Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicentre, open-label, phase 3, randomised, controlled trial

Background The triplet FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab showed improved outcomes for patients with metastatic colorectal cancer, compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizurnab. However, the actual benefit of the upfront exposure to the three cytotoxic drugs compared with a preplanned sequential strategy of doublets was not clear, and neither was the feasibility or efficacy of therapies after disease progression. We aimed to compare a preplanned strategy of upfront FOLFOXIRI followed by the reintroduction of the same regimen after disease progression versus a sequence of mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) and FOLFIRI doublets, in combination with bevacizurnab.Methods TRIBE2 was an open-label, phase 3, randomised study of patients aged 18-75 years with an Eastern Cooperative Oncology Group (ECOG) performance status of 2, with unresectable, previously untreated metastatic colorectal cancer, recruited from 58 Italian oncology units. Patients were stratified according to centre, ECOG performance status, primary tumour location, and previous adjuvant chemotherapy. A randomisation system incorporating a minimisation algorithm was used to randomly assign patients (1:1) via a masked web-based allocation procedure to two different treatment strategies. In the control group, patients received first-line mFOLFOX6 (85 mg/m(2) of intravenous oxaliplatin concurrently with 200 mg/m(2) of leucovorin over 120 min; 400 mg/m(2) intravenous bolus of fluorouracil; 2400 mg/m(2) continuous infusion of fluorouracil for 48 h) plus bevacizumab (5 mg/kg intravenously over 30 min) followed by FOLFIRI (180 mg/m(2) of intravenous irinotecan over 120 min concurrently with 200 mg/m 2 of leucovorin; 400 mg/m(2) intravenous bolus of fluorouracil; 2400 mg/m 2 continuous infusion of fluorouracil for 48 h) plus bevacizumab after disease progression. In the experimental group, patients received FOLFOXIRI (165 mg/m(2) of intravenous irinotecan over 60 min; 85 mg/m(2) intravenous oxaliplatin concurrently with 200 mg/m(2) of leucovorin over 120 min; 3200 mg/m(2) continuous infusion of fluorouracil for 48 h) plus bevacizumab followed by the reintroduction of the same regimen after disease progression. Combination treatments were repeated every 14 days for up to eight cycles followed by fluorouracil and leucovorin (at the same dose administered at the last induction cycle) plus bevacizumab maintenance until disease progression, unacceptable adverse events, or consent withdrawal. Patients and investigators were not masked. The primary endpoint was progression-free survival 2, defined as the time from randomisation to disease progression on any treatment given after first disease progression, or death, analysed by intention to treat. Safety was assessed in patients who received at least one dose of their assigned treatment. Study recruitment is complete and follow-up is ongoing. This trial is registered with Clinicaltrials.gov, NCT02339116.Findings Between Feb 26,2015, and May 15,2017,679 patients were randomly assigned and received treatment (340 in the control group and 339 in the experimental group). At data cut-off (July 30, 2019) median follow-up was 35.9 months (IQR 30-1-41-4). Median progression-free survival 2 was 19.2 months (95% CI 17.3-21-4) in the experimental group and 16.4 months (15.1-17-5) in the control group (hazard ratio [HR] 0-74,95% CI 0.63-0.88; p=0.0005). During the first-line treatment, the most frequent of all-cause grade 3-4 events were diarrhoea (57 [17%] vs 18 [5%1), neutropenia (168 [50%] vs 71 [21%1), and arterial hypertension (25 [7%] vs 35 [10%]) in the experimental group compared with the control group. Serious adverse events occurred in 84 (25%) patients in the experimental group and in 56 (17%) patients in the control group. Eight treatment-related deaths were reported in the experimental group (two intestinal occlusions, two intestinal perforations, two sepsis, one myocardial infarction, and one bleeding) and four in the control group (two occlusions, one perforation, and one pulmonary embolism). After first disease progression, no substantial differences in the incidence of grade 3 or 4 adverse events were reported between the control and experimental groups, with the exception of neurotoxicity, which was only reported in the experimental group (six [5%] of 132 patients). Serious adverse events after disease progression occurred in 20 (15%) patients in the experimental group and 25 (12%) in the control group. Three treatment-related deaths after first disease progression were reported in the experimental group (two intestinal occlusions and one sepsis) and four in the control group (one intestinal occlusion, one intestinal perforation, one cerebrovascular event, and one sepsis).Interpretation Upfront FOLFOXIRI plus bevacizumab followed by the reintroduction of the same regimen after disease progression seems to be a preferable therapeutic strategy to sequential administration of chemotherapy doublets, in combination with bevacizumab, for patients with metastatic colorectal cancer selected according to the study criteria. Copyright (C) 2020 Elsevier Ltd. All rights reserved

