Article  Google Scholar 

  4. 4

    Spivak JL (2005) The anaemia of cancer: death by a thousand cuts. Nat Rev Cancer 5: 543–555

    CAS  PubMed  Article  Google Scholar 

  5. 5

    Miller CB et al. (1990) Decreased erythropoietin response in patients with the anemia of cancer. N Engl J Med 322: 1689–1692

    CAS  PubMed  Article  Google Scholar 

  6. 6

    Wood PA and Hrushesky WJ (1995) Cisplatin-associated anemia: an erythropoietin deficiency syndrome. J Clin Invest 95: 1650–1659

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7

    Ludwig H and Strasser K (2001) Symptomatology of anemia. Semin Oncol 28: 7–14

    CAS  PubMed  Article  Google Scholar 

  8. 8

    Cella D (1997) The Functional Assessment of Cancer Therapy—Anemia (FACT-An) Scale: a new tool for the assessment of outcomes in cancer anemia and fatigue. Semin Hematol 34: 13–19

    CAS  PubMed  Google Scholar 

  9. 9

    Holzner B et al. (2002) The impact of hemoglobin levels on fatigue and quality of life in cancer patients. Ann Oncol 13: 965–973

    CAS  PubMed  Article  Google Scholar 

  10. 10

    Lind M et al. (2002) The level of haemoglobin in anaemic cancer patients correlates positively with quality of life. Br J Cancer 86: 1243–1249

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11

    Vogelzang NJ et al. (1997) Patient, caregiver, and oncologist perceptions of cancer-related fatigue: results of a tripart assessment survey. The Fatigue Coalition. Semin Hematol 34: 4–12

    CAS  PubMed  Google Scholar 

  12. 12

    Ahlberg K et al. (2003) Assessment and management of cancer-related fatigue in adults. Lancet 362: 640–650

    PubMed  Article  Google Scholar 

  13. 13

    Mock V (2004) Evidence-based treatment for cancer-related fatigue. J Natl Cancer Inst Monogr 112–118

  14. 14

    Caro JJ et al. (2001) Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review. Cancer 91: 2214–2221

    CAS  PubMed  Article  Google Scholar 

  15. 15

    Vaupel P and Mayer A (2005) Hypoxia and anemia: effects on tumor biology and treatment resistance. Transfus Clin Biol 12: 5–10

    PubMed  Article  Google Scholar 

  16. 16

    Schrijvers D et al. (1999) Role of red blood cells in pharmacokinetics of chemotherapeutic agents. Anticancer Drugs 10: 147–153

    CAS  PubMed  Article  Google Scholar 

  17. 17

    Hockel M et al. (1993) Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiothe Oncol 26: 45–50

    CAS  Article  Google Scholar 

  18. 18

    Kelleher DK et al. (1996) Blood flow, oxygenation, and bioenergetic status of tumors after erythropoietin treatment in normal and anemic rats. Cancer Res 56: 4728–4734

    CAS  PubMed  Google Scholar 

  19. 19

    Thews O et al. (1998) Enhanced radiosensitivity in experimental tumours following erythropoietin treatment of chemotherapy-induced anaemia. Br J Cancer 78: 752–756

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20

    Silver DF and Piver MS (1999) Effects of recombinant human erythropoietin on the antitumor effect of cisplatin in SCID mice bearing human ovarian cancer: a possible oxygen effect. Gynecol Oncol 73: 280–284

    CAS  PubMed  Article  Google Scholar 

  21. 21

    Thews O et al. (2001) Erythropoietin restores the anemia-induced reduction in cyclophosphamide cytotoxicity in rat tumors. Cancer Res 61: 1358–1361

    CAS  PubMed  Google Scholar 

  22. 22

    Stuben G et al. (2003) Erythropoietin restores the anemia-induced reduction in radiosensitivity of experimental human tumors in nude mice. Int J Radiat Oncol Biol Phys 55: 1358–1362

    PubMed  Article  CAS  Google Scholar 

  23. 23

    Goodnough LT (2005) Risks of blood transfusion. Anesthesiol Clin North America 23: 241–252

    PubMed  Article  Google Scholar 

  24. 24

    Engert A (2000) Recombinant human erythropoietin as an alternative to blood transfusion in cancer-related anaemia. Dis Manage Health Outcomes 8: 259–272

    Article  Google Scholar 

  25. 25

    Toy P et al. (2005) Transfusion-related acute lung injury: definition and review. Crit Care Med 33: 721–726

    PubMed  Article  Google Scholar 

  26. 26

    Goodnough LT et al. (1999) Transfusion medicine: first of two parts—blood transfusion. N Engl J Med 340: 438–447

    CAS  PubMed  Article  Google Scholar 

  27. 27

    Blajchman MA and Hebert PC (2001) Red blood cell transfusion strategies. Transfus Clin Biol 8: 207–210

