Acta Oncologica

ISSN: 0284-186X (Print) 1651-226X (Online) Journal homepage: www.tandfonline.com/journals/ionc20

Intravenous iron supplementation for the

treatment of chemotherapy-induced anaemia
– systematic review and meta-analysis of
randomised controlled trials

Anat Gafter-Gvili, Benaya Rozen-Zvi, Liat Vidal, Leonard Leibovici, Johan

Vansteenkiste, Uzi Gafter & Ofer Shpilberg

To cite this article: Anat Gafter-Gvili, Benaya Rozen-Zvi, Liat Vidal, Leonard Leibovici,
Johan Vansteenkiste, Uzi Gafter & Ofer Shpilberg (2013) Intravenous iron supplementation
for the treatment of chemotherapy-induced anaemia – systematic review and
meta-analysis of randomised controlled trials, Acta Oncologica, 52:1, 18-29, DOI:
10.3109/0284186X.2012.702921

To link to this article: https://doi.org/10.3109/0284186X.2012.702921

Published online: 09 Aug 2012.

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Acta Oncologica, 2013; 52: 18–29

REVIEW ARTICLE

Intravenous iron supplementation for the treatment of

chemotherapy-induced anaemia – systematic review and
meta-analysis of randomised controlled trials

ANAT GAFTER-GVILI1,2,4,∗, BENAYA ROZEN-ZVI3,4,∗, LIAT VIDAL1,4,

LEONARD LEIBOVICI2,4, JOHAN VANSTEENKISTE5, UZI GAFTER3,4 &
OFER SHPILBERG1,4
1Institute
of Hematology, Davidoff Cancer Center, Rabin Medical Center, Beilinson Hospital, Petah-Tiqwa, Israel,
2Department of Medicine E, Rabin Medical Center, Beilinson Hospital, Petah-Tiqwa, Israel, 3Department of Nephrology
and Hypertension, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, Israel, 4Sackler School of Medicine,
Tel-Aviv University, Tel-Aviv, Israel, and 5Respiratory Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium

Abstract
Background: Current guidelines are inconclusive regarding intravenous (IV) iron for treatment of chemotherapy-induced
anaemia (CIA). Material and methods: Systematic review and meta-analysis of randomised controlled trials comparing IV
iron with no iron or oral iron for treatment of chemotherapy induced anaemia (CIA). Primary outcomes: haematopoietic
response and red blood cell (RBC) transfusion requirements. For dichotomous data, relative risks (RR) with 95% confidence
intervals (CIs) were estimated and pooled. For continuous data, weighted mean differences were calculated. Results: Eleven
trials included 1681 patients, the majority examining the addition of IV iron to erythropoiesis stimulating agents (ESA)
(1562 patients, 92.9%). IV iron significantly increased haematopoietic response rate [RR 1.28 (95% CI 1.125–1.45), seven
trials with ESA] and decreased the rate of blood transfusions both in trials with ESA [RR 0.76 (95% CI 0.61–0.95), seven
trials] and without ESA [RR 0.52 (95% CI 0.34–0.80)]. The increase in haematopoietic response rate correlated with total
IV iron dose, regardless of baseline iron status. Mortality and safety profile was comparable between groups. Conclusions:
IV iron added to ESA results in an increase in haematopoietic response and reduction in the need for RBC transfusions,
with no difference in mortality or adverse events.

Anaemia is an almost universal complication in can- [7,8]. However, only 40–70% of patients with cancer
cer patients and an important contributor to morbid- achieve a haematological response with ESA [9].
ity of malignancy [1]. A European prospective survey, One of the most important causes of ESA unre-
found that the prevalence of anaemia in cancer sponsiveness is functional iron deficiency, character-
patients was 39.3% at enrolment, and increased to ised by iron restricted erythropoiesis, meaning, a
67% during the observation period [1]. The pathop- failure to provide iron to the erythroid marrow
hysiology of anaemia in cancer is multifactorial, despite sufficient iron stores [10]. Furthermore,
but in most cases results from anaemia of chronic patients who are not iron deficient may develop iron
disease [2]. Chemotherapy further exacerbates the deficiency on ESA therapy [11]. To avoid it, con-
anaemia due to impaired erythropoiesis [3]. comitant iron treatment was suggested [7–9]. Since
Erythropoiesis stimulating agents (ESAs) have oral iron is poorly absorbed in anaemia of chronic
been shown by several clinical trials to correct che- disease due to increase in inflammatory cytokines
motherapy-induced anaemia (CIA) and reduce the and hepcidin [10], it has not been thoroughly studied
need for transfusions [4,5] and may currently be in clinical trials in the setting of cancer-related anae-
considered for specific settings of cancer patients mia. On the other hand, intravenous (IV) iron may
receiving chemotherapy [6], mainly with palliative have the potential to overcome iron restricted eryth-
intent in order to reduce the need for transfusions ropoiesis in this population [12,13].

∗A. G. and B. R. contributed equally to this work.

Correspondence: A. Gafter-Gvili, Institute of Hematology, Davidoff Cancer Center and Department of Medicine E, Rabin Medical Center, Beilinson Hospital,
Petah-Tikva, Israel 49100. Tel: 972 3 9377906. Fax: 972 3 9376512. E-mail: gn44@bezeqint. net

(Received 3 March 2012 ; accepted 2 June 2012 )

