The role of intravenous (IV) iron as an addition to erythropoiesis-stimulating agents (ESAs) to optimize therapy in patients with anemia from cancer or chemotherapy-induced anemia has been examined in nine prospective, randomized trials,1-9 all of which showed improvement in ESA response, time to maximal response, reduction in ESA dose to reach maximal response, and improvement in quality-oflife parameters (when measured). The observed benefit was independent of baseline iron parameters, and although responses were greater in iron-depleted patients, significant benefit was seen in patients who were iron replete at study entry. One study, which was powered to show a difference in red blood cell transfusions, found a 36% reduction in the number of patients transfused.5 In all these studies, which represent data on more than 1200 patients, no significant toxicity was noted. Despite these data, there remains resistance to the addition of IV iron to the standard treatment paradigm for cancer and chemotherapy-induced anemia. This resistance is, in large part, due to misinformation and misinterpretation about the clinical nature of serious adverse events (AEs) associated with the administration of IV iron. This brief overview aims to change this perception.
History
In the early 20th century, Goetsch and colleagues introduced colloidal ferric hydroxide for IV infusion as therapy for patients with hypochromic anemias. 10 Toxic reactions to this preparation were frequent and severe and set the stage for the admonition that IV iron be reserved for only extreme clinical circumstances. In the 1940s, iron saccharides—and shortly thereafter iron dextran—were introduced for clinical use and were associated with an acceleration of IV iron use for those situations in which oral iron was not adequate. In 1964, Marchasin and Wallerstein showed the felicitousness of total dose infusions of up to 3000 mg of a high-molecular-weight (HMW) iron dextran in 45 iron-deficient patients (Imferon, Fisons PLC; no longer available). All patients responded, and no serious toxicity was observed.11 Yet, it was not until 1980, when Hamstra and colleagues published their prospective experience with 471 iron-deficient patients who received IV iron dextran (Imferon), that the first large series appeared.12 In this study, three patients were considered to have had “anaphylactoid” reactions, with symptoms and signs including respiratory arrest, hypotension, purpura, cyanosis, dyspnea, syncope, wheezing, and hives. There were no deaths. The authors concluded that IV iron should be reserved for conditions in which oral iron could not be used.12 IV iron remained on the pharmacopeia, but its use was limited.
In 1989, recombinant human erythropoietin (EPO) became available for the treatment of dialysis-associated anemia. Shortly thereafter, numerous studies showed the benefit of IV iron in optimizing responses to EPO-treated patients, and the addition of IV iron to the treatment paradigm in dialysis-associated anemia became standard practice. At the end of 1991, low-molecularweight (LMW) iron dextran (INFeD, Schein, now Watson Pharma) was released for clinical use and rapidly replaced HMW iron dextran, which was removed from markets in 1992, as the IV iron formulation used in dialysis centers. In 1996, the initial review of safety was published. The authors concluded that AEs with LMW iron dextran were rare, and only a history of allergies predicted otherwise infrequent AEs.13 At the same time, another HMW iron dextran (Dexferrum, American Regent) was approved as an alternative to INFeD. No comparison safety data were, or subsequently are, available.
In 2002, ferric gluconate (Ferrlecit, Schein, now Watson Pharma) and shortly thereafter iron sucrose (Venofer, American Regent) were introduced as alternatives to iron dextran in patients on dialysis. In two retrospective studies, Michael and colleagues as well as Coyne and colleagues concluded that serious AEs were much more common with iron dextran than with ferric gluconate, 14,15 which rapidly replaced iron dextran for dialysis-associated anemia. In 2004, however, Chertow and colleagues published a retrospective review of 30 million doses of IV iron, reporting that serious AEs were much more likely to occur with the HMW formulation and concluding that when this product is avoided, the other preparations (LMW iron dextran, iron sucrose, ferric gluconate) are safe with an incidence of serious AEs of <1:200,000.16 Five studies, albeit all retrospective, corroborated these findings.17-21 However, a sixth retrospective analysis reported no difference. 22 Nonetheless, use of iron dextran in nephrology patients, for all intents and purposes, remains negligible.