    CAS  PubMed  Article  Google Scholar 

  28. 28

    Hill SR et al. (2006) Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. The Cochrane Database of Systematic Reviews, Issue 1, Art. No CD002042

    Google Scholar 

  29. 29

    Hebert PC et al. (1999) A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med 340: 409–417

    CAS  PubMed  Article  Google Scholar 

  30. 30

    Murphy MF et al. (2001) Guidelines for the clinical use of red cell transfusions. Br J Haematol 113: 24–31

    CAS  PubMed  Article  Google Scholar 

  31. 31

    Simon TL et al. (1998) Practice parameter for the use of red blood cell transfusions: developed by the Red Blood Cell Administration Practice Guideline Development Task Force of the College of American Pathologists. Arch Pathol Lab Med 122: 130–138

    CAS  PubMed  Google Scholar 

  32. 32

    Lai PH et al. (1986) Structural characterization of human erythropoietin. J Biol Chem 261: 3116–3121

    CAS  PubMed  Google Scholar 

  33. 33

    Koury ST et al. (1988) Localization of erythropoietin synthesizing cells in murine kidneys by in situ hybridization. Blood 71: 524–527

    CAS  PubMed  Google Scholar 

  34. 34

    Koury ST et al. (1991) Localization of cells producing erythropoietin in murine liver by in situ hybridization. Blood 77: 2497–2503

    CAS  PubMed  Google Scholar 

  35. 35

    D'Andrea AD et al. (1989) Expression cloning of the murine erythropoietin receptor. Cell 57: 277–285

    CAS  PubMed  Article  Google Scholar 

  36. 36

    Koury MJ and Bondurant MC (1990) Erythropoietin retards DNA breakdown and prevents programmed death in erythroid progenitor cells. Science 248: 378–381

    CAS  PubMed  Article  Google Scholar 

  37. 37

    Goldwasser E et al. (1974) On the mechanism of erythropoietin-induced differentiation: the role of sialic acid in erythropoietin action. J Biol Chem 249: 4202–4206

    CAS  PubMed  Google Scholar 

  38. 38

    Procrit® epoetin alfa full prescribing information [http://www.orthobiotech.com/common/prescribing_information/ PROCRIT/PDF/ProcritBooklet.pdf]

  39. 39

    Roche UK package leafeat [http://www.rocheuk.com/ProductDB/Documents/rx/pil/ NeoRecormon_PFS_PIL.pdf]

  40. 40

    Aranesp® (darbepoetin alfa) prescribing information [http://www.aranesp.com/pdf/aranesp_PI.pdf]

  41. 41

    Egrie JC et al. (2003) Darbepoetin alfa has a longer circulating half-life and greater in vivo potency than recombinant human erythropoietin. Exp Hematol 31: 290–299

    CAS  PubMed  Article  Google Scholar 

  42. 42

    Morreale A et al. (2004) Clinical and economic comparison of epoetin alfa and darbepoetin alfa. Curr Med Res Opin 20: 381–395

    CAS  PubMed  Article  Google Scholar 

  43. 43

    Halstenson CE et al. (1991) Comparative pharmacokinetics and pharmacodynamics of epoetin alfa and epoetin beta. Clin Pharmacol Ther 50: 702–712

    CAS  PubMed  Article  Google Scholar 

  44. 44

    Storring PL et al. (1998) Epoetin alfa and beta differ in their erythropoietin isoform compositions and biological properties. Br J Haematol 100: 79–89

    CAS  PubMed  Article  Google Scholar 

  45. 45

    Glaspy J et al. (2005) Final results of a phase 3, randomized, open-label study of darbepoetin alfa 200 mcg every 2 weeks (Q2W) versus epoetin alfa 40,000 U weekly (QW) in patients with chemotherapy-induced anemia (CIA) [abstract #8125]. J Clin Oncol 23

  46. 46

    Cazzola M et al. (2003) Once-weekly epoetin beta is highly effective in treating anaemic patients with lymphoproliferative malignancy and defective endogenous erythropoietin production. Br J Haematol 122: 386–393

    CAS  PubMed  Article  Google Scholar 

  47. 47

    Rodgers GM et al. (online 2005) Cancer- and treatment-related anemia: NCCN Clinical Practice Guidelines in Oncology 2-2005[2.2005] [www.nccn.org/professionals/physician_gls/PDF/anemia.pdf, NCCN National Comprehensive Cancer Network] (accessed 27 January 2006)

  48. 48

    Waltzman RJ et al. (2005) Final haematologic results: epoetin alfa (EPO) 40,000 U QW vs darbepoetin alfa (DARB) 200 µg Q2W in anemic cancer patients (pts) receiving chemotherapy (CT) [abstract #8030]. Proc Am Soc Clin Oncol 23: a736s

    Article  Google Scholar 

  49. 49

    Weingart O et al. (2005) Is the evidence cited in evidence-based guidelines constructive and sufficient for the development of adapted guidelines? 3rd Guideline International Network Conference, December 2005. Lyon: Guidelines International Network.

