Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Clinical Chemistry and Laboratory Medicine (CCLM)

Published in Association with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)

Editor-in-Chief: Plebani, Mario

Ed. by Gillery, Philippe / Greaves, Ronda / Lackner, Karl J. / Lippi, Giuseppe / Melichar, Bohuslav / Payne, Deborah A. / Schlattmann, Peter


IMPACT FACTOR 2018: 3.638

CiteScore 2018: 2.44

SCImago Journal Rank (SJR) 2018: 1.191
Source Normalized Impact per Paper (SNIP) 2018: 1.205

Online
ISSN
1437-4331
See all formats and pricing
More options …
Volume 51, Issue 9

Issues

Re-evaluation of laboratory predictors of response to current anemia treatment regimens of erythropoiesis stimulating agents in cancer patients

Tilman Steinmetz / Kathrin Kuhr
  • Institute of Medical Statistics, Informatics and Epidemiology (IMSIE), University of Cologne, Cologne, Germany
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Uwe Totzke / Martin Hellmich
  • Institute of Medical Statistics, Informatics and Epidemiology (IMSIE), University of Cologne, Cologne, Germany
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Melanie Heinz / Michael Neise / Johann Mittermüller / Hans-Werner Tessen / Marcel Reiser / Kai Severin / Stephan Schmitz
Published Online: 2013-05-23 | DOI: https://doi.org/10.1515/cclm-2013-0104

Abstract

Background: Anemia is a major cause of morbidity in cancer. Erythropoiesis stimulating agents (ESA) are a mainstay of treatment, although some patients lack response for unknown reasons. Recently, ESA dosing recommendations have changed and iron is increasingly used as an adjunct. Due to these changes, potential laboratory predictors of response were re-evaluated.

Methods: This was a multi-center, observational study in cancer outpatients developing anemia under standard chemotherapy without absolute iron deficiency. For up to 12 weeks, laboratory data was collected while patients were treated with darbepoetin α (DA) either alone or along with intravenous iron. Baseline erythropoietin (Epo), changes in soluble transferrin receptor (sTfR) and in hemoglobin (Hb) early after treatment initiation were re-evaluated as response predictors, based on logistic regression models.

Results: Overall, 279 patients (mean age 66.1 years, 59.5% female) entered the study; 171 (61%) received at least one iron dose along with DA. Response and its predictability hardly increased through adjunct iron, although baseline ferritin <100 mg/L resulted in a 10 times higher probability of response to the combination than to ESA alone. Baseline Epo had low predictive value, regardless of tumor type or use of adjunct iron, although it varied with sex and age. If criteria for all three – Epo, sTfR, and Hb – were met, probability of preventing transfusions was 97%, dropping to 44%, if all three failed.

Conclusions: Changes in ESA treatment recommendations had no impact on the predictability of response. Best prediction is still based on the immediacy of Hb increase.

Keywords: anemia; diagnostics; erythropoietin; intravenous iron; predictor

References

  • 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;40:2293–306.CrossrefPubMedGoogle Scholar

  • 2.

    Demetri GD, Kris M, Wade J, Degos L, Cella D. 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. J Clin Oncol 1998;16:3412–25.Google Scholar

  • 3.

    Littlewood TJ, Bajetta E, Nortier JW, Vercammen E, Rapoport B. 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.PubMedGoogle Scholar

  • 4.

    Witzig TE, Silberstein PT, Loprinzi CL, Sloan JA, Novotny PJ, Mailliard JA, et al. Phase III, randomized, double-blind study of epoetin alfa compared with placebo in anemic patients receiving chemotherapy. J Clin Oncol 2005;23:2606–17.PubMedGoogle Scholar

  • 5.

    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;168:2377–81.Web of ScienceCrossrefPubMedGoogle Scholar

  • 6.

    Schrijvers D. Management of anemia in cancer patients: transfusions. Oncologist 2011;16(Suppl 3):12–8.Web of SciencePubMedCrossrefGoogle Scholar

  • 7.

    Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet 2009;373: 1532–42.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 8.

    Hedley BD, Allan AL, Xenocostas A. The role of erythropoietin and erythropoiesis-stimulating agents in tumor progression. Clin Cancer Res 2011;17:6373–80.PubMedCrossrefGoogle Scholar

  • 9.

    Aapro MS, Link H. September 2007 update on EORTC guidelines and anemia management with erythropoiesis-stimulating agents. Oncologist 2008;13(Suppl 3):33–6.Web of ScienceGoogle Scholar

  • 10.

    Glaspy J, Crawford J, Vansteenkiste J, Henry D, Rao S, Bowers P, et al. Erythropoiesis-stimulating agents in oncology: a study-level meta-analysis of survival and other safety outcomes. Br J Cancer 2010;102:301–15.PubMedCrossrefGoogle Scholar

  • 11.

