Perioperative anemia management in colorectal cancer patients: A pragmatic approach

Table 1 Main laboratory tests for the assessment of iron depletion

Laboratory test	Normal values
	Conventional units	Conversion factor2	SI units
Iron status in the body
Serum iron	50-180 g/dL	× 0.179	9-32 mol/L
Transferrin	200-360 mg/dL	× 0.01	2-3.6 g/L
Transferrin saturation	20%-50%
Ft	30-300 ng/mL	× 2.247	65-670 pmol/L
sTfR1	0.76-1.76 mg/L		6.4-25.7 nmol/L
sTfR/log Ft	< 1
Iron deficient red cell production
Hb	12-16 g/dL ♀	× 0.62063	7.5-10 mmol/L
	13-17 g/dL ♂		8-10.5 mmol/L
Mean corpuscular volume	80-100 fL
Red cell distribution width	11-15
Mean corpuscular Hb	28-35 pg
Hypochromic red cells	< 5%
Reticulocyte Hb content	28-35 pg

¹Normal values may differ depending on the assay used;

²To convert the concentrations values in conventional unit into SI units multiply figures by the conversion factor;

³In fact, although widely used, this factor allows for the calculation the molar concentration of hemoglobin subunits. Thus, the molar concentration of hemoglobin (Mw 64 kDa) is 4-fold times lower (2-3 mmol/L). Ft: Ferritin; sTfR: Soluble transferrin receptors; Hb: Hemoglobin; sTfR/log Ft: Ratio of sTfR to serum Ft.

Table 2 Characteristics of the clinical studies examining the role of preoperative iron replacement in colorectal cancer included in this review

Study	Study design	Patients	Baseline Hb (g/dL)	Iron compound dose (mg)	Duration (wk)	Hb (g/dL)	ABT (% or U/pt)
Oral iron
Okuyama et al[46]	OBS	Iron: 32	8.1 ± 1.4	Ferrous citrate	≥ 2	2.0	9.4%
		No iron: 84	8.0 ± 1.6	(200 mg/d)		0.9	27.4%
Lidder et al[47]	RCT	Iron: 23	13.4 ± 1.9	FS	2-8	-0.3	26.0%
		No iron: 22	12.4 ± 2.1	(200 mg TDS)		-0.6	59.0%
Quinn et al[48]	OBS	Iron: 103	12 (10-14)	FS	1-9		0.69 U/pt
		No iron: 167	NS	(200 mg TDS)			1.69 U/pt
Ferrari et al[49]	RCT	FB: 12	11.6 ± 1.6	FB	8	1 (2) mo	NS
				(28-14 mg/d)		0.8 (1.4)
		FS: 12	11.3 ± 1.2	FS		0.7 (1.4)
				(105 mg/d)
Intravenous iron
Edwards et al[57]	RCT	Iron: 34	13.7 ± 0.5	IS	2	-0.2	14.7%
		Placebo: 26	13.4 ± 0.4	(2 × 300 mg)		-0.5	19.2%
Bisbe et al[64]	OBS	IS: 30	10.1 ± 1.2	IS	2-6	0.9	7.0%
				(100-200 mg, 6 ± 3 doses)
		FCM: 15	9.2 ± 1.0	FCM		2.5	40.0%
				(500-1000 mg, 3 ± 1 doses)
Todman et al[68]	Case series	Iron: 22	< 12	Iron isomaltoside-1000	2-6	0.7, 1-2 w	NS
				(20 mg/kg bw)		1.4, 3-4 w
						3.1, 6-8 w

RCT: Randomized controlled trial; OBS: Observational cohort study; Hb: Increment from baseline; ABT: Allogeneic blood transfusion; FB: Ferrous bisglicinate; FS: Ferrous sulphate; IS: Iron sucrose; FCM: Ferric carboxymaltose.

Table 3 Some characteristics of the different intravenous iron formulations

	Iron gluconate	Iron sucrose	High molecular weight iron dextran	Low molecular weight iron dextran	Ferric carboxymaltose	Iron isomaltoside 1000	Ferumoxytol
Brand name	Ferrlecit®	Venofer®	Dexferrum®	Cosmofer®	Ferinject®	Monofer®	Rienso®
				INFeD®	Injectafer®		FeraHeme®
Carbohydrate shell	Gluconate (monosaccharide)	Sucrose (disaccharide)	Dextran (branched polysaccharide)	Dextran (branched polysaccharide)	Carboxymaltose (branched polysaccharide)	Isomaltoside (linear oligosaccharide)	Polyglucose sorbitol carboxymethylether
Molecular weight (kDa)	289-440	30-60	265	165	150	150	750
Plasma half-life (h)	1	6	60	20	16	20	15
Direct iron donation to transferrin (% injected dose)	5-6	4-5	1-2	1-2	1-2	< 1	< 1
Test dose required1	No	Yes/No	Yes	Yes	No	No	No
Iron content (mg/mL)	12.5	20	50	50	50	100	30
Maximal single dose (mg)	125	200-300	20 mg/kg	20 mg/kg2	20 mg/kg (max 1000 mg in one infusion)	20 mg/kg	5103
Premedication	No	No	TDI only	No	No	No	No
Life-threatening ADE (× 106 doses)	0.9	0.6	11.3	3.3	??	??	??

¹A test dose is no longer recommended by the European Medicines Agency (2013);

²Low molecular weight iron dextran can be safely administered at doses of 1000 mg over 1 h[101];

³Preliminary data indicate that Ferumoxytol may be administered at doses of 1020 mg over 15 min[102].

Table 4 Effects of perioperative administration of erythropoietin and iron on transfusion requirements in patients undergoing elective colorectal cancer resection

Study	+ESA		Placebo		Iron	ESA
	n	ABT, n (%)	n	ABT, n (%)	(route, type, dose, d)	(type, total dose, route, day)
Braga et al[75]	10	1 (10)1	10	5 (50)	iv iron gluconate, 125 mg/d, 4 d	Epoetin alfa,
						500 IU/kg, SC
						(from day -12 to day +8)
Kettelhack et al[76]	48	16 (33)	54	15 (28)	Oral, NS, 5-10 d preOP	Epoetin beta,
					iv, NS, 40 mg, 1 d postOP	3000-4500 IU/kg, SC
						(from day -10 to day +4)
Qvist et al[77]	38	13 (34)2	43	23 (53)	Oral, NS,	Epoetin alfa,
					200 mg/d, 4 d	1350 IU/kg, SC
						(from day -4 to day +7)
Kosmadakis et al[78]	31	9 (29)1	32	19 (59)	iv iron sucrose,	Epoetin alfa,
					100 mg/d, 14 d	4200 IU/kg, SC
						(from day -7 to day +7)
Christodoulakis et al[79]	69 (a)	34 (49)	68	35 (51)	Oral, NS,	Epoetin alfa,
	67 (b)	27 (40)2			200 mg/d, 10 d	1800 IU/kg, SC (a)
						3600 IU/kg, SC (b)
						(from day -10 to day +1)
Norager et al[80]	75	10 (13)	76	9 (12)	Oral, NS,	Darbepoetin alfa,
					200 mg/d, 7d	750-1500 g, SC
						(from day -10 to day +25)
Overall	338	110 (33)	283	106 (37)	OR = 0.89 (95%CI: 0.58-1.12; P = 0.206)

¹Reduction in both percentage of transfused patients and number of transfused units;

²Reduction in the number of transfused units only. ABT: Allogeneic blood transfusion; ESA: Erythropoiesis stimulating agent; NS: Not stated; preOP: Preoperative; postOP: Postoperative; SC: Subcutaneous.