Methods

• Prospective, multicenter, open‐label, randomized, controlled study

• Study length = 6 weeks

• Study conducted during: not reported

Participants

• Eligibility: Hb ≤ 105g/dL; Ferritin ≤ 450pmol/L or ≤ 450pmol/L ; TSAT ≤ 19%; ECOG PS ≤ 2

• Sex (number enrolled): female (65), male (92);

• Mean age: 64.7 years;

• Experimental arm: ESAs + iron dextran total dose infusion (TDI): enrolled 41, analyzed 41

• Control arm: ESAs only: enrolled 36, analyzed 36

• Mean baseline S. Ferritin range (207 to 194 pmol/L); Mean baseline TSAT saturation range (14 to 19%)

Interventions

• Esperimental arm: ESAs + iron dextran TDI

• Control: ESAs only: rHuEPO 40,000 U SC (dose escalation or reduction was not permitted)

Outcomes

• Hematopoietic response

• RBC transfusions

• Time to hematopoietic response

• Change in Hb level

• QOL

• Treatment‐related harms (thromboembolic events are not reported)

Notes

• This is a four‐armed study and the references (Auerbach 2004b) Auerbach2004b and (Auerbach 2004c) Auerbach2004c refer to the same study.

• Hematopoietic response defined as increase in Hb level of ≥2g/dL or achievement of Hb level of ≥12g/dL without transfusion during study

• The number of patients "receiving transfusions" were reported (no separate reporting of RBCs versus other types of transfusions)

• QOL was measured using: LASA, ADL and Overall QOL index

• The total dose of iron dextran was calculated using the formula to reach a desired Hb level of 140 g/L: dose (mL)0.0442 (desired Hb–observed Hb)xLBW(0.26LBW) whereLBWis the patient’s lean body weight in kilograms.

• All patients received iron dextran as INFeD (Watson Pharmaceuticals, Morristown, NJ) except for two patients who received iron dextran as DexFerrum (American Regent Laboratories, Shirley, NY) during a brief period when the first formulation was not available.

• Participants randomly assigned to TDI received methylprednisolone 125 mg before and following the infusion. Patients then received a 25mg test dose given by IV push.One hour after the test dose was administered, patients received the calculated total iron dextran dose in 500 mL of 0.9% NaCl solution administered at a rate of 175 mL/h.

• This was an industry funded trial.

• COI statement included: Acted as a consultant within the last 2 years: Michael Auerbach, Watson Pharmaceuticals; J. Richard Trout, Watson Pharmaceuticals. Received more than $2,000 a year from a company for either of the last 2 years: Michael Auerbach, Watson Pharmaceuticals; J. Richard Trout, Watson Pharmaceuticals; Marilyn McIlwain, Watson Pharmaceuticals.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Trial authors described the study as “randomized controlled” and reported that “patients were centrally randomly assigned…”, however, this information is insufficient to permit judgment about the sequence generation process because details of how sequence was generated are not provided.

Allocation concealment (selection bias)

Low risk

“patients were centrally randomly assigned”

Blinding (performance bias and detection bias)
All outcomes

High risk

There was no blinding (study described as “open‐label”) yet outcome measurement was likely to be influenced by lack of blinding.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Trial authors reported that efficacy data were analyzed according to the "modified ITT principle". Withdrawals and drop‐outs were adequately

Selective reporting (reporting bias)

Low risk

One of outcomes of interest in the review (RBC transfusion) was not reported, however, it was reported that the study was not powered to detect differences in RBC transfusion requirements.

Other bias

Low risk

Pre‐specified values of sample size, alpha and beta errors and delta were provided

Methods

• Prospective, multicenter, open‐label, randomized, controlled study

• Study length: 6 weeks

Participants

• Experimental arm: ESAs + IV iron dextran (bolus): enrolled 37, analyzed 37

• Control arm: ESAs only: enrolled 36, analyzed 36

Interventions

• Experimental arm: ESAs + IV iron dextran 100 mg bolus at each visit

• Control arm: ESAs only: rHuEPO 40,000 U SC (dose escalation or reduction was not permitted)

Outcomes

• Hematopoietic response

• RBC transfusions

• Time to hematopoietic response

• Change in Hb level

• QOL

• Treatment‐related harms (thromboembolic events are not reported)

Notes

• Hematopoietic response defined as increase in Hb level of ≥ 2 g/dL or achievement of Hb level of ≥ 12 g/dL without transfusion during study.

• The number of participants "receiving transfusions" was reported (no separate reporting of RBCs versus other types of transfusions).

• QOL was measured using: LASA, ADL, and overall QOL index.

• The total dose of iron dextran was calculated using the formula to reach a desired Hb level of 140 g/L: dose (mL)0.0442 (desired Hb ‐ observed Hb) x LBW(0.26LBW) where LBW is the participant’s lean body weight in kilograms.

• All participants received iron dextran as INFeD (Watson Pharmaceuticals, Morristown, NJ), except for 2 participants who received iron dextran as Dexferrum (American Regent Laboratories, Shirley, NY) during a brief period when the first formulation was not available.