Barriers to IV iron use Despite the safety and efficacy demonstrated in the nine prospective oncology studies, the clinical community’s larger perception of danger associated with the use of IV iron persists. Although AE rates may be driven higher by HMW iron dextran, all iron supplementation products suffer the stigma. 23 This incorrect perception is further driven by the near lack of prospective comparison studies. Only two small prospective studies and one meta-analysis compared the efficacy and safety of LMW iron dextran with iron sucrose; no difference was seen.24-26
Another reason contributing to the sparse use of IV iron in oncology may be the lack of consensus on how best to administer the different products and the benefit or lack thereof of premedication. Premedication, which has been shown to be responsible for more side effects than IV iron itself27 and of no other clinical benefit, continues to be widely used before IV iron administration. After a test dose, acute myalgias (chest and back tightness) occur infrequently without tachycardia, hypotension, stridor, or periorbital edema.28 This reaction abates within minutes and rarely recurs with rechallenge. It is not rare for physicians and nurses unfamiliar with the innocuous nature of the reaction to intervene with antihistamines and pressors, which cause significant vasoactive reactions that are subsequently attributed to the IV iron.
Lastly, inconvenience may contribute to the lack of widespread use of IV iron. In the United States (but not in Europe), payers do not allow the administration of ESAs and IV iron on the same day. This unsubstantiated regulation is fueled by the lack of ICD-9-CM codes for iron-restricted erythropoiesis or functional iron deficiency. For absolute iron deficiency, ESAs are contraindicated until iron is replete. For those common situations in chemotherapy induced anemia when iron parameters suggest iron repletion, however, functional iron deficiency is often present, and addition of IV but not oral iron to the treatment paradigm, routinely improves responses to ESAs. If the only ICD-9-CM code for iron deficiency, 280.9, is placed on the billing form, the ESA will not be reimbursed; if omitted, however, the IV iron will not be covered. This conundrum remains.
Recent developments The recent update to the National Comprehensive Cancer Network (NCCN) guidelines provides new optimism. 29 The NCCN recommends that if iron is indicated, it should be given intravenously. The guidelines specifically proscribe HMW iron dextran by brand and state that the preferred product is LMW iron dextran (ie, INFeD). Principals at the US Food and Drug Administration (FDA), however, recently published a review of the AE reporting on iron dextrans using the FDA AE reporting system, death certificates, and emergency department visits. They concluded that reactions with all of the products are possible and, using the current system, it is not possible to determine the relative rates of serious AEs with the absence of head-to-head trials.30
Furthermore, three new IV iron products promise to allow complete replacement of iron intravenously in 15 minutes or less. Of these, ferumoxytol (Feraheme, AMAG Pharmaceuticals) is approved in the United States as a 510-mg bolus injection administered over 17 seconds for patients with iron deficiency and chronic renal diseases. Data with higher doses are anticipated in the near future as are safety and efficacy data in other conditions associated with iron deficiency.
The other two products, iron carboxymaltose (Ferinject, Vifor Phar ma) and iron isomaltoside (MonoFer, Pharm acosmos), are approv ed in Europe. Iron carboxymaltose can be administered as a 1-g infusion over 15 minutes, and iron isomaltoside as a 15-minute infusion in doses up to 20 mg/kg.
The safety and efficacy of IV iron have been demonstrated with transferrin saturation up to 50% and serum ferritin levels up to 1000 ng/mL. Although all IV irons are associated with serious AEs, current reporting mechanisms tell us nothing about relative frequency of AEs. Based on the preponderance of published literature, it appears prudent to use HMW iron dextran with caution. These data suggest it may be time to revisit the treatment paradigm to include the routine use of IV iron within these parameters.
References
- Auerbach M, Ballard H, Trout JR, 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;22:1301-1307.
- Henry DH, Dahl NV, Auerbach M, et al. Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy. Oncologist. 2007;12:231-242.
- Hedenus M, Birgegård G, Näsman P, 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;21:627-632.
- 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 alpha. J Clin Oncol. 2008;26:1619-1625.
- Bastit L, Vandebroek A, Altintas S, 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;26:1611-1618.
- Auerbach M, Silberstein PT, Webb RT, et al. Darbepoetin alfa 300 or 500 mmg once every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. Am J Hematol. June 4, 2010. Epub ahead of print.