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The ICaRAS randomised controlled trial: Intravenous iron to treat anaemia in people with advanced cancer - feasibility of recruitment, intervention and delivery
Dickson EA, Ng O, Keeler BD, Wilcock A, Brookes MJ, Acheson AG
Palliative medicine. 2023;:2692163221145604
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Abstract
BACKGROUND Anaemia is highly prevalent in people with advanced, palliative cancer yet sufficiently effective and safe treatments are lacking. Oral iron is poorly tolerated, and blood transfusion offers only transient benefits. Intravenous iron has shown promise as an effective treatment for anaemia but its use for people with advanced, palliative cancer lacks evidence. AIMS To assess feasibility of the trial design according to screening, recruitment, and attrition rates. To evaluate the efficacy of intravenous iron to treat anaemia in people with solid tumours, receiving palliative care. DESIGN A multicentre, randomised, double blind, placebo-controlled trial of intravenous iron (ferric derisomaltose, Monofer(®)). Outcomes included trial feasibility, change in blood indices, and change in quality of life via three validated questionnaires (EQ5D5L, QLQC30, and the FACIT-F) over 8 weeks. (ISRCTN; 13370767). SETTING/PARTICIPANTS People with anaemia and advanced solid tumours who were fatigued with a performance status ⩽2 receiving support from a specialist palliative care service. RESULTS 34 participants were randomised over 16 months (17 iron, 17 placebo). Among those eligible 47% of people agreed to participate and total study attrition was 26%. Blinding was successful in all participants. There were no serious adverse reactions. Results indicated that intravenous iron may be efficacious at improving participant haemoglobin, iron stores and select fatigue specific quality of life measures compared to placebo. CONCLUSION The trial was feasible according to recruitment and attrition rates. Intravenous iron increased haemoglobin and may improve fatigue specific quality of life measures compared to placebo. A definitive trial is required for confirmation.
PICO Summary
Population
People with anaemia and advanced solid tumours, enrolled in the Intravenous Iron for Cancer Related Anaemia Symptoms (ICaRAS) trial (n= 34).
Intervention
Intravenous iron (n= 17).
Comparison
Placebo: sodium chloride (n= 17).
Outcome
Outcomes included trial feasibility, change in blood indices, and change in quality of life via three validated questionnaires over 8 weeks. Among those eligible, 47% of people agreed to participate and total study attrition was 26%. Blinding was successful in all participants. There were no serious adverse reactions. Compared to baseline, there was a significant rise in haemoglobin, ferritin, and transferrin saturation % at weeks 4 and 8 for participants in the iron group but not the placebo group. Anaemia resolution was achieved in 39% of intravenous iron participants by week 8 compared to 8% of the placebo group.
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Intravenous iron is non-inferior to oral iron regarding cell growth and iron metabolism in colorectal cancer associated with iron-deficiency anaemia
Al-Hassi HO, Ng O, Evstatiev R, Mangalika M, Worton N, Jambrich M, Khare V, Phipps O, Keeler B, Gasche C, et al
Scientific reports. 2021;11(1):13699
Abstract
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.
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Preoperative Intravenous Iron Therapy and Survival after Colorectal Cancer Surgery: Long Term Results from the IVICA Randomised Controlled Trial
Dickson EA, Keeler BD, Ng O, Kumar A, Brookes MJ, Acheson AG
Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland. 2020
Abstract
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.
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Randomized clinical trial of preoperative oral versus intravenous iron in anaemic patients with colorectal cancer
Keeler BD, Simpson JA, Ng O, Padmanabhan H, Brookes MJ, Acheson AG
The British Journal of Surgery. 2017;104((3):):214-221
Abstract
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.
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Effects of allogeneic red blood cell transfusions on clinical outcomes in patients undergoing colorectal cancer surgery: a systematic review and meta-analysis
Acheson AG, Brookes MJ, Spahn DR
Annals of Surgery. 2012;256((2)):235-44.
Abstract
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.