Management of anaemia and iron deficiency in patients with cancer: ESMO Clinical Practice Guidelines
Authors: M. Aapro, Y. Beguin, C. Bokemeyer, M. Dicato, P. Gascón, J. Glaspy, A. Hofmann, H. Link, T. Littlewood, H. Ludwig, A. Österborg, P. Pronzato, V. Santini, D. Schrijvers, R. Stauder, K. Jordan, J. Herrstedt
Journal: Annals of Oncology (2017)

Anaemia and iron deficiency (ID) are frequent complications in patients with solid tumours or haematological malignancies, particularly in patients treated with chemotherapeutic agents [1.Ludwig H. Van Belle S. Barrett-Lee P. 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: 2293-2306http://dx.doi.org/10.1016/j.ejca.2004.06.019Abstract Full Text Full Text PDF PubMed Scopus (614) Google Scholar, 2.Ludwig H. Muldur E. Endler G. Hubl W. Prevalence of iron deficiency across different tumors and its association with poor performance status, disease status and anemia.Ann Oncol. 2013; 24: 1886-1892http://dx.doi.org/10.1093/annonc/mdt118Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 3.Delarue R. Tilly H. Salles G.A. et al.Iron parameters and relation to prognosis in elderly patients with aggressive lymphoma receiving first line immunochemotherapy: an analysis of the Lysa LNH 03-6B Study.Blood. 2013; 122 (Abstr 2202)Google Scholar]. Frequently, anaemia is associated with fatigue, impaired physical function and reduced quality of life (QoL) [4.Anker S.D. Comin Colet J. Filippatos G. et al.Ferric carboxymaltose in patients with heart failure and iron deficiency.N Engl J Med. 2009; 361: 2436-2448http://dx.doi.org/10.1056/NEJMoa0908355Crossref PubMed Scopus (1102) Google Scholar, 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: 979-986http://dx.doi.org/10.1093/annonc/mdh235Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar, 6.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: 888-895http://dx.doi.org/10.1002/cncr.10763Crossref PubMed Scopus (366) Google Scholar, 7.Demetri G.D. Anaemia and its functional consequences in cancer patients: current challenges in management and prospects for improving therapy.Br J Cancer. 2001; 84: 31-37Crossref PubMed Google Scholar]. Consequences of anaemia may include impaired response to cancer treatment and reduced overall survival (OS), even though a causal direct relationship has not yet been established [8.Caro J.J. 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: 2214-2221Crossref PubMed Scopus (718) Google Scholar, 9.Hudis C.A. Van Belle S. Chang J. Muenstedt K. rHuEPO and treatment outcomes: the clinical experience.Oncologist. 2004; 9: 55-69Crossref PubMed Scopus (0) Google Scholar]. These new ESMO Clinical Practice Guidelines provide tools to evaluate anaemia, also in patients with myelodysplastic syndromes (MDS), and include recommendations on how to safely manage chemotherapy-induced anaemia (CIA) with erythropoiesis-stimulating agents (ESAs), iron preparations for intravenous (i.v.) or oral administration, red blood cell (RBC) transfusions and combinations of these treatments [10.Aapro M. Österborg A. Gascón P. et al.Prevalence and management of cancer-related anaemia, iron deficiency and the specific role of intravenous iron.Ann Oncol. 2012; 23: 1954-1962Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 11.National Comprehensive Cancer Network. NCCN Practice Guidelines in Oncology; Cancer and Chemotherapy-Induced Anemia – v.1.2018, 2017; http://www.nccn.org/professionals/physician_gls/PDF/anemia.pdf (18 October 2017, date last accessed).Google Scholar, 12.Aapro M. Chernov V.M. Gladkov O.A. et al.Practical recommendations for the treatment of anemia in cancer patients.Malignant Tumors. 2016; 4: 368-377Google Scholar, 13.