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.
We thank all participating sites for their contribution of data. This work was supported by Amgen Germany.
Conflict of interest statement
Authors’ conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article. Research funding played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
Research funding: This work was supported by Amgen Germany.
Employment or leadership: TS is member of speakers bureau of Amgen, BMS, Pharmacosmos, Roche, Vifor, a consultant for Amgen, BMS, Medice, Novartis, Ortho-Biotec, Pharmacosmos, Roche, Vifor, and investigator in studies of Amgen, Pharmacosmos, Roche, Vifor.
Honorarium: None declared.
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;40:2293–306.10.1016/j.ejca.2004.06.019Search in Google 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;16:3412–25.10.1200/JCO.1998.16.10.3412Search in 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;19:2865–74.10.1200/JCO.2001.19.11.2865Search in Google 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;23:2606–17.10.1200/JCO.2004.10.020Search in Google 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;168:2377–81.10.1001/archinte.168.21.2377Search in Google Scholar
6. Schrijvers D. Management of anemia in cancer patients: transfusions. Oncologist 2011;16(Suppl 3):12–8.10.1634/theoncologist.2011-S3-12Search in Google 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: 1532–42.10.1016/S0140-6736(09)60502-XSearch in Google Scholar
8. Hedley BD, Allan AL, Xenocostas A. The role of erythropoietin and erythropoiesis-stimulating agents in tumor progression. Clin Cancer Res 2011;17:6373–80.10.1158/1078-0432.CCR-10-2577Search in Google Scholar PubMed
9. Aapro MS, Link H. September 2007 update on EORTC guidelines and anemia management with erythropoiesis-stimulating agents. Oncologist 2008;13(Suppl 3):33–6.10.1634/theoncologist.13-S3-33Search in Google Scholar PubMed
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;102:301–15.10.1038/sj.bjc.6605498Search in Google Scholar PubMed PubMed Central
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.Search in Google 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;28:4996–5010.10.1200/JCO.2010.29.2201Search in Google Scholar PubMed
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;26:132–49.10.1200/JCO.2007.14.3396Search in Google Scholar PubMed
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;22:1301–7.10.1200/JCO.2004.08.119Search in Google Scholar PubMed
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;12:231–42.10.1634/theoncologist.12-2-231Search in Google Scholar PubMed
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;26:1611–8.10.1200/JCO.2006.10.4620Search in Google Scholar PubMed
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;26:1619–25.10.1200/JCO.2007.12.2051Search in Google Scholar PubMed
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: 655–63.10.1002/ajh.21779Search in Google Scholar PubMed
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;21:627–32.10.1038/sj.leu.2404562Search in Google Scholar PubMed
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;29:97–105.10.1200/JCO.2010.30.3644Search in Google Scholar PubMed PubMed Central
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;23:1954–62.10.1093/annonc/mds112Search in Google Scholar PubMed
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;105:199–204.10.1016/j.ygyno.2006.11.014Search in Google Scholar PubMed
23. Dangsuwan P, Manchana T. Blood transfusion reduction with intravenous iron in gynecologic cancer patients receiving chemotherapy. Gynecol Oncol 2010;116:522–5.10.1016/j.ygyno.2009.12.004Search in Google Scholar PubMed
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;19:261–9.10.1007/s00520-010-0812-2Search in Google Scholar PubMed
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;24:475–82.10.1093/annonc/mds338Search in Google Scholar PubMed PubMed Central
26. Steinmetz HT. The role of intravenous iron in the treatment of anemia in cancer patients. Ther Adv Hematol 2012;3:177–91.10.1177/2040620712440071Search in Google Scholar PubMed PubMed Central
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;142:3–10.10.1111/j.1365-2141.2008.07163.xSearch in Google Scholar PubMed
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;43:258–70.10.1016/j.ejca.2006.10.014Search in Google Scholar PubMed
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;14:209–17.10.3747/co.2007.149Search in Google Scholar PubMed PubMed Central
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.Search in Google Scholar
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;12:748–55.10.1634/theoncologist.12-6-748Search in Google Scholar PubMed
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;122:386–93.10.1046/j.1365-2141.2003.04439.xSearch in Google Scholar PubMed
33. Kolesar JM, Duren BA, Baranski BG. Retrospective evaluation of response to epoetin alfa in patients with hematologic disorders. J Oncol Pharmacy Practice 2004;10:1–6.10.1191/1078155204jp117oaSearch in 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;24:2751–6.10.1185/03007990802377057Search in Google Scholar PubMed
35. Punnonen K, Irjala K, Rajamaki A. Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency. Blood 1997;89:1052–7.10.1182/blood.V89.3.1052Search in Google 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;48:1118–21.10.1093/clinchem/48.7.1118Search in Google 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;33:238–44.10.1159/000335256Search in Google Scholar PubMed
38. Ganz T, Nemeth E. Iron metabolism: interactions with normal and disordered erythropoiesis. Cold Spring Harb Perspect Med 2012;2:a011668.10.1101/cshperspect.a011668Search in Google Scholar PubMed PubMed Central
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;49:207–13.10.1515/CCLM.2011.056Search in Google Scholar PubMed
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: 1523–8.10.1093/annonc/mdp568Search in Google Scholar PubMed
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: 1354–60.10.1373/clinchem.2008.121285Search in Google Scholar PubMed
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;98:448–54.10.3324/haematol.2012.068825Search in Google Scholar PubMed PubMed Central
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: 3262–7.10.1158/1078-0432.CCR-07-4153Search in Google Scholar PubMed
44. Hofmann A, Farmer S, Shandere A. Five drivers shifting the paradigm from product-focused transfusion practice to patient blood management. Oncologist 2011;16:3–11.10.1634/theoncologist.2011-S3-3Search in Google Scholar PubMed
45. Thomson A, Farmer S, Hofmann A, Isbister J, Shander A. Patient blood management – a new paradigm for transfusion medicine? ISBT Science Series 2009;4:423–35.10.1111/j.1751-2824.2009.01251.xSearch in Google Scholar PubMed PubMed Central
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;20:1105–12.10.1093/annonc/mdn750Search in Google Scholar PubMed
©2013 by Walter de Gruyter Berlin Boston
