Total Dose Iron Dextran Infusion in Cancer Patients: Is it SaFe2+?

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  • a From Huntsman Cancer Institute, Department of Pharmacy Services, University of Utah Hospitals and Clinics; Pharmacotherapy Outcomes Research Center, Department of Pharmacotherapy, University of Utah College of Pharmacy; and Departments of Medicine and Pathology, University of Utah Hospitals and Clinics, Salt Lake City, Utah.
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The feasibility of the large, single-dose intravenous iron repletion method, which is known today as total dose infusion (TDI), has been demonstrated over decades. However, this method of iron repletion was chiefly developed for patients with large iron deficits, such as those with pregnancy-induced anemia, chronic bleeding disorders, and absolute iron-deficiency anemia (serum ferritin < 30 ng/mL, transferrin saturation < 15%) who were unable to receive frequent small doses of intravenous iron. Today, 50 years after the advent of TDI, more is known about iron metabolism and storage, but the optimal dosing strategy for intravenous iron in patients with cancer is still not well defined. The proinflammatory state of cancer, or its treatment, may influence the response to intravenous iron therapy. Additionally, the long-term adverse effects of large single doses or smaller more frequent doses have yet to be studied in the oncology population. Historically, safety concerns surrounding the administration of intravenous iron have centered on anaphylaxis. Newer concerns are being raised, such as oxidative stress, iron overload, venous thromboembolism, infection risk, and tumor growth. Therefore, with the original premise of TDI assuming low levels of inflammation, coupled with the recent data surrounding the adverse effects of blood transfusions and erythropoietic-stimulating agents, this article reviews the risks and benefits of TDI administration specifically for patients with cancer.

Correspondence: Jeffrey A. Gilreath, PharmD, Huntsman Cancer Institute – University of Utah Hospitals and Clinics, 1950 Circle of Hope, Suite 2110, Salt Lake City, UT 84112. E-mail: jeffrey.gilreath@hci.utah.edu
  • 1

    Marchasin S, Wallerstein R. The treatment of iron-deficiency anemia with intravenous iron dextran. Blood 1964;23:354358.

  • 2

    Basu S. Rapid administration of iron-dextran in late pregnancy. Lancet 1963;281:1430.

  • 3

    Wallerstein R. Intravenous iron-dextran complex. Blood 1968;32:690695.

  • 4

    Patel KM, Tulloch JA. Total dose imferon (iron-dextran complex) infusion therapy in severe hookworm anaemia. Br Med J 1967;2:605607.

  • 5

    Auerbach M, Ballard H. Clinical use of intravenous iron: administration, efficacy, and safety. Hematology Am Soc Hematol Educ Program 2010;2010:338347.

    • Search Google Scholar
    • Export Citation
  • 6

    Rodgers GM, Auerbach M, Cella D. High-molecular weight iron dextran: a wolf in sheep’s clothing? J Am Soc Nephrol 2008;19:833834.

  • 7

    Auerbach M, Coyne D, Ballard H. Intravenous iron: from anathema to standard of care. Am J Hematol 2008;83:580588.

  • 8

    Case G. Maintaining iron balance with total-dose infusion of intravenous iron dextran. ANNA J 1998;25:6568.

  • 9

    Rodgers GM, Becker PS, Blinder M. NCCN Clinical Practice Guidelines in Oncology: Cancer- and Chemotherapy-Induced Anemia, Version 2, 2012. Available at: NCCN.org. Accessed February 20, 2012.

    • Search Google Scholar
    • Export Citation
  • 10

    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;87:308310.

    • Search Google Scholar
    • Export Citation
  • 11

    Khorana AA, Francis CW, Blumberg N. Blood transfusions, thrombosis, and mortality in hospitalized patients with cancer. Arch Intern Med 2008;168:23772381.

    • Search Google Scholar
    • Export Citation
  • 12

    Auerbach M, Ballard H, Trout JR. 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;22:13011307.

    • Search Google Scholar
    • Export Citation
  • 13

    Rizzo JD, Brouwers M, Hurley P. American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. J Clin Oncol 2010;28:49965010.

    • Search Google Scholar
    • Export Citation
  • 14

    Mhaskar R, Wao H, Kumar A. Role of iron supplementation to erythropoiesis stimulating agents in the management of chemotherapy-induced anemia in cancer patients: a systematic review and meta-analysis [abstract]. Blood 2010;116(Suppl):Abstract 2055.

    • Search Google Scholar
    • Export Citation
  • 15

    Henry DH, Dahl NV, Auerbach M. Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy. Oncologist 2007;12:231242.

    • Search Google Scholar
    • Export Citation
  • 16

    Hess G, Nordyke RJ, Hill J, Hulnick S. Effect of reimbursement changes on erythropoiesis-stimulating agent utilization and transfusions. Am J Hematol 2010;85:838843.

    • Search Google Scholar
    • Export Citation
  • 17

    Vekeman F, Bookhart BK, White J. Impact of limiting erythropoiesis-stimulating agent use for chemotherapy-induced anemia on the United States blood supply margin. Transfusion 2009;49:895902.