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: 4045-4059http://dx.doi.org/10.1182/blood-2010-08-300541Crossref PubMed Scopus (168) Google Scholar]. The major aims of anaemia management are the reduction or resolution of anaemia symptoms, particularly fatigue, and an improved QoL with the minimum invasive treatment that corrects the underlying causes and proves to be safe. Underlying causes of anaemia, mainly impaired erythropoietic activity and disturbed iron homeostasis, can be consequences of increased release of inflammatory cytokines due to the underlying cancer and/or toxicity of cancer therapy. Furthermore, vitamin B12 and folate deficiency are relatively rare causes of anaemia in cancer patients. Notably, also more than half of patients with MDS are characterised by a haemoglobin (Hb) level < 10 g/dL, resulting in reduced functional capacities and health-related QoL, and > 80% of these patients require RBC transfusions [14.Santini V. Clinical use of erythropoietic stimulating agents in myelodysplastic syndromes.Oncologist. 2011; 16: 35-42Crossref PubMed Google Scholar, 15.Malcovati L. Hellström-Lindberg E. Bowen D. et al.Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet.Blood. 2013; 122: 2943-2964Crossref PubMed Scopus (404) Google Scholar, 16.Efficace F. Gaidano G. Breccia M. et al.Prevalence, severity and correlates of fatigue in newly diagnosed patients with myelodysplastic syndromes.Br J Haematol. 2015; 168: 361-370http://dx.doi.org/10.1111/bjh.13138Crossref PubMed Scopus (35) Google Scholar, 17.de Swart L. Smith A. Johnston T.W. et al.Validation of the revised international prognostic scoring system (IPSS-R) in patients with lower-risk myelodysplastic syndromes: a report from the prospective European LeukaemiaNet MDS (EUMDS) registry.Br J Haematol. 2015; 170: 372-383http://dx.doi.org/10.1111/bjh.13450Crossref PubMed Google Scholar]. However, ESAs were not approved by the European Medicines Agency (EMA) for use in MDS patients despite being used effectively in MDS for at least 20 years; their activity has been demonstrated in numerous clinical trials, with published evidence existing for more than 2500 ESA-treated MDS patients [14.Santini V. Clinical use of erythropoietic stimulating agents in myelodysplastic syndromes.Oncologist. 2011; 16: 35-42Crossref PubMed Google Scholar]. Randomised clinical trials are ongoing. Since the publication of the European Society of Medical Oncology (ESMO) anaemia Clinical Practice Guidelines in 2010 [18.Schrijvers D. De Samblanx H. Roila F. Erythropoiesis-stimulating agents in the treatment of anaemia in cancer patients: ESMO Clinical Practice Guidelines for use.Ann Oncol. 2010; 21: v244-v247Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar] and the last review of the European Organisation for Research and Treatment of Cancer (EORTC) anaemia treatment guidelines in 2006 [19.Bokemeyer C. Aapro M. Courdi A. et al.EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer: 2006 update.Eur J Cancer. 2007; 43: 258-270http://dx.doi.org/10.1016/j.ejca.2006.10.014Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar] (last update in 2007 [20.Aapro M.S. Link H. September 2007 update on EORTC guidelines and anemia management with erythropoiesis-stimulating agents.Oncologist. 2008; 13: 33-36Crossref PubMed Scopus (156) Google Scholar]), clinical experience with ESAs and iron preparations and the understanding of iron homeostasis have markedly increased [10.Aapro M. Österborg A. Gascón P. et al.Prevalence and management of cancer-related anaemia, iron deficiency and the specific role of intravenous iron.Ann Oncol. 2012; 23: 1954-1962Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 21.Aapro M. Jelkmann W. Constantinescu S.N. Leyland-Jones B. Effects of erythropoietin receptors and erythropoiesis-stimulating agents on disease progression in cancer.Br J Cancer. 2012; 106: 1249-1258Crossref PubMed Scopus (83) Google Scholar]. Furthermore, specific safety aspects of the different treatment options have been addressed by several analyses and reviews in recent years, although data on the use of blood transfusions in cancer patients are sparse. Therefore, new ESMO guidelines for the diagnosis and treatment of anaemia and ID in cancer patients were deemed necessary. In addition, these guidelines include aspects related to anaemia management in patients with MDS and update the most recent ESMO and European LeukemiaNet (ELN) treatment guidelines for MDS [15.Malcovati L. Hellström-Lindberg E. Bowen D. et al.Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet.Blood. 2013; 122: 2943-2964Crossref PubMed Scopus (404) Google Scholar, 22.Fenaux P. Haase D. Sanz G.F. et al.Myelodysplastic syndromes: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2014; 25: iii57-iii69Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar]. Questions addressed by these guidelines and respective recommendations including levels of evidence and grades of recommendations [23.Dykewicz C.A. Summary of the guidelines for preventing opportunistic infections among haematopoietic stem cell transplant recipients.Clin Infect Dis. 2001; 33: 139-144http://dx.doi.org/10.1086/321805Crossref PubMed Scopus (0) Google Scholar] are summarised in Table 1 for the management of anaemia and ID in patients with solid tumours or haematological malignancies and in Table 2 for the management of MDS. These recommendations are further illustrated in treatment algorithms (Figures 1 and 2). Discussions of specific aspects underlying the recommendations and related to the different treatment options are summarised in this article.Table 1Managing anaemia and ID in patients with solid tumours or haematological malignanciesWhen should ESA treatment be considered?Treatment of anaemia with an ESA should be considered in patients under ChT after correction of ID and other underlying causes other than the cancer or its treatment [I, A].Which patients should receive ESA therapy?ESA therapy is recommended in patients with symptomatic anaemia who receive ChT [I, A] or combined RT-ChT [II, B] and present with an Hb level < 10 g/dL, as well as patients with asymptomatic anaemia who receive ChT and present with an Hb level < 8 g/dL.Should patients who do not receive ChT treatment be treated with an ESA?ESA treatment is not recommended in patients who are not on ChT [I, A].What is the Hb target range for treatment with an ESA?The Hb target is a stable level of ∼ 12 g/dL without RBC transfusions [I, A].At what doses should ESAs be given?Dosing should follow the approved labels of the individual products; the currently recommended dosage is approximately 450 IU/week/kg body weight for epoetins alpha, beta and zeta; 6.75 µg/kg body weight every 3 weeks or 2.25 µg/kg body weight weekly for darbepoetin alpha; and 20 000 IU once weekly for epoetin theta [I, A].Should ESA doses be increased or ESA preparations changed in patients not responding within 4–8 weeks?Except for patients receiving epoetin theta (given at an intentionally low starting dose), ESA dose escalations and changes from one ESA to another in patients not responding within 4–8 weeks are not recommended. Patients who do not show evidence of at least an initial Hb response at this time should stop ESA therapy. The epoetin theta dose may be doubled after 4 weeks if Hb has not increased by at least 1 g/dL, unless functional ID is detected (see next recommendation) [I, A].Which patients should receive iron therapy?Patients receiving ongoing ChT who present with anaemia (Hb ≤ 11 g/dL or Hb decrease ≥ 2 g/dL from a baseline level ≤ 12 g/dL) and absolute ID (serum ferritin < 100 ng/mL) should receive iron treatment with an i.v. iron preparation to correct ID. If ESA treatment is considered, iron treatment should be given before the initiation of and/or during ESA therapy in the case of functional ID (TSAT < 20% and serum ferritin > 100 ng/mL) [I, A].Should patients receive i.v. iron therapy without an ESA?i.v. iron without additional anaemia therapy may be considered in individual patients with functional ID (TSAT < 20% and serum ferritin > 100 ng/mL) [III, C].Should patients who are not on ChT