• Participants randomly assigned to 100 mg bolus injections received a 25 mg test dose of iron dextran by IV push over 1 to 2 minutes, followed by a 75 mg bolus injection before the first 3 epoetin alfa doses (i.e. for the first 3 weeks of the study).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Trial authors described the study as “randomized controlled” and reported that “patients were centrally randomly assigned…,” however this information is insufficient to permit judgment about the sequence generation process because details of how sequence was generated are not provided

Allocation concealment (selection bias)

Low risk

“patients were centrally randomly assigned”

Blinding (performance bias and detection bias)
All outcomes

High risk

There was no blinding (study described as “open‐label”), yet outcome measurement was likely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Trial authors reported that efficacy data were analyzed according to the "modified ITT principle." Withdrawals and dropouts were described adequately

Selective reporting (reporting bias)

Low risk

One outcome of interest in the review (RBC transfusion) was not reported, however it was reported that the study was not powered to detect differences in RBC transfusion requirements

Other bias

Low risk

Prespecified values of sample size, alpha and beta errors and delta were provided

Methods

• Prospective, multicenter, open‐label, randomized, controlled study

• Study length: 6 weeks

Participants

• Experimental arm: ESAs + oral iron: enrolled 43, analyzed 43

• Control arm: ESAs only: enrolled 36, analyzed 36

Interventions

• Experimental arm: ESAs + oral iron (ferrous sulfate) 325 mg twice daily

• Control arm: ESAs only: rHuEPO 40,000 U SC (dose escalation or reduction was not permitted)

Outcomes

• Hematopoietic response

• RBC transfusions

• Time to hematopoietic response

• Change in Hb level

• QOL

• Treatment‐related harms (thromboembolic events are not reported)

Notes

• Hematopoietic response defined as increase in Hb level of ≥ 2 g/dL or achievement of Hb level of ≥ 12 g/dL without transfusion during study.

• The number of participants "receiving transfusions" was reported (no separate reporting of RBCs versus other types of transfusions).

• QOL was measured using: LASA, ADL, and overall QOL index.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Trial authors described the study as “randomized controlled” and reported that “patients were centrally randomly assigned…,” however this information is insufficient to permit judgment about the sequence generation process because details of how sequence was generated are not provided

Allocation concealment (selection bias)

Low risk

“patients were centrally randomly assigned”

Blinding (performance bias and detection bias)
All outcomes

High risk

There was no blinding (study described as “open‐label”), yet outcome measurement was likely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Trial authors reported that efficacy data were analyzed according to the "modified ITT principle." Withdrawals and dropouts were described adequately

Selective reporting (reporting bias)

Low risk

One outcome of interest in the review (RBC transfusion) was not reported, however it was reported that the study was not powered to detect differences in RBC transfusion requirements

Other bias

Low risk

Prespecified values of sample size, alpha and beta errors and delta were provided

Methods

• Phase II, double‐blind, multicenter, 2 x 2 factorial study. The 2 study factors were dose of darbepoetin alfa (500 lg Q3W versus 300 lg Q3W) and IV iron usage (IV iron versus no IV iron). The study was blinded to the dose of darbepoetin alfa administered and open label for IV iron administration.

• Eligible patients were randomized in a 1:1:1:1 ratio to 1 of 4 treatment arms: darbepoetin alfa 300 µg Q3W, darbepoetin alfa 500 µg Q3W, darbepoetin alfa 300 µg Q3W plus IV iron, and darbepoetin alfa 500 µg Q3W plus IV iron. Randomization was stratified by planned chemotherapy (platinum versus non‐platinum) and geographic region (North America versus Europe).

• Study length: 15 weeks

• Study conducted during: 18 December 2006 and 12 December 2007

• Mean baseline serum ferritin range (291 to 332.3 ng/ml); mean baseline TSAT range (25.1% to 27.4%)

Participants

• Eligibility: ≥ 18 years old and had non‐myeloid cancer, CIA (Hb ≤ 10 g/dL), and no iron deficiency; patients were excluded if they had absolute iron deficiency (TSAT < 15% and serum ferritin < 10 ng/mL)

• Experimental arm: ESAs + IV iron: enrolled 122, analyzed 122

• Control arm: ESAs only: enrolled 116, analyzed 116

• Of the 238 participants dosed, 79% were white, 66% were female, and mean age was about 62 years. The most common tumor types were gastrointestinal, breast, and lung.

Interventions

• Experimental arm: darbepoetin alfa + oral iron dextran 400 mg Q3W (darbepoetin alfa was withheld at Hb > 13 g/dL)

• Control arm: ESAs only: darbepoetin alfa 500 mcg Q3W SC

• Darbepoetin alfa (Aranesp, Amgen, Thousand Oaks, CA) was supplied in 1 mL single‐dose vials as a clear, colorless, sterile protein solution. In the US, IV iron (provided as INFeD, Watson Pharma, Morristown, NJ) was supplied by a central pharmacy, CoramRx (Malvern, PA). In Europe, IV iron (provided as CosmoFer, Pharmacosmos, Denmark) was supplied via a central interactive voice response system.

Outcomes

• Hematopoietic response

• RBC transfusions

• Time to hematopoietic response

• QOL

• Treatment‐related harms (thromboembolic events are not reported)

Notes

• Hematopoietic response defined as either a 2 g/dL increase from baseline in hemoglobin or a hemoglobin correction to ≥ 12 g/dL in the absence of any RBC transfusions in the preceding 28 days.