  50. 50

    Rizzo JD et al. (2002) Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol 20: 4083–4107

    CAS  PubMed  Article  Google Scholar 

  51. 51

    Bokemeyer C et al. (2004) EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. Eur J Cancer 40: 2201–2216

    CAS  PubMed  Article  Google Scholar 

  52. 52

    Quirt I et al. and the Systemic Treatment Disease Site Group. (2005) The role of erythropoietin in the management of cancer patients with non-hematologic malignancies receiving chemotherapy [http://www.guideline.gov/summary/summary.aspx?ss=14&doc_id=7217&string=] (accessed 27 January 2006)

  53. 53

    Seidenfeld J et al. (2001) Epoetin treatment of anemia associated with cancer therapy: a systematic review and meta-analysis of controlled clinical trials. J Natl Cancer Inst 93: 1204–1214

    CAS  PubMed  Article  Google Scholar 

  54. 54

    Bottomley A et al. (2002) Human recombinant erythropoietin and quality of life: a wonder drug or something to wonder about? Lancet Oncol 3: 145–153

    CAS  PubMed  Article  Google Scholar 

  55. 55

    Bohlius J et al. Erythropoietin for patients with malignant disease. The Cochrane Database of Systematic Reviews, Issue 3, Art. No CD003407

  56. 56

    Littlewood TJ et al. (2001) 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 19: 2865–2874

    CAS  PubMed  Article  Google Scholar 

  57. 57

    Bohlius J et al. (2005) Recombinant human erythropoietin and overall survival in cancer patients: results of a comprehensive meta-analysis. J Natl Cancer Inst 97: 489–498

    CAS  PubMed  Article  Google Scholar 

  58. 58

    Clark O et al. (2002) Erythropoietin, uncertainty principle and cancer related anaemia. BMC Cancer 2: 23

    PubMed  PubMed Central  Article  Google Scholar 

  59. 59

    Vansteenkiste J et al. (2002) Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst 94: 1211–1220

    CAS  PubMed  Article  Google Scholar 

  60. 60

    Hedenus M et al. (2003) Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study. Br J Haematol 122: 394–403

    CAS  PubMed  Article  Google Scholar 

  61. 61

    Ludwig H et al. (1994) Prediction of response to erythropoietin treatment in chronic anemia of cancer. Blood 84: 1056–1063

    CAS  PubMed  Google Scholar 

  62. 62

    Witzig TE et al. (2005) Phase III, randomized, double-blind study of epoetin alfa compared with placebo in anemic patients receiving chemotherapy. J Clin Oncol 23: 2606–2617

    CAS  PubMed  Article  Google Scholar 

  63. 63

    Glaspy J et al. (1997) Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. J Clin Oncol 15: 1218–1234

    CAS  PubMed  Article  Google Scholar 

  64. 64

    Demetri GD et al. (1998) 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 16: 3412–3425

    CAS  PubMed  Article  Google Scholar 

  65. 65

    Gabrilove JL et al. (2001) 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 19: 2875–2882

    CAS  PubMed  Article  Google Scholar 

  66. 66

    Shasha D et al. (2003) Once-weekly dosing of epoetin-alpha increases hemoglobin and improves quality of life in anemic cancer patients receiving radiation therapy either concomitantly or sequentially with chemotherapy. Cancer 98: 1072–1079

    CAS  PubMed  Article  Google Scholar 

  67. 67

    Osterborg A et al. (2002) Randomized, double-blind, placebo-controlled trial of recombinant human erythropoietin, epoetin beta, in hematologic malignancies. J Clin Oncol 20: 2486–2494

    CAS  PubMed  Article  Google Scholar 

  68. 68

    Boogaerts M et al. (2003) Impact of epoetin beta on quality of life in patients with malignant disease. Br J Cancer 88: 988–995

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69

    Aaronson NK (1991) Methodologic issues in assessing the quality of life in cancer patients. Cancer 67: 844–850

    CAS  PubMed  Article  Google Scholar 

  70. 70

    Henke M et al. (2003) Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 362: 1255–1260

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71

    Leyland-Jones B (2003) Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol 4: 459–460

    PubMed  Article  Google Scholar 

  72. 72

    Leyland-Jones B et al. (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: 5960–5972

    CAS  PubMed  Article  Google Scholar 

  73. 73

    Luksenburg H et al. (2004) FDA Oncologic Drugs Advisory Committee 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, FDA. [http://www.fda.gov/ohrms/dockets/ac/04/briefing/4037b2.htm] (accessed 22 June 2005)

