Intravenous iron is non-inferior to oral iron regarding cell growth and iron metabolism in colorectal cancer associated with iron-deficiency anaemia
Scientific reports. 2021;11(1):13699
Oral iron promotes intestinal tumourigenesis in animal models. In humans, expression of iron transport proteins are altered in colorectal cancer. This study examined whether the route of iron therapy alters iron transport and tumour growth. Colorectal adenocarcinoma patients with pre-operative iron deficiency anaemia received oral ferrous sulphate (n = 15), or intravenous ferric carboxymaltose (n = 15). Paired (normal and tumour tissues) samples were compared for expression of iron loading, iron transporters, proliferation, apoptosis and Wnt signalling using immunohistochemistry and RT-PCR. Iron loading was increased in tumour and distributed to the stroma in intravenous treatment and to the epithelium in oral treatment. Protein and mRNA expression of proliferation and iron transporters were increased in tumours compared to normal tissues but there were no significant differences between the treatment groups. However, intravenous iron treatment reduced ferritin mRNA levels in tumours and replenished body iron stores. Iron distribution to non-epithelial cells in intravenous iron suggests that iron is less bioavailable to tumour cells. Therefore, intravenous iron may be a better option in the treatment of colorectal cancer patients with iron deficiency anaemia due to its efficiency in replenishing iron levels while its effect on proliferation and iron metabolism is similar to that of oral iron treatment.
Preoperative Intravenous Iron Therapy and Survival after Colorectal Cancer Surgery: Long Term Results from the IVICA Randomised Controlled Trial
Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland. 2020
AIM: Preoperative iron is frequently used for the correction of anaemia in colorectal cancer surgery. However, enteral iron intake may promote tumour growth and progression which could influence cancer recurrence and patient survival. We explore the long term outcomes of patients receiving either oral or intravenous iron replacement therapy as part of a previous randomised controlled trial. METHODS The IVICA trial randomised anaemic colorectal cancer patients to receive either oral (OI, control) or intravenous (IVI, treatment) iron prior to their elective operation. Follow up analysis of all patients recruited to this multicentre trial who underwent surgical resection with curative intent was performed. Kaplan-Meier survival estimates, and Cox proportional hazard models were used to compare groups. A pooled group multivariable analysis comparing patients who achieved resolution of anaemia preoperatively to those who did not was also undertaken. RESULTS 110 of the 116 patients previously enrolled were eligible for analysis (OI n=56, IVI n=54). Median overall follow up duration was 61 months (IQR 46-67). No significant difference in 5-year overall survival (HR 1.22, 95% CI 0.65-2.28 P=0.522) or disease free survival (HR 1.08, 95% CI 0.61-1.92 P=0.79) was observed between OI and IVI. Pooled analysis of treatment groups found that preoperative resolution of anaemia led to improved 5 year overall survival on multivariable analysis (HR 3.38 [1.07-11.56, P=0.044). CONCLUSION We recommend IVI for the preoperative correction of anaemia. Route of iron therapy did not significantly influence survival. Preoperative anaemia correction may lead to an overall survival advantage following elective colorectal cancer surgery.
Preoperative anemia and outcomes in cardiovascular surgery: systematic review and meta-analysis
The Annals of thoracic surgery. 2019
BACKGROUND Pre-operative anemia is common in patients scheduled for cardiac surgery. However, its effect on postoperative outcomes remains controversial. This meta-analysis aimed to clarify the impact of anemia on outcomes following cardiac surgery. METHODS A literature search was conducted on MEDLINE, Embase, Cochrane, and Web of Science databases. The primary outcome was 30-day postoperative or in-hospital mortality. Secondary outcomes included acute kidney injury (AKI), stroke, blood transfusion, and infection. A meta-analytic model was used to determine the differences in the above postoperative outcomes between anemic and non-anemic patients. RESULTS Out of 1103 studies screened, 22 met the inclusion criteria. A total of 23624 (20.6%) out of 114277 patients were anemic. Anemia was associated with increased mortality (odds ratio [OR] 2.74, 95% confidence interval [CI] 2.32-3.24; I(2)=69.6%; p<0001), AKI (OR 3.13, 95% CI 2.37-4.12; I(2)=71.1%; p<0001), stroke (OR 1.46, 95% CI 1.24-1.72; I(2)=21.6%; p<0001), and infection (OR 2.65, 95% CI 1.98-3.55; I(2)=46.7%; p<0001). More anemic patients were transfused than non-anemic (33.3 versus 11.9%). No statistically significant association was found between mortality and blood transfusion (OR 1.35, 95% CI 0.92-1.98; I(2)=83.7%; p=0.12) but we were not able to compare mortality with or without transfusion in those who were or were not anemic. CONCLUSIONS Preoperative anemia is associated with adverse outcomes following cardiac surgery. These findings support the addition of preoperative anemia to future risk prediction models, and as a target for risk modification.