• Number of participants receiving RBC transfusions is reported. Participants who had received ≥ 1 RBC transfusions from week 1 to the end of study (Kaplan‐Meier estimates) are used for meta‐analysis.

• QOL was measured using FACT‐F; QOL parameters from baseline to end of treatment were reported

• Dose reductions for participants receiving darbepoetin alfa were allowed as follows: the dose was reduced to 200 µg Q3W or 300 µg Q3W, respectively, if a participant had a Hb level 12 g/dL with no other previous dose reductions or if a participant had a rapid rise in hemoglobin (defined as a > 1.5g/dL increase in hemoglobin within 21 days). After a second rapid rise in hemoglobin, the darbepoetin alfa dose was reduced to 150 µg Q3W or 250 µg Q3W, respectively, and further reduced to 100 µg Q3W or 200 µg Q3W, respectively, after a third rapid rise in hemoglobin. Thereafter, darbepoetin alfa dose was withheld when a subsequent rapid rise in hemoglobin occurred. Darbepoetin alfa dose was also withheld if a hemoglobin threshold (defined as Hb >13 g/dL) was reached, and was reinitiated when Hb fell to < 12 g/dL. Dose reduction and dose withholding rules did not apply if the participant had a RBC transfusion within 21 days prior to the next dosing visit.

• Authors state in the methods section that "patients could receive oral iron if they were not randomized to IV iron treatment." However, authors do not report the number of participants in the "ESAs only arm" who (may have) received oral iron supplementation.

• This was an industry‐funded trial.

• COI statement included: Drs. Auerbach, Webb, and Averyanova do not have conflicts to disclose. Dr. Ciuleanu is a member of the Amgen advisory board; Drs. Ciuleanu and Silberstein have received honoraria from Amgen. Mr. Shao was an employee of Amgen with ownership of Amgen stock at the time the study was conducted. Dr. Bridges is an employee of Amgen and owns Amgen stock.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

A randomization list was created and maintained by an independent randomization group at the study sponsor using permuted blocks. The randomization list was transmitted to an IVRS vendor for execution.
Enrollment and randomization were done by telephone and confirmed by facsimile

Allocation concealment (selection bias)

Low risk

A randomization list was created and maintained by an independent randomization group at the study sponsor using permuted blocks. The randomization list was transmitted to an IVRS vendor for execution.
Enrollment and randomization were done by telephone and confirmed by facsimile

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Participants were assigned blinded boxes of study medication using box numbers, which were recorded and reconciled. The study was blinded while ongoing and unblinded after all participants had completed the study. However, it is not clear whether or not the investigators were blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Efficay data were analyzed according to the ITT principle. Withdrawals and dropouts were described adequately

Selective reporting (reporting bias)

Low risk

Benefits and harms were reported as indicated in a prespecified method

Other bias

High risk

Data on alpha, beta errors, sample size calculation and delta were not reported; authors state in the methods section that "patients could receive oral iron if they were not randomized to IV iron supplementation." However, authors do not report the number of participants in the "ESAs only arm" who (may have) received oral iron supplementation

Methods

• Multicenter, randomized, open‐label, phase III study

• Randomization was stratified by tumor type (lung/gynecologic versus other types) and baseline Hb category (< 10 versus ≥ 10 g/dL).

• Study length: 16 weeks

• Study conducted during: not reported

• Number (%) of participants with functional iron deficiency at baseline: 71 (35%) IV iron arm and 70 (36%) control arm

Participants

• Eligibility: Men and women ≥ 18 years of age with anemia (Hb 11 g/dL within 24 hours before randomization) and non‐myeloid malignancy were enrolled. Participants were required to have an ECOG PS score of 0 to 2, adequate renal and liver function, and 8 weeks of cytotoxic chemotherapy planned. Patients with iron deficiency (TSAT 15% and serum ferritin 10 ng/mL), serum ferritin > 800 ng/mL, or those who had received an RBC transfusion within 14 days or any ESAs within the 4 weeks preceding randomization were excluded.

• Sex (number enrolled): female (240), male (156)

• Experimental arm: ESAs + IV iron: enrolled 201, analyzed 200

• Control arm: ESAs only: enrolled 197, analyzed 196

Interventions

• Experimental arm 1: ESAs + IV ferric gluconate or sucrose 200 mg Q3W

• Experimental arm 2: ESAs + oral ferric gluconate or sucrose 200 mg Q3W

• Control arm: ESAs only: darbepoetin alfa 500 μg Q3W SC

Outcomes

• Hematopoietic response

• RBC transfusions

• Time to hematopoietic response

• QOL

• Treatment‐related harms (thromboembolic events are reported)

Notes

• Hematopoietic response defined as increase in Hb ≥ 12 g/dL or a 2 g/dL increase in Hb during 16‐week treatment period in the absence of RBC transfusions within the previous 28 days.

• Darbepoetin alfa was administered using the Aranesp SureClick autoinjector (Aranesp, Amgen Inc., Thousand Oaks, CA). Participants whose Hb exceeded 14 g/dL had darbepoetin alfa withheld until Hb 13 g/dL. After a protocol amendment, dose adjustments were made to achieve an Hb concentration of 12 g/dL. Darbepoetin alfa doses were withheld if a participant’s Hb level exceeded 13 g/dL and were reinstated with a 40% dose reduction (300 µg) after Hb 12 g/dL. Participants with more than a 2 g/dL Hb increase in a 4‐week period received darbepoetin alfa 300 µg. If a participant’s serum ferritin exceeded 1000 ng/mL, IV iron was withheld and reinstated once ferritin decreased to ≤ 1000 ng/mL.