receive iron therapy?Iron treatment should be limited to patients on ChT. In patients receiving cardiotoxic ChT, i.v. iron should either be given before or after (not on the same day) administration of ChT or at the end of a treatment cycle [III, C].At what doses should i.v. iron be given?Patients with confirmed functional ID should receive a dose of 1000 mg iron given as single dose or multiple doses according to the label of available i.v. iron formulations. Patients with confirmed absolute ID should receive i.v. iron doses according to the approved labels of available products until correction of ID [I, A].Which patients should be considered for RBC transfusions?In patients with Hb < 7–8 g/dL and/or severe anaemia-related symptoms (even at higher Hb levels) and the need for immediate Hb and symptom improvement, the administration of RBC transfusions without delay is justified [II, B].ChT, chemotherapy; ESA, erythropoiesis-stimulating agent; Hb, haemoglobin; ID, iron deficiency; i.v., intravenous; RBC, red blood cell; RT, radiotherapy; TSAT, transferrin saturation. Open table in a new tab Table 2Managing anaemia in patients with MDSWhen should ESA treatment be considered?aESAs are not all EMA-approved for use in patients with MDS. Epoetin alpha is indicated by the EMA for the treatment of symptomatic anaemia (haemoglobin concentration of ≤ 10 g/dL) in adults with low or intermediate-1 risk primary MDS who have low serum EPO (<200 IU/mL).Treatment of anaemia with an ESA should be considered in MDS patients with symptomatic anaemia, Hb < 10 g/dL, low to intermediate-1 risk (IPSS) or very low to intermediate risk (IPSS-R), less than two RBC transfusions per month and/or serum EPO < 500 IU/L [I, A].At what doses should ESAs be given?ESAs should be given as fixed-dose, weekly, subcutaneous treatment at an initial dose in the range of 30 000–80 000 IU recombinant human EPO (epoetin theta starting dose is 20 000 IU) or up to 300 µg darbepoetin alpha [I, A].How should MDS patients who are not responding to ESA treatment be treated?In patients not responding to ESA treatment after 8–12 weeks, G-CSF should be added at ∼ 300 µg/week, given in 2–3 doses. RBC transfusions or investigational medicinal products should be considered as second-line treatment in patients without a 5q deletion, and lenalidomide in patients who acquired a 5q deletion [I, A].How should transfusion-dependent, anaemic MDS patients be treated?Patients who require 2 or more RBC transfusions per month should be considered for treatment with an investigational agent or supportive care with RBC transfusions if they have no 5q deletion, or for lenalidomide if they have a 5q deletion [I, A].EMA, European Medicines Agency; EPO, erythropoietin; ESA, erythropoiesis-stimulating agent; G-CSF, granulocyte colony-stimulating factor; Hb, haemoglobin; IPSS, International Prognostic Scoring System; IPSS-R, revised International Prognostic Scoring System; MDS, myelodysplastic syndrome; RBC, red blood cell.a ESAs are not all EMA-approved for use in patients with MDS. Epoetin alpha is indicated by the EMA for the treatment of symptomatic anaemia (haemoglobin concentration of ≤ 10 g/dL) in adults with low or intermediate-1 risk primary MDS who have low serum EPO (<200 IU/mL). Open table in a new tab Figure 2Management of anaemia in patients with very low to intermediate-risk MDS. aESA-treated patients who are iron deficient and transfusion independent may be considered for i.v. iron treatment. EPO, erythropoietin; ESA, erythropoiesis-stimulating agent; G-CSF, granulocyte colony-stimulating factor; Hb, haemoglobin; IPSS, International Prognostic Scoring System; IPSS-R, revised International Prognostic Scoring System; i.v., intravenous; MDS, myelodysplastic syndrome; RBC, red blood cell; SF, serum ferritin; TSAT, transferrin saturation. Adapted from [22.Fenaux P. Haase D. Sanz G.F. et al.Myelodysplastic syndromes: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2014; 