Iron therapy for preoperative anaemia
The Cochrane database of systematic reviews. 2019;12:Cd011588
BACKGROUND Preoperative anaemia is common and occurs in 5% to 76% of patients preoperatively. It is associated with an increased risk of perioperative allogeneic blood transfusion, longer hospital stay, and increased morbidity and mortality. Iron deficiency is one of the most common causes of anaemia. Oral and intravenous iron therapy can be used to treat anaemia. Parenteral iron preparations have been shown to be more effective in conditions such as inflammatory bowel disease, chronic heart failure and postpartum haemorrhage due to rapid correction of iron stores. A limited number of studies has investigated iron therapy for the treatment of preoperative anaemia. The aim of this Cochrane Review is to summarise the evidence for iron supplementation, both enteral and parenteral, for the management of preoperative anaemia. OBJECTIVES To evaluate the effects of preoperative iron therapy (enteral or parenteral) in reducing the need for allogeneic blood transfusions in anaemic patients undergoing surgery. SEARCH METHODS We ran the search on 30 July 2018. We searched the Cochrane Injuries Group's Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library), Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase Classic and Embase (Ovid), CINAHL Plus (EBSCO), PubMed, and clinical trials registries, and we screened reference lists. We ran a top-up search on 28 November 2019; one study is now awaiting classification. SELECTION CRITERIA We included all randomised controlled trials (RCTs) that compared preoperative iron monotherapy to placebo, no treatment, standard care or another form of iron therapy for anaemic adults undergoing surgery. We defined anaemia as haemoglobin values less than 13 g/dL for males and 12 g/dL for non-pregnant females. DATA COLLECTION AND ANALYSIS Two review authors collected data and a third review author checked all collected data. Data were collected on the proportion of patients who receive a blood transfusion, the amount of blood transfused per patient (units), quality of life, ferritin levels and haemoglobin levels, measured as continuous variables at the following predetermined time points: pretreatment (baseline), preoperatively but postintervention, and postoperatively. We performed statistical analysis using the Cochrane software, Review Manager 5. We summarised outcome data in tables and forest plots. We used the GRADE approach to describe the quality of the body of evidence. MAIN RESULTS Six RCTs, with a total of 372 participants, evaluated preoperative iron therapy to correct anaemia before planned surgery. Four studies compared iron therapy (either oral (one study) or intravenous (three studies)) with no treatment, placebo or usual care, and two studies compared intravenous iron therapy with oral iron therapy. Iron therapy was delivered over a range of periods that varied from 48 hours to three weeks prior to surgery. The 372 participants in our analysis fall far short of the 819 required - as calculated by our information size calculation - to detect a 30% reduction in blood transfusions. Five trials, involving 310 people, reported the proportion of participants who received allogeneic blood transfusions. Meta-analysis of iron therapy versus placebo or standard care showed no difference in the proportion of participants who received a blood transfusion (risk ratio (RR) 1.21, 95% confidence interval (CI) 0.87 to 1.70; 4 studies, 200 participants; moderate-quality evidence). Only one study that compared oral versus intravenous iron therapy measured this outcome, and reported no difference in risk of transfusion between groups. There was no difference between the iron therapy and placebo/standard care groups for haemoglobin level preoperatively at the end of the intervention (mean difference (MD) 0.63 g/dL, 95% CI -0.07 to 1.34; 2 studies, 83 participants; low-quality evidence). However, intravenous iron therapy produced an increase in preoperative postintervention haemoglobin levels compared with oral iron (MD 1.23 g/dL, 95% CI 0.80 to 1.65; 2 studies, 172 participants; low-quality evidence). Ferritin levels were increased by intravenous iron, both when compared to standard care ((MD 149.00, 95% CI 25.84 to 272.16; 1 study, 63 participants; low-quality evidence) or to oral iron (MD 395.03 ng/mL, 95% CI 227.72 to 562.35; 2 studies, 151 participants; low-quality evidence). Not all studies measured quality of life, short-term mortality or postoperative morbidity. Some measured the outcomes, but did not report the data, and the studies which did report the data were underpowered. Therefore, uncertainty remains regarding these outcomes. The inclusion of new research in the future is very likely to change these results. AUTHORS' CONCLUSIONS The use of iron therapy for preoperative anaemia does not show a clinically significant reduction in the proportion of trial participants who received an allogeneic blood transfusion compared to no iron therapy. Results for intravenous iron are consistent with a greater increase in haemoglobin and ferritin when compared to oral iron, but do not provide reliable evidence. These conclusions are drawn from six studies, three of which included very small numbers of participants. Further, well-designed, adequately powered, RCTs are required to determine the true effectiveness of iron therapy for preoperative anaemia. Two studies are currently in progress, and will include 1500 randomised participants.
