Intravenous iron use in cancer related anemia has been popularized with the approval of erythropoiesis-stimulating agents in 1997 in oncology, and iv iron was shown to enhance the response to erythropoietin [5, 9, 11]. Since then ESAs and iv iron combination were commonly used for the treatment of cancer associated anemia. However after popularization of ESAs, certain toxicities associated with their usage, and increased mortality risk has been observed. Among them were increased thromboembolic risk, cardiovascular adverse events and stimulation of disease progression in tumor cells with the expression of erythropoietin receptors [13–15]. Although ESAs with or without iv iron reduced the need for red blood cell transfusions, 13 years after their approval in oncology, certain precautions have been suggested and their use was restricted due to the above mentioned adverse events [13, 16]. Unfortunately iv iron administration which was mostly used as an adjuvant to ESAs to treat cancer associated anemia has been abandoned with the prescription restrictions of ESAs. Red blood cell transfusions became popular again for the correction of cancer associated anemia. However blood transfusion is not devoid of toxicity and is as harmful as ESAs [17–19].
Iv iron on the other hand is a promising strategy and is reported to be an effective treatment for anemia of chronic diseases such as chronic renal failure, chronic kidney disease and cancer [20–22]. Iv iron may be an even more effective treatment alternative for anemia of chronic disease associated with inflammation like cancer, since intravenous administration may overcome resistance to iron absorption especially by erythroid cells and iron recycling which are all controlled by hepcidin.
Although iv iron has been demonstrated to be superior to oral iron in improvement of erythropoietic response to ESAs, there are limited studies of iv iron alone without ESAs in the treatment of cancer associated anemia [5, 9, 22–26]. Iv iron together with ESAs not only increase Hb levels higher than ESAs alone, but also in a shorter time interval than ESAs, besides these advantages, the addition of iv iron to ESAs decreases blood transfusion rates significantly compared to ESAs alone [5, 9, 24, 25].
The first study investigating iv iron alone in oncology practice was performed and published in 2007, and included women with cervical cancer treated with chemoradiotherapy . The primary objective of this study was to prevent exacerbation of anemia and to reduce blood transfusion by iv iron. In this trial the transfusion rate dropped from 64 to 40 %. In 2010, another single-center, prospective, randomized study was published exploring the effect of iv iron administration on blood transfusion rates in anemic gynecologic cancer patients receiving platinum-based chemotherapy . Again, this was a small study with 22 patients in each arm, but iv iron resulted in a significant Hgb increase of 0.9 g/dl and a significant reduction of the transfusion rate from 63.6 to 22.7 %. In both of these studies patients received iv iron regardless of their initial iron status.
We observed in our retrospective study that, iv iron provided a significant increase in Hgb levels in already anemic cancer patients undergoing oncologic treatment either with CT, RT or both. The increase in Hgb levels was fast and observed within a month or two after iv iron administration, and it was more than 1 g/dL. Only 18 out of 63 patients (28.5 %) needed blood transfusion due to further decrease in their Hgb level and the appearance of anemia symptoms within 3 months after iv iron administration. Iv iron prevented high blood transfusion rates in this patient population since a decrease in Hgb level, and a necessity of blood transfusion would be inevitable with the effect of cancer treatment probably in all of these patients in the course of time. Although the study was not randomized and not designed with a control group who did not receive iv iron, these patients have already generated their own controls with their Hgb levels before and after the administration of iv iron. We believe that without any intervention for anemia correction, the Hgb levels of most of these patients would gradually get worse with the effect of cancer treatment and disease per se.
Iv iron although popularized as an adjuvant to ESAs, is in fact nowadays the most evidence based alternative to both ESAs and blood transfusion in the treatment of cancer associated anemia. Acute life-threatening side effects and lethal anaphylactic reactions are the major concerns among clinicians with iv iron administration which is probably the most important factor limiting their usage [27, 28]. The most common difficulty encountered during our study was the fear of medical personnel in outpatient clinics to administer iv iron infusion to the patients. However according to United States Food and Drug Administration (FDA) on adverse drug events reports, life-threatening adverse drug events were 0.6 per million doses for iron sucrose, 0.9 for iron gluconate, and 3.3 for low molecular-weight iron dextran [25–28]. Life-threatening anaphylactic reactions as with older iron-dextran solutions have never been observed in cancer trials [5, 9]. Iron sucrose was reported to have the lowest adverse events especially the hypersensitivity reactions . No serious adverse events have been observed in our patients during the study. A recent observational, prospective study performed in 367 patients with solid or hematologic tumors demonstrated the efficacy and safety of iv iron administration (ferric carboxymaltose) .
