Efficacy of intravenous iron treatment for chemotherapy-induced anemia: A prospective Phase II pilot clinical trial in South Korea

Autoři: Jun Ho Jang aff001;  Youjin Kim aff001;  Silvia Park aff003;  Kihyun Kim aff001;  Seok Jin Kim aff001;  Won Seog Kim aff001;  Chul Won Jung aff001;  Jeeyun Lee aff001;  Se-Hoon Lee aff001
Působiště autorů: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University of School of Medicine, Seoul, South Korea aff001;  Division of Hematology-Oncology, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, South Korea aff002;  Department of Hematology, Catholic Hematology Hospital, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea aff003;  Leukemia Research Institute, College of Medicine, The Catholic University of Korea, Seoul, South Korea aff004
Vyšlo v časopise: Efficacy of intravenous iron treatment for chemotherapy-induced anemia: A prospective Phase II pilot clinical trial in South Korea. PLoS Med 17(6): e32767. doi:10.1371/journal.pmed.1003091
Kategorie: Research Article
doi: 10.1371/journal.pmed.1003091



Anemia is the most common and serious cancer-related complication. This study aimed to evaluate the efficacy of administration of ferric carboxymaltose without erythropoiesis-stimulating agents for treating anemia in cancer patients. Moreover, we identified the biomarkers of hemoglobin response to predict the need for iron therapy.

Methods and findings

We enrolled patients with solid cancers who were treated at a single institute (Samsung Medical Center, South Korea), from April 2015 to July 2017, in this prospective single-arm Phase II clinical trial. Patients received intravenous ferric carboxymaltose (1,000 mg) infusion on the first day (visit 1) of treatment. The primary end point was the number of hemoglobin responders, defined as patients with an increase in hemoglobin level ≥ 1.0 g/dL from the baseline, a hemoglobin level ≥ 11.0 g/dL, or both, within an 8-week observation period (week 3, 6, or 8). Secondary end points included changes in transferrin saturation and levels of soluble transferrin receptors, hepcidin, erythropoietin, interleukin-6, and C-reactive protein (CRP) at each visit. Of the 103 recruited patients, 92 were eligible for analysis. The mean patient age was 57.3 ± 12.5 years, and 54.3% of the patients were women. The most common diagnoses were breast cancer (n = 23, 25.1%), lung cancer (n = 21, 22.9%), gastrointestinal cancer (n = 20, 20.9%), and lymphoma (n = 16, 17.7%). A hemoglobin response was observed in 36 (39.1%), 53 (57.6%), and 61 (66.3%) patients in the third, fifth, and eighth weeks, respectively. The mean increase in hemoglobin levels from the baseline to the end of treatment was 1.77 ± 1.30 g/dL. Baseline values of hepcidin (p = 0.008), total iron binding capacity (p = 0.014), ferritin (p = 0.048), and CRP (p = 0.044) were significantly different between the responder and nonresponder groups. Multiple logistic regression analysis for baseline anemia-related biochemical variable significantly associated with the hemoglobin response showed that only baseline hepcidin level was a significant factor for hemoglobin response (odds ratio = 0.95, 95% confidence interval 0.90–1.0, p = 0.045). Hemoglobin responders had significantly lower hepcidin levels than nonresponders (mean [±standard deviation], 13.45 [±14.71] versus 35.22 [±40.470 ng/ml]; p = 0.007). However, our analysis had some limitations such as the different patient characteristics in the studies that were included, institutional differences in the measurement of hepcidin level, and missing data on long-term safety. Therefore, our findings need further validation.


Intravenous ferric carboxymaltose (1,000 mg) monotherapy increases hemoglobin levels without serious adverse events in patients with cancer. Hepcidin is a useful biomarker for predicting iron requirement in cancer patients.

Trial registration

Clinicaltrials.gov NCT02599012

Klíčová slova:

anémia – Biomarkers – Blood transfusion – Cancer chemotherapy – Cancer treatment – Ferritin – Hemoglobin – Intravenous injections


1. Ludwig H, Van Belle S, Barrett-Lee P, Birgegard G, Bokemeyer C, Gascon P, et al. 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. 2004; 40(15):2293–306. doi: 10.1016/j.ejca.2004.06.019 15454256

2. Busti F, Marchi G, Ugolini S, Castagna A, Girelli D. Anemia and Iron Deficiency in Cancer Patients: Role of Iron Replacement Therapy. Pharmaceuticals (Basel). 2018; 11(4):94. doi: 10.3390/ph11040094 30274354

3. Calabrich A, Katz A. Management of anemia in cancer patients. Future Oncol. 2011; 7(4):507–17. doi: 10.2217/fon.11.24 21463140