• Number of participants receiving RBC transfusions is reported. Participants who had received ≥ 1 RBC transfusions from week 1 to the end of study (Kaplan‐Meier estimates) are used for meta analysis.

• QOL was measured by FACT‐F questionnaires.

• This was an industry‐funded trial.

• COI statement included: 1.Employment: Tamas S. Suto, Amgen; Tony W. Mossman, Amgen; Kay E. Smith, Amgen 2.Leadership: N/A 3.Consultant: N/A 4.Stock: Kay E. Smith, Amgen 5.Honoraria: Johan F. Vansteenkiste, Amgen 6.Research Funds: Johan F. Vansteenkiste, Funds, Educational Amgen Chair in Supportive Cancer Care at the Leuven University 7.Testimony: N/A 8.Other: N/A.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Trial authors described the study as a “randomized controlled trial,” but this information is insufficient to permit judgment about the sequence generation process as it lacks details of how sequence was generated

Allocation concealment (selection bias)

Low risk

Randomization was assigned using an interactive voice response system, which, in our opinion, could prevent participants from foreseeing assignment

Blinding (performance bias and detection bias)
All outcomes

High risk

There was no blinding (study described as “open‐label”), yet outcome measurement was likely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Trial authors reported that efficacy data were analyzed according to the ITT principle. Most participants (67% in the IV iron group, 76% in the control group) completed this study. Nonetheless importantly, the reasons for withdrawal (death, adverse events, disease progression, consent withdrawal, protocol deviations, non‐compliance) were similar across study groups

Selective reporting (reporting bias)

Low risk

Benefits and harms were reported as indicated in a prespecified method

Other bias

Low risk

Prespecified values of sample size, alpha, beta (power), and delta were provided

Methods

• Multicenter, 3‐arm RCT, not placebo controlled, open label (for IV arm)

• Study length: 18 weeks

• Study conducted during: not reported

Participants

• Eligibility*: Male or female; female participants must use a reliable contraception method; age > 16 yrs and < 70 yrs; no terminal organ failure; written informed consent given by participant or his/her guardian if of minor age; adequate iron stores (serum ferritin > 100 Eg/L) on day 21 post‐transplant; adequate marrow recovery, as shown by: neutrophils > 1000/EL, platelet transfusion independence; PBSC (not marrow) transplantation

• Experimental arm: ESAs + IV iron: analyzed = 50

• Control arm: ESAs only: analyzed = 52

Interventions

• Experimental arm: ESAs + IV iron sucrose 200 mg on days 28, 42, and 56 after HCT

• Control arm 1: ESAs only: DA alfa 300 μg QOW starting on day 28 after HCT for a total of 7 doses

• Control arm 2: No treatment

Outcomes

• Hematopoietic response (proportion of complete correctors are reported and used in the analyses)

• RBC transfusions

• Time to hematopoietic response (median time to achieve Hb correction is reported)

Notes

• Hematopoietic response defined as: proportion of complete correctors: participants with increase in Hb ≥ 13 g/dL before day 126 post‐transplant or participants increasing Hb by > 2 g/dL before day 126.

• Number of participants receiving RBC transfusions is reported.

• *Once the target Hb (13 g/dL) was attained, the dose of Aranesp was reduced by half to 150 µg. If the Hb increased to > 14 g/dL, Aranesp was withheld and resumed at a dose of 150 µg when the Hb decreased < 13 g/dL. If the Hb decreased to < 12 g/dL, the dose of Aranesp was increased to 300 µg again.

• *Iron sucrose (Venofer) was administered IV at a dose of 200 mg (2 vials of Venofer) on days 28, 42, and 56 after the transplant. Venofer will be diluted in 250 ml saline and infused over 60 minutes. No iron supplementation was allowed in ESAs‐only arm before day 70 after the transplant. In ESAs‐only and ESAs‐and‐iron arms, if participants had evidence of functional iron deficiency (TSAT < 20%) on day 70 or later, they might have received 300 mg of Venofer over 90 min, for a minimum of 2 doses (details not provided in the text).

• Comparison of ESAs + IV iron sucrose versus no treatment is not included in the meta‐analysis.

• This was a joint industry‐ and publicly funded trial.

• COI statement included (presented as an American Society of Hematology meeting abstract): "I have disclosed to the American Society of Hematology all relevant financial relationships. If I am presenting in a venue sponsored by ASH, I will disclose this information to the audience orally and provide this information as a disclosure slide or in written form."

*Data obtained from www.clinicaltrials.gov records.

