Dan Titcomb

The feasibility of a randomized controlled trial of esophagectomy for esophageal cancer - the ROMIO (Randomized Oesophagectomy: Minimally Invasive or Open) study: protocol for a randomized controlled trial

BackgroundThere is a need for evidence of the clinical effectiveness of minimally invasive surgery for the treatment of esophageal cancer, but randomized controlled trials in surgery are often difficult to conduct. The ROMIO (Randomized Open or Minimally Invasive Oesophagectomy) study will establish the feasibility of a main trial which will examine the clinical and cost-effectiveness of minimally invasive and open surgical procedures for the treatment of esophageal cancer.Methods/DesignA pilot randomized controlled trial (RCT), in two centers (University Hospitals Bristol NHS Foundation Trust and Plymouth Hospitals NHS Trust) will examine numbers of incident and eligible patients who consent to participate in the ROMIO study. Interventions will include esophagectomy by: (1) open gastric mobilization and right thoracotomy, (2) laparoscopic gastric mobilization and right thoracotomy, and (3) totally minimally invasive surgery (in the Bristol center only). The primary outcomes of the feasibility study will be measures of recruitment, successful development of methods to monitor quality of surgery and fidelity to a surgical protocol, and development of a core outcome set to evaluate esophageal cancer surgery. The study will test patient-reported outcomes measures to assess recovery, methods to blind participants, assessments of surgical morbidity, and methods to capture cost and resource use. ROMIO will integrate methods to monitor and improve recruitment using audio recordings of consultations between recruiting surgeons, nurses, and patients to provide feedback for recruiting staff.DiscussionThe ROMIO study aims to establish efficient methods to undertake a main trial of minimally invasive surgery versus open surgery for esophageal cancer.Trial registrationThe pilot trial has Current Controlled Trials registration number ISRCTN59036820(25/02/2013) at http://www.controlled-trials.com; the ROMIO trial record at that site gives a link to the original version of the study protocol.

Demonstration of the IDEAL recommendations for evaluating and reporting surgical innovation in minimally invasive oesophagectomy.

The Idea, Development, Evaluation, Assessment and Long term study (IDEAL) framework makes recommendations for evaluating and reporting surgical innovation and adoption, but remains untested.

Feasibility RCT of definitive chemoradiotherapy or chemotherapy and surgery for oesophageal squamous cell cancer

Background:The optimal treatment for localised oesophageal squamous cell carcinoma (SCC) is uncertain. We assessed the feasibility of an RCT comparing neoadjuvant treatment and surgery with definitive chemoradiotherapy.Methods:A feasibility RCT in three centres examined incident patients and reasons for ineligibility using multi-disciplinary team meeting records. Eligible patients were offered participation in the RCT with integrated qualitative research involving audio-recorded recruitment appointments and interviews with patients to inform recruitment training for staff.Results:Of 375 patients with oesophageal SCC, 42 (11.2%) were eligible. Reasons for eligibility varied between centres, with significantly differing proportions of patients excluded because of total tumour length (P=0.002). Analyses of audio-recordings and patient interviews showed that recruiters had challenges articulating the trial design in simple terms, balancing treatment arms and explaining the need for randomisation. Before analyses of the qualitative data and recruiter training no patients were randomised. Following training in one centre 5 of 16 eligible patients were randomised.Conclusions:An RCT of surgical vs non-surgical treatment for SCC of the oesophagus is not feasible in the UK alone because of the low number of incident eligible patients. A trial comparing diverse treatment approaches may be possible with investment to support the recruitment process.

Comparing open and minimally invasive surgical procedures for oesophagectomy in the treatment of cancer: the ROMIO (Randomised Oesophagectomy: Minimally Invasive or Open) feasibility study and pilot trial.