4. Caro JJ, Salas M, Ward A, Goss G. Anemia as an independent prognostic factor for survival in patients with cancer: a systemic, quantitative review. Cancer. 2001; 91(12):2214–21. https://doi.org/doi:10.1002/1097-0142(20010615)91:12<2214::AID-CNCR1251>3.0.CO;2-P 11413508

5. Cella D, Kallich J, McDermott A, Xu X. The longitudinal relationship of hemoglobin, fatigue and quality of life in anemic cancer patients: results from five randomized clinical trials. Ann Oncol. 2004; 15(6):979–86. doi: 10.1093/annonc/mdh235 15151958

6. Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Somerfield MR, Temin S. 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 Oncol Pract. 2010; 6(6):317–20. doi: 10.1200/JOP.2010.000132 21358963

7. Rizzo JD, Lichtin AE, Woolf SH, Seidenfeld J, Bennett CL, Cella D, 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. Blood. 2002; 100(7):2303–20. doi: 10.1182/blood-2002-06-1767 12239138

8. Khorana AA, Francis CW, Blumberg N, Culakova E, Refaai MA, Lyman GH. Blood transfusions, thrombosis, and mortality in hospitalized patients with cancer. Arch Intern Med. 2008; 168(21):2377–81. doi: 10.1001/archinte.168.21.2377 19029504

9. Vansteenkiste J, Poulsen E, Rossi G, Glaspy J. Darbepoetin alfa: impact on treatment for chemotherapy-induced anemia and considerations in special populations. Oncology (Williston Park). 2002; 16(10 Suppl 11):45–55. 12435173

10. Hedenus M, Adriansson M, San Miguel J, Kramer MH, Schipperus MR, Juvonen E, et al. Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study. Br J Haematol. 2003; 122(3):394–403. doi: 10.1046/j.1365-2141.2003.04448.x 12877666

11. Bennett CL, Silver SM, Djulbegovic B, Samaras AT, Blau CA, Gleason KJ, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA. 2008; 299(8):914–24. doi: 10.1001/jama.299.8.914 18314434

12. Dufraine J, Funahashi Y, Kitajewski J. Notch signaling regulates tumor angiogenesis by diverse mechanisms. Oncogene. 2008; 27(38):5132–7. doi: 10.1038/onc.2008.227 18758482

13. Aapro M, Beguin Y, Bokemeyer C, Dicato M, Gascon P, Glaspy J, et al. Management of anaemia and iron deficiency in patients with cancer: ESMO Clinical Practice Guidelines. Ann Oncol. 2018; 29(Suppl 4):iv96–iv110. doi: 10.1093/annonc/mdx758 29471514

14. Steinmetz HT. The role of intravenous iron in the treatment of anemia in cancer patients. Ther Adv Hematol. 2012; 3(3):177–91. doi: 10.1177/2040620712440071 23556124

15. Dangsuwan P, Manchana T. Blood transfusion reduction with intravenous iron in gynecologic cancer patients receiving chemotherapy. Gynecol Oncol. 2010; 116(3):522–5. doi: 10.1016/j.ygyno.2009.12.004 20051288

16. Park S, Jung CW, Kim K, Kim SJ, Kim WS, Jang JH. Iron deficient erythropoiesis might play key role in development of anemia in cancer patients. Oncotarget. 2015; 6(40):42803–12. doi: 10.18632/oncotarget.5658 26517509

17. Becker PS, Griffiths EA, Alwan L, Bachiashvili K, Brown A, Cool R et al. Hematopoietic growth factors version 1.2020, NCCN clinical practice guidelines in oncology. NCCN; 2019.

18. Jung SH, Owzar K, George SL, Lee T. P-value calculation for multistage phase II cancer clinical trials. J Biopharm Stat. 2006; 16(6):765–75; discussion 77–83. doi: 10.1080/10543400600825645 17146978

19. Jung SH, Kim KM. On the estimation of the binomial probability in multistage clinical trials. Stat Med. 2004; 23(6):881–96. doi: 10.1002/sim.1653 15027078

20. Auerbach M, Ballard H, Trout JR, McIlwain M, Ackerman A, Bahrain H, 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(7):1301–7. doi: 10.1200/JCO.2004.08.119 15051778

21. Steensma DP, Sasu BJ, Sloan JA, Tomita DK, Loprinzi CL. Serum hepcidin levels predict response to intravenous iron and darbepoetin in chemotherapy-associated anemia. Blood. 2015; 125(23):3669–71. doi: 10.1182/blood-2015-03-636407 26045598

22. Hedenus M, Birgegard G, Nasman P, Ahlberg L, Karlsson T, Lauri B, 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(4):627–32. doi: 10.1038/sj.leu.2404562 17252006

23. Takatoku M, Uchiyama T, Okamoto S, Kanakura Y, Sawada K, Tomonaga M, et al. Retrospective nationwide survey of Japanese patients with transfusion-dependent MDS and aplastic anemia highlights the negative impact of iron overload on morbidity/mortality. Eur J Haematol. 2007; 78(6):487–94. doi: 10.1111/j.1600-0609.2007.00842.x 17391310

