The ICaRAS randomised controlled trial: Intravenous iron to treat anaemia in people with advanced cancer - feasibility of recruitment, intervention and delivery
Palliative medicine. 2023;:2692163221145604
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.
People with anaemia and advanced solid tumours, enrolled in the Intravenous Iron for Cancer Related Anaemia Symptoms (ICaRAS) trial (n= 34).
Intravenous iron (n= 17).
Placebo: sodium chloride (n= 17).
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.
Ferric carboxymaltose infusion versus oral iron supplementation for preoperative iron deficiency anaemia in patients with colorectal cancer (FIT): a multicentre, open-label, randomised, controlled trial
The Lancet. Haematology. 2023
BACKGROUND A third of patients with colorectal cancer who are eligible for surgery in high-income countries have concomitant anaemia associated with adverse outcomes. We aimed to compare the efficacy of preoperative intravenous and oral iron supplementation in patients with colorectal cancer and iron deficiency anaemia. METHODS In the FIT multicentre, open-label, randomised, controlled trial, adult patients (aged 18 years or older) with M0 stage colorectal cancer scheduled for elective curative resection and iron deficiency anaemia (defined as haemoglobin level of less than 7·5 mmol/L (12 g/dL) for women and less than 8 mmol/L (13 g/dL) for men, and a transferrin saturation of less than 20%) were randomly assigned to either 1-2 g of ferric carboxymaltose intravenously or three tablets of 200 mg of oral ferrous fumarate daily. The primary endpoint was the proportion of patients with normalised haemoglobin levels before surgery (≥12 g/dL for women and ≥13 g/dL for men). An intention-to-treat analysis was done for the primary analysis. Safety was analysed in all patients who received treatment. The trial was registered at ClincalTrials.gov, NCT02243735, and has completed recruitment. FINDINGS Between Oct 31, 2014, and Feb 23, 2021, 202 patients were included and assigned to intravenous (n=96) or oral (n=106) iron treatment. Treatment began a median of 14 days (IQR 11-22) before surgery for intravenous iron and 19 days (IQR 13-27) for oral iron. Normalisation of haemoglobin at day of admission was reached in 14 (17%) of 84 patients treated intravenously and 15 (16%) of 97 patients treated orally (relative risk [RR] 1·08 [95% CI 0·55-2·10]; p=0·83), but the proportion of patients with normalised haemoglobin significantly increased for the intravenous treatment group at later timepoints (49 [60%] of 82 vs 18 [21%] of 88 at 30 days; RR 2·92 [95% CI 1·87-4·58]; p<0·0001). The most prevalent treatment-related adverse event was discoloured faeces (grade 1) after oral iron treatment (14 [13%] of 105), and no treatment-related serious adverse events or deaths were observed in either group. No differences in other safety outcomes were seen, and the most common serious adverse events were anastomotic leakage (11 [5%] of 202), aspiration pneumonia (5 [2%] of 202), and intra-abdominal abscess (5 [2%] 202). INTERPRETATION Normalisation of haemoglobin before surgery was infrequent with both treatment regimens, but significantly improved at all other timepoints following intravenous iron treatment. Restoration of iron stores was feasible only with intravenous iron. In selected patients, surgery might be delayed to augment the effect of intravenous iron on haemoglobin normalisation. FUNDING Vifor Pharma.
Patients with colorectal cancer and iron deficiency anaemia scheduled for elective curative resection; enrolled in the FIT trial in the Netherlands and Italy (n= 202).
Intravenous ferric carboxymaltose (n= 96).
Oral ferrous fumarate (n= 106).
Treatment began a median of 14 days (IQR 11-22) before surgery for intravenous iron and 19 days (IQR 13-27) for oral iron. Normalisation of haemoglobin at day of admission was reached in 14 (17%) of 84 patients treated intravenously and 15 (16%) of 97 patients treated orally (relative risk [RR] 1.08, 95% CI [0.55, 2.10]), but the proportion of patients with normalised haemoglobin significantly increased for the intravenous treatment group at later timepoints (49 [60%] of 82 vs. 18 [21%] of 88 at 30 days; RR 2.92, 95% CI [1.87, 4.58]).