ISSN 0284-186X print/ISSN 1651-226X online © 2013 Informa Healthcare
DOI: 10.3109/0284186X.2012.702921
 Intravenous iron for chemotherapy-induced anaemia 19
Recommendations of the guidelines regarding IV were included whether patients received chemother-
iron supplementation are inconsistent. The 2010 apy or not, and whether patients received ESA or
ASH/ASCO guidelines do not consider the use of IV not. Any IV iron preparation was included. All types
iron as a standard of care [7]. The EORTC guide- of malignancy were included. Trials were included
lines cite improved response to ESA with IV iron regardless of publication status, date of publication
(but not oral) but indicate the need to define optimal and language.
dose and schedule [9], the 2010 ESMO guidelines Two reviewers (AG, BR) screened all references
suggest iron supplementation for iron deficient identified through our search strategy and applied
patients [6], and the NCCN guidelines consider iron inclusion criteria. For possibly relevant articles or in
supplementation, especially IV, for functional iron the event of disagreement between the two reviewers,
deficiency, if ferritin level is less than 800 ng/ml and we obtained and independently inspected the full
transferrin saturation (TSAT) is less than 20% [8]. text article.
Since these guidelines were published, additional
randomised controlled trials assessing the use of
Data extraction and quality assessment
IV iron with ESA for the treatment of CIA were
published, with conflicting results [14,15]. Two reviewers (AG, BR) independently extracted
As there are no clear recommendations and no data from included trials. In the event of disagree-
consistent approach to the use of IV iron in patients ment between the two reviewers, a third reviewer
with cancer in clinical practice, we undertook this (LV) extracted the data and results were attained by
systematic review and meta-analysis. consensus. Authors of trials were contacted for miss-
ing data when necessary. Both reviewers indepen-
Material and methods dently assessed risk of bias in included trials. We
used the Cochrane Collaboration’s tool for assessing
Data sources risk of bias. We individually assessed the following
We conducted a comprehensive search to identify tri- domains: random sequence generation, allocation
als in PubMed (January 1966 to August 2011), the concealment, blinding of participants and personnel,
Cochrane Central Register of Controlled Trials blinding of outcome assessment, incomplete out-
(CENTRAL) (The Cochrane Library, Issue 3 of 4, come data reporting, selective outcome reporting. We
July 2011), and the following conference proceedings separately assessed each domain and graded it as low
for trials in oncology and haematology (2002–August risk for bias, unclear risk (lack of information or
2011): Annual Meeting of the American Society of uncertainty over the potential for bias), or high risk
Hematology (ASH), Annual Meeting of the European for bias according to the criteria specified in the
Haematology Association (EHA), the American Soci- Cochrane Handbook version 5.1.0. [16]
ety of Clinical Oncology (ASCO), the European Soci-
ety for Medical Oncology (ESMO). In addition we Definition of outcomes
searched databases of ongoing and unpublished trials:
http://www.controlled-trials.com, http://www.clinical- The primary outcomes were: rate of patients achiev-
trials.gov/ct and http://clinicaltrials.nci.nih.gov. ing a haematopoietic response, defined as haemo-
We used the following search term: (iron OR globin (Hb) level increase by more than 2 g/dl or an
sodium ferric gluconate OR iron dextran OR iron increase above 12 g/dl, and the rate of patients who
[MeSH] OR Iron-Dextran Complex [MeSH] OR required blood transfusion during the study period.
ferric citrate OR Ferric Compounds [MeSH] OR For analysis of the primary outcome we included
oral∗ iron OR intravenous iron OR iv iron OR iron- only trials of CIA.
gluconate OR ferrlecit OR iron-gluconate OR venofer Secondary outcomes were divided to efficacy
OR iron-sucrose OR ferrous sulphate) AND (cancer outcomes and safety outcomes. Efficacy outcomes
[MeSH] OR chemotherapy or malignancy or tumor) included: absolute ferritin level and transferrin satu-
AND (Anemia or anemia [Mesh]). For PubMed, we ration (TSAT) level at the end of the trial or change
added the Cochrane highly sensitive search term for in these values from baseline if absolutes value were
identification of clinical trials [16]. The references of unavailable, as recommended [16]. We aimed to
all identified studies were inspected for more trials. assess time to haematopoietic response. We also
assessed the number of patients with improvement
in any of the validated quality of life (QOL) scales
Study selection
for cancer: functional assessment of cancer therapy
We included all randomised controlled trials com- (FACT) score, 100 mm linear analogue scale
paring IV iron with either no iron or oral iron for (LASA) score or Symptom Distress Scale (SDS).
the treatment of anaemia in cancer patients. Trials Safety outcomes included: all-cause mortality at the
20 A. Gafter-Gvili et al.
end of follow-up, any adverse event, adverse events Of these, 46 studies were excluded for various
which were considered serious or required interven- reasons (Figure 1). In addition, two abstracts from
tion, cardiovascular events and thromboembolic conference proceedings were included.
events. For analysis of secondary outcomes we Eleven trials conducted between the years 2004
included all trials. and 2011 and randomising 1681 patients fulfilled
inclusion criteria. Table I depicts the characteristics
of included trials, and Table II depicts the baseline
Data synthesis and analysis
iron status parameters.
Our main analysis was IV iron vs. standard care (no Nine trials used ESA and two trials did not, both
iron or oral iron), for patients with CIA. We con- of which were small trials conducted in gynaecologic
ducted separate analyses for trials that administered cancer patients [18,19]. Chemotherapy was admi-
ESA and trials that did not. For all analyses, in trials nistered in all but one trial, which included indolent
in which the standard care group included separate lymphoproliferative disorders [11]. Most trials inclu-
arms of no iron or oral iron (three arm trials), we ded mainly patients with solid tumours.
preferentially compared IV iron with the “no iron” The baseline ferritin level in the trials ranged
arm. We also conducted a separate analysis of IV between 160 and 460 ng/ml (range 1–1000) (Table II).
iron vs. oral iron. Dichotomous data were analysed The intervention was iron sucrose in five trials [11,18–
by calculating the relative risk (RR) for each 21], ferric gluconate in three trials [14,22,23], IV iron
trial with 95% confidence intervals (CI) (Review dextran in two trials [24,25], and one trial assessed
Manager [RevMan], version 4.2 for Windows, both iron sucrose and ferric gluconate [26]. The total
The Cochrane Collaboration, Oxford, UK). For IV iron dose in the trials ranged from 600 to 3000 mg,
continuous variables, we obtained mean and stan- the average dose being approximately 1200 mg. The
dard deviation. We calculated weighted mean differ- IV iron schedule varied between the trials. Iron was
ence (WMD) for continuous variables reported on administered at a dose of either 100–125 mg every
the same scale. WMD represents the weighted com- week, or 100–200 mg every two weeks, or 187.5–400
bination of absolute differences between the mean mg every three weeks (Table I). IV iron was adminis-
values in the two groups in a clinical trial. This sum- tered over a period of six to 16 weeks.
mary statistic has the same unit of measurement as Risk of bias assessment showed that trials were of
the variable measured. Absolute end values rather low risk for bias. Random allocation sequence was
than change from baseline values were analysed low risk of bias in seven of the trials and allocation
preferentially. Where unavailable, we combined end concealment was low risk of bias in eight trials.
values and change from baseline values.
We assessed heterogeneity of trial results by cal-
culating a χ2-test of heterogeneity and the I2 measure Primary outcome
of inconsistency. We used a fixed-effect model with Haematopoietic response. The main analysis of IV iron
the Mantel-Haenszel method for pooling trial results vs. standard care in patients with CIA receiving ESA
throughout the review unless statistically significant demonstrated that IV iron significantly increased
heterogeneity was found (p  0.10 or I2 50%), in the rate of patients achieving a haematopoietic re-
which case we chose a random-effects model and sponse [RR 1.28 (95% CI 1.125–1.45), seven trials,
used the DerSimonian and Laird method [17]. We I2  68.1%, random effects model], (RR 1 favours
explored potential sources of heterogeneity through the IV iron arm, Figure 2).
sub-group analyses of the primary outcome according Sensitivity analysis including the single trial with-
to different baseline parameters. In addition, we con- out chemotherapy showed similar results [RR 1.31
ducted meta-regression, assessing the effect of the (95% CI 1.15–1.49), eight trials, I2  68.4%, ran-
following variables in each study on effect estimates dom effects model]. There were no data regarding
for the primary outcome: baseline ferritin level, base- haematopietic response in trials without ESA.
line TSAT level, baseline Hb level and total iron dose We analysed haematopoietic response in different
administered. Meta-regression was performed on the trial settings (Table III): there was a significant
log risk ratio (Comprehensive Meta Analysis, version increase in the rate of patients with a haematopoietic
2.2; BioStat, Englewood, NJ). The regression slope response in trials of chemotherapy and the one with
with its standard error and significance are reported. no chemotherapy, and in trials of solid tumours.
When analysed according to type of IV iron prep-
aration, the effect estimates for an increase in the rate
Results
of patients with a haematopoietic response for all
The search yielded 1118 potentially relevant trials, of iron preparations were similar, although significant
which 57 were considered for further investigation. only for iron sucrose.
 Intravenous iron for chemotherapy-induced anaemia 21