Another concern commonly present among clinicians is the fear of iron accumulation in patients with normal iron stores and elevated serum ferritin levels, However this fear is senseless due to the mechanism of functional iron deficiency, and due to the doses of iv iron administered in the treatment of cancer related anemia. Thus iv iron is still efficient in patients irrespective of serum iron and ferritin levels [9, 22]. In this study as well, patients responded to iv iron irrespective of their baseline serum iron and ferritin levels.
The deficiency in red blood cells and decreased functional capacity to deliver oxygen to tissues and low hemoglobin levels result in tumor hypoxia, conferring resistance to chemotherapy and radiotherapy, decreased local control, and ultimately decreased survival [31, 32]. Presence of anemia before cancer treatment and correction of anemia during cancer treatment is closely associated with survival . We observed a statistically significant 1-year survival difference in metastatic patients with increased Hgb levels after iv iron administration during their cancer treatment with CT, RT, or both when compared to the patients without a response (61.1 % vs 35.3 %, p = 0.005). The survival advantage was also significant in metastatic patients who didn’t receive blood transfusion when compared to the ones who received blood transfusion (63 % vs 31.3 %, p = 0.004). However the survival figures should be evaluated with caution since the group was not homogenous with respect to treatment, patient and tumor characteristics. But increase in Hgb levels with iv iron administration may be both prognostic and predictive factor for survival in anemic cancer patients undergoing oncologic treatment. It is worth testing this hypothesis in a prospective trial.
The decrease in Hgb levels despite iv iron administration was observed less in patients with localized disease treated with adjuvant or curative intent in comparison to patients presenting with metastatic disease treated with palliative intent (3.7 vs 50 %, p < 0.001). We think that the lower response rate to iv iron in patients with metastatic disease is due to presence of higher tumor burden and associated presence of chronic inflammatory state and more release of inflammatory cytokines with respect to the patients with localized disease. High tumor burden and associated inflammation may increase the serum hepcidin levels in metastatic patients more than the hepcidin levels in patients with localized tumors. A recent study demonstrated that response to iv iron and erythropoietin is closely related to serum hepcidin levels .
We demonstrated a close relation between response to iv iron and response to cancer treatment. Tumor responses to cancer treatment in metastatic patients correlated with response to iv iron administration and this relation was statistically significant (p < 0.001). We hypothesize that iv iron response is predictive of response to oncologic treatment and it can predict response to oncologic treatment earlier than clinical and radiologic evaluation.
Increase in Hgb levels with iv iron administration were observed in all patients presenting with localized disease except one (1 out of 27 patients), and red blood cell transfusion was necessary only in this patient. Iv iron should be considered in all anemic cancer patients treated with adjuvant or curative intent since it is very effective and safe intervention with respect to blood transfusion. It is very important to prevent adverse effects of blood transfusion in curatively treated patients. We don’t know if iv iron administration provides a survival advantage in patients with localized disease as well, as in the metastatic patients, since all the patients except one had increased Hgb levels after iv iron and we need longer follow-up time in this group. Another important point to investigate in patients with localized tumors is the association of ulterior recurrences with the degree of Hgb increase, but we need more patients and longer follow-up time to demonstrate this interaction.
Anemia is a common problem in patients with cancer [3, 4, 35]. Although it has a negative impact on prognosis and treatment results, anemia is undertreated and is not a major concern among oncologists [4, 35]. The major reason behind this is the lack of effective treatment for anemia and the limitation of ESA’s usage with the understanding of their harms. However iv iron is a safe and effective treatment for anemia in patients even undergoing active cancer treatment either with CT, RT or both [30, 36]. Increase of hemoglobin with iv iron administration is cheap and safe, and it may prevent blood transfusion and its associated complications. Increase in Hgb levels by iv iron is not temporary as in blood transfusion, and may increase the survival in metastatic cancer patients receiving treatment for their cancer.
The major drawback in our retrospective study is the heterogeneity of the study population both in respect to the patient and treatment characteristics, but as a summary, anemia not responding to iv iron and necessitating further red blood cell transfusion indicates a worse prognosis and survival. It will be very promising and practice changing to show the same results in prospectively designed studies. However even in the absence of such studies, iv iron is a safe and best evidence based treatment alternative for anemic cancer patients especially during their oncologic treatment with CT, RT or both.