Iron Supplementation and Erythropoiesis-Stimulatory Agents in the Treatment of Cancer Anemia

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1 Iron Supplementation and Erythropoiesis-Stimulatory Agents in the Treatment of Cancer Anemia Paolo Pedrazzoli, MD 1, Giovanni Rosti, MD 2, Simona Secondino, MD 1, and Salvatore Siena, MD 1 Unresponsiveness to erythropoiesis-stimulatory agents (ESA), which occurs in 30% to 50% of patients, is a major limitation to the treatment of chemotherapy-related anemia (CRA). This may be related in part to the dysregulation of iron metabolism, leading to functional iron deficiency. However, the use of iron supplementation during treatment with ESA has not been pursued as rigorously in anemic patients with cancer as it has in patients with chronic kidney disease. In this article, the authors discuss the role of iron supplementation in the setting of CRA in view of recent reports that have addressed this issue. Cancer 2009; 115: VC 2009 American Cancer Society. KEY WORDS: iron supplementation, erythropoiesis-stimulatory agents, chemotherapy, cancer anemia. When patients with chemotherapy-related anemia (CRA) are treated with erythropoiesis-stimulatory agents (ESAs), a factor that may seriously limit erythropoietic is functional iron deficiency (FID), which represents an imbalance between iron needs in the erythropoietic bone marrow and iron supply. 1 FID, frequently referred to as iron-restricted erythropoiesis, still is not defined universally by standard laboratory tests. In routine clinical management of anemic cancer patients, transferrin saturation (TSAT) between 10% and 20% with normal or increased ferritin is the most accepted indicator of FID. 2 Other laboratory parameters, including the percentage if hypochromic erythrocytes and reticulocyte hemoglobin content, 3-5 are reliable correlates of FID; however, to date, these are not widely available. FID is well recognized in the anemia of chronic kidney disease, in which it has been demonstrated that intravenous (iv) iron, unlike oral iron, improves the hematopoietic to ESAs with substantial cost savings. 6-8 In oncology, surprisingly, the use of iron supplementation during treatment with ESA has not been rigorously as applied in anemic patients with cancer as it has for dialysis patients. This underuse is caused at least in part by 1) the false perception that cancer patients do not have decreased iron stores (as measured by serum ferritin) and thus the belief that they do not to require iron supplementation during ESA therapy; 2) a failure to appreciate the relative blockade in access to storage iron pools or dietary iron that frequently exists in patients with chronic inflammatory illnesses such as cancer; and 3) the misinformation and misinterpretation of the incidence and clinical nature of serious adverse events of iv iron. 9 In fact, parenteral iron still is considered a poorly tolerated medication that not infrequently harbors anaphylactic reactions. This opinion is erroneous and stems Corresponding author: Paolo Pedrazzoli, MD, Oncologia Medica Falck, Ospedale Niguarda Ca Granda 20162, Milan, Italy; Fax: (011) ; paolo.pedrazzoli@ospedaleniguarda.it 1 The Falck Division of Medical Oncology, Niguarda Ca Granda Hospital, Milan, Italy; 2 Medical Oncology, Ca Foncello General Hospital, Treviso, Italy Received: May 27, 2008; Revised: September 17, 2008; Accepted: September 19, 2008 Published online: January 17, 2009, VC 2009 American Cancer Society DOI: /cncr.24115, Cancer March 15,

2 in part from the use of high molecular weight iron dextrans that, for a long time, were the only products available. Currently available iron preparations (low molecular weight iron dextran, iron saccarate, and ferric gluconate) are safe, as demonstrated clearly in dialysis patients, in whom the incidence of severe adverse events is extremely rare (<1:200,000). 10 To our knowledge, there currently are only a limited number of published studies regarding iron supplementation and ESA in oncology. Consequently, the authors of the 2007 American Society of Clinical Oncology/American Society of Hematology (ASCO/ASH) guideline update for use of epoetin and darbepoetin (DA) in patients with cancer 11 could not provide definitive recommendations to be translated into everyday clinical practice. Instead, they suggested that a priority for future research will be obtaining better evidence of the benefits of supplementing ESA therapy with iron, including the dose-sparing effects of ESA, the appropriate dose, and the formulation of iron therapy. This conclusion, as clearly