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.
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.
The efficacy and safety of Trilaciclib in preventing chemotherapy-induced myelosuppression: a systematic review and meta-analysis of randomized controlled trials
Frontiers in pharmacology. 2023;14:1157251
Background: This study aims to assess the clinical efficacy and safety of Trilaciclib in preventing chemotherapy-induced myelosuppression in adult patients through meta-analysis. Methods: The PubMed, Embase, Cochrane Library, Clinical Trials, EU Clinical Trials Register, and International Clinical Trials Registry Platform were searched up to 25 October 2022. Only randomized controlled trials (RCTs) comparing the clinical outcomes of Trilaciclib and Trilaciclib plus chemotherapy for treating malignant cancers in adult patients were included. The primary outcome included the incidence of SN, FN, the DSN, and administration of ESAs, G-CSFs, and RBC or platelet transfusions, while the secondary outcomes included the risk of adverse events (AEs) and severe adverse events (SAEs). Results: In total, four randomized controlled trials (RCTs) involving 345 patients with SCLC or breast cancer were included in this meta-analysis. Results showed that administration of Trilaciclib significantly reduced the occurrence of SN (19.3% vs. 42.2%, OR = 0.31), FN (3.22% vs. 6.72%, OR = 0.47), anemia (20.5% vs. 38.2%, OR = 0.38) and shortened the DSN during treatment. The proportion of patients receiving therapeutic use of ESAs (4.03% vs. 11.8%, OR = 0.31), G-CSF (37.0% vs. 53.5%, OR = 0.52), RBC transfusions (19.8% vs. 29.9%, OR = 0.56) was also statistically lower in the experimental group than in the control group. Meanwhile, the ORR, overall survival, and progress-free survival of the two groups were identical, and no negative impact of Trilaciclib on the clinical outcomes of chemotherapy treatments was found. Other chemotherapy-induced adverse events (AEs) and severe adverse events (SAEs) like diarrhea, fatigue, nausea, and vomiting were identical regardless of Trilaciclib usage. Conclusion: Trilaciclib demonstrated its efficacy in reducing the occurrence of chemotherapy-induced myelosuppression and utilization of supportive care interventions without undermining the clinical benefits of chemotherapy regimens during treatment with an acceptable safety profile.
Oxidized Regenerated Cellulose Versus Calcium Alginate in Controlling Bleeding From Malignant Wounds: A Randomized Controlled Trial
Cancer nursing. 2023
BACKGROUND There is no consensus on the best intervention for topical management of bleeding in malignant wounds. Although surgical hemostatic dressings are recommended, the use of calcium alginate (CA) is frequent among practitioners. OBJECTIVE The aim of this study was to evaluate the hemostatic efficacy of oxidized regenerated cellulose (ORC) and CA dressing in the management of bleeding from malignant wounds resulting from breast cancer. METHODS This was a randomized open clinical trial. The outcomes measured were total time to hemostasis and the number of hemostatic products used. RESULTS Sixty-one patients were potentially eligible for the study, 1 did not consent, and 32 were assessed to be ineligible, resulting in a sample of 28 who were randomized to 2 study groups. Total time to hemostasis was 93.8 seconds in the ORC group, with an average of 30.1 seconds (95% confidence interval, 18.6-189 seconds), and 67 seconds in the CA group, with an average of 30.4 seconds (confidence interval, 21.7 seconds to imprecise upper limit). The main difference was 26.8 seconds. Kaplan-Meier log-rank test, and Cox model showed no statistical significance (P = 0.894). A total of 18 hemostatic products were used in the CA group and 34 in the ORC group. No adverse effects were identified. CONCLUSIONS Although no significant differences were identified in terms of time, more hemostatic products were used in the ORC group, highlighting the effectiveness of CA. IMPLICATIONS FOR PRACTICE Calcium alginate may be the first choice in the management of bleeding in malignant wounds, favoring nursing in the most immediate hemostatic actions.
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.
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.