Intravenous Iron Therapy to Treat Anemia in Oncology: A Mapping Review of Randomized Controlled Trials
Current oncology (Toronto, Ont.). 2023;30(9):7836-7851
Anemia is a common problem when patients present with cancer, and it can worsen during treatment. Anemia can directly impact the cognitive and physical quality of life and may impair fitness for oncological therapy. The most common cause of anemia is iron deficiency. Newer intravenous (IV) iron formulations offer a safe and rapidly effective treatment option. We performed a systematic mapping review of randomized controlled trials (RCTs) evaluating intravenous iron therapy in patients with cancer and anemia and their outcomes. A total of 23 RCTs were identified. The median number of patients enrolled was 104 (IQR: 60-134). A total of 5 were focused on surgical outcomes (4 preoperative, 1 postoperative), and 15 were in adjuvant therapies for a variety of tumor types (breast, colorectal, lung, gynecological, myeloid, and lymphomas), 10 of which were in combination with erythropoietin-stimulating agents (ESAs) therapy, 2 in radiotherapy, and 1 in palliative care. Overall, the studies reported that the use of IV iron increased hemoglobin concentration and decreased transfusion rates during different cancer treatment regimes. IV iron can be administered safely throughout the cancer treatment pathway from primary surgery to the palliative setting. More studies are needed to demonstrate net clinical outcomes.
Effect of erythropoiesis-stimulating agents on breast cancer patients: a meta-analysis
Clinical and experimental medicine. 2022
Erythropoiesis-stimulating agents (ESAs) have been reported to increase the risk of death in cancer patients. In this study, we selected breast cancer, which is currently the most prevalent cancer worldwide, for a meta-analysis to re-examine the advantages and disadvantages of using ESAs. All relevant studies were searched by PubMed, Embase, Web of science, and Cochrane Library. Endpoints including mortality, incidence of thrombo-vascular events, hemoglobin, and transfusion requirements were meta-analyzed based on random-effects model or fixed-effect model. 10 studies were finally included, with a total sample size of 6785 patients. The risk of mortality was higher in patients using ESA than in controls (RR 1.07, 95% CI 1.01-1.13, P = 0.03); subgroup analysis found that the mortality rate was higher in patients treating with ESA for > 6 months (RR 1.27, 95% CI 1.05-1.55, P = 0.01) and epoetin α (RR 1.07, 95% CI 1.01-1.14, P = 0.03). The incidence of thrombo-vascular adverse events was higher in patients using ESA than in controls (RR 1.53, 95% CI 1.27-1.86, P < 0.0001). The ESA group was more effective in improving anemia in cancer patients (MD 1.20, 95% CI 0.77-1.63, P < 0.00001). The blood transfusion needs of patients in the ESA group were significantly lower (RR 0.52, 95%CI 0.44-0.60, P < 0.00001). There was no statistically significant difference between the two groups in disease progression-related conditions (HR 1.03, 95%CI 0.95-1.12, P = 0.52). ESAs increase the risk of mortality and the incidence of thrombo-vascular adverse events in breast cancer patients, while reducing their anemia symptoms and transfusion requirements. Registration PROSPERO CRD42022330450.
Randomized trial of sucrosomial iron supplementation in patients with chemotherapy-related anemia treated with ESA
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2022
BACKGROUND Iron supplementation improves the erythropoiesis-stimulating agents' (ESAs) response in chemotherapy-related anemia. The primary aim of our study is to assess the efficacy of sucrosomial iron, a new oral iron formulation, in cancer patients with chemotherapy-induced anemia treated with ESAs. The secondary objectives included the efficacy into two subgroups of patients (iron replete and functional iron deficiency) between the two study arms, safety and the effect on transfusion need. METHODS In this randomized, multicentre, open-label, phase III clinical trial, 60 cancer patients were enrolled. Each patient was randomly assigned (1:1) to receive 12 weeks of oral sucrosomial iron at the dose of 30 mg daily in combination with ESAs or no supplementation to ESA treatment. The endpoint considered for efficacy was the proportion of patients achieving complete hematological response at 12 weeks (increase in Hb > 2 g/dL from baseline, without RBC transfusions in the previous 28 days or achieving Hb ≥ 12 g/dL). RESULTS There was a statistically significant association between oral sucrosomial iron supplementation in combination with ESAs and the achievement of a complete hematological response. This response was achieved within 12 weeks by 31% of patients in the control group and by 52% of patients supplemented with oral sucrosomial iron. A trend of greater response in sucrosomial iron arm was found in both subgroups. No difference was observed about safety and transfusion need. CONCLUSIONS Sucrosomial iron is well tolerated and its combination with ESAs improves the hematological response in cancer patients with chemotherapy-related anemia. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION This study has been reviewed by the Institutional Ethics Committee of the IRCCS Policlinico San Matteo Foundation, Pavia, Italy (28/04/2015; prot. N. 20,150,002,059), and by the Institutional Ethics Committee of the other Italian oncological centers involved in this study.
