Iron deficiency and anaemia are common in cancer patients and treatment with intravenous iron improves quality of life, increases ESA efficacy and reduces the need for transfusions
Anaemia is one of the most prevalent diseases in the world, affecting an estimated 1.62 billion people, and iron deficiency is involved in about 50% of cases, according to Heinz Ludwig (director of the Centre for Oncology and Haematology, Wilhelminen Hospital, Vienna, Austria). It is most commonly seen in young children, pregnant women and the elderly. It is also common in advanced kidney disease (chronic kidney disease (CKD) stages 4 and 5) and advanced heart failure (New York Heart Association classes 3 and 4). Iron deficiency is seen in 65% and 73% of these two groups respectively.
Iron deficiency can be ‘absolute’, when iron stores are low reflected by transferrin saturation (TSAT) below 20% and serum ferritin levels are low. Iron deficiency can also be ‘functional’, where TSAT is below 20% but iron stores are full and serum ferritin levels are high. However, ferritin is an acute phase protein and is therefore not a reliable marker of iron status in patients with inflammatory diseases such as CKD and cancer. Accordingly, TSAT but not ferritin levels correlate significantly with anaemia in patients with CKD.
Iron deficiency, even without anaemia, is associated with fatigue, impaired cognitive function and reduced physical performance. Anaemia is associated with poor outcomes in CKD, chronic heart failure (CHF) and pregnancy. Anaemia is also a cormorbidity in a significant number of tumour types. In 2004 a study of nearly 15,000 cancer patients showed that 39% had anaemia at baseline, including 10% with moderate or severe anaemia (haemoglobin less than 10g/dl). During a six-month follow up period 67% of patients were anaemic, including 39% with moderate or severe anaemia. Iron deficiency and iron deficiency anaemia are associated with significant morbidity, said Professor Ludwig.
Turning to the question of the impact of ferric carboxymaltose (FCM) treatment, Professor Ludwig noted that a high dose of FCM could be given as a single dose, is well-tolerated and, unlike dextran-based products, is of low immunogenicity. A double blind study of patients with advanced CHF indicated that correction of iron deficiency with and without anaemia had shown that FCM treatment improved exercise capacity (6-minute walk test), quality of life (European Quality of Life-5 Dimensions Visual Scale (EQ-5D) and the self-reported Patient Global Assessment) and improved disease state (New York Heart Association class). In addition, an ongoing observational study on the use of FCM alone in anaemic cancer patients had also shown positive results, noted Professor Ludwig. Additional prospective studies in cancer patients are ongoing and more are planned, he added.
Iron metabolism in cancer
Several factors contribute to the development of anaemia in cancer patients – in addition to the anaemia of cancer there could be treatment-induced anaemia and anaemia due to increased red cell losses or impaired red cell production, explained Yves Beguin (professor of haematology, University of Liège, Belgium).
In the normal situation iron is absorbed from the gut and binds to transferrin for transport to the bone marrow where it is used in the process of making red blood cells (RBCs). At the end of their life cycle RBCs are phagocytosed by macrophages and most of the iron is removed and recycled. Very little iron is lost from the body, noted Professor Beguin. Hepcidin, produced by hepatocytes, inhibits absorption of iron from the gut and release of iron from macrophages. Hepcidin secretion is induced by inflammatory cytokines, eg, IL-6, and is also increased during iron overload and decreases when there is erythroid demand or hypoxia. Hepcidin is a mediator of iron blockade, said Professor Beguin. It works by binding to the iron transport protein, ferroportin, on the surface of macrophages thereby preventing the export of iron and leaving it blocked in macrophages and leading to a low TSAT.
The anaemia of chronic disease is associated with cytokine release from monocytes that triggers a number of changes including increased hepcidin secretion, plasma expansion, and decreased erythropoietin secretion from the kidneys. The net result is functional iron deficiency with a microcytic, hypochromic anaemia, low TSAT in combination with normal or elevated serum ferritin (SF) levels.
Considering how to evaluate iron status in cancer patients, Professor Beguin said that it was a matter of looking at iron in various compartments. Serum ferritin is a marker that reflects the level of iron stores, that is, iron in macrophages and hepatocytes. Iron deficiency is signified by levels below 12–25µg/l. “It is 100% specific for iron deficiency, but the normal range varies with age and gender and it can be falsely elevated in a several conditions”, he said. Where there is inflammation or renal failure, 40–120µg/l should be regarded as the lower limit of normal and therefore levels below this threshold indicate iron deficiency.