25: iii57-iii69Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar].View Large Image Figure ViewerDownload Hi-res image Download (PPT) ChT, chemotherapy; ESA, erythropoiesis-stimulating agent; Hb, haemoglobin; ID, iron deficiency; i.v., intravenous; RBC, red blood cell; RT, radiotherapy; TSAT, transferrin saturation. EMA, European Medicines Agency; EPO, erythropoietin; ESA, erythropoiesis-stimulating agent; G-CSF, granulocyte colony-stimulating factor; Hb, haemoglobin; IPSS, International Prognostic Scoring System; IPSS-R, revised International Prognostic Scoring System; MDS, myelodysplastic syndrome; RBC, red blood cell. ESAs have been shown to increase Hb levels and to reduce the need for RBC transfusions in cancer patients receiving chemotherapy [24.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: 2875-2882http://dx.doi.org/10.1200/JCO.2001.19.11.2875Crossref PubMed Google Scholar, 25.Hedenus M. Adriansson M. San Miguel J. 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: 394-403http://dx.doi.org/10.1046/j.1365-2141.2003.04448.xCrossref PubMed Scopus (287) Google Scholar, 26.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: 2865-2874http://dx.doi.org/10.1200/JCO.2001.19.11.2865Crossref PubMed Scopus (918) Google Scholar, 27.Vansteenkiste J. Pirker R. Massuti B. et al.Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy.J Natl Cancer Inst. 2002; 94: 1211-1220http://dx.doi.org/10.1093/jnci/94.16.1211Crossref PubMed Google Scholar] and are approved for the treatment of CIA since 1993 [28.Aapro M. An update on twenty years of anemia management with erythropoiesis-stimulating agents in nephrology and oncology/hematology.Oncologist. 2009; 14: 1-5Crossref PubMed Scopus (14) Google Scholar]. Furthermore, a meta-analysis of 23 studies that reported QoL results and included 5584 patients showed a statistically significant difference between patients treated with ESAs and controls when combining QoL parameters and fatigue-related symptoms well as anaemia-related symptoms [29.Tonia T. Mettler A. Robert N. et al.Erythropoietin or darbepoetin for patients with cancer.Cochrane Database Syst Rev. 2012; 12: CD003407.PubMed Google Scholar] (Table 3). However, the authors considered this finding to be not clinically important. Conversely, experience with patients responding to therapy and a recently published meta-analysis of 37 randomised, controlled trials with 10 581 patients suggest a small but clinically important improvement in anaemia-related symptoms [30.Bohlius J. Tonia T. Nüesch E. et al.Effects of erythropoiesis-stimulating agents on fatigue- and anaemia-related symptoms in cancer patients: systematic review and meta-analyses of published and unpublished data.Br J Cancer. 2014; 111: 33-45Crossref PubMed Scopus (37) Google Scholar].Table 3Benefit-risk profiles of treatments for anaemia and ID in cancer patientsBenefitsRisks or limitationsESAs•Reduction of RBC transfusions•Improvement in anaemia-related symptoms•Increase in thrombotic events•PRCA in rare casesaDocumented only in non-cancer chronic kidney disease patients.•Increased mortality in patients receiving no cancer therapy or only RT•Only effective in 60% of patients•Induction of functional ID and decreasing response over timei.v. ironbOral iron to be considered only for patients with both absolute ID (ferritin < 100 ng/mL) and non-inflammatory conditions (CRP < 5 mg/L).