Efficacy of early PET-CT directed switch to carboplatin and paclitaxel based definitive chemoradiotherapy in patients with oesophageal cancer who have a poor early response to induction cisplatin and capecitabine in the UK: a multi-centre randomised controlled phase II trial

Somnath Mukherjee; Christopher N Hurt; Richard Adams; Andrew Bateman; Kevin M Bradley; Sarah Bridges; Stephen Falk; Gareth Griffiths; Sarah Gwynne; Christopher M Jones; Philip J Markham; Tim Maughan; Lisette S Nixon; Ganesh Radhakrishna; Rajarshi Roy; Simon Schoenbuchner; Hamid Sheikh; Emiliano Spezi; Maria Hawkins; Thomas D L Crosby

doi:10.1016/j.eclinm.2023.102059

Efficacy of early PET-CT directed switch to carboplatin and paclitaxel based definitive chemoradiotherapy in patients with oesophageal cancer who have a poor early response to induction cisplatin and capecitabine in the UK: a multi-centre randomised controlled phase II trial

EClinicalMedicine. 2023 Jun 26:61:102059. doi: 10.1016/j.eclinm.2023.102059. eCollection 2023 Jul.

Authors

Somnath Mukherjee¹, Christopher N Hurt^{2

3}, Richard Adams², Andrew Bateman⁴, Kevin M Bradley⁵, Sarah Bridges², Stephen Falk⁶, Gareth Griffiths³, Sarah Gwynne⁷, Christopher M Jones⁸, Philip J Markham², Tim Maughan⁹, Lisette S Nixon², Ganesh Radhakrishna¹⁰, Rajarshi Roy¹¹, Simon Schoenbuchner², Hamid Sheikh¹⁰, Emiliano Spezi¹², Maria Hawkins¹³, Thomas D L Crosby¹⁴

Affiliations

¹ Oxford Cancer Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
² Centre for Trials Research, Cardiff University, Cardiff, UK.
³ Southampton Clinical Trials Unit, University of Southampton, Southampton, UK.
⁴ University Hospital Southampton NHS Foundation Trust, Southampton, UK.
⁵ Wales Research and Diagnostic Positron Emission Tomography Centre (PETIC), Cardiff University, Cardiff, UK.
⁶ University Hospitals Bristol NHS Foundation Trust, Bristol, UK.
⁷ South West Wales Cancer Centre, Swansea Bay University Health Board, Swansea, UK.
⁸ Department of Oncology, University of Cambridge, Cambridge, UK.
⁹ Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
¹⁰ The Christie Hospital, The Christie Hospitals NHS Foundation Trust, Manchester, UK.
¹¹ Queen's Centre for Oncology, Hull University Teaching Hospitals NHS Trust, UK.
¹² School of Engineering, Cardiff University, Cardiff, UK.
¹³ Department of Medical Physics & Biomedical Engineering, University College London, London, UK.
¹⁴ Velindre Cancer Centre, Velindre University NHS Trust, Cardiff, UK.

Abstract

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 (SUV_max) 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.

Keywords: Chemoradiotherapy; Oesophageal adenocarcinoma; Oesophageal squamous cell carcinoma.

Associated data

ClinicalTrials.gov/NCT02741856