Use of Iron
Anemia of cancer is characterized by ineffective erythropoiesis, which is due to a number of factors. One of the most important among these is abnormal iron metabolism. Iron deficiency can occur rapidly in patients with cancer due to blood loss or inadequate intake or absorption of iron by the digestive tract. There is also 'functional failure' due to retention of iron in macrophages and decreased iron availability for erythropoiesis despite adequate iron stores in the reticuloendothelial system.
The acute-phase protein hepcidin is currently considered to be the main culprit of the abnormal iron metabolism because it leads to a decrease of both intestinal iron absorption and the release of iron by macrophages.[1,48] Cytokines released in inflammatory processes, particularly IL-6, are able to increase the production of hepcidin and consequently decrease the amount of circulating iron.[2,49] Several studies have demonstrated that chemotherapy increases the production of inflammatory cytokines, including IL-6. In addition to the aforementioned consequences, another mechanism contributing to iron deficiency in cancer patients is the low bioavailability of orally administered iron.
Iron deficiency in patients with cancer is mainly characterized by low (<20%) transferrin saturation (TfSat) and low (<26 pg/cell) reticulocyte hemoglobin content (CHr). Serum ferritin may be falsely elevated in patients with cancer because it is an acute-phase protein; however, values of serum ferritin of less than 15 ng/ml are very specific for detecting iron deficiency, at the cost of low sensitivity. One study evaluated hematological parameters in patients with cancer who would start treatment with EPO; 17% of the patients had serum ferritin levels of less than 100 ng/ml, 59% had TfSat of less than 20% and 27% had CHr of less than 32 g/dl. The National Comprehensive Cancer Network (NCCN) recommends iron supplementation in all patients with cancer who have absolute iron deficiency determined by serum ferritin of less than 30 ng/ml and TfSat of less than 15%, as well as in those with relative iron deficiency, characterized by serum ferritin of less than 800 ng/ml and TfSat of less than 20%. The recommendations of the ASCO and ASH are less specific with regard to the use of iron supplementation.
Due to abnormal iron metabolism and low compliance with the use of oral iron, the administration of intravenous iron in clinical oncology has received increasing attention. Among the options available are iron dextran, iron saccharate and ferric gluconate. Despite the lack of superiority of one of these formulations over the others, the latter two are considered safer and are therefore recommended more frequently. High-molecular-weight iron dextran has produced a higher incidence of hypersensitivity reactions when compared with other formulations.
Several randomized studies have evaluated the benefit of administering intravenous iron associated with the use of ESAs. Auerbach and colleagues evaluated the use of iron associated with EPO in 157 cancer patients receiving chemotherapy and who had hemoglobin levels of less than or equal to 10.5 g/dl associated with serum ferritin of less than or equal to 200 ng/dl or TfSat of less than or equal to 19%. The increases in hemoglobin levels were higher in patients who received iron, especially in intravenous form (p < 0.02); in addition, this group has demonstrated a significant improvement in QOL with iron supplementation. In another study, 187 patients receiving chemotherapy and with serum ferritin of greater than or equal to 100 ng/dl or TfSat of greater than or equal to 15% were randomized to EPO without iron, oral iron or intravenous iron. Increased levels of hemoglobin (≥2 g/dl) occurred more frequently in patients receiving intravenous iron (73%) than in those given oral iron (46%; p < 0.01) or not receiving iron (41%; p < 0.003). Bellet et al. initially treated 375 patients with chemotherapy-induced anemia (hemoglobin <10 g/dl) with ESAs for 8 weeks. In a subsequent stage of the study, patients were randomized to receive an ESA plus or minus intravenous iron sucrose for an additional period of 12 weeks. It is interesting to note that the use of intravenous iron was able to improve hemoglobin level in both prior ESA responders and nonresponders.
One small study with 67 patients with lymphoproliferative diseases and hemoglobin levels between 9 and 11 g/dl has also demonstrated an increase in hemoglobin levels with the use of parenteral iron, along with decreased global need for EPO. The use of intravenous iron associated with ESAs was also able to expedite erythroid recovery after autologous hematopoietic stem cell transplantation in a study conducted by Beguin et al..
Recently, Bastit and colleagues randomized 396 patients with nonmyeloid malignancies receiving chemotherapy and with hemoglobin levels of less than 11 g/dl to receive darbepoetin with or without intravenous iron. The hematologic response rate, determined by hemoglobin levels of greater than or equal to 12 g/dl or an increase of greater than or equal to 2 g/dl, was numerically greater with the combination of darbepoetin and intravenous iron (86 vs 73%; p = 0.11); moreover, there was a reduction in blood transfusion requirements. One study has evaluated the role of intravenous iron associated with ESA in patients without iron deficiency. A total of 149 patients with solid tumors undergoing chemotherapy and with hemoglobin levels of less than or equal to 11 g/dl, but serum ferritin of greater than or equal to 100 ng/ml and TfSat of greater than or equal to 20%, were randomized to ESAs with or without intravenous iron. This study has suggested an increase in hematologic response (76.7 vs 61.8%; p = 0.495) resulting from the use of the combined treatment. These data were confirmed by a recently published study in which there was increase in hemoglobin levels when intravenous iron was associated with ESAs, even in patients without iron deficiency. The EORTC guidelines have also explored the question of whether oral or intravenous iron supplementation increases the response rate to EPO. No evidence of improved response with the addition of oral iron supplementation was found, but there was evidence of enhanced responses to EPO with the use of intravenous iron. However, the doses and schedules for intravenous iron supplementation are not yet well defined, and more studies in this area will be necessary. In contrast to all of these previously reported studies, there is one negative trial in which 502 iron-repleted patients receiving chemotherapy for nonmyeloid malignancies with hemoglobin levels of less than 11 g/dl were randomized to receive darbepoetin with either intravenous iron, oral iron or placebo. The authors could not demonstrate any significant differences between the groups in terms of erythropoietic response rate, blood cell transfusion or QOL.
In the 2010 ASH annual meeting, two meta-analyses evaluating the use of intravenous iron supplementation in the treatment of chemotherapy-induced anemia were presented.[63,64] In both of these abstracts, the total number of patients who participated in the trials included in the analyses exceeded 1600. ESAs were administered in most of the studies. Treatment with intravenous iron significantly increased the number of patients achieving a hematopoietic response and significantly reduced the number of patients who required blood cell transfusions, with no increase in the incidence of adverse events or mortality. The benefit of intravenous iron was independent of the type of ESA used.[63,64]
Therefore, in all cancer patients with any degree of anemia, it is important to investigate whether there is iron deficiency. If the parameters indicate low levels of ferritin, TfSat or CHr, iron supplementation is indicated, preferably through parenteral administration. Such treatment could also be considered in patients who will start treatment with an ESA, due to the improved responses in terms of hemoglobin levels resulting from the combined treatment. At present, there appears to be enough scientific support for the use of intravenous iron supplementation to improve hemoglobin responses in anemic patients with cancer, and this has been included in various guidelines. Nevertheless, prospective studies on the long-term efficacy and safety of intravenous iron are warranted. Moreover, recommendations for the optimal formulation, doses and treatment schemes of iron supplementation concurrently with ESA treatment in cancer-related anemia are awaiting data from prospective, randomized trials.
Future Oncol. 2011;7(4):507-517. © 2011 Future Medicine Ltd.
Cite this: Management of Anemia in Cancer Patients - Medscape - Apr 01, 2011.