24. Nemeth E, Ganz T. Regulation of iron metabolism by hepcidin. Annu Rev Nutr. 2006; 26:323–42. doi: 10.1146/annurev.nutr.26.061505.111303 16848710

25. Girelli D, Nemeth E, Swinkels DW. Hepcidin in the diagnosis of iron disorders. Blood. 2016; 127(23):2809–13. doi: 10.1182/blood-2015-12-639112 27044621

26. Shu T, Jing C, Lv Z, Xie Y, Xu J, Wu J. Hepcidin in tumor-related iron deficiency anemia and tumor-related anemia of chronic disease: pathogenic mechanisms and diagnosis. Eur J Haematol. 2015; 94(1):67–73. doi: 10.1111/ejh.12402 24954786

27. Rivera S, Liu L, Nemeth E, Gabayan V, Sorensen OE, Ganz T. Hepcidin excess induces the sequestration of iron and exacerbates tumor-associated anemia. Blood. 2005; 105(4):1797–802. doi: 10.1182/blood-2004-08-3375 15479721

28. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005; 352(10):1011–23. doi: 10.1056/NEJMra041809 15758012

29. Wrighting DM, Andrews NC. Interleukin-6 induces hepcidin expression through STAT3. Blood. 2006; 108(9):3204–9. doi: 10.1182/blood-2006-06-027631 16835372

30. Verga Falzacappa MV, Vujic Spasic M, Kessler R, Stolte J, Hentze MW, Muckenthaler MU. STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood. 2007; 109(1):353–8. doi: 10.1182/blood-2006-07-033969 16946298

31. Roy CN, Andrews NC. Anemia of inflammation: the hepcidin link. Curr Opin Hematol. 2005; 12(2):107–11. doi: 10.1097/00062752-200503000-00001 15725899

32. Grotto HZ. Anaemia of cancer: an overview of mechanisms involved in its pathogenesis. Med Oncol. 2008; 25(1):12–21. doi: 10.1007/s12032-007-9000-8 18188710

33. Tanno T, Bhanu NV, Oneal PA, Goh SH, Staker P, Lee YT, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med. 2007; 13(9):1096–101. doi: 10.1038/nm1629 17721544

34. Peyssonnaux C, Nizet V, Johnson RS. Role of the hypoxia inducible factors HIF in iron metabolism. Cell Cycle. 2008; 7(1):28–32. doi: 10.4161/cc.7.1.5145 18212530

35. Bregman DB, Morris D, Koch TA, He A, Goodnough LT. Hepcidin levels predict nonresponsiveness to oral iron therapy in patients with iron deficiency anemia. Am J Hematol. 2013; 88(2):97–101. doi: 10.1002/ajh.23354 23335357

36. Bokemeyer C, Aapro MS, Courdi A, Foubert J, Link H, Osterborg A, et al. EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. Eur J Cancer. 2004; 40(15):2201–16. doi: 10.1016/j.ejca.2004.07.015 15454245

37. Aapro M, Osterborg A, Gascon P, Ludwig H, Beguin Y. Prevalence and management of cancer-related anaemia, iron deficiency and the specific role of i.v. iron. Ann Oncol. 2012; 23(8):1954–62. doi: 10.1093/annonc/mds112 22575608

38. Ludwig H, Aapro M, Bokemeyer C, Macdonald K, Soubeyran P, Turner M, 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(9):1603–15. doi: 10.1016/j.ejca.2009.02.003 19278851

39. Gabrilove JL, Cleeland CS, Livingston RB, Sarokhan B, Winer E, Einhorn LH. 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(11):2875–82. doi: 10.1200/JCO.2001.19.11.2875 11387360

40. Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, et al. Erythropoietin or Darbepoetin for patients with cancer—meta-analysis based on individual patient data. Cochrane Database Syst Rev. 2009(3):CD007303. doi: 10.1002/14651858.CD007303.pub2 19588423

41. Infusino I, Braga F, Dolci A, Panteghini M. Soluble transferrin receptor (sTfR) and sTfR/log ferritin index for the diagnosis of iron-deficiency anemia. A meta-analysis. Am J Clin Pathol. 2012; 138(5):642–9. doi: 10.1309/AJCP16NTXZLZFAIB 23086764

42. Baillie FJ, Morrison AE, Fergus I. Soluble transferrin receptor: a discriminating assay for iron deficiency. Clin Lab Haematol. 2003; 25(6):353–7. doi: 10.1046/j.0141-9854.2003.00548.x 14641138

43. Theurl I, Aigner E, Theurl M, Nairz M, Seifert M, Schroll A, et al. Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. Blood. 2009; 113(21):5277–86. doi: 10.1182/blood-2008-12-195651 19293425

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