    • Search Google Scholar
    • Export Citation
  • 18

    Shander A, Spence RK, Auerbach M. Can intravenous iron therapy meet the unmet needs created by the new restrictions on erythropoietic stimulating agents? Transfusion 2010;50:719732.

    • Search Google Scholar
    • Export Citation
  • 19

    Henderson PA, Hillman RS. Characteristics of iron dextran utilization in man. Blood 1969;34:357375.

  • 20

    CosmoFer [package insert]. Holbaek, Denmark: Pharmacosmos A/S; 2009.

  • 21

    INFeD [package insert]. Parsippany, NJ: Watson Pharmaceuticals, Inc.; 2009.

  • 22

    Sinha S, Chiu D, Peebles G. Accelerated total dose infusion of low molecular weight iron dextran is safe and efficacious in chronic kidney disease patients. QJM 2011;104:221230.

    • Search Google Scholar
    • Export Citation
  • 23

    Auerbach M, Winchester J, Wahab A. A randomized trial of three iron dextran infusion methods for anemia in EPO-treated dialysis patients. Am J Kidney Dis 1998;31:8186.

    • Search Google Scholar
    • Export Citation
  • 24

    Koutroubakis IE, Oustamanolakis P, Karakoidas C. Safety and efficacy of total-dose infusion of low molecular weight iron dextran for iron deficiency anemia in patients with inflammatory bowel disease. Dig Dis Sci 2010;55:23272331.

    • Search Google Scholar
    • Export Citation
  • 25

    Kwa S. Iron deficiency anaemia treated by total dose infusion of iron dextran complex. Singapore Medical Journal 1966;7:105109.

  • 26

    Low C, Bailie G, Eisele G. Changes in hematocrit, serum ferritin and transferrin saturation after intravenous iron dextran [abstract]. J Am Soc Nephrol 1996;7:Abstract 1392.

    • Search Google Scholar
    • Export Citation
  • 27

    Ganzoni A. Intravenous iron-dextran: therapeutic and experimental possibilities. Schweiz Med Wochenschr 1970;100:301303.

  • 28

    Hanson D. Guide to total dose intravenous iron dextran therapy. Am J Hosp Pharm 1974;31:592595.

  • 29

    Venofer [package insert]. Shirley, NY: American Regent, Inc.; 2011.

  • 30

    Auerbach M, Witt D, Toler W. Clinical use of the total dose intravenous infusion of iron dextran. J Lab Clin Med 1988;111:566570.

  • 31

    Bastit L, Vandebroek A, Altintas S. Randomized, multicenter, controlled trial comparing the efficacy and safety of darbepoetin alpha administered every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. J Clin Oncol 2008;26:16111618.

    • Search Google Scholar
    • Export Citation
  • 32

    Pedrazzoli P, Farris A, Del Prete S. Randomized trial of intravenous iron supplementation in patients with chemotherapy-related anemia without iron deficiency treated with darbepoetin alpha. J Clin Oncol 2008;26:16191625.

    • Search Google Scholar
    • Export Citation
  • 33

    Hedenus M, Birgegård G, Näsman P. 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;21:627632.

    • Search Google Scholar
    • Export Citation
  • 34

    Loo M, Beguin Y. The effect of recombinant human erythropoietin on platelet counts is strongly modulated by the adequacy of iron supply. Blood 1999;93:32863293.

    • Search Google Scholar
    • Export Citation
  • 35

    Keung YK. Iron deficiency and thrombosis: literature review. Clin Appl Thromb Hemost 2004;10:387391.

  • 36

    Franchini M, Targher G, Montagnana M, Lippi G. Iron and thrombosis. Ann Hematol 2007;87:167173.

  • 37

    Gross S, Keefer V, Newman AJ. The platelets in iron-deficiency anemia. I. The response to oral and parenteral iron. Pediatrics 1964;34:315323.

    • Search Google Scholar
    • Export Citation
  • 38

    Olsen K, Coniglione T, Barton C. Response of platelets to intravenous iron dextran in reactive thrombocytosis. Clin Pharm 1987;6:417420.

  • 39

    Maguire JL, deVeber G, Parkin PC. Association between iron-deficiency anemia and stroke in young children. Pediatrics 2007;120:10531057.

  • 40

    Munot P, De Vile C, Hemingway C. Severe iron deficiency anaemia and ischaemic stroke in children. Arch Dis Child 2011;96:276279.

  • 41

    Peebles G, Stanley S. Evaluation of service reconfiguration for managing intravenous iron supplementation in non-hemodialysis patients with chronic renal failure. Journal of Outcomes Research 2004;8:1525.

    • Search Google Scholar
    • Export Citation
  • 42

    Fletes R, Lazarus JM, Gage J, Chertow GM. Suspected iron dextran-related adverse drug events in hemodialysis patients. Am J Kidney Dis 2001;37:743749.

