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Background: The utility of early metabolic response assessment to guide selection of the systemic component of definitive chemoradiotherapy (dCRT) for oesophageal cancer is uncertain. Methods: In this multi-centre, randomised, open-label, phase II substudy of the radiotherapy dose-escalation SCOPE2 trial we evaluated the role of 18F-Fluorodeoxyglucose positron emission tomography (PET) at day 14 of cycle 1 of three-weekly induction cis/cap (cisplatin (60 mg/m2)/capecitabine (625 mg/m2 days 1-21)) in patients with oesophageal squamous cell carcinoma (OSCC) or adenocarcinoma (OAC). Non-responders, who had a less than 35% reduction in maximum standardised uptake value (SUVmax) from pre-treatment baseline, were randomly assigned to continue cis/cap or switch to car/pac (carboplatin AUC 5/paclitaxel 175 mg/m2) for a further induction cycle, then concurrently with radiotherapy over 25 fractions. Responders continued cis/cap for the duration of treatment. All patients (including responders) were randomised to standard (50Gy) or high (60Gy) dose radiation as part of the main study. Primary endpoint for the substudy was treatment failure-free survival (TFFS) at week 24. The trial was registered with International Standard Randomized Controlled Trial Number 97125464 and ClinicalTrials.govNCT02741856. Findings: This substudy was closed on 1st August 2021 by the Independent Data Monitoring Committee on the grounds of futility and possible harm. To this point from 22nd November 2016, 103 patients from 16 UK centres had participated in the PET-CT substudy; 63 (61.2%; 52/83 OSCC, 11/20 OAC) of whom were non-responders. Of these, 31 were randomised to car/pac and 32 to remain on cis/cap. All patients were followed up until at least 24 weeks, at which point in OSCC both TFFS (25/27 (92.6%) vs 17/25 (68%); p = 0.028) and overall survival (42.5 vs. 20.4 months, adjusted HR 0.36; p = 0.018) favoured cis/cap over car/pac. There was a trend towards worse survival in OSCC + OAC cis/cap responders (33.6 months; 95%CI 23.1-nr) vs. non-responders (42.5 (95%CI 27.0-nr) months; HR = 1.43; 95%CI 0.67-3.08; p = 0.35). Interpretation: In OSCC, early metabolic response assessment is not prognostic for TFFS or overall survival and should not be used to personalise systemic therapy in patients receiving dCRT. Funding: Cancer Research UK.
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INTRODUCTION: The BATCH trial is a multi-centre randomised controlled trial to compare procalcitonin-guided management of severe bacterial infection in children with current management. PRECISE is a mechanistic sub-study embedded into the BATCH trial. This paper describes the statistical analysis plan for the BATCH trial and PRECISE sub-study. METHODS: The BATCH trial will assess the effectiveness of an additional procalcitonin test in children (aged 72 h to 18 years) hospitalised with suspected or confirmed bacterial infection to guide antimicrobial prescribing decisions. Participants will be enrolled in the trial from randomisation until day 28 follow-up. The co-primary outcomes are duration of intravenous antibiotic use and a composite safety outcome. Target sample size is 1942 patients, based on detecting a 1-day reduction in intravenous antibiotic use (90% power, two-sided) and on a non-inferiority margin of 5% risk difference in the composite safety outcome (90% power, one-sided), while allowing for up to 10% loss to follow-up. RESULTS: Baseline characteristics will be summarised overall, by trial arm, and by whether patients were recruited before or after the pause in recruitment due to the COVID-19 pandemic. In the primary analysis, duration of intravenous antibiotic use will be tested for superiority using Cox regression, and the composite safety outcome will be tested for non-inferiority using logistic regression. The intervention will be judged successful if it reduces the duration of intravenous antibiotic use without compromising safety. Secondary analyses will include sensitivity analyses, pre-specified subgroup analyses, and analysis of secondary outcomes. Two sub-studies, including PRECISE, involve additional pre-specified subgroup analyses. All analyses will be adjusted for the balancing factors used in the randomisation, namely centre and patient age. CONCLUSION: We describe the statistical analysis plan for the BATCH trial and PRECISE sub-study, including definitions of clinical outcomes, reporting guidelines, statistical principles, and analysis methods. The trial uses a design with co-primary superiority and non-inferiority endpoints. The analysis plan has been written prior to the completion of follow-up. TRIAL REGISTRATION: BATCH: ISRCTN11369832, registered 20 September 2017, doi.org/10.1186/ISRCTN11369832. PRECISE: ISRCTN14945050, registered 17 December 2020, doi.org/10.1186/ISRCTN14945050.