Transferrin saturation reflects iron in plasma and is normally about 40%. TSAT can go down in functional iron deficiency due to inflammation or disease when iron is blocked in macrophages and during erythropoietin treatment when demand is increased. Infection can also reduce TSAT, commented Professor Beguin.
The amount of soluble transferrin receptor (sTfR) is proportional to the number of erythroblasts in the marrow. “It is a quantitative marker of erythropoietic activity and also a marker of iron deficiency”, said Professor Beguin. “The level of sTfR is not raised in the anaemia of chronic disease (ACD) and so this parameter can be used to distinguish between ACD and iron deficiency anaemia”, he added.
Red cell indices reflect the iron status of circulating red cells. If more than 5–10% of RBCs are hypochromic then iron deficiency is likely. However, this indicator is slow to change because the lifetime of a RBC is 120 days. Reticulocyte (young red cell) haemoglobin (CHr) is a more sensitive indicator and a level of less than 26pg indicates iron deficiency. “CHr changes much more rapidly and offers a real time assessment of iron status in the bone marrow”, said Professor Beguin.
Anaemia treatment options
The main goal in treating anaemia is to prevent or minimise the need for blood transfusions but recent reports have raised concerns about the safety of erythropoietin stimulating agents (ESAs) Matti Aapro (dean of the Multidisciplinary Oncology Clinic, Genolier, Switzerland) told the audience. A Cochrane meta-analysis in 2006 showed higher rates of thromboembolism with ESAs and alterations in labelling had followed. More recent analyses have shown better results. However, treatment with ESAs alone was not producing the response rate required. “We should have understood earlier – people treating CKD knew for years that iron had to be given as well”, said Dr Aapro. Oral iron is ineffective in cancer because hepcidin activity prevents absorption, but studies have shown the value of intravenous iron.
Since 2004, five randomised controlled trials of IV iron versus oral or no iron, as a supplement to ESA therapy, have been published – all demonstrated an improvement in response rate in patients treated with IV iron compared with those treated with oral or no iron supplementation. In addition, IV iron supplementation reduced the need for blood transfusions, reduced the mean weekly ESA dose and improved quality of life. Furthermore, in some settings, when IV iron is added to ESA therapy in patients with chemotherapy-induced anaemia and anaemia of cancer, the response to ESA therapy can be increased up to 90%.
International guidelines currently recommend that IV iron be given to correct iron deficiency. An ongoing observational study is currently evaluating the impact of IV iron alone (as FCM) in the treatment of iron deficiency anaemia in cancer patients. An analysis of interim results after 12 week showed that there had been a steady rise in haemoglobin from 10.1g/dl to 11.8g/dl. Importantly, other studies had shown that IV iron sucrose alone reduces the need for blood transfusions in patients receiving chemotherapy said Dr Aapro. Treatment with IV iron alone may prove suitable for the correction of anaemia in cancer patients, he noted.
Tolerability of IV iron
In the past, iron was said to be dangerous for cancer patients as it was thought to encourage tumour growth, but this was not borne out by recent studies, according to Anders Österborg (professor of oncology, Karolinska Institute and Karolinska Hospital Stockholm, Sweden).
Considering first the safety of intravenous iron, he said that free iron (non transferrin-bound iron) is toxic and the ideal product would have iron bound in a carbohydrate shell that is released slowly. Currently available products are based on carboxymaltose, sucrose, dextran or gluconate as carbohydrate ligands. Ideally, intravenous iron products should be non-immunogenic and allow administration of large doses of iron by bolus and/or infusion. If iron is released too fast and TSAT levels reach 60–100%, non-transferrin bound iron can be released and induce symptoms of iron toxicity including a metallic taste, nausea and abdominal pain. The rate of iron release from the available compounds varies between 2% for high molecular weight iron dextran and nearly 6% for iron gluconate – iron release from FCM falls in the middle of this range, explained Professor Österborg. Iron dextran is associated with a high rate of infusion-related anaphylactic reactions . Such reactions do not occur with iron gluconate or iron sucrose. When high-dose ferric gluconate – 188mg over 90 minutes – (off-label) was given, side effects typical of those seen with free iron release develop, presumably due to rapid release of free iron, said Professor Österborg. When FCM was compared with placebo in patients with iron deficiency, side effects, including injection site problems and dizziness, were somewhat more frequent with the FCM. Another concern related to IV iron treatment is exacerbation of infections. However, a study of IV iron in treatment in haemodialysis patients showed that the risk of infection was reduced and overall survival was improved. Keeping the TSAT in the range 30–50% was associated with the best survival.