Potentially relevant trials identified and

screened for retrieval (n=1118)
Excluded due to non-
random design (n=1061)
RCTs retrieved in full text for more
detailed evaluation (n=57)

RCTs Excluded due to (n=46):

IV/IM iron vs. oral iron in pregnant or post-partum women (n=12)

Trials comparing oral iron with no iron in pregnant or post-partum
women (n=3)
IV iron vs. IV iron +ESA in pregnant/post-partum women (n=3)
IV iron vs. oral/no iron in CHF patients (n=3)
IV iron vs. oral in CKD patients (n=4)
IV iron vs. no iron in peritoneal dialysis patients (n=1)
IV iron vs. IV iron +ESA in CKD patients (n=1)
Different doses of IV iron in CKD patients (n=1)
IV iron vs. no iron in IBD patients (n=2)
ESA vs. no ESA in cancer patients (n=4)
ESA vs. no ESA in CHF patients (n=4)
Different doses and schedules of ESA in cancer patients (n=1)
Different doses and schedules of ESA in CKD patients (n=6)
Different doses and schedules of ESA in CHF patients (n=1)
IV iron vs. lactoferrin in cancer patients receiving ESA (n=1)

Abstracts retrieved from

conference proceedings
(n=2)

Ongoing trials (Excluded) (n=2):

IV iron (isomaltoside) vs. oral iron (without ESA) in non-myeloid
cancer patients (NCT01145638)
IV iron (ferric carboxymaltose) vs. no iron (without ESA) in
patients with lymphoproliferative malignancies (NCT01101399)

RCTs included in the meta-analysis

(n=11)

CHF, congestive heart failure; CKD, chronic kidney disease; ESA, erythropoiesis stimulating agents; IBD,
inflammatory bowel disease; IM, intramuscular; IV, intravenous; RCTs, randomised controlled trials
included in the meta-analysis.

Figure 1. Trial flow according to QUOROM (quality of reporting meta-analysis) showing flow of trials included in the meta-analysis.

Meta-regression showed a statistical significant Transfusion requirements. The main analysis of IV iron vs.
correlation between the total IV iron dose and the standard care in patients with chemotherapy induced
log risk ratio for haematopoietic response, with a anaemia receiving ESA demonstrated that IV iron sig-
change in the iron dose of 1 g resulting in a change nificantly decreased the rate of patients who required
of 1.25 (95% CI 1.10–1.42) in the risk ratio for blood transfusions [RR 0.76 (95% CI 0.61–0.95), sev-
haematopoietic response, p  0.00056, Figure 3). en trials]. Similar results were shown in the two trials
However, we did not observe an effect of the baseline without ESA [RR 0.52 (95% CI 0.34–0.80)], Figure 4,
ferritin, TSAT or baseline Hb level on effect esti- (RR 1 favours the IV iron arm).
mates by meta-regression.
We analysed separately the trials of CIA in which
Secondary outcomes
IV iron was compared to no iron [RR 1.21(95% CI
1.12–1.31), six trials, random effects model], and the Ferritin level at the end of the trial was significantly
trials in which IV iron was compared to oral iron [RR increased in the IV iron arm compared with the stan-
1.37 (95% CI 0.92–2.05), three trials, random effects dard care [WMD 360.18 (95% CI 179.64–540.73),
model]. random effects model, six trials], as was TSAT
Table I. Characteristics of included studies.
22

Number of
patients IV iron type Age (y)
Study Treatment arms randomised and dosing schedule ESA type and dosing Type of Malignancy Mean  SD

