Intravenous iron supplementation for the treatment of chemotherapy-induced anaemia – systematic review and meta-analysis of randomised controlled trials

Figures & data

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

Table I. Characteristics of included studies.

Study	Treatment arms	Number of patients randomised	IV iron type and dosing schedule	ESA type and dosing	Type of Malignancy	Age (y) Mean ± SD
Auerbach 2004	IV iron bolus	37	Bolus: IV iron dextran 100 mg/w, for a total calculated dose according to formula (1100–2400 mg) TDI: IV iron dextran for a total calculated dose according to formula (1000–3000 mg)	Epoetin alpha 40000 units/w for 6 w	Solid 77%: lung 27%, breast 18%, GI 22%, gynaecologic 1%, Lymphoproliferative 19%, NHL 6%, MM 4%, CLL 3%, HD 2%	63 ± 13
	IV iron TDI	41				64 ± 11
	Oral iron	43				66 ± 12
	No iron	36				65 ± 11
Auerbach 2010	IV iron	116	Low molecular weight IV iron dextran, 400 mg/3 w, for 12 w total dose of 2 g	Darbepoetin alpha 500 mcg or 300 mcg/3 w for 12 w	Solid: lung 25%, breast 16%, GI 18%, other 41%	500 mcg DA: 62 ± 13 300 mcg DA: 61 ± 12
	No iron	122			Lung 28%, breast 17%, GI 28%, other 27%	500 mcg DA: 62 ± 13 300 mcg DA: 61 ± 12
Bastit 2008	IV iron	201	Ferric gluconate/iron sucrose 200 mg/3 w on weeks 1, 4, 7, 10, 13 for a total of 1 g	Darbepoetin alpha 500 mcg/ 3 w X5 for 12 w	Non-myeloid: lung 15%, breast 18%, GI 19%, gynaecologic 14%, ovary 8%, NHL 7%	61.7 ± 11.6
	Oral iron/no iron	197			Lung 13%, breast 14%, GI 18%, gynaecologic 15%, ovary 12%, NHL7%	60.3 ± 11.4
Beguin 2008	IV iron, with ESA	50	Iron sucrose 200 mg on day 28, 42, 56, total 600 mg	Darbepoetin alpha 300 mcg/ 3 w from day 28 X7 doses	Autologous stem cell transplant for lymphoid malignancies: MM 63%, NHL 24%, HD 4%	56 ± 9
	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, total 1500 mg	Darbepoetin alpha 100 mcg/w or 200 mcg/2 w or epoetin alpha 40000 units/w, for 8 w. Then randomisation to IV iron or no iron, and 12 w of ESA	NR	NR
	No iron
Dangsuwan 2010	IV iron	22	Iron sucrose 200 mg (one single dose after chemotherapy infusion)	ESA not administered	All patients with ovarian or endometrial cancer receiving platinum based chemotherapy Ovary 86.3%, endometrial 5%, two primaries 9.1%	49.6 ± 8.1
	Oral iron	22			Ovary 86.3%, two primaries 13.6%	53.0 ± 8.7
Hedenus 2007	IV iron	33	Iron sucrose 100 mg/w for 0–6 w, then 100 mg/2 w for 8–14, total 1.1 g	Epoetin beta 30000 units/w for 16 w	All patients with indolent lympho-proliferative disorders not requiring chemotherapy: MM 36%, NHL 33%, CLL 30%	77 ± 8
	No iron	34			MM 38%, NHL 24%, CLL 38%	74 ± 10
Henry 2007	IV iron	63	Ferric gluconate 125 mg/w for 8 w, total of 1000 mg	Epoetin alpha 40000 units/w for 12 w	Non-myeloid: lung 26.8%, breast 34.1%, GI 7.3%, gynaecologic 2.4%, ovary 9.8%, NHL 7.3%	63 ± 13.1
	Oral iron	61			Lung 27.3%, breast 13.6%, GI 13.6%, gynaecologic 9.1%, ovary 9.1%, NHL 6.8%	65.4 ± 11.6
	No iron	63			Lung 22.7%, breast 4.5%, GI 15.9%, gynaecologic 2.3%, ovary 6.8%, NHL 6.8%	67.4 ± 11.1
Kim 2007	IV iron	30	Iron sucrose 200 mg/w for maximum of 6 w, with each chemotherapy cycle	ESA not administered	All patients with cervical cancer treated with concurrent chemo-radiotherapy	55.1(41–77)*
	No iron	45				50.1(38–75)*
Pedrazzoli 2008	IV iron	73	Ferric gluconate 125 mg/w for 6 w total 750 mg	Darbepoetin alpha 150 mcg/w for 12 w	All Solid: lung 17.8%, breast 31.5%, GI 26%, gynaecologic 23.3%	NR
	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 5 doses, total 937.5 mg	Darbepoetin alpha 500 mcg/3 w until Hb> 11, then 300 mcg/3 w	Solid: 96% Haematologic: 4%	64 ± 11.4
	Oral iron	163			Solid: 94% Haematologic: 5%	63 ± 12.4
	No iron	163			Solid: 93% Haematologic: 7%	63 ± 11.3

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)

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

Study	Treatment arms	Hb (g/dl) inclusion criteria	Iron status in clusion criteria	Target Hb level (g/dl)	Baseline Hb (g/dl)	Baseline ferritin (ng/ml)	Baseline TSAT (%)
Auerbach 2004	IV iron bolus	Hb <10.5	Ferritin <450 pmol/l, or ferritin <675 pmol/l and TSAT<19%	Hb >12 or an increase >2	9.7 ± 0.8	207 ± 153	19 ± 17
	IV iron TDI				9.4 ± 1	240 ± 175	14 ± 10
	Oral iron				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 >15%, ferritin >10 ng/ml	Hb >11	9.3 ± 1	322.6 ± 253.7	25.5 ± 17
	No iron				9.4 ± 1	301.8 ± 216.6	27 ± 18.3
Bastit 2008	IV iron	Hb <10	No iron deficiency-ferritin >10 ng/ml, TSAT>15%	Hb >12 or an increase >2	9.94 ± 0.83	279.9 ± 248	28.3 ± 22.2
	Oral iron/no iron				9.96 ± 0.89	278.9 ± 269.7	29.9 ± 23.7
Beguin 2008	IV iron, with ESA	NR	No iron deficiency-ferritin >100 ng/ml	Hb >13	9.9 ± 1	900	NR
	No iron, with ESA				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 NR
	No iron
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 iron in bone marrow	Increase >2	10.3 ± 0.5	128(22–570)*	21 (6–45)*
	No iron				10.3 ± 0.5	130(25–794)*	22 (5–39)*
Henry 2007	IV iron	Hb <11	Ferritin >100 ng/ml; TSAT >15%	Increase >2	10.1 ± 0.9	321.5 ± 209.6	29.4 ± 26.5
	Oral iron				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 >100 ng/ml, TSAT >20%	Hb >12 or an increase >2	9.9 ± 0.78	350.7 ± 258.3	30.6 ± 14.6
	No iron				9.9 ± 0.82	333 ± 232	27.6 ± 11.3
Steensma 2011	IV iron	Hb<11	Ferritin >20 ng/ml TSAT <60%	Hb>12 or an increase >2	9.94 ± 0.705	460.5 ± 526.99	22.5 ± 12.81
	Oral iron				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%.

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.

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

	Relative risk	95% Confidence interval	Number 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

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