    • Search Google Scholar
    • Export Citation
  • 43

    Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmen J. Update on adverse drug events associated with parenteral iron. Nephrol Dial Transplant 2005;21:378382.

    • Search Google Scholar
    • Export Citation
  • 44

    Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmen J. On the relative safety of parenteral iron formulations. Nephrol Dial Transplant 2004;19:15711575.

    • Search Google Scholar
    • Export Citation
  • 45

    Barton JC, Barton EH, Bertoli LF. Intravenous iron dextran therapy in patients with iron deficiency and normal renal function who failed to respond to or did not tolerate oral iron supplementation. Am J Med 2000;109:2732.

    • Search Google Scholar
    • Export Citation
  • 46

    Laman CA, Silverstein SB, Rodgers GM. Parenteral iron therapy: a single institution’s experience over a 5-year period. J Natl Compr Canc Netw 2005;3:791795.

    • Search Google Scholar
    • Export Citation
  • 47

    Lim R, Irvine T, Ahmed MS. A permanent tan from iron. Kidney Int 2008;73:898.

  • 48

    Feldman HI. Administration of parenteral iron and mortality among hemodialysis patients. J Am Soc Nephrol 2004;15:16231632.

  • 49

    Toyokuni S. Role of iron in carcinogenesis: cancer as a ferrotoxic disease. Cancer Sci 2009;100:916.

  • 50

    Deugnier Y, Turlin B. Iron and hepatocellular carcinoma. J Gastroenterol Hepatol 2001;16:491494.

  • 51

    Yamada Y, Shigetomi H, Onogi A. Redox-active iron-induced oxidative stress in the pathogenesis of clear cell carcinoma of the ovary. Int J Gynecol Cancer 2011;21:12001207.

    • Search Google Scholar
    • Export Citation
  • 52

    Toyokuni S. Mechanisms of asbestos-induced carcinogenesis. Nagoya J Med Sci 2009;71:110.

  • 53

    Chua AC. Iron: an emerging factor in colorectal carcinogenesis. World J Gastroenterol 2010;16:663672.

  • 54

    Wu T, Sempos CT, Freudenheim JL. Serum iron, copper and zinc concentrations and risk of cancer mortality in US adults. Ann Epidemiol 2004;14:195201.

    • Search Google Scholar
    • Export Citation
  • 55

    Zacharski LR, Chow BK, Howes PS. Decreased cancer risk after iron reduction in patients with peripheral arterial disease: results from a randomized trial. J Natl Cancer Inst 2008;100:9961002.

    • Search Google Scholar
    • Export Citation
  • 56

    Kato J, Miyanishi K, Kobune M. Long-term phlebotomy with low-iron diet therapy lowers risk of development of hepatocellular carcinoma from chronic hepatitis C. J Gastroenterol 2007;42:830836.

    • Search Google Scholar
    • Export Citation
  • 57

    Gutteridge JM, Rowley DA, Halliwell B. Superoxide-dependent formation of hydroxyl radicals and lipid peroxidation in the presence of iron salts. Detection of “catalytic” iron and anti-oxidant activity in extracellular fluids. Biochem J 1982;206:605609.

    • Search Google Scholar
    • Export Citation
  • 58

    Fenton HJ. Oxidation of tartaric acid in presence of iron. J Chem Soc Trans 1894;65:899910.

  • 59

    Shah SV, Alam MG. Role of iron in atherosclerosis. Am J Kidney Dis 2003;41(3 Suppl 1):S8083.

  • 60

    Ramakrishna G, Rooke TW, Cooper LT. Iron and peripheral arterial disease: revisiting the iron hypothesis in a different light. Vasc Med 2003;8:203210.

    • Search Google Scholar
    • Export Citation
  • 61

    Strippoli GF, Tognoni G, Navaneethan SD. Haemoglobin targets: we were wrong, time to move on. Lancet 2007;369:346350.

  • 62

    Drüeke TB, Locatelli F, Clyne N. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006;355:20712084.

    • Search Google Scholar
    • Export Citation
  • 63

    Besarab A, Bolton WK, Browne JK. 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;339:584590.

    • Search Google Scholar
    • Export Citation
  • 64

    Auerbach M, Pappadakis JA, Bahrain H. Safety and efficacy of rapidly administered (one hour) one gram of low molecular weight iron dextran (INFeD) for the treatment of iron deficient anemia. Am J Hematol 2011;86:860862.

    • Search Google Scholar
    • Export Citation
  • 65

    Steensma DP, Sloan JA, Dakhil SR. 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;29:97105.

    • Search Google Scholar
    • Export Citation
  • 66

    Nakanishi T, Kuragano T, Nanami M. Importance of ferritin for optimizing anemia therapy in chronic kidney disease. Am J Nephrol 2010;32:439446.

    • Search Google Scholar
    • Export Citation
  • 67

    Ifudu O. Parenteral iron: pharmacology and clinical use. Nephron 1998;80:249256.

  • 68

    Fix O, Kowdley K. Hereditary hemochromatosis. Minerva Med 2008;99:605617.

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