#Some data for 'Risk of bias' assessment were obtained from www.druglib.com records.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomization was carried out following a computer‐generated randomization list

Allocation concealment (selection bias)

Low risk

# Randomization will be carried out centrally in Liege by faxing the inclusion form at the following number: 32‐4‐3668855. This was done around day 21 post‐transplant

Blinding (performance bias and detection bias)
All outcomes

Low risk

Personnel involved in clinical care of the participants were blinded

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

There was no reporting of data on attrition/exclusion to permit judgment about adequacy of completeness of outcome reporting

Selective reporting (reporting bias)

Low risk

Benefits and harms were reported as indicated in a prespecified method

Other bias

Unclear risk

There was insufficient information in the abstract for us to assess whether an important risk of bias existed or not

Methods

• Prospective, multicenter, randomized, open‐label, phase III clinical trial

• Two‐stage trial: during Stage I (8‐wk duration), participants received treatment with fixed ESAs doses (100 mcg of darbepoetin or 40,000 units epoetin wkly or 200 mcg of darbepoetin QOW). Participants were classified as either ESAs responders (= 1 g/dL increase in Hb) or ESAs non‐responders with each group randomized (Stage 2) separately to receive either 12 weeks of fixed doses of ESAs plus up to 1500 mg of iron sucrose (given in 3 divided doses of up to 500 mg) or 12 weeks of fixed doses of ESAs alone.

• Study length: 20 weeks

• Study conducted during: not reported

Participants

• Eligibility: Hb ≤ 10 g/dL; KPS ≤ 60% to 100%; age > 18 years

• A total of 375 participants were enrolled in this RCT. The study is published as a meeting abstract only. The distribution of participants in the individual study arms is not reported.

Interventions

• Experimental arm: ESAs + iron sucrose: darbepoetin 100 μg or epoetin 40,000 U OR darbepoetin 200 μg QOW plus iron sucrose 1500 mg 3 divided doses up to 500 mg

• Control arm: ESAs only: darbepoetin 100 μg or epoetin 40,000 U OR darbepoetin 200 μg QOW

Outcomes

• Hematopoietic response

• Change in Hb level

• Treatment‐related harms

Data reported were not amenable to statistical analysis (data are not reported per study arm). The distribution of participants in the individual study arms is not reported.

Notes

• Hematopoietic response defined as increase in Hb level of ≥ 2 g/dL.

• Although quantitative data were not reported, information on significance of results was reported, thus we included such qualitative data.

• This was an industry‐funded trial.

• This was presented as a poster at the 2007 American Society of Clincal Oncology annual meeting. COI statement is not available.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Trial authors described the study as “randomized phase III clinical trial,” but this information is insufficient to permit judgment about the sequence generation process as it lacks details of how sequence was generated

Allocation concealment (selection bias)

Unclear risk

Method of concealment is not described in the abstract

Blinding (performance bias and detection bias)
All outcomes

High risk

There was no blinding (study described as “open‐label”), yet outcome measurement was likely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

There was insufficient data to permit judgment regarding attrition bias

Selective reporting (reporting bias)

Unclear risk

Abstract lacks information to make a judgment regarding reporting biases

Other bias

Unclear risk

There was insufficient information in the abstract to assess whether an important risk of bias existed

Methods

• Open‐label, randomized, controlled, multicenter, prospective trial

• Study length: 12 weeks

• Study conducted during: not reported

Participants

• Eligibility: Hb ≤ 11 g/dL; serum ferritin ≥ 100 ng/ml; TSAT between 15% and 35%; ECOG PS: 0 to 2; received no epoetin alfa or IV iron within 30 days and no oral iron within 7 days before enrollment; age ≥ 18 years old; life expectancy ≥ 24 weeks

• Sex (number enrolled): female (89), male (40)

• Experimental arm: ESAs + IV sodium ferric gluconate: enrolled 63, analyzed 41

• Control arm: ESAs only: enrolled 63, analyzed 44

• Mean baseline serum ferritin range (321.5 to 388.2 ng/ml); mean baseline TSAT range (29.1% to 36.3%)

Interventions

• Experimental arm: ESAs + IV sodium ferric gluconate 125 mg IV once weekly

• Control arm: ESAs only: epoetin alfa 40,000 U SC once weekly

Outcomes

• Hematopoietic response

• RBC transfusions

• Change in Hb levels

• Treatment‐related harms (thromboembolic events are not reported)

Notes

• This is a 3‐armed study, and the reference Henry 2007b refers to the same study.

• Hematopoietic response defined as increase in Hb level of ≥ 2 g/dL.

• Number of participants receiving transfusions are reported and are used for RBC transfusion outcomes meta‐analysis.

• Patients were excluded for hemolysis, gastrointestinal bleeding, folate or vitamin B12 deficiency, elevated serum ferritin (900 ng/ml) or TSAT (35%), pregnancy or lactation,liver dysfunction (grade 2 based on National Cancer Institute Common Toxicity Criteria), renal dysfunction (serum creatinine 2.0 mg/dl), active infection requiring systemic antibiotics, personal or family history of hemochromatosis, comorbidities precluding study participation, hypersensitivity to ferric gluconate or its components, contraindication to epoetin alfa therapy, RBC transfusion within the past 2 weeks, or any investigational agent within 30 days before enrollment.

• If TSAT increased to 50%, ferric gluconate was withheld until TSAT decreased to 50%, and was then restarted at the original dose.

• For epoetin alfa treatment: if after 4 weeks Hb did not increase by ≥ 1 g/dl, the dose was increased to 60,000 U once weekly. If Hb increased > 1.3 g/dl in any 2‐week period, the dose was reduced by 25%. If Hb increased to > 13 g/dl, epoetin alfa was discontinued until Hb decreased to ≤ 12 g/dl, and was then resumed at 75% of the previous dose.

• Grading for treatment‐related harms was not reported.

• This was an industry‐funded trial.

