Pre-operative proton versus photon-based chemoradiotherapy as an addition to best systemic therapy in the management of oesophageal cancer: protocol for the UK multi-centre randomised phase 2 PROTIEUS study.

backgroundOesophageal cancer is a major cause of morbidity and mortality. Around 40% of patients present with locally advanced disease. Outcomes are poor, with 5-year survival of around 50% for locally advanced oesophageal adenocarcinoma (OAC) and 60% for oesophageal squamous cell carcinoma (OSCC). Over a fifth of recurrences are locoregional. These may be reduced by the addition of chemoradiotherapy (CRT) to best pre-operative systemic anti-cancer therapy (SACT). However, photon-based CRT is associated with a higher frequency of complications than chemotherapy alone. This study will explore whether, in patients with locally advanced OAC and OSCC managed with hypofractionated CRT following best pre-operative systemic therapy, the use of proton beam therapy (PBT) reduces post-operative complications when compared with photon-based treatment. METHODS/

designPROTIEUS is an investigator-initiated randomised multi-centre phase 2 trial aiming to recruit 170 patients with locally advanced OAC (n = 130) or OSCC (n = 40) from the UK National Health Service. Patients with locally advanced cT ≥ 2, N0-2 non-metastatic disease are eligible for inclusion and will be randomised 1:1 to receive 40.05 Gy (RBE) in 15 fractions over three weeks using either PBT or intensity modulated/rotational arc photon radiotherapy. All patients will receive three one-week cycles of concurrent intravenous carboplatin/paclitaxel. CRT will be delivered following best pre-operative SACT. The primary endpoint is the rate of severe post-operative complications within 90 days post-surgery (grade 3 or higher Clavien-Dindo classification and CTCAE v5.0). Secondary endpoints relate to efficacy (pathological complete response and clear resection margin rate, disease-free and overall survival), tolerability (completion of planned CRT regime, time to and completion of adjuvant therapy), morbidity (long-term quality of life measures) and health economics (cost-effectiveness analyses using EQ-5D-5 L and resource use assessments). DISCUSSION: There is a need to improve local control in OAC and OSCC. Given only modest gains with perioperative immune checkpoint inhibition and a disease landscape in which there are few targets for precision or personalised therapies, there are limited options to achieve further gains across the disease population using SACT. This study will therefore determine which of PBT or photon-based pre-operative CRT is the most tolerable and least toxic for integration into existing systemic treatment paradigms.

trial registrationhttps://doi.org/10.1186/ISRCTN50098578 .