•Correction of ID anaemia•Reduction of RBC transfusions•Increase response to ESAs•Long-term safety in oncology not yet fully establishedRBC transfusions•Immediate increase of Hb and haematocrit levels in 100%•Rapid improvement in anaemia-related symptoms•Increase in thrombotic events•Transfusion reactions and circulatory overload•Transmission of known/unknown pathogens•Possibly decreased survival in certain types of cancer treated by surgery•Increased risk of infections due to immunosuppressionCRP, C-reactive protein; ESA, erythropoiesis-stimulating agent; Hb, haemoglobin; ID, iron deficiency; i.v., intravenous; PRCA, pure red cell aplasia; RBC, red blood cell; RT, radiotherapy.a Documented only in non-cancer chronic kidney disease patients.b Oral iron to be considered only for patients with both absolute ID (ferritin < 100 ng/mL) and non-inflammatory conditions (CRP < 5 mg/L). Open table in a new tab CRP, C-reactive protein; ESA, erythropoiesis-stimulating agent; Hb, haemoglobin; ID, iron deficiency; i.v., intravenous; PRCA, pure red cell aplasia; RBC, red blood cell; RT, radiotherapy. Since early dose finding studies with epoetin beta did not show a difference in Hb response to 5000 and 10 000 IU/day (corresponding to 500 and 1000 IU/kg/week in a 70 kg individual) [31.Cazzola M. Messinger D. Battistel V. et al.Recombinant human erythropoietin in the anemia associated with multiple myeloma or non-Hodgkin’s lymphoma: dose finding and identification of predictors of response.Blood. 1995; 86: 4446-4453Crossref PubMed Google Scholar], and since there is not a single study on dose escalations showing a benefit, dose escalations in patients who do not respond within 4–8 weeks are not recommended (except for epoetin theta’s low starting dose to be doubled after 4 weeks if Hb response is < 1 g/dL). Instead, ESA treatment should be stopped at this time point if there is no emerging sign of Hb response. There is no evidence of differing efficacy among ESAs (Table 4) and no recommendation can be made to change from one product to another in the case of an insufficient response. Because of possible safety issues, we continue to recommend that products should not be used interchangeably without adequate traceability and without notifying the treating physician [V, C].Table 4Approved ESAs and i.v. iron compounds and their approved dosing in patients with solid tumours and haematological malignanciesaEpoetin alpha is EMA-approved for low or intermediate-1 risk MDS (see text).,bBoth originator products and biosimilars approved by the EMA have been shown to have similar safety and therapeutic equivalence in clinical practice.ESAsEpoetin alpha450 IU/kg subcutaneously once weekly or 150 IU/kg subcutaneously 3 times per weekEpoetin beta30 000 IU subcutaneously (i.e. ∼ 450 IU/kg body weight in a 70 kg patient) given once weekly or divided over 3–7 times per weekEpoetin theta20 000 IU subcutaneously independent of body weight given once weekly, dose may be doubled after 4 weeks if Hb has not increased by at least 1 g/dLEpoetin zeta450 IU/kg subcutaneously once weekly, or 150 IU/kg subcutaneously 3 times per weekDarbepoetin alpha500 μg (6.75 μg/kg body weight) subcutaneously given once every 3 weeks or 2.25 μg/kg body weight subcutaneously once weeklyi.v. ironcFollow the label indications in your country.Ferric gluconateMaximum infusion dose: 125 mg ironMinimum infusion time: 60 minIron sucroseMaximum infusion dose: 200–500 mg ironMinimum infusion time: 30–210 minIron dextrandLow molecular weight iron dextran.Maximum infusion dose: depends on exact iron dextran type; refer to label.Minimum infusion time: 240–360 minIron isomaltosideMaximum infusion dose: 20 mg/kg body weight (up to 1000 mg ironeThe authors suggest a dose up to 1000 mg, while drug labels might allow more.)Minimum infusion time: 15 minfIf dose is up to 1000 mg; if dose exceeds 1000 mg iron, more than 30 min is recommended, as per label.Ferric carboxymaltoseMaximum infusion dose: 20 mg/kg body weight (up to 1000 mg iron per week)Minimum infusion time: 15 minEMA, European Medicines Agency; ESA, erythropoiesis-stimulating agent; Hb, haemoglobin; i.v., intravenous; MDS, myelodysplastic syndrome.a Epoetin alpha is EMA-approved for low or intermediate-1 risk MDS (see text).b Both originator products and biosimilars approved by the EMA have been shown to have similar safety and therapeutic equivalence in clinical practice.c Follow the label indications in your country.d Low molecular weight iron dextran.e The authors suggest a dose up to 1000 mg, while drug labels might allow more.f If dose is up to 1000 mg; if dose exceeds 1000 mg iron, more than 30 min is recommended, as per label. Open table in a new tab EMA, European Medicines Agency; ESA, erythropoiesis-stimulating agent; Hb, haemoglobin; i.v., intravenous; MDS, myelodysplastic syndrome. In the late 2000s, the safety of ESAs was discussed when meta-analyses suggested that ESA treatment may affect mortality in cancer patients [32.Bennett C.L. Silver S.M. Djulbegovic B. et al.Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia.JAMA. 2008; 299: 914-924http://dx.doi.org/10.1001/jama.299.8.914Crossref PubMed Scopus (603) Google Scholar, 33.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; 3: CD007303PubMed Google Scholar], particularly if target Hb levels exceeded 12 g/dL [34.Henke M. Laszig R. Rübe C. et al.Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial.Lancet. 2003; 362: 1255-1260Abstract Full Text Full Text PDF PubMed Scopus (1123) Google Scholar, 35.Hoff C.M. Hansen H.S. Overgaard M. et al.The importance of haemoglobin level and effect of transfusion in HNSCC patients treated with radiotherapy—results from the randomized DAHANCA 5 study.Radiother Oncol. 2011; 98: 28-33Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 36.Leyland-Jones B. Semiglazov V. Pawlicki M. et al.Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study.J Clin Oncol. 2005; 23: 5960-5972http://dx.doi.org/10.1200/JCO.2005.06.150Crossref PubMed Scopus (581) Google Scholar, 37.Smith Jr, R.E. Aapro M.S. Ludwig H. et al.Darbepoetin alpha for the treatment of anemia in patients with active cancer not receiving chemotherapy or radiotherapy: results of a phase III, multicenter, randomized, double-blind, placebo-controlled study.J Clin Oncol. 2008; 26: 1040-1050http://dx.doi.org/10.1200/JCO.2007.14.2885Crossref PubMed Scopus (179) Google Scholar, 38.Wright J.R. Ung Y.C. Julian J.A. et al.Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia.J Clin Oncol. 2007; 25: 1027-1032http://dx.doi.org/10.1200/JCO.2006.07.1514Crossref PubMed Scopus (355) Google Scholar]. Consequently, the recommended Hb target range for ESA treatment is 10–12 g/dL, and an Hb rise of > 2 g/dL over a 4-week period should be avoided. In 2014, a study in anaemic patients with metastatic breast cancer suggested that addition of erythropoietin (EPO) to standard of care with a target Hb > 12 g/dL did not meet the non-inferiority criteria for progression-free survival (PFS) versus standard of care alone [39.Leyland-Jones B. Bondarenko I. Nemsadze G. et al.A randomized, open-label, multicenter, phase III study of epoetin alfa (EPO) plus standard supportive care versus standard supportive care in anemic patients with metastatic breast cancer (MBC) receiving standard chemotherapy.J Clin Oncol. 2016; 34: 1197-1207http://dx.doi.org/10.1200/JCO.2015.63.5649Crossref PubMed Scopus (0) Google Scholar]. However, the late separation of the PFS and OS curves can hardly be explained by a few weeks of EPO exposure. Notably, the most recent Cochrane review included subgroup analyses and showed statistically significant on-study mortality in patients with baseline Hb > 12 g/dL but not for Hb categories Hb < 10 g/dL and Hb = 10–12 g/dL that correspond to the currently approved cut-off for initiation and the target Hb range of ESA therapy [29.Tonia T. Mettler A. Robert N. et al.Erythropoietin or darbepoetin for patients with cancer.Cochrane Database Syst Rev. 2012; 12: CD003407.PubMed Google Scholar]. When excluding one study with a target Hb range above the labelled guidance (BEST, target Hb = 12–14 g/dL [36.Leyland-Jones B. Semiglazov V. Pawlicki M. et al.Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study.J Clin Oncol. 2005; 23: 5960-5972http://dx.doi.org/10.1200/JCO.2005.06.150Crossref PubMed Scopus (581) Google Scholar]), the effect lost statistical significance [od