• COI statement included: DHH has acted as a consultant for and received support from Watson Laboratories. MA has been a consultant/advisor to Watson Laboratories and has received consulting fees from Watson that are unrelated to the content or conduct of this study. LRL received research funding from Millennix and Watson (awarded to Hematology Oncology Consultants, Inc.) more than 2 years ago for research activity reported in this manuscript. NVD is employed by Watson Laboratories. ST indicates no potential conflicts of interest.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Study described as “randomized controlled,” but this information is insufficient to permit judgment about the sequence generation process as it lacks details of how randomization sequence was generated

Allocation concealment (selection bias)

Low risk

“randomization was conducted centrally to avoid selection bias”

Blinding (performance bias and detection bias)
All outcomes

High risk

There was no blinding (study described as “open‐label”); outcome measurement was likely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes

High risk

Trial authors reported that “except for number of transfusions and patients receiving transfusions,” analysis of primary and secondary efficacy endpoints was based on “evaluable population,” that is performed per protocol. In addition, the imputation method used, that is “last observed data recorded for each parameter before receiving a transfusion were carried forward through the endpoint,” could potentially bias the results

Selective reporting (reporting bias)

Low risk

Benefits and harms were reported as indicated in a prespecified method

Other bias

Low risk

Prespecified values of sample size, alpha, beta (power), and delta were provided

Methods

• Open‐label, randomized, controlled, multicenter, prospective trial

• Study length: 12 weeks

Participants

• Eligibility: Hb ≤ 11 g/dL; serum ferritin ≥ 100 ng/ml; TSAT between 15% and 35%; ECOG PS: 0 to 2; received no epoetin alfa or IV iron within 30 days and no oral iron within 7 days before enrollment; age ≥ 18 years old; life expectancy ≥ 24 weeks

• Sex (number enrolled): female (89), male (40)

• Experimental arm: ESAs + oral ferrous sulfate: enrolled 61, analyzed 44

• Control arm: ESAs only: enrolled 63, analyzed 44

Interventions

• Experimental arm: ESAs + oral ferrous sulfate 325 mg 3 daily

• Control arm: ESAs only: epoetin alfa 40,000 U SC once weekly

Outcomes

• Hematopoietic response

• RBC transfusions

• Change in Hb levels

• Treatment‐related harms (thromboembolic events are not reported)

Notes

• Hematopoietic response defined as increase in Hb level of ≥ 2 g/dL.

• Patients were excluded for hemolysis, gastrointestinal bleeding, folate or vitamin B12 deficiency, elevated serum ferritin (900 ng/ml) or TSAT (35%), pregnancy or lactation,liver dysfunction (grade 2 based on National Cancer Institute Common Toxicity Criteria), renal dysfunction (serum creatinine 2.0 mg/dl), active infection requiring systemic antibiotics, personal or family history of hemochromatosis, comorbidities precluding study participation, hypersensitivity to sodium ferric gluconate complex or its components, contraindication to epoetin alfa therapy, RBC transfusion within the past 2 weeks, or any investigational agent within 30 days before enrollment.

• For epoetin alfa treatment: if after 4 weeks Hb did not increase by ≥ 1 g/dl, the dose was increased to 60,000 U once weekly. If Hb increased > 1.3 g/dl in any 2‐week period, the dose was reduced by 25%. If Hb increased to > 13 g/dl, epoetin alfa was discontinued until Hb decreased to ≤ 12 g/dl, and was then resumed at 75% of the previous dose.

• Grading for treatment‐related harms was not reported.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Study described as “randomized controlled,” but this information is insufficient to permit judgment about the sequence generation process as it lacks details of how sequence was generated

Allocation concealment (selection bias)

Low risk

“randomization was conducted centrally to avoid selection bias”

Blinding (performance bias and detection bias)
All outcomes

High risk

There was no blinding (study described as “open‐label”), yet outcome measurement was likely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes

High risk

Trial authors reported that “except for number of transfusions and patients receiving transfusions,” analysis of primary and secondary efficacy endpoints was based on “evaluable population,” that is performed per protocol. In addition, the imputation method used, that is “last observed data recorded for each parameter before receiving a transfusion were carried forward through the endpoint,” could potentially bias the results

Selective reporting (reporting bias)

Low risk

Benefits and harms were reported as indicated in a prespecified method

Other bias

Low risk

Prespecified values of sample size, alpha, beta (power), and delta were provided

Methods

• Randomized, open‐label, multicenter study

• Study length: 12 weeks

• Study conducted during: December 2004 to February 2006

Participants

• Eligibility: Hb ≤ 11 g/dL within 24 hours of randomization; participants were required not to harbor absolute or functional iron deficiency (i.e. serum ferritin level ≥ 100 ng/mL and TSAT ≥ 20%); ECOG ≤ 2

• Age: ≥ 18 years; life expectancy ≥ 6 weeks

• Sex (number enrolled): female (104), male (45)

• Experimental arm: ESAs + IV iron: enrolled 73, analyzed 73

• Control arm: ESAs only: enrolled 76, analyzed 76

• Mean baseline serum ferritin range (333 to 350.7 ng/ml); mean baseline TSAT range (27.6% to 30.6%)

Interventions

• Experimental arm: ESAs + IV sodium ferric gluconate 125 mg/wk for the first 6 weeks

• Control arm: ESAs only: SC darbepoetin 150 μg/wk for 12 weeks (dose adjustments were done)

Outcomes

• Hematopoietic response

• RBC transfusions

• Time to hematopoietic response

• Treatment‐related harms (thromboembolic events are reported)

Notes

• Hematopoietic response defined as increase in Hb level of ≥ 2 g/dL or achievement of Hb level of ≥ 12 g/dL in the absence of RBC transfusion within the previous 28 days.