Auerbach 2004 IV iron bolus 37 Bolus: IV iron dextran 100 mg/w, Epoetin alpha 40000 units/w Solid 77%: lung 27%, breast 18%, 63  13
IV iron TDI 41 for a total calculated dose for 6 w GI 22%, gynaecologic 1%, 64  11
Oral iron 43 according to formula Lymphoproliferative 19%, NHL 66  12
No iron 36 (1100–2400 mg) 6%, MM 4%, CLL 3%, HD 2% 65  11
TDI: IV iron dextran for a total
calculated dose according to
A. Gafter-Gvili et al.

formula (1000–3000 mg)

Auerbach 2010 IV iron 116 Low molecular weight IV iron Darbepoetin alpha Solid: lung 25%, breast 16%, 500 mcg DA:
dextran, 400 mg/3 w, for 12 w 500 mcg or GI 18%, other 41% 62  13
total dose of 2 g 300 mcg/3 w 300 mcg DA:
for 12 w 61  12
No iron 122 Lung 28%, breast 17%, GI 28%, 500 mcg DA:
other 27% 62  13
300 mcg DA:
61  12
Bastit 2008 IV iron 201 Ferric gluconate/iron sucrose Darbepoetin alpha 500 mcg/ Non-myeloid: lung 15%, breast 18%, 61.7  11.6
200 mg/3 w on weeks 1, 4, 7, 3 w X5 for 12 w GI 19%, gynaecologic 14%, ovary
10, 13 for a total of 1 g 8%, NHL 7%
Oral iron/no iron 197 Lung 13%, breast 14%, GI 18%, 60.3  11.4
gynaecologic 15%, ovary 12%,
NHL7%
Beguin 2008 IV iron, with ESA 50 Iron sucrose Darbepoetin alpha 300 mcg/ Autologous stem cell transplant for 56  9
200 mg on day 28, 42, 56, 3 w from day 28 X7 doses lymphoid malignancies:
total 600 mg MM 63%, NHL 24%, HD 4%
No iron, with ESA 52 MM 62%, NHL 31%, HD 6%, 56  10
No iron, no ESA 25 MM 44%, NHL 40%, HD 12% 53  9
Bellet 2007 IV iron Total 375 Iron sucrose 500 mg, 3 doses, Darbepoetin alpha 100 NR NR
total 1500 mg mcg/w or 200 mcg/2 w
or epoetin alpha 40000
units/w, for 8 w.
No iron Then randomisation to IV
iron or no iron, and 12 w
of ESA
Dangsuwan 2010 IV iron 22 Iron sucrose ESA not administered All patients with ovarian or 49.6  8.1
200 mg endometrial cancer receiving
(one single dose after platinum based chemotherapy
chemotherapy infusion) Ovary 86.3%, endometrial 5%, two
primaries 9.1%
Oral iron 22 Ovary 86.3%, two primaries 13.6% 53.0  8.7

(Continued )
Table I. (Continued ).

Number of
patients IV iron type Age (y)
Study Treatment arms randomised and dosing schedule ESA type and dosing Type of Malignancy Mean  SD

Hedenus 2007 IV iron 33 Iron sucrose Epoetin beta 30000 units/w All patients with indolent 77  8
100 mg/w for 0–6 w, then for 16 w lympho-proliferative disorders
100 mg/2 w for 8–14, not requiring chemotherapy:
total 1.1 g MM 36%, NHL 33%, CLL 30%
No iron 34 MM 38%, NHL 24%, CLL 38% 74  10
Henry 2007 IV iron 63 Ferric gluconate 125 mg/w for 8 w, Epoetin alpha 40000 units/w Non-myeloid: lung 26.8%, breast 63  13.1
total of 1000 mg for 12 w 34.1%, GI 7.3%, gynaecologic
2.4%, ovary 9.8%, NHL 7.3%
Oral iron 61 Lung 27.3%, breast 13.6%, 65.4  11.6
GI 13.6%, gynaecologic 9.1%,
ovary 9.1%, NHL 6.8%
No iron 63 Lung 22.7%, breast 4.5%, GI 15.9%, 67.4  11.1
gynaecologic 2.3%, ovary 6.8%,
NHL 6.8%
Kim 2007 IV iron 30 Iron sucrose 200 mg/w for ESA not administered All patients with cervical cancer 55.1(41–77)∗
No iron 45 maximum of 6 w, with each treated with concurrent chemo- 50.1(38–75)∗
chemotherapy cycle radiotherapy
Pedrazzoli 2008 IV iron 73 Ferric gluconate 125 mg/w for 6 w Darbepoetin alpha All Solid: NR
total 750 mg 150 mcg/w for 12 w lung 17.8%, breast 31.5%, GI 26%,
gynaecologic 23.3%
No iron 76 Lung 23.7%, breast 34.2%, GI
23.7%, gynaecologic 18.4%
Steensma 2010 IV iron 164 Ferric gluconate 187.5 mg/3 w for Darbepoetin alpha Solid: 96% 64  11.4
5 doses, total 937.5 mg 500 mcg/3 w until Haematologic: 4%
Oral iron 163 Hb 11, then 300 mcg/3 w Solid: 94% 63  12.4
Haematologic: 5%
No iron 163 Solid: 93% 63  11.3
Haematologic: 7%

CLL, chronic lymphocytic leukemia; DA, darbepoetin alpha; ESA, erythropoiesis-stimulating agent; GI, gastrointestinal; Hb, haemoglobin; HD, Hodgkin’s disease; IV, intravenous; MM, multiple
myeloma; N, no; NHL, non-Hodgkin’s lymphoma; NR, not reported; SD, standard deviation; TDI, total dose infusion; w, week; Y, yes.
∗Median (range)
Intravenous iron for chemotherapy-induced anaemia
23
 24

Table II. Baseline haematologic and iron status of included studies.

Hb (g/dl)
inclusion Iron status in Target Hb Baseline Baseline Baseline
Study Treatment arms criteria clusion criteria level (g/dl) Hb (g/dl) ferritin (ng/ml) TSAT (%)
A. Gafter-Gvili et al.

