3rd Mediterranean Multidisciplinary Course on Iron Anemia

Management of iron-deficiency anemia and funcional iron-deficiency in cancer patients Pere Gascon Director, Division of Medical Oncology, Hospital Clinic, University of Barcelona, Spain Anemia is a common manifestation in oncology. It develops in more than 80% of cancer patients undergoing chemotherapy. Anemia in the oncology patient can be caused by the same tumor or by the effects or complications of cancer treatments. Anemia is multifactorial: bone marrow infiltration by cancer cells; nutritional deficits such as vitamin B12, folic acid or iron; hemolysis; myelosupression secondary to chemotherapy or radiotherapy; blood loss; toxicity induced by the new anti-targeted therapies; low endogenous erythropoietin levels; and anemia of chronic disease, also known as ‘functional iron deficiency’ (FID) (FIGURE 1). Anemia in cancer can also be caused indirectly by the same inflammatory process associated with the disease. In this case, some cytokines are produced and play a role in anemia. Two of them, interleukin-1 (IL-1a,b) and tumor necrosis factor (TNF-a), are known to inhibit the production of erythropoietin by the kidneys. Another important cytokine is IL-6, a pro-inflamamatory cytokine, that acts on the liver to induce the production of hepcidin, a small peptide, that has an important role in iron regulation. It is considered the most important factor in the anemia of ‘chronic disease’ also known as FID. Hepcidin works in the duodenum by inhibiting the oral absorption of iron and, in the bone marrow by blocking the release of the iron contained in the macrophages. It is understandable that with this scenario, the red blood cells progenitors lack the two major sources of iron for new red blood cell formation: the gastrointestinal tract where the enterocytes are unable to absorb either nutritional or therapeutic iron and, the bone marrow where the macrophages, scavenger cells do not release the sequestrated iron obtained from the senescent red blood cells. Because the complexity of causes leading to anemia in the cancer setting, the correction and management of anemia should always consider ruling out common causes such as pure iron deficiency (bleeding in a GI tumor) or folic acid or vitamin B12. Once, these causes are ruled out, we would know that we are dealing with chemotherapy-induced anemia and FID. How to manage then cancerassociated anemia? Two agents will play a major role: Erythropoiesis stimulating agents (ESAs) and iv. iron. Since cancer patients present a poor erythropoietin response to low hemoglobin levels, the use of ESAs will compensate for the low endogenous levels of erythropoietin, The use of iv. iron is to provide bio-available iron for the production of red blood cells since there is a significant poor absorption of oral iron, at least with the common preparations, due to the effect of hepcidin. Although ESAs are widely used in oncology to correct the anemia associated with chemotherapy and most patients benefit from their use, the fact is that their response rate has been suboptimal, ranging from 50 to 70.5% in most published clinical trials. Several explanations have been found, but in general it is accepted that the cause is FID. The remarkable improvements in the response rate observed with the concommittant administration of iv. iron to ESAs strongly suggests this possibility. Parenteral iron therapy has subsequently become an important adjunct to obtaining and maintaining adequate haemoglobin levels in patients with cancer receiving chemotherapy. A new type of oral iron, a liposomial preparation, that is being absorbed by the Gastrointestinal tract independtly of hepcidin levels may prove to be another and new tool for oncologists to correct the anemia in cancer patients. Over the last few years, seven studies have been conducted and their results published over the use of iv. iron supplementation. In all cases, iv. iron was delivered concomitantly with ESAs in the treatment of anemia secondary to chemotherapy. Except in one study, the study all others were favorable to the arm of iv. iron. On adding iv. iron to ESAs, responses are faster and more robust. Most guidelines (ASH/ASCO, EORTC and NCCN) recommend initiating ESAs for Hb < 10 g/dl and to stop when Hb levels reach 12 g/dl. ESAs are safe as long as they are used according to label. There are no alarm signals when ESAs are used in chemotherapy-induced anemia and according to guidelines. The use of blood transfusions shoul be restricted for acute The tumor itself Infiltration of the bone marrow Myelosuppression by chemotherapy/radiotherapy Hemolysis Blood loss Anemia of chronic disease functional iron deficiency Nutritional deficits (Iron, Vitamin B12, Folic acid) Abnormal iron metabolism Low erythropoetin levels Anemia Figure 1. Causes of anemia in the cancer patient. S2 3rd Mediterranean Multidisciplinary Course on Iron Anemia Proceedings