Cancer Patient Survival and Erythropoietin

Cancer patients are frequently anemic. Treatment of anemic patients with erythropoiesis-stimulating proteins (ESPs) such as epoetin and darbepoetin is associated with benefits that include a reduced transfusion risk and improved quality of life. The recent reports of two randomized trials in which ESP treatment was associated with a decreased survival raised valid concerns regarding the safety of these agents in oncology practice. Reports of erythropoietin receptors on non-hematologic human tumor cells have increased the level of concern and provided a relatively simple model for the effects of ESPs on tumor progression and resistance to treatment. This article reviews available data, which lead to a number of conclusions: 1) the two trials suggesting a negative impact on survival have serious methodologic issues that may compromise interpretation; 2) when used to treat rather than prevent anemia in cancer patients, ESPs show no significant negative impact on survival outcomes; 3) with the exception of erythroleukemia cell lines, the presence of functional erythropoietin receptors on human tumor cells has not been conclusively shown; and 4) a sound theoretical basis exists, supported by preclinical evidence, that any effect of ESP therapy on tumor outcomes may depend on baseline hemoglobin levels, with different effects when anemic and non-anemic individuals are treated. For the present, it is prudent to withhold ESP therapy unless hemoglobin concentrations fall below 12 g/dL and to titrate treatment to maintain a target of 12 g/dL, with adjustments in therapy to insure that levels do not exceed 13 g/dL.

If the inline PDF is not rendering correctly, you can download the PDF file here.

Correspondence: John A. Glaspy, MD, the Division of Hematology-Oncology, UCLA School of Medicine, 100 UCLA Medical Plaza, Suite 550, Los Angeles, CA 90095-6956. E-mail: jglaspy@mednet.ucla.edu

References

  • 1

    CellaDZagariMJVandorosC. Epoetin alfa treatment results in clinically significant improvements in quality of life in anemic cancer patients when referenced to the general population. J Clin Oncol2003;21:366373.

    • Search Google Scholar
    • Export Citation
  • 2

    CellaDKallichJMcDermottAXuX. The longitudinal relationship of hemoglobin, fatigue and quality of life in anemic cancer patients: results from five randomized clinical trials. Ann Oncol2004;15:979986.

    • Search Google Scholar
    • Export Citation
  • 3

    BerndtEKallichJMcDermottA. Reductions in anaemia and fatigue are associated with improvements in productivity in cancer patients receiving chemotherapy. Pharmacoeconomics2005;23:505514.

    • Search Google Scholar
    • Export Citation
  • 4

    HenkeMLaszigRRubeC. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet2003;362:12551260.

    • Search Google Scholar
    • Export Citation
  • 5

    Leyland-JonesB. Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol2003;4:459460.

  • 6

    CasadevallNNatafJVironB. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med2002;346:469475.

    • Search Google Scholar
    • Export Citation
  • 7

    BennettCLLuminariSNissensonAR. Pure red-cell aplasia and epoetin therapy. N Engl J Med2004;351:14031408.

  • 8

    WunTPaglieroniTHammondWP. Thrombopoietin is synergistic with other hematopoietic growth factors and physiologic platelet agonists for platelet activation in vitro. Am J Hematol1997;54:225232.

    • Search Google Scholar
    • Export Citation
  • 9

    YoussoufianHLongmoreGNeumannD. Structure, function, and activation of the erythropoietin receptor. Blood1993;81:22232236.

  • 10

    ConstantinescuSNGharrariSLodishHF. The erythropoietin receptor: structure, activation, and intracellular signal transduction. Trends Endocrinol Metab1999;10:1823.

    • Search Google Scholar
    • Export Citation
  • 11

    ZhuangHNiuZHeTC. Erythropoietin-dependent inhibition of apoptosis is supported by carboxyl-truncated receptor forms and blocked by dominant-negative forms of Jak2. J Biol Chem1995;270:1450014504.

    • Search Google Scholar
    • Export Citation
  • 12

    RemyIWilsonIAMichnickSW. Erythropoietin receptor activation by a ligand-induced conformation change. Science1999;283:990993.

  • 13

    SuzukiNOhnedaOTakahashiS. Erythroid-specific expression of the erythropoietin receptor rescued its null mutant mice from lethality. Blood2002;100:22792288.

    • Search Google Scholar
    • Export Citation
  • 14

    SemenzaGL. Regulation of hypoxia-induced angiogenesis: a chaperone escorts VEGF to the dance. J Clin Invest2001;108:3940.

  • 15

    SemenzaGL. HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol Med2002;8[suppl 4]: S62S67.

  • 16

    VaupelPBriestSHockelM. Hypoxia in breast cancer: pathogenesis, characterization and biological/therapeutic implications. Wien Med Wochenschr2002;152:334342.

    • Search Google Scholar
    • Export Citation
  • 17

    KrishnamacharyBBerg-DixonSKellyB. Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res2003;63:11381143.

    • Search Google Scholar
    • Export Citation
  • 18

    SemenzaGL. Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit Rev Biochem Mol Biol2000;35:71103.

  • 19

    StoeltzingOMcCartyMFWeyJS. Role of hypoxia-inducible factor 1alpha in gastric cancer cell growth, angiogenesis, and vessel maturation. J Natl Cancer Inst2004;96:946956.

    • Search Google Scholar
    • Export Citation
  • 20

    DunstJKuhntTStraussHG. Anemia in cervical cancers: impact on survival, patterns of relapse, and association with hypoxia and angiogenesis. Int J Radiat Oncol Biol Phys2003;56:778787.

    • Search Google Scholar
    • Export Citation
  • 21

    BrizelDMDodgeRKCloughRWDewhirstMW. Oxygenation of head and neck cancer: changes during radiotherapy and impact on treatment outcome. Radiother Oncol1999;53:113117.

    • Search Google Scholar
    • Export Citation
  • 22

    SemenzaGL. Intratumoral hypoxia, radiation resistance, and HIF-1. Cancer Cell2004;5:405406.

  • 23

    TeicherBAHoldenSAal-AchiAHermanTS. Classification of antineoplastic treatments by their differential toxicity toward putative oxygenated and hypoxic tumor subpopulations in vivo in the FSaIIC murine fibrosarcoma. Cancer Res1990;50:33393344.

    • Search Google Scholar
    • Export Citation
  • 24

    Van BelleSJCocquytV. Impact of haemoglobin levels on the outcome of cancers treated with chemotherapy. Crit Rev Oncol Hematol2003;47:111.

    • Search Google Scholar
    • Export Citation
  • 25

    KallinowskiFZanderRHoeckelMVaupelP. Tumor tissue oxygenation as evaluated by computerized-pO2- histography. Int J Radiat Oncol Biol Phys1990;19:953961.

    • Search Google Scholar
    • Export Citation
  • 26

    FylesAWMilosevicMPintilieMHillRP. Cervix cancer oxygenation measured following external radiation therapy. Int J Radiat Oncol Biol Phys1998;42:751753.

    • Search Google Scholar
    • Export Citation
  • 27

    BeckerAStadlerPLaveyRS. Severe anemia is associated with poor tumor oxygenation in head and neck squamous cell carcinomas. Int J Radiat Oncol Biol Phys2000;46:459466.

    • Search Google Scholar
    • Export Citation
  • 28

    ThewsOKoenigRKelleherDK. Enhanced radiosensitivity in experimental tumours following erythropoietin treatment of chemotherapy-induced anaemia. Br J Cancer1998;78:752756.

    • Search Google Scholar
    • Export Citation
  • 29

    ThewsOKelleherDKVaupelP. Erythropoietin restores the anemia-induced reduction in cyclophosphamide cytotoxicity in rat tumors. Cancer Res2001;61:13581361.

    • Search Google Scholar
    • Export Citation
  • 30

    CarvalhoGLefaucheurCCherbonnierC. Chemosensitization by erythropoietin through inhibition of the NF- kappaB rescue pathway. Oncogene2005;24:737745.

    • Search Google Scholar
    • Export Citation
  • 31

    BlackwellKLKirkpatrickJPSnyderSA. Human recombinant erythropoietin significantly improves tumor oxygenation independent of its effects on hemoglobin. Cancer Res2003;63:61626165.

    • Search Google Scholar
    • Export Citation
  • 32

    VaupelPThewsOMayerA. Oxygenation status of gynecologic tumors: what is the optimal hemoglobin level?Strahlenther Onkol2002;178:727731.

    • Search Google Scholar
    • Export Citation
  • 33

    AnagnostouALiuZSteinerM. Erythropoietin receptor mRNA expression in human endothelial cells. Proc Natl Acad Sci U S A1994;91:39743978.

    • Search Google Scholar
    • Export Citation
  • 34

    RibattiDPrestaMVaccaA. Human erythropoietin induces a pro-angiogenic phenotype in cultured endothelial cells and stimulates neovascularization in vivo. Blood1999;93:26272636.

    • Search Google Scholar
    • Export Citation
  • 35

    Beleslin-CokicBBCokicVPYuX. Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells. Blood2004;104:20732080.

    • Search Google Scholar
    • Export Citation
  • 36

    StohlawetzPJDzirloLHergovichN. Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans. Blood2000;95:29832989.

    • Search Google Scholar
    • Export Citation
  • 37

    ArcasoyMOAminKKarayalAF. Functional significance of erythropoietin receptor expression in breast cancer. Lab Invest2002;82:911918.

  • 38

    AcsGZhangPJRebbeckTR. Immunohistochemical expression of erythropoietin and erythropoietin receptor in breast carcinoma. Cancer2002;95: 969981.

    • Search Google Scholar
    • Export Citation
  • 39

    ArcasoyMOAminKVollmerRT. Erythropoietin and erythropoietin receptor expression in human prostate cancer. Mod Pathol2005;18:421430.

  • 40

    ArcasoyMOAminKChouSC. Erythropoietin and erythropoietin receptor expression in head and neck cancer: relationship to tumor hypoxia. Clin Cancer Res2005;11:2027.

    • Search Google Scholar
    • Export Citation
  • 41

    SinclairABusseLRogersN. EPO receptor transcription is not elevated nor predictive of surface expession in human tumor cells. Proc Am Assoc Cancer Res2005;46:1287.

    • Search Google Scholar
    • Export Citation
  • 42

    BusseLSinclairARogersN. Is EPO receptor over-expressed in human tumor cells?Proc Am Assoc Cancer Res2005;46:1077.

  • 43

    AcsGAcsPBeckwithSM. Erythropoietin and erythropoietin receptor expression in human cancer. Cancer Res2001;61:35613565.

  • 44

    ShannonAMBouchier-HayesDJCondronCMToomeyD. Correction of anaemia through the use of darbepoetin alfa improves chemotherapeutic outcome in a murine model of Lewis lung carcinoma. Br J Cancer2005;93:224232.

    • Search Google Scholar
    • Export Citation
  • 45

    YasudaYMushaTTanakaH. Inhibition of erythropoietin signalling destroys xenografts of ovarian and uterine cancers in nude mice. Br J Cancer2001;84:836843.

    • Search Google Scholar
    • Export Citation
  • 46

    AcsGChenMXuX. Autocrine erythropoietin signaling inhibits hypoxia-induced apoptosis in human breast carcinoma cells. Cancer Lett2004;214:243251.

    • Search Google Scholar
    • Export Citation
  • 47

    CaroJJSalasMWardAGossG. Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review. Cancer2001;91:22142221.

    • Search Google Scholar
    • Export Citation
  • 48

    BlohmerJUDunstJHarrisonL. Cancer-related anemia: biological findings, clinical implications and impact on quality of life. Oncology2005;1:1221.

    • Search Google Scholar
    • Export Citation
  • 49

    LittlewoodTJBajettaENortierJW. 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 Oncol2001;19:28652874.

    • Search Google Scholar
    • Export Citation
  • 50

    VansteenkisteJPirkerRMassutiB. Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst2002;94:12111220.

    • Search Google Scholar
    • Export Citation
  • 51

    BohliusJLangensiepenSSchwarzerG. Erythropoietin for patients with malignant disease. Cochrane Database Syst Rev2004;3.

  • 52

    BohliusJLangensiepenSSchwarzerG. Recombinant human erythropoietin and overall survival in cancer patients: results of a comprehensive meta-analysis. J Natl Cancer Inst2005;97:489498.

    • Search Google Scholar
    • Export Citation
  • 53

    HedenusMVansteenkisteJKotasekD. Darbepoetin alfa for the treatment of chemotherapy-induced anemia: disease progression and survival analysis from four randomized, double-blind, placebo-controlled trials. J Clin Oncol2005;23:69416948.

    • Search Google Scholar
    • Export Citation
  • 54

    OsterborgABrandbergYHedenusM. Impact of epoetin-beta on survival of patients with lymphoproliferative malignancies: long-term follow up of a large randomized study. Br J Haematol2005;129:206209.

    • Search Google Scholar
    • Export Citation
  • 55

    WitzigTESilbersteinPTLoprinziCL. Phase III, randomized, double-blind study of epoetin alfa compared with placebo in anemic patients receiving chemotherapy. J Clin Oncol2005;23:26062617.

    • Search Google Scholar
    • Export Citation
  • 56

    LaiSYChildsEEXiS. Erythropoietin-mediated activation of JAK-STAT signaling contributes to cellular invasion in head and neck squamous cell carcinoma. Oncogene2005;24:44424449.

    • Search Google Scholar
    • Export Citation
  • 57

    GlaserCMMillesiWKornekGV. 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 Phys2001;50:705715.

    • Search Google Scholar
    • Export Citation
  • 58

    Leyland-JonesBSemiglazovVPawlickiM. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol2005;23:58655868.

    • Search Google Scholar
    • Export Citation
  • 59

    VallesJSantosMTAznarJ. Erythrocytes metabolically enhance collagen-induced platelet responsiveness via increased thromboxane production, adenosine diphosphate release, and recruitment. Blood1991;78:154162.

    • Search Google Scholar
    • Export Citation
  • 60

    VallesJSantosMTAznarJ. Platelet-erythrocyte interactions enhance alpha(IIb)beta(3) integrin receptor activation and P-selectin expression during platelet recruitment: down-regulation by aspirin ex vivo. Blood2002;99:39783984.

    • Search Google Scholar
    • Export Citation
  • 61

    WunTLawLHarveyD. Increased incidence of symptomatic venous thrombosis in patients with cervical carcinoma treated with concurrent chemotherapy, radiation, and erythropoietin. Cancer2003;98:15141520.

    • Search Google Scholar
    • Export Citation

Article Information

PubMed

Google Scholar

Related Articles

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 42 42 2
PDF Downloads 38 38 0
EPUB Downloads 0 0 0