Auerbach 2004 IV iron bolus Hb 10.5 Ferritin 450 pmol/l, or Hb 12 or 9.7  0.8 207  153 19  17
IV iron TDI ferritin 675 pmol/l an increase 2 9.4  1 240  175 14  10
Oral iron and TSAT19% 9.7  0.7 294  238 15  8
No iron 9.5  0.9 290  160 18  14
Auerbach 2010 IV iron Hb 10 No iron deficiency TSAT Hb 11 9.3  1 322.6  253.7 25.5  17
No iron 15%, ferritin 10 ng/ml 9.4  1 301.8  216.6 27  18.3
Bastit 2008 IV iron Hb 10 No iron deficiency-ferritin Hb 12 or 9.94  0.83 279.9  248 28.3  22.2
Oral iron/no iron 10 ng/ml, TSAT15% an increase 2 9.96  0.89 278.9  269.7 29.9  23.7
Beguin 2008 IV iron, with ESA NR No iron deficiency-ferritin Hb 13 9.9  1 900 NR
No iron, with ESA 100 ng/ml 10.3  1.2 800 NR
No iron, no ESA 10.4  1.1 900 NR
Bellet 2007 IV iron Hb 10 NR NR NR NR NR
No iron NR
Dangsuwan 2010 IV iron Hb 10 NR NR 8.9  0.6 NR NR
Oral iron 9  0.6
Hedenus 2007 IV iron Hb 9–11 No iron deficiency-stainable Increase 2 10.3  0.5 128(22–570)∗ 21 (6–45)∗
No iron iron in bone marrow 10.3  0.5 130(25–794)∗ 22 (5–39)∗
Henry 2007 IV iron Hb 11 Ferritin 100 ng/ml; Increase 2 10.1  0.9 321.5  209.6 29.4  26.5
Oral iron TSAT 15% 10.3  0.7 373.9  270.1 29.1  21
No iron 10.5  0.8 388.2  266.1 36.3  26.6
Kim 2007 IV iron Hb 12∗∗ NR Hb 12 11.27  1.94 NR NR
No iron 11.33  2.14
Pedrazzoli 2008 IV iron Hb 11 No iron deficiency-ferritin Hb 12 or an 9.9  0.78 350.7  258.3 30.6  14.6
No iron 100 ng/ml, TSAT 20% increase 2 9.9  0.82 333  232 27.6  11.3
Steensma 2011 IV iron Hb11 Ferritin 20 ng/ml TSAT 60% Hb12 or an 9.94  0.705 460.5  526.99 22.5  12.81
Oral iron increase 2 9.91  0.656 479.5  484.15 19.6  11.7
No iron 9.97  0.721 456  479.27 22.2  13.36

Note: All values are mean and standard deviation unless stated otherwise.
ESA, erythropoiesis-stimulating agent; Hb, hemoglobin; IV, intravenous; NR, not reported; TSAT, transferrin saturation.
∗Median (range).
∗∗Baseline anaemia was not an inclusion criteria in this trial, but iron was administered only if Hb 12 g%.
 Intravenous iron for chemotherapy-induced anaemia 25

Figure 2. Intravenous iron vs. standard of care: Rate of patients who achieved a haematopoietic response. Black squares represent the point
estimate, their sizes represent their weight in the pooled analysis, and the horizontal bars represent the 95% CI. The black diamond at the
bottom represents the pooled point estimate. CI, confidence interval; IV, intravenous; RR, relative risk; STD, standard.

[WMD 6.61 (95% CI 1.57, 11.65), random effects There was no difference in the rate of any adverse
model, five trials]. event [RR 0.99 (95% CI 0.93, 1.04), four trials], adverse
Five trials reported time to haematopoietic events that required discontinuation of iron [RR 1.01
response. Four trials reported time to response in (95% CI 0.59, 1.70), four trials], or serious adverse
medians [11,23,25,26] and one reported in means events requiring intervention [RR 1.06 (95% CI 0.89,
[24]. The median time to response for the standard 1.27), seven trials]. In addition, there was no difference
care group ranged between 46 and 94 days and the in the occurrence of thromboembolic events [RR 1.03
median time to response in the IV iron group ranged (95% CI 0.59, 1.80), four trials] or of cardiovascular
between 36 and 54 days. events [RR 1.08 (95% CI 0.65, 1.78), six trials].
Six trials reported QOL outcomes. For the pooled
analysis of QOL we included trials which reported
the number of patients with an improvement in
Discussion
FACT-Fatigue scale (a clinically significant increase
was usually regarded as a  3 point increase [22,25,26] Our systematic review compiles all trials assessing IV
and trials that reported improvement in the SDS- iron treatment for patients with anaemia and cancer.
Fatigue scale [14]. There was a significant increase The vast majority of data comes from trials where
in the number of patients with improvement in QOL IV iron was added to ESA therapy for chemothera-
scales for cancer in the IV iron arm [RR 1.25 (95% py-induced anaemia. We demonstrated that treat-
CI 1.05, 1.49), four trials, I2  71%, random effects ment with IV iron for CIA was associated with a
model]. statistically significant increase of 28% in the rate of
haematopoietic response, and a statistically signifi-
cant decrease of 26% in the number of patients who
Safety
require blood transfusions. In addition, there was a
There was no difference in all-cause mortality at the statistically significant increase in iron metabolism
end of follow-up between the IV iron arm and the parameters (ferritin, TSAT) and in QOL scores.
standard care arm [RR 1.13 (95% CI 0.75, 1.70), Our main finding that IV iron improves anaemia
seven trials, 1470 patients]. is of great importance. Anaemia at presentation was

Table III. Subgroup analyses of primary outcome, haematopoietic response (IV iron vs. standard
of care).

Relative 95% Confidence Number

risk interval of trials

Analysis according to chemotherapy

Trials with chemotherapy 1.28 1.12–1.45 7
Trials without chemotherapy 1.66 1.18–2.34 1
Analysis according to type of malignancy
Solid tumours 1.30 1.12–1.50 6
Lymphoproliferative malignancies 1.34 0.90–2.00 2
Analysis according to type of IV iron preparation
Iron sucrose 1.22 1.06–1.41 3
Ferric gluconate 1.19 1.00–1.41 3
Iron dextran 1.67 0.95–2.95 2
26 A. Gafter-Gvili et al.