Intravenous iron versus oral iron versus no iron with or without erythropoiesis- stimulating agents (ESA) for cancer patients with anaemia: a systematic review and network meta-analysis
The Cochrane Database of Systematic Reviews. 2022;6(6):Cd012633
BACKGROUND Anaemia is common among cancer patients and they may require red blood cell transfusions. Erythropoiesis-stimulating agents (ESAs) and iron might help in reducing the need for red blood cell transfusions. However, it remains unclear whether the combination of both drugs is preferable compared to using one drug. OBJECTIVES To systematically review the effect of intravenous iron, oral iron or no iron in combination with or without ESAs to prevent or alleviate anaemia in cancer patients and to generate treatment rankings using network meta-analyses (NMAs). SEARCH METHODS We identified studies by searching bibliographic databases (CENTRAL, MEDLINE, Embase; until June 2021). We also searched various registries, conference proceedings and reference lists of identified trials. SELECTION CRITERIA We included randomised controlled trials comparing intravenous, oral or no iron, with or without ESAs for the prevention or alleviation of anaemia resulting from chemotherapy, radiotherapy, combination therapy or the underlying malignancy in cancer patients. DATA COLLECTION AND ANALYSIS Two review authors independently extracted data and assessed risk of bias. Outcomes were on-study mortality, number of patients receiving red blood cell transfusions, number of red blood cell units, haematological response, overall mortality and adverse events. We conducted NMAs and generated treatment rankings. We assessed the certainty of the evidence using GRADE. MAIN RESULTS Ninety-six trials (25,157 participants) fulfilled our inclusion criteria; 62 trials (24,603 participants) could be considered in the NMA (12 different treatment options). Here we present the comparisons of ESA with or without iron and iron alone versus no treatment. Further results and subgroup analyses are described in the full text. On-study mortality We estimated that 92 of 1000 participants without treatment for anaemia died up to 30 days after the active study period. Evidence from NMA (55 trials; 15,074 participants) suggests that treatment with ESA and intravenous iron (12 of 1000; risk ratio (RR) 0.13, 95% confidence interval (CI) 0.01 to 2.29; low certainty) or oral iron (34 of 1000; RR 0.37, 95% CI 0.01 to 27.38; low certainty) may decrease or increase and ESA alone (103 of 1000; RR 1.12, 95% CI 0.92 to 1.35; moderate certainty) probably slightly increases on-study mortality. Additionally, treatment with intravenous iron alone (271 of 1000; RR 2.95, 95% CI 0.71 to 12.34; low certainty) may increase and oral iron alone (24 of 1000; RR 0.26, 95% CI 0.00 to 19.73; low certainty) may increase or decrease on-study mortality. Haematological response We estimated that 90 of 1000 participants without treatment for anaemia had a haematological response. Evidence from NMA (31 trials; 6985 participants) suggests that treatment with ESA and intravenous iron (604 of 1000; RR 6.71, 95% CI 4.93 to 9.14; moderate certainty), ESA and oral iron (527 of 1000; RR 5.85, 95% CI 4.06 to 8.42; moderate certainty), and ESA alone (467 of 1000; RR 5.19, 95% CI 4.02 to 6.71; moderate certainty) probably increases haematological response. Additionally, treatment with oral iron alone may increase haematological response (153 of 1000; RR 1.70, 95% CI 0.69 to 4.20; low certainty). Red blood cell transfusions We estimated that 360 of 1000 participants without treatment for anaemia needed at least one transfusion. Evidence from NMA (69 trials; 18,684 participants) suggests that treatment with ESA and intravenous iron (158 of 1000; RR 0.44, 95% CI 0.31 to 0.63; moderate certainty), ESA and oral iron (144 of 1000; RR 0.40, 95% CI 0.24 to 0.66; moderate certainty) and ESA alone (212 of 1000; RR 0.59, 95% CI 0.51 to 0.69; moderate certainty) probably decreases the need for transfusions. Additionally, treatment with intravenous iron alone (268 of 1000; RR 0.74, 95% CI 0.43 to 1.28; low certainty) and with oral iron alone (333 of 1000; RR 0.92, 95% CI 0.54 to 1.57; low certainty) may