Iron Supplementation of Erythropoiesis-Stimulating Agents Increases Hematopoietic Response Rates in Patients With Cancer and Chemotherapy-Induced Anemia

ORLANDO, Fla.—When compared with using erythropoiesis-stimulating agents (ESA) alone or placebo, iron supplementation of ESAs significantly increases hematopoietic response rates and reduces the number of red blood cell (RBC) transfusions in patients with chemotherapy-induced anemia (CIA), results of the first systematic review and meta-analysis have found.

In addition, intravenous (IV) iron appears to be superior to oral iron in achieving hematopoietic response, Rahul Mhaskar, MD, MPH, of the University of South Florida, Tampa, Fla., and colleagues have found. Both IV and oral iron were found to be well tolerated, with no significant differences in adverse events.

The investigators conducted the meta-analysis because numerous clinical trials have indicated approximately half of patients treated with ESAs fail to show an increase in (Hb) levels or a reduction in RBC transfusions following treatment. While this failure may be attributed to functional iron deficiency (FID)—and iron is often used to supplement ESAs to correct FID—no systematic review has been conducted that examines the role of iron supplementation, the investigators told those attending the 52nd American Society of Hematology Annual Meeting and Exposition.

Investigators conducted a literature search of PubMed, Cochrane databases, and meeting abstracts from the American Society of Clinical Oncology, American Society of Hematology, and European Hematology Association to identify phase 3 randomized controlled trials published as of June 2010. Data were extracted on hematopoietic response rate, time to hematopoietic response, RBC transfusions, mean change in Hb level, quality of life (QOL), overall survival (OS), and grade 3/4 treatment-related adverse events. Subgroup analyses were conducted based on iron type and route of administration. Time to event data, dichotomous data, and ratio level data were pooled as hazard ratios, risk ratios (RR), and mean difference (MD), respectively, under the random effects model.

Seven randomized controlled trials (5 articles and 2 abstracts) enrolling 1777 patients were included in the meta-analysis. For hematopoietic response, iron supplementation of ESAs resulted in a beneficial effect compared with ESAs alone (RR=0.65, 95% CI, 0.53-0.79). Studies that used IV iron favored ESAs plus iron (RR=0.57, 95% CI, 0.44-0.74), whereas no differences were found in studies using oral iron (RR=0.81, 95% CI, 0.64-1.03) (P=0.02). No differences were found in median time to hematopoietic response between patients receiving ESAs plus iron vs those receiving ESAs alone. Significantly fewer patients treated with ESAs plus iron required RBC transfusions compared with those treated with ESAs alone (RR= 0.67, 95% CI, 0.52-0.86). Please click here for more study data. None of the studies reported OS estimates.

Based on route of administration of iron, no differences in RBC transfusions were found. Mean change in Hb level was reported in 5 of 7 studies (71%); however, data were extractable for the meta-analysis only from 3 studies (43%). Mean change in Hb level was significantly greater in patients receiving ESAs plus iron (MD=0.77, 95% CI, 0.27-1.28) vs ESAs alone.

QOL was reported in three studies, but due to variation in the scales used (FACT-F and LASA), data could not be pooled. Bastit et al found no differences in QOL between patients treated with ESA plus iron vs those treated with ESAs alone. However, Auerbach et al reported patients receiving ESAs plus iron had significantly better QOL than those receiving ESAs alone. No differences were found in risk of grade 3/4 thromboembolic events between patients receiving ESAs plus iron vs ESAs alone (RR=1.09, 95% CI, 0.55-2.18, P=0.807, 3 studies, n=614). Type of iron used (gluconate, dextran, sucrose, or sulphate) did not affect any of the outcomes, they concluded.

None of the studies reported OS estimates.