    Marchal C, Misset JL, Casadevall N, Marec-Berard P, Chastagner P, Kassab-Chahmi D, et al. [Standards & options: recommendations for the use of erythropoiesis-stimulating agents (ESA) in anaemic cancer patients undergoing radiotherapy (2007 update)]. Cancer Radiother 2008;12: 126–33.Web of ScienceGoogle Scholar

  • 12.

    Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy MO, Spivak JL, et al. 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;28:4996–5010.Google Scholar

  • 13.

    Rizzo JD, Somerfield MR, Hagerty KL, Seidenfeld J, Bohlius J, Bennett CL, et al. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update. J Clin Oncol 2008;26:132–49.Web of ScienceGoogle Scholar

  • 14.

    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;22:1301–7.CrossrefPubMedGoogle Scholar

  • 15.

    Henry DH, Dahl NV, Auerbach M, Tchekmedyian S, Laufman LR. 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.Web of ScienceCrossrefPubMedGoogle Scholar

  • 16.

    Bastit L, Vandebroek A, Altintas S, Gaede B, Pinter T, Suto TS, 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 chemotherapy-induced anemia. J Clin Oncol 2008;26:1611–8.Google Scholar

  • 17.

    Pedrazzoli P, Farris A, Del Prete S, Del Gaizo F, Ferrari D, Bianchessi C, 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.CrossrefWeb of ScienceGoogle Scholar

  • 18.

    Auerbach M, Silberstein PT, Webb RT, Averyanova S, Ciuleanu TE, Shao J, et al. Darbepoetin alfa 300 or 500 mug once every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. Am J Hematol 2010;85: 655–63.Web of ScienceGoogle Scholar

  • 19.

    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;21:627–32.PubMedWeb of ScienceGoogle Scholar

  • 20.

    Steensma DP, Sloan JA, Dakhil SR, Dalton R, Kahanic SP, Prager DJ, 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.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 21.

    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;23:1954–62.CrossrefWeb of ScienceGoogle Scholar

  • 22.

    Kim YT, Kim SW, Yoon BS, Cho HJ, Nahm EJ, Kim SH, et al. Effect of intravenously administered iron sucrose on the prevention of anemia in the cervical cancer patients treated with concurrent chemoradiotherapy. Gynecol Oncol 2007;105:199–204.Web of SciencePubMedCrossrefGoogle Scholar

  • 23.

    Dangsuwan P, Manchana T. Blood transfusion reduction with intravenous iron in gynecologic cancer patients receiving chemotherapy. Gynecol Oncol 2010;116:522–5.Web of SciencePubMedCrossrefGoogle Scholar

  • 24.

    Steinmetz HT, Tsamaloukas A, Schmitz S, Wiegand J, Rohrberg R, Eggert J, et al. A new concept for the differential diagnosis and therapy of anaemia in cancer patients. Support Care Cancer 2010;19:261–9.PubMedGoogle Scholar

  • 25.

    Steinmetz T, Tschechne B, Harlin O, Klement B, Franzem M, Wamhoff J, et al. Clinical experience with ferric carboxymaltose in the treatment of cancer- and chemotherapy-associated anaemia. Ann Oncol 2013;24:475–82.CrossrefPubMedGoogle Scholar

  • 26.

    Steinmetz HT. The role of intravenous iron in the treatment of anemia in cancer patients. Ther Adv Hematol 2012;3:177–91.CrossrefPubMedGoogle Scholar

  • 27.

    Katodritou E, Zervas K, Terpos E, Brugnara C. Use of erythropoiesis stimulating agents and intravenous iron for cancer and treatment-related anaemia: the need for predictors and indicators of effectiveness has not abated. Br J Haematol 2008;142:3–10.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 28.

    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: 2006 update. Eur J Cancer 2007;43:258–70.PubMedGoogle Scholar

  • 29.

    Mikhael J, Melosky B, Cripps C, Rayson D, Kouroukis CT. Canadian supportive care recommendations for the management of anemia in patients with cancer. Curr Oncol 2007;14:209–17.PubMedCrossrefWeb of ScienceGoogle Scholar

  • 30.

    NCCN. Practice guidelines in oncology: cancer and chemotherapy-induced anemia. Available from: http://www.nccn.org/professionals/physician_gls/pdf/anemia.pdf. (a) accessed March 2007, (b) Version 1. 2013, accessed March 2013.

  • 31.

    Steinmetz T, Hellmich M, Neise M, Aldaud A, Lerchenmuller C, Tsamaloukas A, et al. Prediction of the responsiveness to treatment with erythropoiesis-stimulating factors: a prospective clinical study in patients with solid tumors. Oncologist 2007;12:748–55.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 32.

    Cazzola M, Beguin Y, Kloczko J, Spicka I, Coiffier B. Once-weekly epoetin beta is highly effective in treating anaemic patients with lymphoproliferative malignancy and defective endogenous erythropoietin production. Br J Haematol 2003;122:386–93.CrossrefPubMedGoogle Scholar

  • 33.