The impact of pre-operative intravenous iron on quality of life after colorectal cancer surgery: outcomes from the intravenous iron in colorectal cancer-associated anaemia (IVICA) trial
Anaemia is associated with a reduction in quality of life, and is common in patients with colorectal cancer . We recently reported the findings of the intravenous iron in colorectal cancer-associated anaemia (IVICA) trial comparing haemoglobin levels and transfusion requirements following intravenous or oral iron replacement in anaemic colorectal cancer patients undergoing elective surgery. In this follow-up study, we compared the efficacy of intravenous and oral iron at improving quality of life in this patient group. We conducted a multicentre, open-label randomised controlled trial. Anaemic colorectal cancer patients were randomly allocated at least two weeks pre-operatively, to receive either oral (ferrous sulphate) or intravenous (ferric carboxymaltose) iron. We assessed haemoglobin and quality of life scores at recruitment, immediately before surgery and at outpatient review approximately three months postoperatively, using the Short Form 36, EuroQoL 5-dimension 5-level and Functional Assessment of Cancer Therapy - Anaemia questionnaires. We recruited 116 anaemic patients across seven UK centres (oral iron n = 61 (53%), and intravenous iron n = 55 (47%)). Eleven quality of life components increased by a clinically significant margin in the intravenous iron group between recruitment and surgery compared with one component for oral iron. Median (IQR [range]) visual analogue scores were significantly higher with intravenous iron at a three month outpatient review (oral iron 70, (60-85 [20-95]); intravenous iron 90 (80-90 [50-100]), p = 0.001). The Functional Assessment of Cancer Therapy - Anaemia score comprises of subscales related to cancer, fatigue and non-fatigue items relevant to anaemia. Median outpatient scores were higher, and hence favourable, for intravenous iron on the Functional Assessment of Cancer Therapy - Anaemia subscale (oral iron 66 (55-72 [23-80]); intravenous iron 71 (66-77 [46-80]); p = 0.002), Functional Assessment of Cancer Therapy - Anaemia trial outcome index (oral iron 108 (90-123 [35-135]); intravenous iron 121 (113-124 [81-135]); p = 0.003) and Functional Assessment of Cancer Therapy - Anaemia total score (oral iron 151 (132-170 [69-183]); intravenous iron 168 (160-174 [125-186]); p = 0.005). These findings indicate that intravenous iron is more efficacious at improving quality of life scores than oral iron in anaemic colorectal cancer patients.
Anaemic colorectal cancer patients undergoing elective surgery across seven UK centres, enrolled in the IVICA trial (n= 116).
Oral (ferrous sulphate) iron (n= 61).
Intravenous (ferric carboxymaltose) iron (n= 55).
Eleven quality of life components increased by a clinically significant margin in the intravenous iron group between recruitment and surgery compared with one component for oral iron three months post-surgery. Median outpatient scores were higher, and hence favourable, for intravenous iron on the Functional Assessment of Cancer Therapy.
