• Rahul Mhaskar, Hesborn Wao, Branko Miladinovic, Ambuj Kumar, and Benjamin Djulbegovic.
• Center for Evidence Based Medicine and Health Outcomes Research, University of South Florida, Tampa, Florida, USA.
• Cochrane Db Syst Rev. 2016 Feb 4; 2 (2): CD009624CD009624.

BackgroundErythropoiesis-stimulating agents (ESAs) are commonly used to treat chemotherapy-induced anemia (CIA). However, about half of patients do not benefit.ObjectivesTo evaluate the benefits and harms related to the use of iron as a supplement to ESA and iron alone compared with ESA alone in the management of CIA.Search MethodsWe searched for relevant trials from the Cochrane Central Register of Controlled Trials (CENTRAL) (issue 1 January 2016), MEDLINE (1950 to February 2016), and www.clinicaltrials.gov without using any language limits.Selection CriteriaAll randomized controlled trials (RCTs) comparing 'iron plus ESA' or 'iron alone' versus 'ESA alone' in people with CIA were eligible for inclusion.Data Collection And AnalysisWe used standard methodological procedures expected by Cochrane.Main ResultsWe included eight RCTs (12 comparisons) comparing ESA plus iron versus ESA alone enrolling 2087 participants. We did not find any trial comparing iron alone versus ESAs alone in people with CIA. None of the included RCTs reported overall survival. There was a beneficial effect of iron supplementation to ESAs compared with ESAs alone on hematopoietic response (risk ratio (RR) 1.17, 95% confidence interval (CI) 1.09 to 1.26; P < 0.0001; 1712 participants; 11 comparisons; high-quality evidence). Assuming a baseline risk of 35% to 80% for hematopoietic response without iron supplementation, between seven and 16 patients should be treated to achieve hematopoietic response in one patient. In subgroup analyses, RCTs that used intravenous (IV) iron favored ESAs and iron (RR 1.20 (95% CI 1.10 to 1.31); P < 0.00001; 1321 participants; eight comparisons), whereas we found no evidence for a difference in hematopoietic response in RCTs using oral iron (RR 1.04 (95% CI 0.87 to 1.24); P = 0.68; 391 participants; three comparisons). There was no evidence for a difference between the subgroups of IV and oral iron (P = 0.16). There was no evidence for a difference between the subgroups of types of iron (P = 0.31) and types of ESAs (P = 0.16) for hematopoietic response.The iron supplementation to ESAs might be beneficial as fewer participants treated with iron supplementation required red blood cell (RBC) transfusions compared to the number of participants treated with ESAs alone (RR 0.74 (95% CI 0.60 to 0.92); P = 0.007; 1719 participants; 11 comparisons; moderate-quality evidence). Assuming a baseline risk of 7% to 40% for RBC transfusion without iron supplementation, between 10 and 57 patients should be treated to avoid RBC transfusion in one patient.We found no evidence for a difference in the median time to hematopoietic response with addition of iron to ESAs (hazard ratio (HR) 0.93 (95% CI 0.67 to 1.28); P = 0.65; 1042 participants; seven comparisons; low-quality evidence). In subgroup analyses, RCTs in which dextran (HR 0.95 (95% CI 0.36 to 2.52); P = 0.92; 340 participants; three comparisons), sucrose iron (HR 1.15 (95% CI 0.60 to 2.21); P = 0.67; 102 participants; one comparison) and sulfate iron (HR 1.24 (95% CI 0.99 to 1.56); P = 0.06; 55 participants; one comparison) were used showed no evidence for difference between iron supplementation versus ESAs alone compared with RCTs in which gluconate (HR 0.78 (95% CI 0.65 to 0.94); P = 0.01; 464 participants; two comparisons) was used for median time to hematopoietic response (P = 0.02). There was no evidence for a difference between the subgroups of route of iron administration (P = 0.13) and types of ESAs (P = 0.46) for median time to hematopoietic response.Our results indicated that there could be improvement in the hemoglobin (Hb) levels with addition of iron to ESAs (mean difference (MD) 0.48 (95% CI 0.10 to 0.86); P = 0.01; 827 participants; seven comparisons; low-quality evidence). In RCTs in which IV iron was used there was evidence for a difference (MD 0.84 (95% CI 0.21 to 1.46); P = 0.009; 436 participants; four comparisons) compared with oral iron (MD 0.07 (95% CI -0.19 to 0.34); P = 0.59; 391 participants; three comparisons) for mean change in Hb level (P = 0.03). RCTs in which dextran (MD 1.55 (95% CI 0.62 to 2.47); P = 0.001; 102 participants; two comparisons) was used showed evidence for a difference with iron supplementation versus ESAs alone compared with RCTs in which gluconate (MD 0.54 (95% CI -0.15 to 1.22); P = 0.12; 334 participants; two comparisons) and sulfate iron (MD 0.07 (95% CI -0.19 to 0.34); P = 0.59; 391 participants; three comparisons) were used for mean change in Hb level (P = 0.007). RCTs in which epoetin was used showed evidence for a difference with iron supplementation versus ESAs alone (MD 0.77 (95% CI 0.25 to 1.29); P = 0.004; 337 participants; five comparisons) compared with darbepoetin use (MD 0.10 (95% CI -0.13 to 0.33); P = 0.38; 490 participants; two comparisons) for mean change in Hb level (P = 0.02).We found no evidence for a difference in quality of life with addition of iron to ESAs (standardized mean difference 0.01 (95% CI -0.10 to 0.12); P = 0.88; 1124 participants; three RCTs; high-quality evidence).We found no evidence for a difference in risk of grade III-IV thromboembolic events (RR 0.95 (95% CI 0.54 to 1.65); P = 0.85; 783 participants; three RCTs; moderate-quality evidence). The incidence of treatment-related mortality (TRM) was 0% (997 participants; four comparisons; high-quality evidence).Other common adverse events included vomiting, asthenia, and leukopenia, and were similar in both arms.Overall the risk of bias across outcomes was high to low. Since the included RCTs had shorter follow-up duration (up to 20 weeks), the long-term effects of iron supplementation are unknown. Our main reasons for downgrading the quality of evidence were inconsistency across the included studies and imprecision of results.Authors' ConclusionsOur systematic review shows that addition of iron to ESAs offers superior hematopoietic response, reduces the risk of RBC transfusions, and improves Hb levels, and appears to be well tolerated. None of the included RCTs reported overall survival. We found no evidence for a difference in quality of life with iron supplementation.

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