Anemias and iron deficiency in cancer patients

V.V. Ptushkin

Federal Scientific and Clinical Centre of Pediatric Hematology, Oncology and Immunology named after Dmitriy Rogachev, Moscow, Russian Federation


Anemia is frequent in cancer patients and its incidence increases with chemotherapy. Anemia negatively impacts survival and accentuates fatigue in cancer patients. Cancer promotes inflammatory cytokine production, which suppresses erythropoiesis and erythropoietin production. Erythropoiesis-stimulating agents improve erythropoiesis and reduce transfusion needs in anemic cancer patients receiving chemotherapy. However, meta-analyses have shown an increased risk of thromboembolic events with еrythropoiesis-stimulating agents use during chemotherapy, but not increased on-study mortality or reduced overall survival. Inflammatory cytokine production in patients with cancer, reduce the availability of iron for effective erythropoiesis. This review summarises clinical consequences of iron deficiency and anaemia in cancer patients, mechanisms how impaired iron homeostasis affects diagnosis and treatment of iron deficiency, and data from clinical trials evaluating i.v. iron with or without concomitant erythropoiesis-stimulating agents.

Keywords: Anemia, cancer, erythropoietin, iron propagates, ferric carboxymaltose, ferritin, transferrin

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  1. Ludwig H., Van B.S., Barrett-Lee P. et al. The European Cancer AnaemiaSurvey (ECAS): a large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients. Eur. J. Cancer 2004; 40: 2293–306.
  2. Groopman J.E., Itri L.M. Chemotherapy-induced anemia in adults: incidence and treatment. J. Natl. Cancer Inst. 1999; 91: 1616–34.
  3. Beale A.L., Penney M.D., Allison M.C. The prevalence of iron deficiency among patients presenting with colorectal cancer. Colorectal. Dis. 2005; 7: 398–402.
  4. Kuvibidila S.R., Gauthier T., Rayford W. Serum ferritin levels and transferrin saturation in men with prostate cancer. J. Natl. Med. Assoc. 2004; 96: 641–9.
  5. Steinmetz H.T., Tsamaloukas A., Schmitz S. et al. A new concept for the differential diagnosis and therapy of anaemia in cancer patients. Support Care Cancer 2010; 19: 261–9.
  6. Beguin Y., Lybaert W., Bosly A. A prospective observational study exploring the impact of iron status on response to darbepoetin alfa in patients with chemotherapy induced anemia. Blood 2009; 114 (Abstr 2007).
  7. Ludwig H., Muldur E., Endler G. et al. High prevalence of iron deficiency across different tumors correlates with anemia, increases during cancer treatment and is associated with poor performance status. Haematologica 2011; 96 (Abstr 982).
  8. Anker S.D., Comin C.J., Filippatos G. et al. Ferric carboxymaltose in patients with heart failure and iron deficiency. N. Engl. J. Med. 2009; 361: 2436–48.
  9. Crawford J., Cella D., Cleeland C.S. 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.
  10. Auerbach M., Ballard H., Trout J.R. 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: 1301–7.
  11. Rizzo J.D., Brouwers M., Hurley P. 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: 4045–59.
  12. Auerbach M., Silberstein P.T., Webb R.T. et al. Darbepoetin alfa 300 or 500 mg once every 3 weeks with or without intravenous iron in patients with chemotherapyinduced anemia. Am. J. Hematol. 2010; 85: 655–63.
  13. Henry D.H., Dahl N.V., Auerbach M. et al. 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.
  14. Pedrazzoli P., Farris A., Del P.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: 1619–25.
  15. Beguin Y. Prediction of response and other improvements on the limitations of recombinant human erythropoietin therapy in anemic cancer patients. Haematologica 2002; 87: 1209–21.
  16. Wish J.B. Assessing iron status: beyond serum ferritin and transferrin saturation. Clin. J. Am. Soc. Nephrol. 2006; 1(Suppl. 1): S4–S8.
  17. Hedenus M., Birgegard G., Nasman 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: 627–32.
  18. Ludwig H., Endler G., Hubl W. et al. High prevalence of iron deficiency in patients with various hematological and malignant diseases: a single center study in 1989 sequential patients. Haematologica 2010; 95 (Abstr 1819).
  19. Ludwig H., Aapro M., Bokemeyer C. et al. Treatment patterns and outcomes in the management of anaemia in cancer patients in Europe: findings from the Anaemia Cancer Treatment (ACT) study. Eur. J. Cancer 2009; 45: 1603–15.
  20. Aapro M.S., Link H. September 2007 update on EORTC guidelines and anemia management with erythropoiesis-stimulating agents. Oncologist 2008; 13(Suppl. 3): 33–6.
  21. Vamvakas E.C., Blajchman M.A. Transfusion-related mortality: the ongoing risks of allogeneic blood transfusion and the available strategies for their prevention. Blood 2009; 113: 3406–17.
