Should intravenous iron be the standard of care in oncology?

Before 1989, when epoetin was introduced for dialysisassociated anemia, the use of intravenous (IV) iron in the United States was typically avoided. Shortly thereafter, it was shown that responses to epoetin could be improved by IV iron supplementation. By 1998, IV iron had become standard of care in dialysis patients receiving epoetin,and the use of erythropoiesis-stimulating agents (ESAs) in oncology patients was in its infancy. In the ensuing decade, we have witnessed improvements in quality of life and fewer transfusions among patients receiving ESAs for the anemia associated with cancer and cancer chemotherapy. Some studies have shown the maximum improvement in energy, activity, and quality of life occurs when the hemoglobin (Hb) increases from 11 to 13 g/dL. In August 2007, the Committee on Medicare and Medicaid Services issued a Decision Memo restricting ESA usage when patients’ Hb levels are 10 g/dL. These new regulations were recommended on the basis of data suggesting harm with ESAs when used outside of established guidelines. To date, no study has shown a negative impact on cancer outcomes or survival in patients when ESAs were used in accordance with previously established American Society of Hematology, American Society of Clinical Oncology, or National Comprehensive Cancer Network guidelines. Recent data in the renal literature suggest that it is not the Hb level, but ESA exposure, that is associated with negative outcomes. The success of IV iron supplementation in improving responses to ESAs in the anemia of end-stage renal disease has yet to be realized by the oncology community. Oncologists spend three times more on ESAs than nephrologists. A 50% reduction in transfusions has been accomplished in oncology patients, whereas transfusions have been virtually eliminated in the dialysis population. Is it possible that it is the suboptimal use of these expensive drugs that played a role in the restrictions recently imposed? Two articles in this issue of the Journal of Clinical Oncology represent the fourth and fifth of five recent publications showing that administration of IV iron to oncology patients receiving ESAs results in significantly greater increments in Hb and hematopoietic response rates compared with ESAs alone or with oral iron (Table 1). In all five studies, the benefit was independent of baseline iron parameters. These two studies add unique and useful information to a rapidly growing body of data supporting the routine use of IV iron as an adjunct to ESA therapy in appropriately selected oncology patients. Bastit et al studied 396 patients with nonmyeloid malignancies receiving chemotherapy, with Hb less than 10.5 g/dL and ferritin more than 10 ng/mL or transferrin saturation (TSAT) more than 15%. Patients were treated with 500 g of subcutaneous darbepoietin alpha (DA) every 3 weeks alone or with weekly or twice weekly IV iron (iron sucrose or ferric gluconate). Statistically significant improvements in Hb and hematopoietic responses and time to reach the target Hb were seen in the IV iron group. Unlike the other four studies, this trial showed a statistically significant reduction in the number of RBC transfusions administered (nine v 20) in the IV iron group. Although this trial can be criticized for including overtly or functionally iron deficient patients with ferritin less than 100 ng/mL or TSAT less than 20%, a majority of patients in the trial were iron replete based on iron/total iron binding capacity and ferritin levels. This is the largest study of intravenous iron’s synergy with ESAs and the only one to show a significant difference in RBC usage. For both of these trials, a double-blind design (for IV iron) with well-defined transfusion criteria would have been optimal, but this was logistically impractical. Pedrazzoli et al studied 149 patients with solid tumors receiving chemotherapy who were anemic but iron replete. Patients were treated with 150 g of subcutaneous DA weekly with or without iron sucrose. The dose of DA was doubled at four weeks if less than a 1-g Hb increment was observed, per the Italian guidelines for ESA usage. The authors correctly point out that, unlike other studies, this trial excluded all patients with absolute or functional iron deficiency. Eligibility for randomization required serum ferritin levels greater than 100 ng/mL and TSATs greater than 20%. There were statistically significant improvements in Hb and hematopoietic responses in the IV iron group. This was the first study to enroll only patients generally considered to have adequate iron stores based on both a high serum ferritin and TSAT. The results of this study are supported by an earlier trial by Henry et al, in which patients were randomly assigned to weekly epoetin alone or with IV ferric gluconate. There was a significantly higher response rate (73%) for intravenous iron and epoetin, compared with a 41% response rate in the epoetin only group. More than 90% of the study’s patients had a ferritin level greater than 100 ng/mL, and the mean TSAT in both groups was greater than 20%, making it unlikely that iron deficiency accounted for the low responder rate in the epoetin only group. Another interesting observation in the Italian trial is that unresponsive patients at 4 weeks in the DA/iron arm were far more likely (P .0199) to respond to a subsequent doubling of the DA dose (15 [68.2%] of 22) than initial nonresponders in the DA only arm (eight [32%] of 25). As the authors state, “Because of the timing of the DA dose-doubling (nonresponders after 4 weeks), a possible interaction JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 10 APRIL 1 2008