Romiplostim for chemotherapy-induced thrombocytopenia: Efficacy and safety of extended use
Research and practice in thrombosis and haemostasis. 2022;6(3):e12701
BACKGROUND Chemotherapy-induced thrombocytopenia (CIT) is common during treatment with antineoplastic therapies and may adversely impact chemotherapy dose intensity. There is no approved therapy for CIT. In our recent phase II randomized study, romiplostim led to correction of platelet counts in 85% of treated patients and allowed resumption of chemotherapy, with low rates of recurrent CIT in the first two cycles or 8 weeks of chemotherapy. However, there is a lack of long-term data on the efficacy and safety of romiplostim in CIT. OBJECTIVES To analyze efficacy and safety of romiplostim in the patients in the phase 2 study, who received romiplostim for ≥1 year. PATIENTS/METHODS Twenty-one patients remained on romiplostim for ≥1 year. We analyzed the effect of romiplostim on platelet counts, absolute neutrophil counts, and hemoglobin, as well as impact on ongoing chemotherapy. We also tracked venous or arterial thrombotic events. RESULTS During the study period, romiplostim was effective in preventing reduction of chemotherapy dose intensity due to CIT. Fourteen of the 20 (70%) analyzable patients experienced no episode of CIT, 4 subjects experienced a single chemotherapy dose delay due CIT, and 2 patients required a chemotherapy dose reduction. Platelet counts were preserved throughout the duration of the extension analysis. One patient experienced a proximal deep vein thrombosis, and one patient experienced multiple tumor-related ischemic events. CONCLUSIONS Long-term use of romiplostim for treatment of CIT was effective and safe, with no evidence of resistance or increased risk of thrombosis.
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.
Avatrombopag for chemotherapy-induced thrombocytopenia in patients with non-haematological malignancies: an international, randomised, double-blind, placebo-controlled, phase 3 trial
The Lancet. Haematology. 2022;9(3):e179-e189
BACKGROUND Chemotherapy-induced thrombocytopenia is common and causes chemotherapy dose reductions or treatment delays, bleeding, and suboptimal oncological outcomes. We aimed to evaluate avatrombopag, a thrombopoietin receptor agonist that increases platelet counts, in patients with non-haematological cancer and platelet counts lower than 50 ×10(9) cells per L. METHODS In this randomised, double-blind, placebo-controlled, phase 3 study, patients aged 18 years or older at 71 hospitals or cancer treatment centres in China, Hungary, Poland, Russia, Serbia, Ukraine, and the USA and with ovarian, bladder, or lung cancer receiving chemotherapy who had severe thrombocytopenia were randomly assigned (2:1) to oral avatrombopag 60 mg or oral placebo once daily given 5 days before and after chemotherapy, with randomisation stratified by number of chemotherapy drugs used. Patients, investigators, and data collectors were masked to group allocation. Eligibility required two previous lines of chemotherapy or fewer, an ECOG performance status of 2 or less, and no previous history of chemotherapy-induced thrombocytopenia. The composite primary endpoint was the proportion of responders not requiring platelet transfusion or either a 15% or more chemotherapy dose reduction or a 4-day or more chemotherapy delay due to thrombocytopenia following study treatment until the start of the subsequent cycle. Analyses were done on the intention-to-treat and per protocol populations. Safety was analysed in all patients who received at least one dose of avatrombopag. The trial is registered with ClinicalTrials.gov, NCT03471078, and has been completed. FINDINGS Between Oct 12, 2018, and June 28, 2020, 122 patients were enrolled and randomly assigned to receive avatrombopag (n=82) or placebo (n=40). Median follow-up was 31 days (IQR 22-61). Similar proportions of patients reached the primary endpoint in the avatrombopag and placebo groups (intention-to-treat: 57 [70%, 95% CI 58-79] of 82 vs 29 [73%, 95% CI 56-85] of 40; difference -3·0% (95% CI -21·6 to 15·6); p=0·72; per protocol: 51 [85%, 95% CI 73-93] of 60 vs 27 [84%, 95% CI 67-95] of 32; 0·6% (95% CI -20·8 to 22·1); p=0·96). 15 (18%) of 82 patients had serious adverse events in the avatrombopag group and eight (20%) of 40 in the placebo group, of which thrombocytopenia was most common (4 [5%] of 82 and 4 [10%] of 40 patients). Common grade 3-4 treatment-emergent adverse events were neutropenia (22 [27%] of 82 and 16 [40%] of 40 patients), leukopenia (19 [23%] of 82 and 5 [13%] of 40), anaemia (16 [20%] of 82 and 9 [23%] of 40), and thrombocytopenia (16 [20%] of 82 and 14 [35%] of 40). Most adverse events were considered unrelated to study drug. No treatment-related deaths were reported. INTERPRETATION In this population of patients with non-haematological malignancies who are relatively chemotherapy naive, chemotherapy-induced thrombocytopenia treatment outcomes were similar between the avatrombopag and placebo groups. Given its safety and ability to augment platelet counts in patients with chemotherapy-induced thrombocytopenia, evaluation of avatrombopag in populations with more persistent chemotherapy-induced thrombocytopenia is warranted. FUNDING Dova Pharmaceuticals, a Sobi company.