  22. Marik P.E., Corwin H.L. Efficacy of red blood cell transfusion in the critically ill: a systematic review of the literature. Crit. Care Med. 2008; 36: 2667–74.
  23. Thomson A., Farmer S., Hofmann A. et al. Patient blood management—a new paradigm for transfusion medicine? ISBT Sci. Series 2009; 4: 423–35.
  24. Amato A.C., Pescatori M. Effect of perioperative blood transfusions on recurrence of colorectal cancer: meta-analysis stratified on risk factors. Dis. Colon Rectum 1998; 41: 570–85.
  25. 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; CD007303.
  26. Gabrilove J.L., Cleeland C.S., Livingston R.B. 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. J. Clin. Oncol. 2001; 19: 2875–82.
  27. Littlewood T.J., Bajetta E., Nortier J.W. 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. J. Clin. Oncol. 2001; 19: 2865–74.
  28. US Food and Drug Administration. Epoetin Alfa (Marketed as Epoetin, Procrit) Label. label/2010/103234s5199lbl.pdf (5 September 2011, date last accessed).
  29. US Food and Drug Administration. Darbepoetin Alfa (Marketed as Aransep) Label. label/2010/103951s5197lbl.pdf (5 September 2011, date last accessed).
  30. Macdougall I.C. Strategies for iron supplementation: oral versus intravenous. Kidney Int. Suppl. 1999; 69: S61–S66.
  31. Bastit L., Vandebroek A., Altintas S. et al. Randomized, multicenter, controlled trial comparing the efficacy and safety of darbepoetin alpha administered every 3 weeks with or without intravenous iron in patients with chemotherapyinduced anemia. J. Clin. Oncol. 2008; 26: 1611–8.
  32. Steensma D.P., Sloan J.A., Dakhil S.R. 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.
  33. Gafter-Gvili A., Rozen-Zvi B., Vidal L. et al. Intravenous iron supplementation for the treatment of cancer-related anemia—systematic review and metaanalysis. Blood 2010; 116 (Abstr 4249).
  34. Petrelli F., Borgonovo K., Cabiddu M. et al. Addition of iron to erythropoiesis-stimulating agents in cancer patients: a meta-analysis of randomized trials. J. Cancer Res. Clin. Oncol. 2012; 138: 179–87.
  35. Dangsuwan P., Manchana T. Blood transfusion reduction with intravenous iron in gynecologic cancer patients receiving chemotherapy. Gynecol. Oncol. 2010; 116: 522–5.
  36. Steinmetz T., Tschechne B., Virgin G. et al. Ferric carboxymaltose for the correction of cancer- and chemotherapy-associated anemia in clinical practice. Haematologica 2011; 96 (Abstr 983).
  37. Evstatiev R., Marteau P., Iqbal T. et al. FERGIcor, a randomized controlled trial on ferric carboxymaltose for iron deficiency anemia in inflammatory bowel disease. Gastroenterology 2011; 141: 846–53.
  38. Kulnigg S., Stoinov S., Simanenkov V. et al. A novel intravenous iron formulation for treatment of anemia in inflammatory bowel disease: the ferric carboxymaltose (FERINJECT) randomized controlled trial. Am. J. Gastroenterol. 2008; 103: 1182–92.
  39. Aapro M., Beguin Y., Birgegard G. et al. Too-low iron doses and too many dropouts in negative iron trial? J. Clin. Oncol. 2011; 29: e525–e526.
  40. Bailie G.R., Horl W.H., Verhof J.J. Differences in spontaneously reported hypersensitivity and serious adverse events for intravenous iron preparations: comparison of Europe and North America. Drug Res. 2011; 61: 267–75.
  41. Bailie G.R., Clark J.A., Lane C.E. et al. Hypersensitivity reactions and deaths associated with intravenous iron preparations. Nephrol. Dial. Transplant. 2005; 20: 1443–9.
  42. Chertow G.M., Mason P.D., Vaage-Nilsen O. et al. Update on adverse drug events associated with parenteral iron. Nephrol. Dial. Transplant. 2006; 21: 378–82.
  43. Zhang F., Wang W., Tsuji Y. et al. Post-transcriptional modulation of iron homeostasis during p53-dependent growth arrest. J. Biol. Chem. 2008; 283: 33911–8.
  44. Baliga R., Zhang Z., Baliga M. et al. In vitro and in vivo evidence suggesting a role for iron in cisplatin-induced nephrotoxicity. Kidney Int. 1998; 53: 394–401.
  45. Toyokuni S. Role of iron in carcinogenesis: cancer as a ferrotoxic disease. Cancer Sci. 2009; 100: 9–16.
  46. Bergeron R.J., Streiff R.R., Elliott G.T. Influence of iron on in vivo proliferation and lethality of L1210 cells. J. Nutr. 1985; 115: 369–74.
  47. Carthew P., Nolan B.M., Smith A.G. et al. Iron promotes DEN initiated GST-P foci in rat liver. Carcinogenesis 1997; 18: 599–603.
  48. Auerbach M., Glaspy J. What is the right balance between iron and erythropoiesis stimulating agents in chemotherapy induced anemia? Eur. J. Clin. Med. Oncol. 2009; 1: 7–12.
  49. Beguin Y., Maertens J., De Prijck B. et al. Darbepoetin-alfa and i.v. iron administration after autologous hematopoietic stem cell transplantation: a prospective randomized multicenter trial. Blood 2008; 112 (Abstr 54).