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.
Efficacy of UVC-treated, pathogen-reduced platelets versus untreated platelets: a randomized controlled non-inferiority trial
Pathogen reduction (PR) technologies for blood components have been established to reduce the residual risk of known and emerging infectious agents. THERAFLEX UVPlatelets, a novel UVC light-based PR technology for platelet concentrates, works without photoactive substances. This randomized, controlled, double-blind, multicenter, noninferiority trial was designed to compare the efficacy and safety of UVC-treated platelets to that of untreated platelets in thrombocytopenic patients with hematologic-oncologic diseases. Primary objective was to determine non-inferiority of UVC-treated platelets, assessed by the 1-hour corrected count increment (CCI) in up to eight per-protocol platelet transfusion episodes. Analysis of the 171 eligible patients showed that the defined non-inferiority margin of 30% of UVC-treated platelets was narrowly missed as the mean differences in 1-hour CCI between standard platelets versus UVC-treated platelets for intention-to-treat and perprotocol analyses were 18.2% (95% confidence interval [CI]: 6.4%; 30.1) and 18.7% (95% CI: 6.3%; 31.1%), respectively. In comparison to the control, the UVC group had a 19.2% lower mean 24-hour CCI and was treated with an about 25% higher number of platelet units, but the average number of days to next platelet transfusion did not differ significantly between both treatment groups. The frequency of low-grade adverse events was slightly higher in the UVC group and the frequencies of refractoriness to platelet transfusion, platelet alloimmunization, severe bleeding events, and red blood cell transfusions were comparable between groups. Our study suggests that transfusion of pathogen-reduced platelets produced with the UVC technology is safe but non-inferiority was not demonstrated. (The German Clinical Trials Register number: DRKS00011156).
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 Safety of Ferric Carboxymaltose Infusion in Reducing Anemia in Patients Receiving Chemotherapy for Nonmyeloid Malignancies: a Randomized, Placebo-Controlled Study (IRON CLAD)
American journal of hematology. 2021
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.
Patients receiving chemotherapy for non-myeloid malignancies with chemotherapy-induced anaemia (CIA), enrolled in the IRON-CLAD study conducted at 58 sites in the United States, Bulgaria, Georgia, Hungary, and Poland (n= 244).
Ferric carboxymaltose (FCM) infusions (n= 122).
Placebo (n= 122).
The percentage of patients 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%). 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). The percent with >= 1 g/dL increase from baseline was significantly higher with FCM versus placebo (71% vs. 54%), occurring in a median 43 versus 85 days. Common adverse events in the FCM arm included neutropenia (17%), hypophosphatemia (16%), and fatigue (15%). FCM monotherapy effectively maintained Hb and was well tolerated in CIA.
Estimating Bleeding Risk in Patients with Cancer-Associated Thrombosis: Evaluation of Existing Risk Scores and Development of a New Risk Score
Thrombosis and haemostasis. 2021
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.
Preoperative tranexamic acid does not reduce transfusion rates in major oncologic surgery: Results of a randomized, double-blind, and placebo-controlled trial
J Surg Oncol. 2020
BACKGROUND AND OBJECTIVES Allogeneic blood transfusions are associated with worse postoperative outcomes in oncologic surgery. The aim of this study was to introduce a preoperative intervention to reduce transfusion rates in this population. METHODS Adult patients undergoing major oncologic surgery in five categories with similar transfusion rates were recruited. Enrollees received a single preoperative intravenous dose of placebo or tranexamic acid (1000 mg). The primary outcome measure was perioperative transfusion rate. Secondary outcome measures included: estimated blood loss, thromboembolic events, morbidity, hospital length of stay, and readmission rate. RESULTS Seventy-six patients were enrolled, 39 in the tranexamic acid group and 37 in the placebo group, respectively. Demographics and surgery type were equivalent between groups. The transfusion rates were 8 out of 39 (20.5%) in the tranexamic acid group and 5 out of 37 (13.5%) in the placebo group, respectively (P = .418). Median estimated blood loss was 400 mL (interquartile range [IQR] = 150-600) in the tranexamic acid group compared with 300 mL (IQR = 150-800) in the placebo group (P = .983). There was one pulmonary embolism in each arm and no deep venous thrombosis (P > .999). CONCLUSION Preoperative administration of tranexamic acid at a 1000 mg intravenous dose does not decrease transfusion rates or estimated blood loss in patients undergoing major oncologic surgery.
Patients undergoing major oncologic surgery (n= 76).
Preoperative intravenous dose of tranexamic acid (n= 39).
Placebo (n= 37).
Transfusion rates were 8 out of 39 (20.5%) in the tranexamic acid group and 5 out of 37 (13.5%) in the placebo group. Median estimated blood loss was 400 mL (interquartile range [IQR] = 150-600) in the tranexamic acid group compared with 300 mL (IQR = 150-800) in the placebo group. There was one pulmonary embolism in each arm and no deep venous thrombosis.
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.