Figure 3. Meta-regression of total IV iron dose on log risk ratio for haematopoietic response.

previously found to be a negative prognostic factor iron dose and haematopoietic response, suggesting
in various malignancies, both solid and haemato- better response with a higher dose. This is also in
logical [27]. The increase in haematopoietic response accordance with the results of the Steensma et al.
may be associated with better long-term overall trial [14,15], which is the largest trial included in the
survival. However, it could not be assessed due to meta-analysis and the only trial that showed negative
the short follow-up period of 15 to 18 weeks. results. The planned iron dose was quite low (937.5
The second finding of a 24% reduction in trans- mg) and the actual administered dose was even lower
fusion requirements is clinically important. Blood (650 mg) [29].
transfusions are associated with various risks as acute Trials differed in inclusion criteria regarding
reaction, transfusion related acute lung injury, baseline iron parameters. Most trials excluded
volume overload, and infections [4,13,28]. There- patients with iron deficiency. Of the nine trials that
fore, reduction in transfusion requirement may reported baseline iron status, only two trials allowed
minimise these risks. inclusion of true iron deficient patients [24,26], but
The increase in haematopoietic response with IV their actual number in these trials was low. Despite
iron was consistent in almost all settings, and was the differences in baseline iron status, meta-regres-
independent of baseline iron status. Moreover, meta- sion demonstrated no association between baseline
regression revealed a direct correlation between IV ferritin and TSAT and haematopoietic response.