Survey of neonatal respiratory care and surfactant administration in very preterm infants in the Italian neonatal network

Introduction: Variation of respiratory care is described between centers around the world.The Italian Neonatal Network (INN), as a national group of the Vermont-Oxford Network (VON) allows to perform a wide analysis of respiratory care in very low birth weight infants. Methods:We analyzed the dataset of infants enrolled in the INN in 2009 and 2010 and, for surfactant administration only, from 2006 to 2010 from 83 participating centers. All definitions are those of the (VON). A questionnaire analysis was also performed with a questionnaire on centers practices. Results: We report data for 8297 infants. Data on ventilator practices and outcomes are outlined. Variation for both practices and outcome is found. Trend in surfactant administration is also analyzed. Conclusions. The great variation across hospitals in all the surveyed techniques points to the possibility of implementing potentially better practices with the aim of reducing unwanted variation. These data also show the power of large neonatal networks in identifying areas for potential improvement. \ua9 Mattioli 1885

Survey of neonatal respiratory care and surfactant administration in very preterm infants in the Italian neonatal network

Introduction: Variation of respiratory care is described between centers around the world.The Italian Neonatal Network (INN), as a national group of the Vermont-Oxford Network (VON) allows to perform a wide analysis of respiratory care in very low birth weight infants. Methods:We analyzed the dataset of infants enrolled in the INN in 2009 and 2010 and, for surfactant administration only, from 2006 to 2010 from 83 participating centers. All definitions are those of the (VON). A questionnaire analysis was also performed with a questionnaire on centers practices. Results: We report data for 8297 infants. Data on ventilator practices and outcomes are outlined. Variation for both practices and outcome is found. Trend in surfactant administration is also analyzed. Conclusions. The great variation across hospitals in all the surveyed techniques points to the possibility of implementing potentially better practices with the aim of reducing unwanted variation. These data also show the power of large neonatal networks in identifying areas for potential improvement. © Mattioli 1885

Association of maternal hypertension and chorioamnionitis with preterm outcomes

OBJECTIVES: We compared the relative effect of hypertensive disorders of pregnancy and chorioamnionitis on adverse neonatal outcomes in very preterm neonates, and studied whether gestational age (GA) modulates these effects. METHODS: A cohort of neonates 23 to 30 weeks' GA, born in 2008 to 2011 in 82 hospitals adhering to the Italian Neonatal Network, was analyzed. Infants born from mothers who had hypertensive disorders (N = 2096) were compared with those born after chorioamnionitis (N = 1510). Statistical analysis employed logistic models, adjusting for GA, hospital, and potential confounders. RESULTS: Overall mortality was higher after hypertension than after chorioamnionitis (odds ratio [OR], 1.39; 95% confidence interval [CI], 1.08-1.80), but this relationship changed across GA weeks; the OR for hypertension was highest at low GA, whereas from 28 weeks' GA onward, mortality was higher for chorioamnionitis. For other outcomes, the relative risks were constant across GA; infants born after hypertension had an increased risk for bronchopulmonary dysplasia (OR, 2.20; 95% CI, 1.68-2.88) and severe retinopathy of prematurity (OR, 1.48; 95% CI, 1.02-2.15), whereas there was a lower risk for early-onset sepsis (OR, 0.25; 95% CI, 0.19-0.34), severe intraventricular hemorrhage (OR, 0.65; 95% CI, 0.48-0.88), periventricular leukomalacia (OR, 0.70; 95% CI, 0.48-1.01), and surgical necrotizing enterocolitis or gastrointestinal perforation (OR, 0.47; 95% CI, 0.31-0.72). CONCLUSIONS: Mortality and other adverse outcomes in very preterm infants depend on antecedents of preterm birth. Hypertension and chorioamnionitis are associated with different patterns of outcomes; for mortality, the effect changes across GA weeks. Copyright \uc2\ua9 2014 by the American Academy of Pediatrics