Title: ROMIO (Randomized Oesophagectomy: Minimally Invasive or Open): Definitive Trial
Funder: Department of Health and Social Care

Abstract: DESIGN: Parallel group multi-centre RCT SETTING: Seven UK UGI centres: Plymouth, Salford, Lancaster, Edinburgh, Leicester, Bristol & Southampton. Criteria will be set for surgeons who want to joining the trial and quality of surgery will be assessed prior to & during the trial. POPULATION: Patients with localised oesophageal cancer selected for primary oesophagectomy or surgery following neoadjuvant treatment by a UGI MDT. INCLUSION: Age 18 yrs+, oesophageal cancer, referred for surgery by UGI MDT, tumour >5cm below crico-pharyngeus, tumour involving <4cm of gastric wall. Final pre-treatment tumour stage is between T1N0 and T4aN1M0. EXCLUSION: Evidence of previous complex thoracotomies or laparotomies. Previous/concomitant malignancy which would interfere with the surgery. Pregnancy. High grade dysplasia. INTERVENTIONS: Open oesophagectomy (OO), laparoscopically-assisted oesophagectomy (LAO), and, in two centres totally minimally invasive oesophagectomy (MIO). Quality assurance of surgery will be monitored using methods developed in the feasibility study (HTA 10/50/65). An enhanced recovery protocol will apply. COSTS: The in-theatre costs for LAO are likely to be higher, but if quicker recovery results then post-surgical costs may be reduced & a better clinical outcome secured. Therefore the balance of costs & benefits between surgical approaches will be established using schedules & interviews piloted in the feasibility study, to measure the costs of in-theatre, in-hospital, community care, & personal social services. Cost-effectiveness assessed at twelve weeks, based upon quality adjusted life years using the EQ5D and estimated from NHS & personal social services perspectives. ROUTINE DATA: Medical records review for health care contacts & NHS Central Register for vital status. OUTCOME MEASURES: The primary outcome will be the mean EORTC QLQ-C30 physical function scale, assessed 3 and 6 weeks post-surgery and 12 weeks post-randomisation, a validated measure of recovery. Secondary outcomes include all-cause complications, lung function, post-surgical pain, quality assurance of surgery, other aspects of HRQL, hospital stay, overall & disease-free survival to 24 months. RECRUITMENT: The ROMIO feasibility study integrated a qualitative recruitment intervention using audio-recording of consultations between surgeons & patients. This will continue in the definitive trial. Screening logs will record the numbers of patients referred for surgery, eligible for ROMIO, and randomised. Logs and qualitative data will be used to train clinical teams to recruit. Each centre needs to recruit a mean of two patients per month over 30 months to meet the sample size target; this is being achieved in the feasibility study. SAMPLE SIZE: 203 patients in each of the LAO and OO groups will allow a minimum clinically important difference of 0.4 standard deviations on the primary outcome to be detected with more than 90% power at the 5% significance level, allowing for 15% of patients not following their allocated procedure, & 10% failure to complete the primary outcome. THE LITERATURE: Our systematic review will be updated annually. TIMETABLE: 6 months set up, 30 months recruitment, 24 months follow-up, 6 months close out; hence 66 months in total TEAM: Surgeons & other clinical expertise, trial methodologists, and PPI. SUBSTUDY: A sub-study at two centres will also randomly allocate patients to a fully minimally invasive oesophagectomy, giving unbiased early information on this novel approach.

Lay abstract: Summary (in Plain English) Oesophageal (gullet) cancer is relatively common in the UK. If detected early, it may be cured with surgery (oesophagectomy). Traditionally this was performed with large incisions in the abdomen, the chest, and sometimes the neck, to remove the cancer and replace the gullet with the stomach. The operation is complex, 30% of patients experience complications, and about 3% of patients die soon afterwards (England & Wales audit 2011-12). The benefit of surgery is survival, about 40% of patients living for 3 years. However, surgery is followed by a reduction in quality of life; it is important to establish refinements to the surgery which lessen this impact and quicken recovery. Minimally invasive ‘keyhole’ surgery for oesophageal cancer may achieve the same survival benefit, but with better recovery than open surgery. However, this impression is largely based on observational studies, and the apparent faster recovery may be due to the selection of fitter patients for the minimally invasive procedure. There are just two randomised controlled trials (RCTs) with modest sample sizes (115 & 200 patients) and methodological shortcomings. We are refining the methodology for a trial in a preparatory study which we are currently bringing to a successful close. We are now in a strong position to conduct a methodologically robust RCT which is large enough to detect clinically important improvements in recovery with minimally invasive surgery. Our proposal is for a RCT at 7 UK centres, involving surgeons who can provide evidence of their skill using minimally invasive techniques. Patients with localised oesophageal cancer, referred for surgery by their multi-disciplinary cancer care team, will be invited into the study. The only major factors preventing participation are previous surgery or cancer where these will make the oesophagectomy more difficult, and pregnancy. Following informed consent, patients will be randomly allocated to open oesophagectomy or “laparoscopically-assisted” oesophagectomy, with the abdominal surgery conducted using minimally invasive methods in the latter case. The primary measure of outcome will be a validated measure of physical function, assessed over the 12 week post-randomisation period. We will recruit 406 patients in total, allowing clinically important differences in post-surgical recovery to be detected. Other outcome measures will include survival, days in hospital, complications, pathological specimen quality, and health-related quality of life. We will also collect resource use data, to allow a comparison of the cost-effectiveness of the two approaches. All participants will be followed for at least two years post-surgery; a 66 month study allowing this. In the ROMIO feasibility study we have developed strong links with the Bristol Gastro Oesophageal Support and Help (GOSH) group via our PPI co-applicant and management group member Mrs Jackie Elliott. Mrs Elliott and other GOSH members have advised on recruitment and outcome measurement. Our Steering Group also has a PPI member, Dr Tony Ingold. We will publicise the trial results to surgeons through publication in open access journals and presentation at conferences. The GOSH group will advise on how to present our results to be informative for patients.

Research activity codes: 6.4 SURGERY
Health categories: CANCER AND NEOPLASMS