• Number of RBC transfusions given is reported and used for the RBC transfusion outcome meta‐analysis.

• Patients with anemia attributable to factors other than cancer or chemotherapy (i.e. vitamin B12 or folate deficiency, hemolysis, gastrointestinal bleeding, or myelodysplastic syndromes) were not eligible to participate in the study. Patients were excluded if they had iron overload (defined as serum ferritin 800 g/L and TSAT 40%); had received more than 2 RBC transfusions within 4 weeks of random assignment or any RBC transfusions within 14 days of the first dose of DA; had received therapy with ESAs within 4 weeks of random assignment; or were pregnant, breastfeeding, or not using adequate birth control measures. Patients were also excluded if they had a history of seizure disorders, active cardiac disease, thromboembolic disease, uncontrolled hypertension, or active infection.

• If no response was seen after 4 weeks (Hb increase ≤ 1.0 g/dL), the dose of DA was doubled to 300 µg/wk until the end of the study. At any time during the study, DA was withheld if the participant’s Hb increased to more than 13.0 g/dL. Administration of DA was restarted at 150 µg every 2 weeks if the Hb decreased to ≤ 12.0 g/dL.

• This was an industry‐funded trial.

• COI statement included: Certain relationships marked with a 'U' are those for which no compensation was received; those relationships marked with a 'C' were compensated. Employment or leadership position: Enrico Crucitta, Dompé (C); Federica Apolloni, Dompé (C); Antonio Del Santo, Dompé (C). Consultant or advisory role: Paolo Pedrazzoli, Dompé (C); Teresa Gamucci, Dompé (C). Stock ownership: None. Honoraria: Giuseppe Colucci, Dompé; Roberto Labianca, Dompé; Francesco Di Costanzo, Dompé; Salvatore Siena, Dompé. Research funding: None. Expert testimony: None. Other remuneration: None.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Trial authors described the study as “randomized trial,” but this information was insufficient to permit judgment about the sequence generation process

Allocation concealment (selection bias)

Low risk

Randomization was centrally conducted to avoid selection bias

Blinding (performance bias and detection bias)
All outcomes

High risk

There was no blinding (study described as “open‐label”), yet outcome measurement was likely to be influenced by lack of blinding

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Data were analyzed using both ITT and per‐protocol principles

Selective reporting (reporting bias)

Low risk

Benefits and harms were reported as indicated in a prespecified method

Other bias

Low risk

Prespecified values of sample size, alpha, beta (power), and delta were provided

Methods

• Prospective, multicenter, placebo‐controlled, randomized trial

• Random assignment was stratified by participant sex, tumor type (solid tumors versus hematologic malignancies), severity of anemia on the basis of the WHO classification (mild: Hb ≥ 9.5 g/dL; severe: Hb < 9.5 g/dL), and whether or not participants were receiving a platinum‐containing chemotherapy regimen.

• Study length: 15 weeks

• Study conducted during: February 2006 to December 2008

Participants

• Eligibility: Hb ≤ 11 g/dL; ferritin > 20 ng/mL; TSAT < 60%; ECOG PS ≤ 2; and must not have received either ESAs or RBC transfusion within 14 days prior to randomization

• Sex (number enrolled): female (320), male (170)

• Mean age (SD): 63 (11.8) years; median age: 64 years

• Experimental arm: ESAs + IV sodium ferric gluconate: enrolled 167, analyzed 164

• Control arm: ESAs + oral placebo: enrolled 167, analyzed 163

• Mean baseline serum ferritin range (456 to 479.5 μg/ml); mean baseline TSAT range (19.6% to 22.5%)

Interventions

• Experimental arm: ESAs + IV sodium ferric gluconate 187.5 mg Q3W (5 doses)

• Control arm: ESAs + oral placebo: darbepoetin alfa 500 μg SC Q3W

Outcomes

• Hematopoietic response

• RBC transfusions

• Change in Hb level

• QOL

• Treatment‐related harms (thromboembolic events are not reported)

Notes

• This is a 3‐armed study, and the reference Steensma 2011b refers to the same study.

• Eryhthropoietic response defined as Hb increment of ≥ 2 g/dL from baseline or achievement of Hb ≥ 12 g/dL in absence of transfusion during the preceding 28 days.

• The number of RBC transfusions administered are reported and used for the meta‐analysis for the outcome of RBC transfusion.

• Patients with a history of thromboembolism within 1 year of enrollment, genetic hemochromatosis, or recent surgery were excluded, as were patients with anemia caused by a myelodysplastic syndrome, nutritional deficiency, or a non‐neoplastic hematologic disorder such as thalassemia. Patients were also temporarily excluded if they had received an ESA within 3 months or RBC transfusion within 14 days.

