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Published on 16 September 2009

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Intravenous iron increases efficacy of erythropoiesis-stimulating agents

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Ferric carboxymaltose is the most economic intravenous iron when treating cancer-related anaemia with ESAs, experts concluded at a Vifor symposium at the European Haematology Association Congress held in Berlin in June

A recent European survey involving nearly 14,000 cancer patients showed that almost 40% were anaemic at the start of the survey, and this figure rose to 67% during the six months of the study, according to Michael Hedenus (head of haematology, Department of Internal Medicine, Sundsvall Hospital, Sweden). There is a direct relationship between haemoglobin levels and quality of life, he added.

Cancer-related anaemia (CRA) is usually hypogenerative, normocytic and normochromic, characterised by normal or reduced serum iron and transferrin saturation despite a normal or elevated ferritin level, according to Mohammad Nowrousian (professor of internal medicine, Haematology/Oncology, West German Cancer Centre and Medical School, Essen, Germany). The mechanism appears to be a shortened red blood cell (RBC) survival and a failure of the erythropoiesis system to compensate sufficiently for the reduced RBC mass. Functional iron deficiency occurs in 10–39% of anaemic cancer patients and in up to 87% of patients during treatment with erythropoiesis-stimulating agents (ESAs).

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Guidelines currently recommend the use of ESAs for alleviating anemia, reducing transfusion use and improving the quality of life in symptomatic anaemic patients, said Matti Aapro (dean of the Multidisciplinary Oncology Institute, Genolier, Switzerland). In cancer patients receiving chemotherapy, a safe haemoglobin level for initiating ESA therapy is 9–11 g/dl. However, ESA therapy is associated with a 1.6-fold increase in the risk of venous thromboembolic events. RBC transfusions are associated with increased risk of venous and arterial thromboses – 7.2% and 5.2% of patients receiving RBC transfusions developed venous and arterial thromboembolisms respectively. International guidelines vary in their recommendations for the use of intravenous iron in cancer patients with anaemia (see Table 1).

Trials of ESAs in patients receiving chemotherapy and/or radiotherapy show that 50–70% of them obtain a significant increase in haemoglobin concentration, a reduction in transfusion need and an improvement on quality of life, Tim Littlewood (consultant haematologist, John Radcliffe Hospital, Oxford, and lecturer in medicine, Christ Church, University of Oxford, UK) told the audience. In the past five years, five randomised clinical trials of ESAs with intravenous iron supplements versus oral or no iron have been published. All reports show an improvement in response in the patients treated with intravenous iron. In addition, intravenous iron supplements reduced the need for blood transfusions in one study and in another increased haemoglobin levels at a faster rate and reduced ESA doses. The addition of intravenous iron therapy may therefore increase the cost-effectiveness of treating anaemic patients, said Dr Littlewood. These trials
showed no evidence of increased infection, increased cardiovascular morbidity or increased tumour incidence or progression in the intravenous iron group compared with the non-iron or oral iron groups. The incidence of serious adverse events with intravenous iron was less than 1 in 400,000 when high-molecularweight iron dextran was avoided. Dr Littlewood concluded that the combination of intravenous iron with ESAs is more effective than ESAs alone in increasing haemoglobin concentration. However, sufficient data are not yet available to determine whether the ESA intravenous iron combination will have any adverse effect on thrombotic or mortality risk.

Several intravenous iron preparations are used in clinical practice for the treatment of iron-deficiency anaemia, including ferric carboxymaltose, iron sucrose, sodium ferric gluconate and iron dextran, said Dr Hedenus. Each drug has a different molecular weight, physicochemical characteristics, degradation kinetics and side-effect profile. All intravenous iron compounds
comprise a central core containing polynuclear ferric hydroxide, surrounded by a carbohydrate shell. In general, the smaller-molecular-weight iron complexes have shorter plasma half-lives and release larger amounts of free iron into circulation. Rapid release of large amounts of free iron may in theory lead to oxidative stress and cell membrane damage, Dr Hedenus continued. The free iron released from low-molecular- weight complexes limits the maximum iron that can be given with one administration. Anaphylactic and anaphylactoid reactions are rare but clinically significant, with severe adverse events most commonly associated with iron dextran administration, resulting from hypersensitivity to the dextran moiety. A higher incidence of type I adverse events has been reported in patients receiving either ferric gluconate or iron dextran compared with iron sucrose. Selection of an appropriate intravenous iron preparation should involve not only consideration of safety and efficacy but also the practical aspects such as duration of administration and dosage regimen. Recently a new intravenous iron compound, ferric carboxymaltose, has become available. This can be administered as a single dose of up to 1,000 mg over 15 minutes.

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Treating anaemia in cancer patients reduces healthcare costs. Even though ferric carboxymaltose is the most expensive iron product, the associated savings make it the most economic option in a Swiss health economic model, explained Thomas Szucs (professor of medicine, University of Zurich, Switzerland). The health economic impact of intravenous iron supplementation is based not only on acquisition costs but also on the costs of administration, he continued. The addition of intravenous iron to ESA therapy can reduce the mean weekly ESA dosage by approximately 25%, saving more than 10,000 units of epoetin during treatment (see Figure 1). The economic impact is calculated by subtracting the acquisition cost and the
cost of administration of intravenous iron from the ESA savings (see Figure 2). The acquisition costs of the different intravenous iron preparations vary considerably, with ferric carboxymaltose having the highest cost. However, as up to 1,000 mg can be given as a single dose over 15 minutes, without the need for a test dose, the total administration costs are considerably lower than for other intravenous iron products, which may require up to five weekly visits for 30-minute infusions in order to deliver the equivalent dose (see Figure 3).

Treatment of cancer-related anaemia with intravenous iron and ESAs has the potential to reduce the financial burden on healthcare systems and in turn allow greater access to treatment for patients, improving their quality of life and disease outcomes.

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