Nanoparticle Albumin-bound Paclitaxel Plus Carboplatin Induction Followed by Nanoparticle Albumin-bound Paclitaxel Maintenance in Squamous Non-Small-cell Lung Cancer (ABOUND.sqm): A Phase III Randomized Clinical Trial
Clinical lung cancer. 2020
BACKGROUND We evaluated maintenance nanoparticle albumin-bound (nab) paclitaxel in the treatment of advanced squamous non-small-cell lung cancer. PATIENTS AND METHODS Patients with treatment-naive squamous non-small-cell lung cancer received four 21-day cycles of nab-paclitaxel 100 mg/m(2) on days 1, 8, 15 plus carboplatin area under the curve 6 on day 1 as induction therapy. Patients without disease progression after induction were randomized 2:1 to maintenance nab-paclitaxel 100 mg/m(2) (days 1 and 8 every 21 days) plus best supportive care (BSC) or BSC alone. The primary endpoint was progression-free survival (PFS). Secondary endpoints included safety and overall survival (OS). RESULTS Overall, 420 patients had received induction therapy; 202 (nab-paclitaxel plus BSC, 136; BSC, 66) had received maintenance therapy. Enrollment was discontinued after a preplanned interim futility analysis (patients could remain in the study at the investigator's discretion). The median PFS was 3.12 months for nab-paclitaxel plus BSC and 2.60 months for BSC; the difference was not statistically significant (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.61-1.19; P = .36). The median OS (median follow-up, 24.2 months) was 17.18 months for nab-paclitaxel plus BSC and 12.16 months for BSC (HR, 0.70; 95% CI, 0.48-1.02; nominal P = .07). An updated analysis (median follow-up, 28.4 months) revealed a median OS of 17.61 months for nab-paclitaxel plus BSC and 12.16 months for BSC (HR, 0.68; 95% CI, 0.47-0.98; nominal P = .037). The most frequent grade 3 and 4 treatment-emergent adverse events for the entire study were neutropenia (53.1% [nab-paclitaxel plus BSC] vs. 50.0% [BSC]) and anemia (33.1% [nab-paclitaxel plus BSC] vs. 32.3% [BSC]). Only peripheral neuropathy had occurred in ≥ 5% of patients during maintenance therapy (13.1%; nab-paclitaxel plus BSC). CONCLUSIONS The results of the ABOUND.sqm did not meet the primary endpoint of PFS. An updated OS analysis revealed a trend favoring nab-paclitaxel plus BSC.
A Randomized Controlled Trial of Novel Treatment for Hemorrhagic Radiation Proctitis
Asian Pacific journal of cancer prevention : APJCP. 2020;21(10):2927-2934
BACKGROUND Various methods have been used for treatment of hemorrhagic radiation proctitis (HRP) with variable results. Currently, the preferred treatment is formalin application or endoscopic therapy with argon plasma coagulation. Recently, a novel therapy with colonic water irrigation and oral antibiotics showed promising results and more effective compared to 4% formalin application for HRP. The study objective is to compare the effect of water irrigation and oral antibiotics versus 4% formalin application in improving per rectal bleeding due to HRP and related symptoms such as diarrhoea, tenesmus, stool frequency, stool urgency and endoscopic findings. METHODS We conducted a study on 34 patients with HRP and randomly assigned the patients to two treatment arm groups (n=17). The formalin group underwent 4% formalin dab and another session 4 weeks later. The irrigation group self-administered daily rectal irrigation at home for 8 weeks and consumed oral metronidazole and ciprofloxacin during the first one week. We measured the patients' symptoms and endoscopic findings before and after total of 8 weeks of treatment in both groups. RESULTS Our study showed that HRP patients had reduced per rectal bleeding (p = 0.003) in formalin group, whereas irrigation group showed reduced diarrhoea (p=0.018) and tenesmus (p=0.024) symptoms. The comparison between the two treatment arms showed that irrigation technique was better than formalin technique for tenesmus (p=0.043) symptom only. CONCLUSION This novel treatment showed benefit in treating HRP. It could be a new treatment option which is safe and conveniently self-administered at home or used as a combination with other therapies to improve the treatment outcome for HRP.
Platelet-rich fibrin: an autologous biomaterial for healing assistance of pharyngeal repair in total laryngectomy
European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery. 2020
OBJECTIVES The aim of this study was to evaluate the potential role of platelet-rich fibrin (PRF) application on the pharyngeal repair on decreasing the incidence of pharyngocutaneous fistula (PCF) after total laryngectomy. METHODS This randomized controlled clinical trial was conducted on 67 patients with advanced laryngeal carcinoma who underwent total laryngectomy, over 2 years in the Otorhinolaryngology Department, Mansoura University Hospitals, Egypt. Patients were randomly assigned into two groups: PRF group (n = 35) and control group (n = 32). Risk factors for development of PCF as well as the incidence of PCF were studied in both groups. RESULTS There was no statistically significant difference between groups regarding demographic data, medical comorbidities, basal hemoglobin and albumin levels, data related to the tumor (location, grade and TNM staging) and surgical details (preoperative tracheotomy and neck dissection). However, regarding the incidence of PCF, there was a statistically significant difference between groups as shown in Table 2. PCF was detected in 2/35 patients (5.7%) in the PRF group and in 10/32 patients (31.3%) in the control group (p = 0.004). CONCLUSION PRF application on the pharyngeal repair after total laryngectomy enhances the healing process and consequently decreases the incidence of PCF.