BACKGROUND Localised oesophageal cancer can be curatively treated with surgery (oesophagectomy) but the procedure is complex with a risk of complications, negative effects on quality of life and a recovery period of 6-9 months. Minimal-access surgery may accelerate recovery. OBJECTIVES The ROMIO (Randomised Oesophagectomy: Minimally Invasive or Open) study aimed to establish the feasibility of, and methodology for, a definitive trial comparing minimally invasive and open surgery for oesophagectomy. Objectives were to quantify the number of eligible patients in a pilot trial; develop surgical manuals as the basis for quality assurance; standardise pathological processing; establish a method to blind patients to their allocation in the first week post surgery; identify measures of postsurgical outcome of importance to patients and clinicians; and establish the main cost differences between the surgical approaches. DESIGN Pilot parallel three-arm randomised controlled trial nested within feasibility work. SETTING Two UK NHS departments of upper gastrointestinal surgery. PARTICIPANTS Patients aged ≥ 18 years with histopathological evidence of oesophageal or oesophagogastric junctional adenocarcinoma, squamous cell cancer or high-grade dysplasia, referred for oesophagectomy or oesophagectomy following neoadjuvant chemo(radio)therapy. INTERVENTIONS Oesophagectomy, with patients randomised to open surgery, a hybrid open chest and minimally invasive abdomen or totally minimally invasive access. MAIN OUTCOME MEASURE The primary outcome measure for the pilot trial was the number of patients recruited per month, with the main trial considered feasible if at least 2.5 patients per month were recruited. RESULTS During 21 months of recruitment, 263 patients were assessed for eligibility; of these, 135 (51%) were found to be eligible and 104 (77%) agreed to participate, an average of five patients per month. In total, 41 patients were allocated to open surgery, 43 to the hybrid procedure and 20 to totally minimally invasive surgery. Recruitment is continuing, allowing a seamless transition into the definitive trial. Consequently, the database is unlocked at the time of writing and data presented here are for patients recruited by 31 August 2014. Random allocation achieved a good balance between the arms of the study, which, as a high proportion of patients underwent their allocated surgery (69/79, 87%), ensured a fair comparison between the interventions. Dressing patients with large bandages, covering all possible incisions, was successful in keeping patients blind while pain was assessed during the first week post surgery. Postsurgical length of stay and risk of adverse events were within the typical range for this group of patients, with one death occurring within 30 days among 76 patients. There were good completion rates for the assessment of pain at 6 days post surgery (88%) and of the patient-reported outcomes at 6 weeks post randomisation (74%). CONCLUSIONS Rapid recruitment to the pilot trial and the successful refinement of methodology indicated the feasibility of a definitive trial comparing different approaches to oesophagectomy. Although we have shown a full trial of open compared with minimally invasive oesophagectomy to be feasible, this is necessarily based on our findings from the two clinical centres that we could include in this small preliminary study. TRIAL REGISTRATION Current Controlled Trials ISRCTN59036820. FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 48. See the NIHR Journals Library website for further project information.

Methods for evaluating innovative surgery: a nested ideal phase 2 study within an external randomised pilot (the ROMIO trial).

Pragmatic surgical RCTs are needed but it is unclear how to design studies with evolving innovative interventions. The aim of this paper was to describe how a pilot RCT comparing two standard techniques incorporated an additional randomised group with a nested IDEAL (Idea, Development, Evaluation, Assessment and Long-term evaluation of innovative surgery) Phase 2b evaluation of an evolving technique to inform main trial design.

OC-078 Evaluating innovative surgery: a nested ideal phase 2 study within an external randomised pilot (the romio trial)

Introduction There is a need for well designed and conducted pragmatic randomised controlled trials (RCTs) of open and minimally invasive approaches for oesophageal cancer, but totally minimally invasive techniques are still evolving. The NIHR ROMIO pilot RCT was designed to inform a definitive trial. This paper describes how the ROMIO Study informed the main trial design and incorporated a nested IDEAL (Idea, Development, Evaluation, Assessment and Long-term evaluation of innovative surgery) Phase 2a evaluation of totally minimally invasive oesophagectomy (TMIO). Method The pilot ROMIO trial was conducted in two centres. In one centre (with a team of 3 surgeons) patients were randomised to open gastric mobilisation and right thoracotomy (open surgery) or laparoscopic gastric mobilisation and right thoractomy (hybrid surgery) and in the other centre (team of 6 surgeons) patients were randomised into three groups, also including totally TMIO. The surgical protocol for open and hybrid surgery was agreed and monitored during the trial, where as the protocol for TMIO was deliberately flexible to monitor development of the technique and to document changes in the procedure and collect prospective data. Results During 20 months of recruitment, 256 patients were assessed for eligibility, 132 (52%) were found to be eligible and 101 (76.5%) agreed to participate. A high proportion of patients received their randomised allocation (87%). Dressing patients with large bandages, covering all possible incisions, was successful in keeping patients blind whilst pain was assessed during the first week post-surgery (patients were unable to guess the type of surgery they had received). In the TMIO group three-phase surgery was undertaken by three of the six surgeons in one centre. This evolved to two-phase TMIO surgery with continuing modifications to the anastomotic technique. During the study period the national audit data showed that only 14% of oesophagectomies are TMIO. Conclusion Rapid recruitment to the pilot ROMIO trial and the successful refinement of methodology indicated that a definitive two group trial comparing open and hybrid surgery is feasible. Techniques for TMIO are however still evolving and the procedure is not widely undertaken. The main ROMIO trial, therefore, is designed within a continuing IDEAL Phase 2b study to monitor when this complex technique has stabilised and ready for full evaluation within a pragmatic trial design. Disclosure of interest None Declared.