Intravenous iron does not effectively correct preoperative anaemia in cardiac surgery: a pilot randomized controlled trial
Interactive Cardiovascular and Thoracic Surgery. 2018
OBJECTIVES Preoperative anaemia is a strong predictor of blood transfusion requirements and must be assessed for appropriate optimization before elective surgery. Iron therapy is a transfusion-sparing approach effective for increasing haemoglobin concentrations. However, its role in elective cardiac surgery and the optimal route of administration remain unknown. This single-centre, non-blinded, randomized, controlled trial compared the effectiveness of intravenous ferric carboxymaltose therapy with oral iron for anaemic patients undergoing elective cardiac surgery. METHODS Fifty anaemic patients scheduled for elective cardiac surgery were randomized to receive either oral or intravenous iron therapy 3-8 weeks preoperatively. Changes in haemoglobin concentration were measured. Blood transfusion and postoperative outcome data were collected. RESULTS Preoperative median increases in haemoglobin were 1.0 g/l (interquartile range -3.25 to 7.25 g/l) and 3.0 g/l (interquartile range -1.25 to 6.25 g/l) for patients receiving intravenous and oral iron, respectively (P = 0.42). The median first 12-h blood loss was significantly higher in the intravenous group (655 ml; interquartile range 162-1540 ml) compared to the oral group (313 ml; interquartile range 150-1750 ml; P < 0.007). Median increments in serum ferritin were superior for the intravenous group (median difference 313 microg/l; interquartile range 228-496) compared to the oral group (median difference 5.5 microg/l; interquartile range -1.4 to 19.4; P < 0.001). CONCLUSIONS Increases in ferritin after intravenous iron administration were significantly greater than those after oral iron administration. There was no significant difference in haemoglobin increments between groups. Despite significantly higher intraoperative blood loss in the group receiving intravenous iron, blood transfusion requirements for both groups were not statistically different. Clinical trial registration: ISRCTN22158788.
Randomized clinical trial of preoperative oral versus intravenous iron in anaemic patients with colorectal cancer
The British Journal of Surgery. 2017;104((3):):214-221
BACKGROUND Treatment of preoperative anaemia is recommended as part of patient blood management, aiming to minimize perioperative allogeneic red blood cell transfusion. No clear evidence exists outlining which treatment modality should be used in patients with colorectal cancer. The study aimed to compare the efficacy of preoperative intravenous and oral iron in reducing blood transfusion use in anaemic patients undergoing elective colorectal cancer surgery. METHODS Anaemic patients with non-metastatic colorectal adenocarcinoma were recruited at least 2 weeks before surgery and randomized to receive oral (ferrous sulphate) or intravenous (ferric carboxymaltose) iron. Perioperative changes in haemoglobin, ferritin, transferrin saturation and blood transfusion use were recorded until postoperative outpatient review. RESULTS Some 116 patients were included in the study. There was no difference in blood transfusion use from recruitment to trial completion in terms of either volume of blood administered (P = 0.841) or number of patients transfused (P = 0.470). Despite this, increases in haemoglobin after treatment were higher with intravenous iron (median 1.55 (i.q.r. 0.93-2.58) versus 0.50 (-0.13 to 1.33) g/dl; P < 0.001), which was associated with fewer anaemic patients at the time of surgery (75 versus 90 per cent; P = 0.048). Haemoglobin levels were thus higher at surgery after treatment with intravenous than with oral iron (mean 11.9 (95 per cent c.i. 11.5 to 12.3) versus 11.0 (10.6 to 11.4) g/dl respectively; P = 0.002), as were ferritin (P < 0.001) and transferrin saturation (P < 0.001) levels. CONCLUSION Intravenous iron did not reduce the blood transfusion requirement but was more effective than oral iron at treating preoperative anaemia and iron deficiency in patients undergoing colorectal cancer surgery.
Iron therapy for pre-operative anaemia
Cochrane Database of Systematic Reviews.. 2015;((12)):CD011588.