decrease or increase the need for transfusions. Overall mortality We estimated that 347 of 1000 participants without treatment for anaemia died overall. Low-certainty evidence from NMA (71 trials; 21,576 participants) suggests that treatment with ESA and intravenous iron (507 of 1000; RR 1.46, 95% CI 0.87 to 2.43) or oral iron (482 of 1000; RR 1.39, 95% CI 0.60 to 3.22) and intravenous iron alone (521 of 1000; RR 1.50, 95% CI 0.63 to 3.56) or oral iron alone (534 of 1000; RR 1.54, 95% CI 0.66 to 3.56) may decrease or increase overall mortality. Treatment with ESA alone may lead to little or no difference in overall mortality (357 of 1000; RR 1.03, 95% CI 0.97 to 1.10; low certainty). Thromboembolic events We estimated that 36 of 1000 participants without treatment for anaemia developed thromboembolic events. Evidence from NMA (50 trials; 15,408 participants) suggests that treatment with ESA and intravenous iron (66 of 1000; RR 1.82, 95% CI 0.98 to 3.41; moderate certainty) probably slightly increases and with ESA alone (66 of 1000; RR 1.82, 95% CI 1.34 to 2.47; high certainty) slightly increases the number of thromboembolic events. None of the trials reported results on the other comparisons. Thrombocytopenia or haemorrhage We estimated that 76 of 1000 participants without treatment for anaemia developed thrombocytopenia/haemorrhage. Evidence from NMA (13 trials, 2744 participants) suggests that treatment with ESA alone probably leads to little or no difference in thrombocytopenia/haemorrhage (76 of 1000; RR 1.00, 95% CI 0.67 to 1.48; moderate certainty). None of the trials reported results on other comparisons. Hypertension We estimated that 10 of 1000 participants without treatment for anaemia developed hypertension. Evidence from NMA (24 trials; 8383 participants) suggests that treatment with ESA alone probably increases the number of hypertensions (29 of 1000; RR 2.93, 95% CI 1.19 to 7.25; moderate certainty). None of the trials reported results on the other comparisons. AUTHORS' CONCLUSIONS When considering ESAs with iron as prevention for anaemia, one has to balance between efficacy and safety. Results suggest that treatment with ESA and iron probably decreases number of blood transfusions, but may increase mortality and the number of thromboembolic events. For most outcomes the different comparisons within the network were not fully connected, so ranking of all treatments together was not possible. More head-to-head comparisons including all evaluated treatment combinations are needed to fill the gaps and prove results of this review.
The addition of oral iron improves chemotherapy-induced anemia in patients receiving erythropoiesis-stimulating agents
International journal of cancer. 2022
Although many studies have shown that supplementation with iron and erythropoiesis-stimulating agents (ESA) is frequently used for managing chemotherapy-induced anemia (CIA), optimal combination therapy using these agents together to ameliorate anemia is not well characterized. To assess the effects of ESA combined with oral or intravenous (IV) iron on relieving CIA, PubMed, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI) were searched for articles. Data collected in the articles were meta-analyzed using RevMan 5.3 software with a random-effects model. Our comprehensive search yielded 1666 potentially relevant trials. A total of 41 trials randomizing 4200 patients with CIA fulfilled inclusion criteria, including 34 Chinese articles and 7 English articles. Meta-analysis showed that treatment with both ESA and iron more effectively improved CIA relative to iron supplementation alone, with increased hemoglobin, hematocrit, red blood cell count and haematopoietic response rate. Subgroup analyses revealed iron administration, both oral and IV iron, improved anemia in ESA-treated cancer patients with CIA. Our analysis demonstrates that iron supplementation combined with ESA more effectively ameliorates CIA relative to iron supplementation alone, without regard to whether IV or oral iron was used. Together, our findings may contribute to the clinical treatment of CIA using iron therapy with or without ESA. This article is protected by copyright. All rights reserved.