  74. 74

    Acs G et al. (2001) Erythropoietin and erythropoietin receptor expression in human cancer. Cancer Res 61: 3561–3565

    CAS  PubMed  Google Scholar 

  75. 75

    Arcasoy MO et al. (2002) Functional significance of erythropoietin receptor expression in breast cancer. Lab Invest 82: 911–918

    CAS  PubMed  Article  Google Scholar 

  76. 76

    Jelkmann W and Wagner K (2004) Beneficial and ominous aspects of the pleiotropic action of erythropoietin. Ann Hematol 83: 673–686

    CAS  PubMed  Article  Google Scholar 

  77. 77

    Arcasoy MO et al. (2005) Erythropoietin and erythropoietin receptor expression in head and neck cancer: relationship to tumor hypoxia. Clin Cancer Res 11: 20–27

    CAS  PubMed  Google Scholar 

  78. 78

    Rosen FR et al. (2003) Multicenter randomized phase II study of paclitaxel (1-hour infusion), fluorouracil, hydroxyurea, and concomitant twice daily radiation with or without erythropoietin for advanced head and neck cancer. Clin Cancer Res 9: 1689–1697

    CAS  PubMed  Google Scholar 

  79. 79

    Machtay M et al. (2004) Definitive radiotherapy +/− erythropoietin for squamous cell carcinoma of the head and neck: preliminary report of RTOG 99-03. Int J Radiat Oncol Biol Phys 60 (Suppl 1): S132

    Article  Google Scholar 

  80. 80

    Antonadou D et al. (2001) Erythropoietin enhances radiation treatment efficacy in patients with pelvic malignancies: final results of a randomized phase III study. Eur J Cancer 37 (Suppl 6): S144

    Article  Google Scholar 

  81. 81

    Blohmer JU et al. (2004) Results with sequential adjuvant chemo-radiotherapy [abstract #447PD]. Ann Oncol 15 (Suppl 3)

  82. 82

    Besarab A et al. (1998) 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 339: 584–590

    CAS  Article  PubMed  Google Scholar 

  83. 83

    Wun T et al. (2003) Increased incidence of symptomatic venous thrombosis in patients with cervical carcinoma treated with concurrent chemotherapy, radiation, and erythropoietin. Cancer 98: 1514–1520

    CAS  PubMed  Article  Google Scholar 

  84. 84

    Valles J et al. (2002) Platelet-erythrocyte interactions enhance αIIbβ3 integrin receptor activation and P-selectin expression during platelet recruitment: down-regulation by aspirin ex vivo. Blood 99: 3978–3984

    CAS  PubMed  Article  Google Scholar 

  85. 85

    Stohlawetz PJ et al. (2000) Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans. Blood 95: 2983–2989

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Nowrousian MR et al. (1996) rh-Erythropoietin in Cancer Supportive Treatment, 13–34 New York: Marcel Dekker

    Google Scholar 

  87. 87

    Abels R (1993) Erythropoietin for anemia in cancer patients. Eur J Cancer 29A (Suppl 2): S2–S8

    PubMed  Article  Google Scholar 

  88. 88

    Case DC et al. (1993) Recombinant human erythropoietin therapy for anemic cancer patients on combination chemotherapy. J Natl Cancer Inst 85: 801–806

    PubMed  Article  Google Scholar 

  89. 89

    Henry DH et al. (1995) Recombinant human erythropoietin therapy for anemic cancer patients receiving cisplatin chemotherapy. Cancer J Sci Am 1: 252–260

    CAS  PubMed  Google Scholar 

  90. 90

    Oberhoff C et al. (1998) Recombinant human erythropoietin in the treatment of chemotherapy-induced anemia and prevention of transfusion requirement associated with solid tumors: a randomized, controlled study. Ann Oncol 9: 255–260

    CAS  PubMed  Article  Google Scholar 

  91. 91

    Chang J et al. (2005) Once weekly epoetin alfa maintains hemoglobin, improves quality of life, and reduces transfusion in breast cancer patients receiving chemotherapy. J Clin Oncol 23: 2597–2605

    CAS  PubMed  Article  Google Scholar 

  92. 92

    Savonije JH et al. (2005) Effects of early intervention with epoetin alfa on transfusion requirement, hemoglobin level and survival during platinum-based chemotherapy: results of a multicenter randomised controlled trial. Eur J Cancer 41: 1560–1569

    CAS  PubMed  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Andreas Engert.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bohlius, J., Weingart, O., Trelle, S. et al. Cancer-related anemia and recombinant human erythropoietin—an updated overview. Nat Rev Clin Oncol 3, 152–164 (2006). https://doi.org/10.1038/ncponc0451

Download citation

Further reading

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing