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

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.

[1]  D. S. Gordon,et al.  Recombinant human erythropoietin therapy for anemic cancer patients receiving cisplatin chemotherapy. , 1995, The cancer journal from Scientific American.

[2]  R. Greil,et al.  The impact of hemoglobin levels on fatigue and quality of life in cancer patients. , 2002, Annals of oncology : official journal of the European Society for Medical Oncology.

[3]  M. Arcasoy,et al.  Erythropoietin and erythropoietin receptor expression in head and neck cancer: relationship to tumor hypoxia. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[4]  D. Cella,et al.  The Functional Assessment of Cancer Therapy-Anemia (FACT-An) Scale: a new tool for the assessment of outcomes in cancer anemia and fatigue. , 1997, Seminars in hematology.

[5]  W. Jelkmann,et al.  Beneficial and ominous aspects of the pleiotropic action of erythropoietin , 2004, Annals of Hematology.

[6]  M. Kris,et al.  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. Procrit Study Group. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  M. Koury,et al.  Localization of erythropoietin synthesizing cells in murine kidneys by in situ hybridization. , 1988, Blood.

[8]  V. Bramwell,et al.  The role of erythropoietin in the management of cancer patients with non-hematologic malignancies receiving chemotherapy , 2003 .

[9]  P. Vaupel,et al.  Enhanced radiosensitivity in experimental tumours following erythropoietin treatment of chemotherapy-induced anaemia. , 1998, British Journal of Cancer.

[10]  A. Rademaker,et al.  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. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[11]  P. Vaupel,et al.  Erythropoietin restores the anemia-induced reduction in radiosensitivity of experimental human tumors in nude mice. , 2003, International journal of radiation oncology, biology, physics.

[12]  J. Ryu,et al.  Increased incidence of symptomatic venous thrombosis in patients with cervical carcinoma treated with concurrent chemotherapy, radiation, and erythropoietin , 2003, Cancer.

[13]  C. Halstenson,et al.  Comparative pharmacokinetics and pharmacodynamics of epoetin alfa and epoetin beta , 1991, Clinical pharmacology and therapeutics.

[14]  J. Y. Lee,et al.  Epoetin alpha and beta in their erythropoetin isoform compositions and biological properties , 1998 .

[15]  M. Fiegl,et al.  Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. , 2002, Journal of the National Cancer Institute.

[16]  L. Neamtiu,et al.  A phase II study of weekly or 3-weekly docetaxel in patients with metastatic breast cancer , 2005 .

[17]  S. Wade,et al.  Prevalence and outcomes of anemia in cancer: a systematic review of the literature. , 2004, The American journal of medicine.

[18]  J. Glaspy,et al.  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) , 2005 .

[19]  P. Novotny,et al.  Phase III, randomized, double-blind study of epoetin alfa compared with placebo in anemic patients receiving chemotherapy. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  V. Mock,et al.  Assessment and management of cancer-related fatigue in adults , 2003, The Lancet.

[21]  H. Samonigg,et al.  Prediction of response to erythropoietin treatment in chronic anemia of cancer [see comments] , 1994 .

[22]  M. Puglisi,et al.  Erythropoietin enhances radiation treatment efficacy in patients with pelvic malignancies. final results of a randomized phase III study , 2001 .

[23]  Mark J. Koury,et al.  Localization of cells producing erythropoietin in murine liver by in situ hybridization , 1991 .

[24]  V. Hasselblad,et al.  Epoetin treatment of anemia associated with cancer therapy: a systematic review and meta-analysis of controlled clinical trials. , 2001, Journal of the National Cancer Institute.

[25]  C. Bokemeyer,et al.  EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. , 2004, European journal of cancer.

[26]  Michael H. Kanter,et al.  Transfusion medicine. First of two parts--blood transfusion. , 1999 .

[27]  H. Eichler,et al.  Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans. , 2000, Blood.

[28]  M. Murphy,et al.  Serendipity and the use of random donor platelets in fetomaternal alloimmune thrombocytopenia (FMAIT) , 2001, British journal of haematology.

[29]  B. Coiffier,et al.  Impact of epoetin β on quality of life in patients with malignant disease , 2003, British Journal of Cancer.

[30]  B. Coiffier,et al.  Once‐weekly epoetin beta is highly effective in treating anaemic patients with lymphoproliferative malignancy and defective endogenous erythropoietin production , 2003, British journal of haematology.

[31]  D. Cella,et al.  Patient, caregiver, and oncologist perceptions of cancer-related fatigue: results of a tripart assessment survey. The Fatigue Coalition. , 1997, Seminars in hematology.

[32]  J D Milam,et al.  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. , 1998, Archives of pathology & laboratory medicine.

[33]  K. Van Steen,et al.  Human recombinant erythropoietin and quality of life: a wonder drug or something to wonder about? , 2002, The Lancet. Oncology.

[34]  M. Gordon,et al.  Recombinant Human Erythropoietin and Overall Survival in Cancer Patients: Results of a Comprehensive Meta-analysis , 2006 .

[35]  J. Kugler,et al.  Recombinant human erythropoietin therapy for anemic cancer patients on combination chemotherapy. , 1993, Journal of the National Cancer Institute.

[36]  C. Taylor,et al.  Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Procrit Study Group. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  J. Groopman,et al.  Chemotherapy-induced anemia in adults: incidence and treatment. , 1999, Journal of the National Cancer Institute.

[38]  S. Woolf,et al.  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. , 2002, Blood.

[39]  P Vaupel,et al.  Erythropoietin restores the anemia-induced reduction in cyclophosphamide cytotoxicity in rat tumors. , 2001, Cancer research.

[40]  H. Samonigg,et al.  Prediction of response to erythropoietin treatment in chronic anemia of cancer. , 1994, Blood.

[41]  G. Acs,et al.  Erythropoietin and erythropoietin receptor expression in human cancer. , 2001, Cancer research.

[42]  M. Suntharalingam,et al.  Definitive radiotherapy ± erythropoietin for squamous cell carcinma of the head and neck: Preliminary report of RTOG 99–03 , 2004 .

[43]  Y. Brandberg,et al.  Randomized, double-blind, placebo-controlled trial of recombinant human erythropoietin, epoetin Beta, in hematologic malignancies. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[44]  D. Amadori,et al.  Recombinant human erythropoietin in the treatment of chemotherapy-induced anemia and prevention of transfusion requirement associated with solid tumors: a randomized, controlled study. , 1998, Annals of oncology : official journal of the European Society for Medical Oncology.

[45]  B. Djulbegovic,et al.  Erythropoietin, uncertainty principle and cancer related anaemia , 2002, BMC Cancer.

[46]  H. Lodish,et al.  Expression cloning of the murine erythropoietin receptor , 1989, Cell.

[47]  N. Aaronson Methodologic issues in assessing the quality of life of cancer patients , 1991, Cancer.

[48]  J. Nortier,et al.  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. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[49]  A. Engert Recombinant Human Erythropoietin as an Alternative to Blood Transfusion in Cancer-Related Anaemia , 2000 .

[50]  A. Morreale,et al.  Clinical and economic comparison of epoetin alfa and darbepoetin alfa , 2004, Current medical research and opinion.

[51]  L. Harrison,et al.  Once‐weekly dosing of epoetin‐α increases hemoglobin and improves quality of life in anemic cancer patients receiving radiation therapy either concomitantly or sequentially with chemotherapy , 2003, Cancer.

[52]  N. Roubinian,et al.  Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. , 2016, The Cochrane database of systematic reviews.

[53]  V. Mock Evidence-based treatment for cancer-related fatigue. , 2004, Journal of the National Cancer Institute. Monographs.

[54]  W. Hrushesky,et al.  Cisplatin-associated anemia: an erythropoietin deficiency syndrome. , 1995, The Journal of clinical investigation.

[55]  M. J. Broekman,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. , 2002, Blood.

[56]  Dirk Schrijvers,et al.  The European Cancer Anaemia Survey (ECAS): a large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients. , 2004, European journal of cancer.

[57]  M. Piver,et al.  Effects of recombinant human erythropoietin on the antitumor effect of cisplatin in SCID mice bearing human ovarian cancer: A possible oxygen effect. , 1999, Gynecologic oncology.

[58]  J. Spivak The anaemia of cancer: death by a thousand cuts , 2005, Nature Reviews Cancer.

[59]  Denise Williams,et al.  Final hematologic results: Epoetin alfa (EPO) 40,000 U QW vs darbepoetin alfa (DARB) 200 μg Q2W in anemic cancer patients (pts) receiving chemotherapy (CT) , 2005 .

[60]  Edward Abraham,et al.  Transfusion-related acute lung injury: definition and review. , 2005, Critical care medicine.

[61]  B. Rafferty,et al.  Epoetin alfa and beta differ in their erythropoietin isoform compositions and biological properties. , 1998, British journal of haematology.

[62]  J. Duguid,et al.  Guidelines for the clinical use of red cell transfusions , 2001, British journal of haematology.

[63]  D. Cruickshank,et al.  The level of haemoglobin in anaemic cancer patients correlates positively with quality of life , 2002, British Journal of Cancer.

[64]  P. Hebert,et al.  Red blood cell transfusion strategies. , 2001, Transfusion clinique et biologique : journal de la Societe francaise de transfusion sanguine.

[65]  G. Wells,et al.  A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. , 1999, The New England journal of medicine.

[66]  M. Arcasoy,et al.  Functional Significance of Erythropoietin Receptor Expression in Breast Cancer , 2002, Laboratory Investigation.

[67]  H. Ludwig,et al.  Symptomatology of anemia. , 2001, Seminars in oncology.

[68]  Brian Leyland-Jones,et al.  Breast cancer trial with erythropoietin terminated unexpectedly. , 2003, The Lancet. Oncology.

[69]  M. Millenson,et al.  Cancer- and treatment-related anemia: Clinical Practice Guidelines in Oncology , 2005 .

[70]  P. Vaupel,et al.  Blood flow, oxygenation, and bioenergetic status of tumors after erythropoietin treatment in normal and anemic rats. , 1996, Cancer research.

[71]  C. Rübe,et al.  Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial , 2003, The Lancet.

[72]  M. Koury,et al.  Erythropoietin retards DNA breakdown and prevents programmed death in erythroid progenitor cells. , 1990, Science.

[73]  C. V. van Groeningen,et al.  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. , 2005, European journal of cancer.

[74]  J. Caro,et al.  Anemia as an independent prognostic factor for survival in patients with cancer , 2001 .

[75]  J. Baselga,et al.  Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[76]  P. Vaupel,et al.  Hypoxia and anemia: effects on tumor biology and treatment resistance. , 2005, Transfusion clinique et biologique : journal de la Societe francaise de transfusion sanguine.

[77]  J. Miguel,et al.  Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double‐blind, placebo‐controlled study , 2003, British journal of haematology.

[78]  J. Egrie,et al.  Darbepoetin alfa has a longer circulating half-life and greater in vivo potency than recombinant human erythropoietin. , 2003, Experimental hematology.

[79]  R. Abels Erythropoietin for anaemia in cancer patients. , 1993, European journal of cancer.

[80]  S. Piantadosi,et al.  Decreased erythropoietin response in patients with the anemia of cancer. , 1990, The New England journal of medicine.

[81]  L. Goodnough Risks of blood transfusion. , 2005, Critical care medicine.

[82]  T. Arakawa,et al.  Structural characterization of human erythropoietin. , 1986, The Journal of biological chemistry.

[83]  B. S. Neporent,et al.  On The Mechanism of , 1975 .

[84]  E. Goldwasser,et al.  On the mechanism of erythropoietin-induced differentiation. 13. The role of sialic acid in erythropoietin action. , 1974, The Journal of biological chemistry.

[85]  Avid,et al.  THE EFFECTS OF NORMAL AS COMPARED WITH LOW HEMATOCRIT VALUES IN PATIENTS WITH CARDIAC DISEASE WHO ARE RECEIVING HEMODIALYSIS AND EPOETIN , 2000 .

[86]  G. Schwarzer,et al.  Erythropoietin for patients with malignant disease. , 2004, The Cochrane database of systematic reviews.

[87]  C. Lau,et al.  Weekly epoetin alfa maintains hemoglobin, improves quality of life, and reduces transfusion in breast cancer patients receiving chemotherapy. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[88]  P Vaupel,et al.  Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. , 1993, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[89]  M. Highley,et al.  Role of red blood cells in pharmacokinetics of chemotherapeutic agents. , 1999, Anti-cancer drugs.

[90]  E. Winer,et al.  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. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.