    Kolesar JM, Duren BA, Baranski BG. Retrospective evaluation of response to epoetin alfa in patients with hematologic disorders. J Oncol Pharmacy Practice 2004;10:1–6.Google Scholar

  • 34.

    Steinmetz T, Totzke U, Soling U, Groschek M, Mittermuller J, Schweigert M, et al. Hemoglobin levels that trigger erythropoiesis-stimulating agent treatment decisions for cancer-associated anemia – examination of practice in Germany. Curr Med Res Opin 2008;24:2751–6.Web of SciencePubMedCrossrefGoogle Scholar

  • 35.

    Punnonen K, Irjala K, Rajamaki A. Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency. Blood 1997;89:1052–7.PubMedGoogle Scholar

  • 36.

    Lee EJ, Oh EJ, Park YJ, Lee HK, Kim BK. Soluble transferrin receptor (sTfR), ferritin, and sTfR/log ferritin index in anemic patients with nonhematologic malignancy and chronic inflammation. Clin Chem 2002;48:1118–21.PubMedGoogle Scholar

  • 37.

    Mallick S, Rafiroiu A, Kanthety R, Iqbal S, Malik R, Rahman M. Factors predicting erythropoietin resistance among maintenance hemodialysis patients. Blood Purif 2012;33:238–44.CrossrefWeb of SciencePubMedGoogle Scholar

  • 38.

    Ganz T, Nemeth E. Iron metabolism: interactions with normal and disordered erythropoiesis. Cold Spring Harb Perspect Med 2012;2:a011668.Web of ScienceGoogle Scholar

  • 39.

    Thomas C, Kobold U, Thomas L. Serum hepcidin-25 in comparison to biochemical markers and hematological indices for the differentiation of iron-restricted erythropoiesis. Clin Chem Lab Med 2011;49:207–13.Web of SciencePubMedGoogle Scholar

  • 40.

    Pavese I, Satta F, Todi F, Di Palma M, Piergrossi P, Migliore A, et al. High serum levels of TNF-alpha and IL-6 predict the clinical outcome of treatment with human recombinant erythropoietin in anaemic cancer patients. Ann Oncol 2010;21: 1523–8.PubMedCrossrefGoogle Scholar

  • 41.

    Ukarma L, Johannes H, Beyer U, Zaug M, Osterwalder B, Scherhag A. Hepcidin as a predictor of response to epoetin therapy in anemic cancer patients. Clin Chem 2009;55: 1354–60.PubMedCrossrefGoogle Scholar

  • 42.

    den Elzen WP, de Craen AJ, Wiegerinck ET, Westendorp RG, Swinkels DW, Gussekloo J. Plasma hepcidin levels and anemia in old age. The Leiden 85-Plus Study. Haematologica 2013;98:448–54.CrossrefGoogle Scholar

  • 43.

    Sharma S, Nemeth E, Chen YH, Goodnough J, Huston A, Roodman GD, et al. Involvement of hepcidin in the anemia of multiple myeloma. Clin Cancer Res 2008;14: 3262–7.PubMedCrossrefGoogle Scholar

  • 44.

    Hofmann A, Farmer S, Shandere A. Five drivers shifting the paradigm from product-focused transfusion practice to patient blood management. Oncologist 2011;16:3–11.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 45.

    Thomson A, Farmer S, Hofmann A, Isbister J, Shander A. Patient blood management – a new paradigm for transfusion medicine? ISBT Science Series 2009;4:423–35.CrossrefGoogle Scholar

  • 46.

    Ray-Coquard I, Dussart S, Goillot C, Mayeur D, Debourdeau P, Ghesquieres H, et al. A risk model for severe anemia to select cancer patients for primary prophylaxis with epoetin alpha: a prospective randomized controlled trial of the ELYPSE study group. Ann Oncol 2009;20:1105–12.Google Scholar

About the article

Corresponding author: Dr. H. Tilman Steinmetz, Praxis für Hämatologie und Onkologie, Sachsenring 69, 50677 Cologne, Germany, Phone: +49 221 9318220, Fax: +49 221 9318229


Received: 2013-02-07

Accepted: 2013-04-10

Published Online: 2013-05-23

Published in Print: 2013-09-01


Citation Information: Clinical Chemistry and Laboratory Medicine, Volume 51, Issue 9, Pages 1849–1857, ISSN (Online) 1437-4331, ISSN (Print) 1434-6621, DOI: https://doi.org/10.1515/cclm-2013-0104.

Export Citation

©2013 by Walter de Gruyter Berlin Boston.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

[1]
H. Tilman Steinmetz
Im Focus Onkologie, 2014, Volume 17, Number 4, Page 39
[2]
Jeffrey A. Gilreath, David D. Stenehjem, and George M. Rodgers
American Journal of Hematology, 2014, Volume 89, Number 2, Page 203

Comments (0)

Please log in or register to comment.
Log in