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.

Abstract

BACKGROUND The impact of blood transfusion on ovarian cancer survival is uncertain. OBJECTIVE To investigate whether peri-operative blood transfusion negatively impacted progression-free survival, overall survival, and quality of life in patients with advanced ovarian cancer. METHODS We performed an ancillary analysis of the European Organization for Research and Treatment (EORTC) 55971 phase III trial, in which patients were randomized to primary debulking surgery versus neoadjuvant chemotherapy. Patients included in the per-protocol analysis were categorized by receipt of a transfusion. RESULTS 612 of 632 (97%) of patients had adequate data for analysis. Of those, 323 (53%) received a transfusion. The transfusion cohort was more likely to have had better Word Health Organization (WHO) performance status, serous histology, undergone primary debulking surgery, and received more aggressive surgery, with higher rates of no gross residual disease. Median overall survival was 34.0 vs 35.2 months in the no transfusion and transfusion cohorts (p=0.97). The adjusted HR for death was 1.18 (95% CI 0.94 to 1.48) in favor of the transfusion cohort. Median progression-free survival was 13.6 vs 12.6 months in the no transfusion and transfusion cohorts (p=0.96). The adjusted HR for progression was 1.14 (95% CI 0.91 to 1.43). There were no significant differences in global quality of life, fatigue, dyspnea, or physical functioning between the two cohorts at baseline or at any of the four assessment times. Grade 3 and 4 surgical site infections were more common in the transfusion cohort. CONCLUSION Transfusion did not negatively impact progression-free survival or overall survival; however, it was associated with increased peri-operative morbidity without improvements in quality of life.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

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.

Abstract

BACKGROUND  Bleeding risk is highly relevant for treatment decisions in cancer-associated thrombosis (CAT). Several risk scores exist, but have never been validated in patients with CAT and are not recommended for practice. OBJECTIVES  To compare methods of estimating clinically relevant (major and clinically relevant nonmajor) bleeding risk in patients with CAT: (1) existing risk scores for bleeding in venous thromboembolism, (2) pragmatic classification based on cancer type, and (3) new prediction model. METHODS  In a posthoc analysis of the Hokusai VTE Cancer study, a randomized trial comparing edoxaban with dalteparin for treatment of CAT, seven bleeding risk scores were externally validated (ACCP-VTE, HAS-BLED, Hokusai, Kuijer, Martinez, RIETE, and VTE-BLEED). The predictive performance of these scores was compared with a pragmatic classification based on cancer type (gastrointestinal; genitourinary; other) and a newly derived competing risk-adjusted prediction model based on clinical predictors for clinically relevant bleeding within 6 months after CAT diagnosis with nonbleeding-related mortality as the competing event ("CAT-BLEED"). RESULTS  Data of 1,046 patients (149 events) were analyzed. Predictive performance of existing risk scores was poor to moderate (C-statistics: 0.50-0.57; poor calibration). Internal validation of the pragmatic classification and "CAT-BLEED" showed moderate performance (respective C-statistics: 0.61; 95% confidence interval [CI]: 0.56-0.66, and 0.63; 95% CI 0.58-0.68; good calibration). CONCLUSION  Existing risk scores for bleeding perform poorly after CAT. Pragmatic classification based on cancer type provides marginally better estimates of clinically relevant bleeding risk. Further improvement may be achieved with "CAT-BLEED," but this requires external validation in practice-based settings and with other DOACs and its clinical usefulness is yet to be demonstrated.

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.

Abstract

PURPOSE Erythropoiesis-stimulating agents (ESA) are effective for chemotherapy-induced anemia (CIA) but associated with serious adverse events. Safer alternatives would be beneficial in this population. The efficacy and safety of ferric carboxymaltose (FCM) as monotherapy for CIA was evaluated. METHODS This Phase 3, 18-week, double-blind, placebo-controlled study randomized adults with ≥4 weeks of chemotherapy remaining for treatment of nonmyeloid malignancies with CIA to FCM (two 15 mg/kg infusions 7 days apart; maximum dose, 750 mg single/1500 mg total) or placebo. The primary efficacy endpoint was percentage of patients with decreases in hemoglobin (Hb) ≥0.5 g/dL from weeks 3 to 18; the key secondary efficacy endpoint was change in Hb from baseline to week 18. Inclusion criteria included: (Hb) 8-11 g/dL, ferritin 100-800 ng/mL, and transferrin saturation (TSAT) ≤35%. RESULTS In 244 patients (n=122, both groups), the percent who maintained Hb within 0.5 g/dL of baseline from weeks 3 to 18 was significantly higher with FCM versus placebo (50.8% vs 35.3%; P=0.01). Mean change in Hb from baseline to week 18 was similar between FCM and placebo (1.04 vs 0.87 g/dL) but significantly greater with FCM with baseline Hb ≤9.9 g/dL (1.08 vs 0.42 g/dL; P=0.01). The percent with ≥1 g/dL increase from baseline was significantly higher with FCM versus placebo (71% vs 54%; P=0.01), occurring in a median 43 versus 85 days (P=0.001). Common adverse events in the FCM arm included neutropenia (17%), hypophosphatemia (16%), and fatigue (15%). CONCLUSION FCM monotherapy effectively maintained Hb and was well tolerated in CIA. This article is protected by copyright. All rights reserved.

Abstract

BACKGROUND Endoscopic submucosal dissection (ESD) is associated with a risk of bleeding. Bleeding is usually treated with diathermy, although this does carry a risk of mucosal thermal injury. Purastat is a topical hemostat that may be effective in controlling bleeding during ESD, thereby reducing the use of heat therapy. The aim of this study was to assess the reduction in heat therapy used in the interventional group (Purastat) compared with the control group. The secondary aims were to compare the procedure length, time for hemostasis, delayed bleeding rate, adverse events, and wound healing between the groups. METHODS This was a single-center randomized controlled trial of 101 patients undergoing ESD. Participants were randomized to a control group where diathermy was used to control bleeding or an interventional group where Purastat could be used. Follow-up endoscopy was performed at 4 weeks to assess wound healing. RESULTS There was a significant reduction in the use of heat therapy for intraprocedural hemostasis in the interventional group compared with controls (49.3 % vs. 99.6 %, P < 0.001). There were no significant differences in the procedure length, time for hemostasis, and delayed bleeding rate between the groups. Complete wound healing at 4 weeks was noted in 48.8 % of patients in the interventional group compared with 25.0 % of controls (P = 0.02). CONCLUSIONS This study has demonstrated that Purastat is an effective hemostat that can reduce the need for heat therapy for bleeding during ESD. It may also have a role in improving post-resection wound healing.