Figure 4. Intravenous iron vs. standard of care: Rate of patients who required blood transfusions. Black squares represent the point estimate,
their sizes represent their weight in the pooled analysis, and the horizontal bars represent the 95% CI. The black diamond at the bottom
represents the pooled point estimate. CI, confidence interval; IV, intravenous; RR, relative risk; STD, standard.
 Intravenous iron for chemotherapy-induced anaemia 27
Of all the different iron preparations the [36]. For the individual patient, the improved feeling
improved haematopoietic response was statistically of well being may be more important than the mere
significant for iron sucrose only. However, the effect increase in Hb level.
estimates were quite similar, suggesting a class effect Iron supplementation has been shown to allow
for IV iron. reduction of ESA dosage in the setting of chronic
The reduction in blood transfusions was evi- kidney disease [37]. However, this outcome was not
dent irrespective of the use of ESA. Although the reported in most trials. The single trial which assessed
two trials without ESA included only 119 patients, this issue, indeed found a decrease in the total ESA
a significant reduction of 48% in blood transfu- dose in the IV iron arm [11] suggesting a potential
sions was observed. Nowadays there is controversy benefit of IV iron.
regarding the use of ESA in cancer patients. ESA Our review demonstrates no increase in adverse
treatment in patients with CIA demonstrated clear events in the IV iron arm compared to standard care,
benefits in haematopoietic response and reduction and no difference in mortality. This is consistent with
in transfusions [5]. Recently, FDA alerted physi- a recent meta-analysis of IV iron for patients with
cians to an association of shortened survival with chronic renal failure [37]. However, this should be
ESA treatment. This was based on several ran- interpreted with caution due to a small sample size
domised controlled trials, two of which adminis- and a short follow-up.
tered ESA to patients with anaemia and cancer, not Of note, our review showed no difference in the
receiving chemotherapy [30,31]. The largest indi- rate of thromboembolic events between the IV iron
vidual patient data meta-analysis [32] demon- arm and the standard care arm. This is in concert
strated an increase in mortality with ESAs in all with a recent post hoc analysis of the Henry et al.
patients (including both CIA and cancer without trial [38] that showed that patients treated with IV
treatment) and a study level meta-analysis demon- iron were less likely to develop an elevated platelet
strated both increase in mortality and venous count and even had a decrease in thromboembolic
thromboembolic events [33]. However, another events. The authors suggest that ESA-induced
pooled analysis of individual patient level data from thromboemboli may be related to thrombocytosis
randomised trials of darbepoetin alfa for treatment due to iron-restricted erythropoiesis, and the IV
of patients with CIA showed no increase in mortal- iron possibly has a platelet lowering effect.
ity or disease progression, and an expected increase
in the risk for venous thromboemboli [34]. In this
Limitations
analysis the increase in adverse outcomes was seen
in both treatment arms (ESA or not) only in Several limitations of our analysis merit consider-
patients who required transfusions. While Euro- ation. The included studies were heterogeneous
pean guidelines still consider ESA use with caution regarding the type of patients, different types of
in patients receiving chemotherapy [6,9], current malignancies and different chemotherapy regimens,
American guidelines do not recommend ESA use different iron preparations, schedule, and total
when chemotherapy with curative intent is admin- dose of IV iron administered, different control
istered [7,8] and consider it mainly for chemother- groups (oral iron or no iron), and different types
apy with a palliative intent. Due to this unresolved of ESA and schedule. Moreover, the trials applied
issue, the pure platform to assess IV iron is in tri- different inclusion criteria regarding baseline hae-
als of chemotherapy-induced anaemia in which matologic and iron status parameters, and did not
ESA is not administered, as in the two trials in our report results separately for absolute iron deficient
meta-analysis [18,19]. Due to the ESA controversy, patients, functional iron deficient patients, and
especially regarding administration without che- iron-replete patients. Therefore, we were unable to
motherapy, we decided to exclude the single trial conduct subgroup analyses according to baseline
in which chemotherapy was not given from the iron status.
primary analysis. Our primary outcome was transfusion require-
Of note, recently another meta-analysis assessing ments, but transfusion use was not standardised in
iron supplementation for cancer patients was pub- the trials included in our systematic review.
lished. As in our meta-analysis, an increase in hae- Our main analysis was the comparison of IV iron
matopoietic response and a reduction in transfusion with standard care. In most trials the comparator
rate was shown with IV iron. However, IV iron was was no iron, but in three trials [14,22,24] it was oral
assessed only as an adjunct to ESA [35]. iron. The separate analysis for these three trials of
Our study shows improvement in quality of life IV iron vs. oral iron showed a similar effect estimate,
(QOL) scores. QOL is an important outcome in although not reaching statistical significance. Due to
clinical trials, and especially in trials of cancer patients the small number of trials, our meta-analysis does
28 A. Gafter-Gvili et al.
not enable to draw conclusions regarding the effi- References
cacy of oral iron. [1] Ludwig H, Van Belle S, Barrett-Lee P, Birgegard G,
Another limitation regarding methodology is that Bokemeyer C, Gascon P, et al. The European Cancer Anaemia
none of the trials were blinded, leaving them open to Survey (ECAS): A large, multinational, prospective survey
observer bias. defining the prevalence, incidence, and treatment of anaemia
Finally, the definition of the primary outcome in cancer patients. Eur J Cancer 2004;40:2293–306.
[2] Weiss G, Goodnough LT . Anemia of chronic disease. N Engl
(haematopoietic response) was an increase of Hb to J Med 2005;352:1011–23.
greater than 12 g/dl. However, this goal is less rele- [3] Bohlius J, Weingart O, Trelle S, Engert A. Cancer-related
vant given current recommendation of guidelines to anemia and recombinant human erythropoietin – an updated
initiate ESA only when Hb concentration has overview. Nat Clin Pract Oncol 2006;3:152–64.
decreased to less than 10 g/dl in order to decrease [4] Wauters I, Vansteenkiste J. Erythropoiesis-stimulating agents
in cancer patients: Reflections on safety. Expert Rev Clin
transfusions [7]. Pharmacol 2011;4:467–76.
[5] Bohlius J, Langensiepen S, Schwarzer G, Seidenfeld J, Piper
M, Bennett C, et al. Recombinant human erythropoietin and
Implications for practice overall survival in cancer patients: Results of a comprehen-
sive meta-analysis. J Natl Cancer Inst 2005;97:489–98.
Our systematic review and meta-analysis supports
[6] Schrijvers D, De Samblanx H, Roila F. Erythropoiesis-
the use of supplemental IV iron for treatment of stimulating agents in the treatment of anaemia in cancer
CIA in patients with solid tumours, and concomi- patients: ESMO Clinical Practice Guidelines for use. Ann
tantly treated with ESA. Although based on only Oncol 2010;21(Suppl 5):v244–7.
two small trials, IV iron also reduced transfusions [7] Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy MO,
Spivak JL, et al. American Society of Clinical Oncology/
in cancer patients receiving chemotherapy without
American Society of Hematology clinical practice guideline
ESA. The results mainly apply to patients without update on the use of epoetin and darbepoetin in adult
iron deficiency, since these were the majority of patients with cancer. J Clin Oncol 2010;28:4996–5010.
patients in the trials. Although optimal dosage is [8] NCCN. Clinical Practice Guidelines in Oncology: Cancer-
not clear yet, it appears that higher doses led to and chemotherapy-induced anemia, version 2. 2011.
a greater haematopoietic response, without an Available at: http://www. nccn. org/professionals/physician_