BACKGROUND Pre-operative anaemia is common and occurs in up to 76% of patients. It is associated with increased peri-operative allogeneic blood transfusions, longer hospital lengths of stay and increased morbidity and mortality. Iron deficiency is one of the most common causes of this anaemia. Oral iron therapy has traditionally been used to treat anaemia but newer, safer parenteral iron preparations have been shown to be more effective in other conditions such as inflammatory bowel disease, chronic heart failure and post-partum haemorrhage. A limited number of studies look at iron therapy for the treatment of pre-operative anaemia. The aim of this Cochrane review is to summarise the evidence for use of iron supplementation, both enteral and parenteral, for the management of pre-operative anaemia. OBJECTIVES The objective of this review is to evaluate the effects of pre-operative iron therapy (enteral or parenteral) in reducing the need for allogeneic blood transfusions in anaemic patients undergoing surgery. SEARCH METHODS We ran the search on 25 March 2015. We searched the Cochrane Injuries Group's Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), EMBASE Classic and EMBASE (Ovid), CINAHL Plus (EBSCO), PubMed, clinical trials registries, conference abstracts, and we screened reference lists. SELECTION CRITERIA We included all randomised controlled trials (RCTs) which compared pre-operative iron monotherapy to placebo, no treatment, standard of care or another form of iron therapy for anaemic adults undergoing surgery. Anaemia was defined by haemoglobin values less than 13 g/dL for males and 12 g/dL for non-pregnant females. DATA COLLECTION AND ANALYSIS Data were collected by two authors on the proportion of patients who receive a blood transfusion, amount of blood transfused per patient (units) and haemoglobin measured as continuous variables at pre-determined time-points: pre-treatment, pre-operatively but post-treatment, and post-operatively. Statistical analysis was performed using the Cochrane statistical software, Review Manager 2014. Outcome data were summarised in tables and a forest plot. MAIN RESULTS Three prospective randomised controlled studies evaluated pre-operative iron therapy to correct anaemia (two in colorectal and one in gynaecological surgery) and included 114 patients in total. One compared oral iron versus standard care (Lidder 2007); one intravenous iron versus control (Edwards 2009); and one study compared oral versus intravenous iron (Kim 2009). Both colorectal trials reported the primary outcome (proportion of patients who received allogeneic blood transfusions) and meta-analysis showed a reduction in blood transfusions with the administration of iron therapy, but the reduction was not statistically significant (risk ratio (RR) 0.56, 95% confidence interval (CI) 0.27 to 1.18). All studies reported haemoglobin change but data for the anaemic patients were only available for two studies (Edwards 2009 and Kim 2009). Edwards 2009 showed no difference in haemoglobin at the end of treatment pre-operatively. The intravenous versus oral iron study showed an increase in haemoglobin with intravenous iron at the end of treatment pre-operatively (MD 1.90 g/dL, 95% CI 1.16 to 2.64; participants = 56), but the results are at high risk of bias because participants with less than 80% compliance with therapy were excluded from the analysis and compliance was lower in the oral iron group due to the side-effects of treatment (Kim 2009).None of the studies reported quality of life, short- or long-term mortality or post-operative morbidity. AUTHORS' CONCLUSIONS The use of iron therapy for pre-operative anaemia does not show a statistically significant reduction in the proportion of patients who received an allogeneic blood transfusion compared to no iron therapy. However, the 38 patients in our analysis falls far short of the 8
Effects of allogeneic red blood cell transfusions on clinical outcomes in patients undergoing colorectal cancer surgery: a systematic review and meta-analysis
Annals of Surgery. 2012;256((2)):235-44.
OBJECTIVE To determine the effect of allogeneic blood transfusion (ABT) on clinical outcomes in patients with colorectal cancer undergoing surgery. BACKGROUND Perioperative ABTs may be associated with adverse clinical outcomes. METHODS Systematic review of the literature with odds ratio (OR) and incidence rate ratio (IRR) meta-analyses of predefined clinical outcomes based on a MEDLINE search. RESULTS In total, 20,795 colorectal cancer (CRC) patients observed for more than 59.2 +/- 26.1 months (108,838 patient years) were included, of which 58.8% were transfused. ABT was associated with increased all-cause mortality OR = 1.72 (95% confidence interval [CI] 1.55-1.91, P < 0.001); I(2) = 23.3% (0-51.1) and IRR = 1.31 (1.23-1.39, P < 0.001), I(2) = 0.0% (0-37.0). ABT was also associated with increased ORs (95% CI, P) for cancer-related mortality of 1.71 (1.43-2.05, P <0.001), combined recurrence-metastasis-death 1.66 (1.41-1.97, P < 0.001), postoperative infection 3.27 (2.05-5.20, P < 0.001), and surgical reintervention 4.08 (2.18-7.62, <0.001). IRR (95% CI, P) was 1.45 (1.26-1.66, <0.001) for cancer-related mortality and 1.32 (1.19-1.46, <0.001) for recurrence-metastasis-death. Mean length of hospital stay was significantly longer in transfused compared with nontransfused patients (17.8 +/- 4.8 vs 13.9 +/- 4.7 days, P = 0.005). CONCLUSIONS In patients with colorectal cancer (CRC) undergoing surgery, ABTs are associated with adverse clinical outcomes, including increased mortality. Measures aimed at limiting the use of ABTs should be investigated further.