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Meta-Analysis
. 2016 Feb 4;2(2):CD009624.
doi: 10.1002/14651858.CD009624.pub2.

The role of iron in the management of chemotherapy-induced anemia in cancer patients receiving erythropoiesis-stimulating agents

Rahul Mhaskar  1 , Hesborn Wao, Branko Miladinovic, Ambuj Kumar, Benjamin Djulbegovic
Affiliations
Meta-Analysis

The role of iron in the management of chemotherapy-induced anemia in cancer patients receiving erythropoiesis-stimulating agents

Rahul Mhaskar et al. Cochrane Database Syst Rev. .

Abstract

Background: Erythropoiesis-stimulating agents (ESAs) are commonly used to treat chemotherapy-induced anemia (CIA). However, about half of patients do not benefit.

Objectives: To 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 methods: We 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 criteria: All 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 analysis: We used standard methodological procedures expected by Cochrane.

Main results: We 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' conclusions: Our 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.

PubMed Disclaimer

Conflict of interest statement

Rahul Mhaksar: None

Hesborn Wao: None

Branko Miladinovic: None

Ambuj Kumar: None

Benjamin Djulbegovic: None

Figures

1
1
Study flow diagram.
2
2
Risk of bias summary: Review authors' judgments about risk of bias in each included study.
3
3
Meta‐regression: total IV iron dose and hematopoietic response
4
4
Meta‐regression: baseline serum ferritin and hematopoietic response.
1.1
1.1. Analysis
Comparison 1 Benefits and harms of iron supplementation, Outcome 1 Hematopoietic response.
1.2
1.2. Analysis
Comparison 1 Benefits and harms of iron supplementation, Outcome 2 RBC transfusion.
1.3
1.3. Analysis
Comparison 1 Benefits and harms of iron supplementation, Outcome 3 Time to hematopoietic response.
1.4
1.4. Analysis
Comparison 1 Benefits and harms of iron supplementation, Outcome 4 Mean change in Hb.
1.5
1.5. Analysis
Comparison 1 Benefits and harms of iron supplementation, Outcome 5 Quality of life.
1.6
1.6. Analysis
Comparison 1 Benefits and harms of iron supplementation, Outcome 6 Thromboembolic events.
1.7
1.7. Analysis
Comparison 1 Benefits and harms of iron supplementation, Outcome 7 Mean change in serum ferritin.
1.8
1.8. Analysis
Comparison 1 Benefits and harms of iron supplementation, Outcome 8 Mean change in TSAT.
2.1
2.1. Analysis
Comparison 2 Subgroup analyses, Outcome 1 Hematopoietic response by type of iron.
2.2
2.2. Analysis
Comparison 2 Subgroup analyses, Outcome 2 Hematopoietic response by route of administration.
2.3
2.3. Analysis
Comparison 2 Subgroup analyses, Outcome 3 Hematopoietic response by type of ESA.
2.4
2.4. Analysis
Comparison 2 Subgroup analyses, Outcome 4 Time to hematopoietic response by route of administration.
2.5
2.5. Analysis
Comparison 2 Subgroup analyses, Outcome 5 Time to hematopoietic response by type of iron.
2.6
2.6. Analysis
Comparison 2 Subgroup analyses, Outcome 6 Time to hematopoietic response by type of ESA.
2.7
2.7. Analysis
Comparison 2 Subgroup analyses, Outcome 7 Mean change in Hb by route of administration.
2.8
2.8. Analysis
Comparison 2 Subgroup analyses, Outcome 8 Mean change in Hb by type of iron.
2.9
2.9. Analysis
Comparison 2 Subgroup analyses, Outcome 9 Mean change in Hb by type of ESA.
2.10
2.10. Analysis
Comparison 2 Subgroup analyses, Outcome 10 Mean change in serum ferritin by route of administration.
2.11
2.11. Analysis
Comparison 2 Subgroup analyses, Outcome 11 Mean change in serum ferritin by type of iron.
2.12
2.12. Analysis
Comparison 2 Subgroup analyses, Outcome 12 Mean change in serum ferritin by type of ESA.
2.13
2.13. Analysis
Comparison 2 Subgroup analyses, Outcome 13 Mean change in TSAT by route of administration.
2.14
2.14. Analysis
Comparison 2 Subgroup analyses, Outcome 14 Mean change in TSAT by type of iron.
2.15
2.15. Analysis
Comparison 2 Subgroup analyses, Outcome 15 Mean change in TSAT by type of ESA.
3.1
3.1. Analysis
Comparison 3 Sensitivity analyses, Outcome 1 Random sequence generation.
3.2
3.2. Analysis
Comparison 3 Sensitivity analyses, Outcome 2 Allocation concealment.
3.3
3.3. Analysis
Comparison 3 Sensitivity analyses, Outcome 3 Blinding.
3.4
3.4. Analysis
Comparison 3 Sensitivity analyses, Outcome 4 Incomplete outcome data.
3.5
3.5. Analysis
Comparison 3 Sensitivity analyses, Outcome 5 Selective reporting.
3.6
3.6. Analysis
Comparison 3 Sensitivity analyses, Outcome 6 Other bias.
3.7
3.7. Analysis
Comparison 3 Sensitivity analyses, Outcome 7 Hematopoietic response by definition(s).
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References

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