gls/PDF/anemia. pdf 2011 (accessed 2012 February 1)
increase in adverse events. Thus, it may be reason- [9] Bokemeyer C, Aapro MS, Courdi A, Foubert J, Link H,
able to use the higher dose range reported in the Osterborg A, et al. EORTC guidelines for the use of eryth-
trials, at the range of 1 to 1.5 g total, given over six ropoietic proteins in anaemic patients with cancer: 2006
to 16 weeks. update. Eur J Cancer 2007;43:258–70.
[10] Goodnough LT . Erythropoietin and iron-restricted erythro-
poiesis. Exp Hematol 2007;35:167–72.
Implications for research [11] Hedenus M, Birgegard G, Nasman P, Ahlberg L, Karlsson
T, Lauri B, et al. Addition of intravenous iron to epoetin beta
The main question is whether IV iron alone improves increases hemoglobin response and decreases epoetin dose
clinical endpoints and needs further study. Thus, it requirement in anemic patients with lymphoproliferative
malignancies: A randomized multicenter study. Leukemia
may be worthwhile to conduct more randomised
2007;21:627–32.
controlled trials of IV iron vs. no iron without ESA. [12] Hedenus M, Birgegard G. The role of iron supplementation
Currently two randomised controlled trials assess- during epoietin treatment for cancer-related anemia. Med
ing IV iron without ESA are recruiting patients Oncol 2009;26:105–15.
[39,40]. [13] Henry DH. Parenteral iron therapy in cancer-associated
anemia. Hematology Am Soc Hematol Educ Program 2010;
Open questions still exist regarding the
2010:351–6.
optimal formulation, doses, schedule and duration [14] Steensma DP, Sloan JA, Dakhil SR, Dalton R, Kahanic SP,
of IV iron. These should be compared in future Prager DJ, et al. Phase III, randomized study of the effects
trials. of parenteral iron, oral iron, or no iron supplementation on
the erythropoietic response to darbepoetin alfa for patients
with chemotherapy-associated anemia. J Clin Oncol 2010;
Acknowledgements 29:97–105.
[15] Steensma DP, Sasu BJ, Sloan JA, Tomita D, Loprinzi CL,
We thank Dr. David Henry, Dr. Michael Hedenus, et al. The relationship between serum hepcidin levels and
Dr. Yves Beguin, and Dr. David Steensma who clinical outcomes in patients with chemotherapy-associated
responded to our letters and supplied additional data anemia treated in a controlled trial. J Clin Oncol 2011 ASCO
Annual meeting proceedings 2011;29(15 Suppl):9031.
regarding their trials.
[16] Higgins JPT, Green S, editors. Cochrane handbook for sys-
tematic reviews of interventions: version 5.1.0. The Cochrane
Collaboration, 2011. Available from http://www. cochrane-
Declaration of interest: The authors report no handbook. org (accessed 2011 December 1)
conflicts of interest. The authors alone are respon- [17] DerSimonian R, Laird N. Meta-analysis in clinical trials.
sible for the content and writing of the paper. Control Clin Trials 1986;7:177–88.
 Intravenous iron for chemotherapy-induced anaemia 29
[18] Dangsuwan P, Manchana T. Blood transfusion reduction negative iron trial? J Clin Oncol 2011;29:e525–6; author
with intravenous iron in gynecologic cancer patients receiv- reply e527–8.
ing chemotherapy. Gynecol Oncol 2010;116:522–5. [30] Smith RE, Jr., Aapro MS, Ludwig H, Pinter T, Smakal M,
[19] Kim YT, Kim SW, Yoon BS, Cho HJ, Nahm EJ, Kim SH, Ciuleanu TE, et al. Darbepoetin alpha for the treatment of
et al. Effect of intravenously administered iron sucrose on anemia in patients with active cancer not receiving chemo-
the prevention of anemia in the cervical cancer patients therapy or radiotherapy: Results of a phase III, multicenter,
treated with concurrent chemoradiotherapy. Gynecol Oncol randomized, double-blind, placebo-controlled study. J Clin
2007;105:199–204. Oncol 2008;26:1040–50.
[20] Beguin Y, Maertens J, De Prijck B, Schots R, Frere P, Bonnet [31] Wright JR, Ung YC, Julian JA, Pritchard KI, Whelan TJ,
C, et al. Darbepoetin-alfa and i. v. iron administration after Smith C, et al. Randomized, double-blind, placebo-
autologous hematopoietic stem cell transplantation: A pro- controlled trial of erythropoietin in non-small-cell lung
spective randomized multicenter trial. Blood (ASH Annual cancer with disease-related anemia. J Clin Oncol 2007;25:
Meeting Abstracts) 2008;112. Abstract 54. 1027–32.
[21] Bellet RE, Ghazal H, Flam M, Drelichman A, Gabrail N, [32] Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S,
Woytowitz D, et al. A phase III randomized controlled study Seidenfeld J, et al. Recombinant human erythropoiesis-
comparing iron sucrose intravenously (IV) to no iron treat- stimulating agents and mortality in patients with cancer: A
ment of anemia in cancer patients undergoing chemotherapy meta-analysis of randomised trials. Lancet 2009;373:
and erythropoietin stimulating agent (ESA) therapy. J Clin 1532–42.
Oncol 2007 ASCO Annual Meeting Proceedings 2007;25: [33] Bennett CL, Silver SM, Djulbegovic B, Samaras AT, Blau
9109. CA, Gleason KJ, et al. Venous thromboembolism and mortal-
[22] Henry DH, Dahl NV, Auerbach M, Tchekmedyian S, ity associated with recombinant erythropoietin and darbepo-
Laufman LR. Intravenous ferric gluconate significantly etin administration for the treatment of cancer-associated
improves response to epoetin alfa versus oral iron or no iron anemia. JAMA 2008;299:914–24.
in anemic patients with cancer receiving chemotherapy. [34] Ludwig H, Crawford J, Osterborg A, Vansteenkiste J, Henry
Oncologist 2007;12:231–42. DH, Fleishman A, et al. Pooled analysis of individual patient-
[23] Pedrazzoli P, Farris A, Del Prete S, Del Gaizo F, Ferrari D, level data from all randomized, double-blind, placebo-
Bianchessi C, et al. Randomized trial of intravenous iron sup- controlled trials of darbepoetin alfa in the treatment of
plementation in patients with chemotherapy-related anemia patients with chemotherapy-induced anemia. J Clin Oncol
without iron deficiency treated with darbepoetin alpha. J Clin 2009;27:2838–47.
Oncol 2008;26:1619–25. [35] Petrelli F, Borgonovo K, Cabiddu M, Lonati V, Barni S.
[24] Auerbach M, Ballard H, Trout JR, McIlwain M, Ackerman Addition of iron to erythropoiesis-stimulating agents in can-
A, Bahrain H, et al. Intravenous iron optimizes the response cer patients: A meta-analysis of randomized trials. J Cancer
to recombinant human erythropoietin in cancer patients with Res Clin Oncol 2012;138:179–87.
chemotherapy-related anemia: A multicenter, open-label, [36] Husain A, Myers J, Selby D, Thomson B, Chow E . Sub-
randomized trial. J Clin Oncol 2004;22:1301–7. groups of advanced cancer patients clustered by their symp-
[25] Auerbach M, Silberstein PT, Webb RT, Averyanova S, tom profiles: Quality-of-life outcomes. J Palliat Med 2011;
Ciuleanu TE, Shao J, et al. Darbepoetin alfa 300 or 500 mcg 14:1246–53.
once every 3 weeks with or without intravenous iron in [37] Rozen-Zvi B, Gafter-Gvili A, Paul M, Leibovici L, Shpilberg
patients with chemotherapy-induced anemia. Am J Hematol O, Gafter U. Intravenous versus oral iron supplementation
2010;85:655–63. for the treatment of anemia in CKD: Systematic review and
[26] Bastit L, Vandebroek A, Altintas S, Gaede B, Pinter T, meta-analysis. Am J Kidney Dis 2008;52:897–906.
Suto TS, et al. Randomized, multicenter, controlled trial [38] Henry DH, Dahl NV, Auerbach MA . Thrombocytosis and
comparing the efficacy and safety of darbepoetin alpha venous thromboembolism in cancer patients with chemo-
administered every 3 weeks with or without intravenous iron therapy induced anemia may be related to ESA induced iron
in patients with chemotherapy-induced anemia. J Clin Oncol restricted erythropoiesis and reversed by administration of
2008;26:1611–8. IV iron. Am J Hematol 2012;87:308–10.
[27] Clarke H, Pallister CJ. The impact of anaemia on outcome [39] The Clinical Trials. gov website, a service of the U.S National
in cancer. Clin Lab Haematol 2005;27:1–13. institutes of Health. Available from: http://clinicaltrials.gov/
[28] Goodnough LT. Risks of blood transfusion. Anesthesiol Clin ct2/show/NCT01101399 (accessed 2012 January 17)
Nth Am 2005;23:241–52. [40] The Clinical Trials.gov website, a service of the U.S National
[29] Aapro M, Beguin Y, Birgegard G, Gascon P, Hedenus M, institutes of Health. Available from: http://clinicaltrials.gov/
Osterborg A . Too-low iron doses and too many dropouts in ct2/show/NCT01145638 (accessed 2012 January 17)