Perioperative changes in haemoglobin and ferritin concentrations from preoperative intravenous iron isomaltoside for iron deficiency anaemia in patients with colorectal cancer: A pilot randomised controlled trial
PloS one. 2022;17(6):e0270640
BACKGROUND Patients with colorectal cancer have a high risk of iron deficiency anaemia (IDA) due to chronic tumour induced blood loss, a reduced dietary iron intake from poor nutrition or gastrointestinal malabsorption. This pilot, double blinded, randomised controlled trial (RCT) examined the effect and feasibility of using preoperative iron isomaltoside for treating iron deficiency anaemia. METHODS Forty eligible adults with IDA were randomised to receive either intravenous iron isomaltoside (20 mg.kg-1 up to 1000 mg over 30 minutes) or usual preoperative care (control) three weeks before scheduled colorectal surgery. The primary outcomes were perioperative changes in haemoglobin and ferritin concentrations. RESULTS The recruitment rate was 78% of all eligible referred patients (1.9 patients/month). The haemoglobin and ferritin concentrations were higher in the iron isomaltoside group than the control group over the perioperative period (group*time interaction P = 0.042 and P < 0.001 respectively). Mean haemoglobin change from baseline to before surgery was higher in the iron isomaltoside group (7.8, 95% CI: 3.2 to 12.3 g.l-1) than the control group (1.7, 95% CI: -1.9 to 5.3 g.l-1) [mean difference 6.1, 95% CI: 0.3 to 11.8 g.l-1; P = 0.040]. The ferritin change from baseline to before surgery between groups was large in favour of the iron isomaltoside group (mean difference 296.9, 95% CI: 200.6 to 393.2 μg.l-1; P < 0.001]. There were no differences between groups in packed red blood cell transfusions needed, surgical complications, quality of recovery and days (alive and) at home within 30 days after surgery. CONCLUSION Iron isomaltoside therapy was safe and had a minimal effect on perioperative changes in haemoglobin concentration. Given the slow recruitment and new evidence emerging during the conduct of this study, conducting a multi-centre RCT based on the current pilot trial protocol is unlikely to be feasible. TRIAL REGISTRATION ClinicalTrials.gov NCT03565354.
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.
Efficacy and Cardiovascular Adverse Effects of Erythropoiesis Stimulating Agents in the Treatment of Cancer-Related Anemia: A Systematic Review of Randomized Controlled Trials
Anemia is a common complication of cancer. Treatment of anemia in cancer is crucial as anemia adversely affects the quality of life, therapeutic outcomes, and overall survival. Erythropoiesis stimulating agents (ESAs) are valuable drugs for treating cancer-related anemia. Cardiovascular adverse effects are a significant concern with ESA therapy, and there is wide variability in therapeutic goals and characteristics of patients who undergo treatment with ESAs. As a result, a careful analysis of the currently available data on the efficacy and safety of these drugs is necessary. This data analysis will aid in the rational use of ESAs for the treatment of anemia in cancer. The objective of this systematic review is to elucidate the pathogenesis of anemia in cancer, assess the effectiveness of ESAs in treating anemia in cancer, and the overall risk of cardiovascular adverse effects associated with the use of ESAs and their impact on prognosis. We searched literature from online databases - PubMed, PubMed Central, MEDLINE, Cochrane Library, and clinical trials register (clinicaltrials.gov) to identify prospective phase II and phase III randomized controlled trials (RCTs). We chose RCTs that directly compared patients with cancer who were treated with ESAs to those who were not treated with ESAs. January 2008 was taken as the lower date limit and May 2021 as the upper date limit. Only English language literature and human studies were included. The quality appraisal was completed using the Cochrane risk bias assessment tool, and data from a total of 10,738 patients with cancer in 17 RCTs were identified and included for systematic review. Our review concludes that ESAs effectively reduce the necessity for blood transfusions and increase mean hemoglobin levels in anemic cancer patients. ESA therapy is associated with cardiovascular adverse effects, including venous thromboembolism, thrombophlebitis, hypertension, ischemic heart disease, cardiac failure, arrhythmia, arterial thromboembolism, and cardiac arrest. Aggressive ESA dosing to achieve higher hemoglobin levels and preexisting uncontrolled hypertension increases these cardiovascular side effects. Venous thromboembolism is the most significant adverse effect attributed to ESA therapy. However, there is no major change in overall survival with ESA therapy, and administration of ESAs can be carried out in anemic cancer patients with careful assessment of thromboembolism risk factors, risk-benefit ratio, and monitoring of hemoglobin levels.