stated in the guideline article, 11 was based on 3 randomized controlled trials published in the last few years, which are discussed briefly below. A Swedish study 12 demonstrated the efficacy of iv iron in improving hematopoietic to epoetin b in a small series of 67 patients with lymphoproliferative who did not receive concurrent chemotherapy. By examining serum ferritin levels and TSAT during the course of ESA with or without iron therapy, the authors provided evidence that iron availability accounted for the difference in hemoglobin. The report provided data indicating that parenteral iron is ESA dose sparing in cancer patients, a point that has remained unexplored in larger trials. A limitation of the study by Hedenus et al is that ESA treatment is not indicated, and potentially is harmful, in anemic cancer patients with CRA who no longer are receiving cytotoxic treatment. 15 Two large US studies, 13,14 both of which included patients with nonmyeloid who were receiving chemotherapy, examined the different routes of iron administration (iv or oral) versus none in conjunction with the use of epoetin a. The results were consistent across these studies: The patients who received iv iron had a significant improvement in their hematopoietic compared with a no-iron control group. Both studies also indicated that there was no difference between the no-iron or oral iron groups, confirming what has been observed previously in dialysis patients. The lack of efficacy of oral iron most likely is related to increased synthesis by the liver (which occurs in chronic inflammatory states) of the iron regulatory peptide, hepcidin, which decreases the gastrointestinal absorption of iron. 16 Results of studies of iron supplementation in CRA cannot be interpreted without a close look at the iron status of enrolled patients. This crucial aspect usually is poorly discussed in the literature, and the ASCO/ASH guidelines 11 do not emphasize this point either. Patients in the Swedish study 12 had adequate body iron stores, because they were selected if they had positive staining for bone marrow hemosiderin. This method is not routinely applicable in patients with solid tumors, in whom iron status, as discussed earlier, commonly is assessed using serum ferritin and TSAT values. The study by Auerbach et al 13 included only patients with CRA who had iron deficiency (functional in most patients). When FID is present in patients who are receiving an ESA, iron repletion already is recommended based on indirect evidence and biologic inferences, as stated literally in the 2002 ASCO/ASH guidelines. 17 Moreover, in the limited fraction of patients with absolute iron deficiency, iron supplementation well may be responsible per se for any hematopoietic. Patients enrolled in the study reported by Henry et al 14 were required to have a serum ferritin level 100 ng/ml or a TSAT 15%. In chronic inflammatory states, including cancer, these parameters are not stringent enough to define an iron-replete population. 2 The study had a low hemoglobin rate (41%) in the epoetinonly arm, which may have been a consequence of the shorter duration of the study (9 weeks vs weeks), or it may have been caused at least in part by the inclusion of some patients with FID. In that study, FID developed in significantly more patients who received oral iron or no iron than in patients who received parenteral iron, as demonstrated by much greater increases in the percentage of hypochromic erythrocytes and decreases in TSAT and reticulocyte hemoglobin levels in the nonparenteral iron arm. For the reason noted earlier, these studies cannot provide an answer regarding whether iron supplementation is capable of increasing the fraction of patients without iron deficiency (the majority of CRA patients) who respond to ESA Cancer March 15, 2009

3 Table 1. Summary of Published Studies Evaluating Iron Supplementation and Erythopoiesis-stimulating Agents in Cancer Anemia Reference No. of Patients Enrolled Diagnosis Baseline Iron Status Randomization Type and Total Dose of IV Iron Response Parameter Results/ Statistics Comment Auerbach Nonmyeloid (19% lymphoid tumors) Hedenus Lymphoproliferative Henry Nonmyeloid Bastit Nonmyeloid Pedrazzoli Solid tumors (colorectal, lung, breast, gynecologic) Ferritin 450 pmol/l or 675 pmol/l with TSAT 19% Stainable iron in the bone marrow Serum ferritin >100 ng/ ml or TSAT >15% Serum ferritin >10 ng/ml or TSAT >15% Ferritin >100 ng/ml and TSAT >20% Epoetin-a 40,000 U/wk vs epoetin-a plus oral iron vs epoetin-a plus iv iron every wk vs epoetin-a plus iv iron TDI