Turning to the use of iron in oncology patients Professor Österborg explained that the five trials in which ESAs had been given with and without IV iron showed that there was no increase in the risk of infection or tumour progression and neither were there any differences in progression-free survival or overall survival. Longer follow-up and extended trials are warranted in oncology. One study with a longer observation period has shown that IV iron therapy did not affect progression-free survival rates in 127 patients with lymphoid malignancies undergoing autologous haematopoietic stem cell transplantation after three-year follow-up.
The nature of the relationship between iron and cancer progression is unclear. Free iron is toxic and causes DNA damage through the formation of reactive oxygen species. However, iron is also essential for cell growth, playing a key role in DNA synthesis. Iron has been linked to both angiogenic and anti-angiogenic effects and both iron loading and iron depletion have been linked to metastasis. Clinical observations had given conflicting results. Studies had shown that blood donors and patients undergoing frequent phlebotomy had lower risks of developing cancer but this could have been because of other factors such as healthier lifestyles. Preclinical and clinical studies of the effects of iron chelators had been inconclusive.
Professor Österborg concluded that there is no evidence for an increased risk of infections or risk of tumour induction or progression in nephrology or oncology randomised trials associated with administration of IV iron at recommended doses. In general, preclinical models of iron overload do not reflect the clinical setting of IV iron therapy that attempts to restore a normal iron status in iron-deficient or anaemic patients with cancer. Furthermore, modern IV iron preparations minimise the release of labile iron and deposition of reactive iron in the parenchyma instead of the reticulo-endothelial system.
Safety of blood transfusions
“The statement “Blood is safer than it has ever been”, is true with regard to HIV, HCV and HBV in highly economically developed countries – but not in connection with the risks of emerging infectious agents, administration errors and transfusion-related pathological effects”, Axel Hofman (adjunct senior research fellow, Centre for Population Health Research, Curtin Health Innovation Research Institute (CHIRI) Curtin University, Western Australia) told the audience. For example, transfusion-related acute lung injury (TRALI) affects an estimated 1000 people in the USA out of the five million who receive blood transfusions.
In one study liberal use of blood transfusions had been compared with ‘restrictive’ use in intensive care patients. The results showed that for patients under 55 years there was one additional death for every 14 patients in the liberal group. Similarly, for those with Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of less than 20, there was one additional death for every 13 patients in the liberal group. In studies performed with cancer patients, blood transfusions were associated with thromboembolism and reduced overall survival. In fact, numerous studies with large numbers of patients of many different types have shown that there are always adverse outcomes associated with blood transfusions.
A recent study had shown that higher death rates occurred with the use of blood that had been stored compared with fresh blood. In addition, cytoscans of microcirculation suggest impaired performance after blood transfusions. Numerous changes occur during storage of blood, including decreased red cell flexibility, red cell aggregation, release of free iron and haemoglobin and release of enzyme and vaso-active substances. These changes are believed to lead to compromised oxygenation and pre-thrombotic events after transfusion, said Mr Hofman. Looking at the studies performed with cancer patients blood transfusions are associated with thromboembolism and reduced overall survival
These findings have prompted the development of a ‘blood management’ paradigm that involves relying on a patient’s own blood rather than on donor blood, explained Mr Hofman. This is based on three pillars or principles – first, optimising red cell mass through stimulated haematopoiesis, second, minimising bleeding and blood loss and third, harnessing and optimising physiological tolerance of anaemia. Life-threatening anaemia occurs when the haemoglobin level is below 5g/dl but currently most transfusions are given above this level when they are not really needed, he warned.
Overall, this educational symposium highlighted the increasingly important role of intravenous iron therapy in the treatment of anaemia in patients with cancer. The meeting provided an overview of the latest data regarding the diagnosis and treatment of iron deficiency and anaemia. Furthermore, the safety of IV iron therapy and the myth of the safe blood transfusion were discussed in relation to the oncology setting.