• All participants were scheduled to receive darbepoetin alfa (Aranesp, Amgen, Thousand Oaks, CA) 500 µg SC Q3W until Hb reached > 11.0 g/dL and thereafter to receive maintenance darbepoetin 300 µg Q3W. Darbepoetin was to be held for Hb > 13.0 g/dL, until Hb decreased to < 12.0 g/dL, then darbepoetin was restarted with a 25% dose reduction.

• QOL was measured using 4 validated instruments:

  • FACT‐An

  • LASA

  • BFI

  • SDS

• Participants and investigators were blinded in assessment of participants in oral iron or oral placebo but not in IV iron versus oral iron. 

• This was an industry‐funded trial.

• COI statement included: Employment or leadership position: None. Consultant or advisory role: None. Stock ownership: None. Honoraria: None. Research funding: Charles L. Loprinzi, Amgen. Expert testimony: None. Other remuneration: None.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

In the online appendix of the paper, trial authors reported that “patients were randomly assigned at a central randomization center by using the method of Pocock and Simon, which balances the marginal distributions of each stratification factor in each of the treatment arms"

Allocation concealment (selection bias)

Low risk

Trial authors reported (in the online appendix) that “random assignment was done by calling the central randomization center by telephone [which] randomly assigned the patient on the basis of the stratification factors and notified the enrolling/treating institution which bottles to use for treatment. Treatment bottles (oral iron versus oral placebo) were labelled with random numbers assigned by the study statisticians by using blocked randomization…”

Blinding (performance bias and detection bias)
All outcomes

High risk

Patients and investigators were blinded to assignment of oral iron or oral placebo. However, trial authors stated that "for practical reasons, assignment to IV iron versus an oral product was not blinded," which in our opinion could bias study results

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Efficacy data were analyzed using ITT principle

Selective reporting (reporting bias)

Low risk

Benefits and harms were reported as indicated in a prespecified method

Other bias

Low risk

Prespecified values of sample size, alpha, and beta (power) were provided

Methods

• Prospective, multicenter, placebo‐controlled, randomized trial

• Random assignment was stratified by participant sex, tumor type (solid tumors versus hematologic malignancies), severity of anemia on the basis of the WHO classification (mild: Hb ≥ 9.5 g/dL; severe: Hb < 9.5 g/dL), and whether or not participants were receiving a platinum‐containing chemotherapy regimen.

• Study length: 15 weeks

Participants

• Eligibility: Hb ≤ 11 g/dL; ferritin > 20 ng/mL; TSAT < 60%; ECOG PS ≤ 2; and must not have received either ESAs or RBC transfusion within 14 days prior to randomization

• Sex (number enrolled): female (320), male (170)

• Mean age (SD): 63 (11.8) years; median age: 64 years

• Experimental arm: ESAs + oral ferrous sulfate: enrolled 168, analyzed 163

• Control arm: ESAs + oral placebo: enrolled 167, analyzed 163

Interventions

• Experimental arm: ESAs + oral ferrous sulfate 325 mg once daily

• Control arm: ESAs + oral placebo: darbepoetin alfa 500 μg SC Q3W

Outcomes

• Hematopoietic response

• Transfusion requirements

• Total ESA dose used

• QOL

• Treatment‐related harms

Notes

• Eryhthropoietic response defined as Hb increment of ≥ 2 g/dL from baseline or achievement of Hb ≥ 12 g/dL in absence of transfusion during the preceding 28 days.

• Patients with a history of thromboembolism within 1 year of enrollment, genetic hemochromatosis, or recent surgery were excluded, as were patients with anemia caused by a myelodysplastic syndrome, nutritional deficiency, or a non‐neoplastic hematologic disorder such as thalassemia. Patients were also temporarily excluded if they had received an ESA within 3 months or RBC transfusion within 14 days.

• All participants were scheduled to receive darbepoetin alfa (Aranesp, Amgen, Thousand Oaks, CA) 500 µg SC Q3W until Hb reached > 11.0 g/dL and thereafter to receive maintenance darbepoetin 300 µg Q3W. Darbepoetin was to be held for Hb > 13.0 g/dL, until Hb decreased to < 12.0 g/dL, then darbepoetin was restarted with a 25% dose reduction.

• QOL was measured using 4 validated instruments:

  • FACT‐An

  • LASA

  • BFI

  • SDS

• Participants and investigators were blinded in assessment of participants in oral iron or oral placebo but not in IV iron versus oral iron.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

In the online appendix of the paper, trial authors reported that “patients were randomly assigned at a central randomization center by using the method of Pocock and Simon, which balances the marginal distributions of each stratification factor in each of the treatment arms"

Allocation concealment (selection bias)

Low risk

Trial authors reported (in the online appendix) that “random assignment was done by calling the central randomization center by telephone [which] randomly assigned the patient on the basis of the stratification factors and notified the enrolling/treating institution which bottles to use for treatment. Treatment bottles (oral iron versus oral placebo) were labelled with random numbers assigned by the study statisticians by using blocked randomization…”

Blinding (performance bias and detection bias)
All outcomes

High risk

Patients and investigators were blinded to assignment of oral iron or oral placebo. However, trial authors stated that "for practical reasons, assignment to IV iron versus an oral product was not blinded," which in our opinion could bias study results

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Efficacy data were analyzed using ITT principle

Selective reporting (reporting bias)

Low risk

Benefits and harms were reported as indicated in a prespecified method

Other bias

Low risk

Prespecified values of sample size, alpha, and beta (power) were provided