Epoetin-b 30,000 U/wk vs epoetin-b plus iv iron Epoetin-a 40,000 U/wk vs epoetin-a plus oral iron vs epoetin-a plus iv iron every wk Darbepoetin 500 mcg every 3 wks oral iron vs darbepoetin plus iv iron every 3 wks Darbepoetin (150 mcg/wk) vs darbepoetin plus iv iron every wk Iron dextran 1100 to 2400 mg (every wk group) vs 1000 to 3000 mg (TDI group) Mean Hb increase (g/dl) Iron sucrose 1000 mg Mean Hb change (g/dl) from baseline to end of treatment Ferric gluconate 1000 mg Ferric gluconate or iron sucrose 1200 mg Ferric gluconate 750 mg Increase in Hb from baseline to last value (g/dl) Hematopoietic (Hb >12 g/dl or >2 g/dl increase); RBC transfusions Hematopoietic ITT: 0.9 vs 15 (vs 2.5 vs 2.4 (IV iron groups vs no-iron and oral-iron groups (P ¼.02) PP: 1.5 vs 2.91 (P ¼.0001) 1.5 vs 1.6 vs 2.4 (P ¼.0092) vs oral iron (P ¼.0044) vs no iron 73% vs 86% (P ¼.011), 20% vs 9% (P ¼.005) PP: 70% vs 92.5% (P ¼.0033) Only patients with iron deficiency were included Patients not receiving chemotherapy; demonstrated ESA dose sparing Also patients with iron deficiency included; assesses the role of FID in blunted epoetin To authors knowledge, the largest study to date; the only study to demonstrate a reduction in RBC transfusions in the iron arm Strictest to enroll truly iron-replete patients iv indicates intravenous; TSAT, transferring saturation; TDI, total dose infusion; Hb, hemoglobin; ITT, intention to treat population; PP, per protocol population; ESA, erythopoiesis-stimulating agents; FID, functional iron deficiency; RBC, red blood cells (erythrocytes).

4 Two prospective trials that were published after thereleaseoftheasco/ashguidelineshaveprovided additional information relevant to the use of iron supplementation in CRA. Three hundred ninety-six anemic patients with nonmyeloid who received chemotherapy and DA every 3 weeks were assigned randomlybybastitetal 18 to receive either iv iron at a dose of 200 lg every 3 weeks (or the same dose within a 3- week period) or standard practice for iron administration (no iron or oral iron). Hematopoietic, the primary endpoint of the study, significantly favored the iv iron group, and there were no safety concerns in either arm. Unlike the other studies of iron supplementation, this trial, which to our knowledge is the largest published to date, also demonstrated a statistically significant reduction in the number of erythrocyte transfusions administered in the iv iron group. The study did not consider stringent iron parameters for patient enrolment, thus including approximately 35% of overtly or functionally iron-deficient patients. An Italian multicenter study 19 randomized 149 iron-replete patients, who were defined as having serum ferritin levels 100 ng/ml and TSAT 20%, to receive conventional weekly darbepoetin either alone or in conjunction with ferric gluconate at a dose of 125 mg weekly for the first 6 weeks. The study demonstrated that iv iron supplementation significantly reduced treatment failures on ESA with no additional toxicity. The percentage of responders in the control group was comparable to rates reported in previous studies using DA. 20 It is noteworthy that, when investigating the patients who strictly fulfilled the eligibility criteria and who received at least 4 administrations of DA, the rate of patients achieving a hematopoietic in the iv iron group was >90%. These findings confirm that preventing the development of FID by means of iv iron supplementation is the mechanism most likely involved in improving the hematopoietic in iron-replete patients who are receiving ESA. 12,14 Published studied of iron supplementation and ESA are summarized in Table 1. Evidence from these studies, 12-14,18,19 which, overall, included 920 patients, and well established clinical notions allow the following practical considerations for the management of anemic cancer patients. Iron parameters should always be measured in patients with cancer/cra. Iron supplements should be given iv rather then orally, because it has been demonstrated that oral iron largely is ineffective in cancer patients, which also is true for anemia in other chronic diseases. Patients with an absolute iron deficiency (TSAT <10% or ferritin below normal range) should receive iv iron supplementation only; until iron parameters are normalized, the administration of ESA would be ineffective. Intravenous iron supplementation should be given when ESA therapy is instituted both in patients with FID and in iron-replete patients. This issue is relevant clinically, because appropriate iron supplementation, apart from allowing more patients to benefit from ESA therapy, well may represent a strategy to improve the cost-effectiveness of ESA in oncology, which has occurred in nephrology. 12,21 The iv administration of 100 to 300 mg of elemental iron every week or every other week for a total dose of 750 to 1000 mg (in iron-replete patients) and up to 2000 mg (in patients with FID) during the correction phase of anemia will maximize the effectiveness of ESA. Patients with iron overload (in oncology, safety data exist up to TSAT >45% and serum ferritin >1000 lg/l) should not receive iron to avoid toxicity from iron excess. 22,23 In conclusion, iv iron supplementation, alone or in conjunction with ESA, is a valid therapeutic tool for the treatment of cancer anemia, and its use should be considered more extensively in medical oncology. Baseline and periodic monitoring of iron parameters is necessary to avoid unneeded or potentially harmful therapies. Conflict of Interest Disclosures Supported in part by grants from the Associazione Italiana Ricerca sul Cancro (AIRC) and Oncologia Ca Granda Onlus (OCGO) Fondazione. References 1. Cazzola M, Mercuriali F, Brugnara C. Use of recombinant human erythropoietin outside the setting of uremia. Blood. 1997;89: Beguin Y. Prediction of and other improvements on the limitations of recombinant human erythropoietin therapy in anemic cancer patients. Haematologica. 2002;87: Cancer March 15, 2009

5 Iron Supplementation for Cancer Anemia/Pedrazzoli et al 3. Macdougall IC, Cavill I, Hulme B, et al. Detection of functional iron deficiency during erythropoietin treatment: a new approach. BMJ. 1992;304: Tessitore N, Solero GP, Lippi G, et al. The role of iron status markers in predicting to intravenous iron in hemodialysis patients on maintenance erythropoietin. Nephrol Dial Transplant. 2001;16: Katodritou E, Terpos E, Zervas K, et al. Hypochromic erythrocytes (%): a reliable marker for recognizing iron-restricted erythropoiesis and predicting to erythropoietin in anemic patients with myeloma and lymphoma. Ann Hematol. 2007;86: Fishbane S, Frei GL, Mesaka J. Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. Am J Kidney Dis. 1995;26: Macdougall IC, Tucker B, Thompson J, et al. A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney Int. 1996;50: Besarab A, Amin N, Ahsan M, et al. Optimization of epoetin therapy with intravenous iron therapy in hemodialysis patients. J Am Soc Nephrol. 2000;1: Auerbach M, Ballard H, Glaspy J. Clinical update: intravenous iron for anaemia. Lancet. 2007;369: Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmen J. Update on adverse drug events associated with parenteral iron. Nephrol Dial Transplant. 2006;21: Rizzo JD, Somerfield MR, Hagerty KL, 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. JClinOncol. 2008;26: Hedenus M, Birgegard G, Nasman P, et al. Addition of intravenous iron to epoetin beta increases hemoglobin and decreases epoetin dose requirement in anemic patients with lymphoproliferative : a randomized multicenter study. Leukemia. 2007;21: Auerbach M, Ballard H, Trout JR, et al. Intravenous iron optimizes the to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multicenter, open label, randomized trial. J Clin Oncol. 2004;22: Henry DH, Dahl NV, Auerbach M, et al. Intravenous ferric gluconate improves to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy. Oncologist. 2007;12: Khuri FR. Weighing the hazards of erythropoiesis stimulation in patients with cancer. N Engl J Med. 2007;356: Andrews NC. Anemia of inflammation: the cytokine-hepcidin link. J Clin Invest. 2004;113: Rizzo JD, Lichtin AE, Woolf SH, 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. J Clin Oncol. 2002;20: Bastit L, Vandebroek A, Altintas S, et al. Randomized, multicenter, controlled trial comparing the efficacy and safety of darbepoetin alfa administered every 3 weeks with or without intravenous iron in patients with chemotherapyinduced anemia. J Clin Oncol. 2008;25: Pedrazzoli P, Farris A, Del Prete S, et al. Randomized trial of intravenous iron supplementation in patients with chemotherapy-related anemia without iron deficiency treated with darbepoetin alfa. J Clin Oncol. 2008;25: 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. 2007;94: Auerbach M. Should intravenous iron be the standard of care in oncology? J Clin Oncol. 2008;25: Beguin Y. Erythropoietic agents and iron. In: Bokemeyer C, Ludwig H, eds. Anaemia in Cancer. ESO Scientific Updates. Vol 6. 2nd ed. Edinburgh, Scotland: Elsevier; 2005: Auerbach M, Ballard H. Intravenous iron in oncology. J Natl Compr Canc Netw. 2008;6: Cancer March 15,