ROMIO is a two-year external feasibility study with a pilot parallel group RCT at its core. The pilot trial is recruiting at two UK centers: University Hospitals Bristol NHS Foundation Trust and Plymouth Hospitals NHS Trust. Both centers have a team of upper gastrointestinal cancer surgeons (six in Bristol and five in Plymouth) and each undertake 50 to 100 resections for esophago-gastric cancer per year.
Participants
All referrals of patients with esophageal cancer or high-grade dysplasia requiring surgery for primary esophagectomy or neoadjuvant chemotherapy before esophagectomy at the Bristol and Plymouth centers are considered for eligibility. Patients recommended for neoadjuvant chemotherapy and surgery are registered in the screening log but full eligibility is only confirmed once chemotherapy is completed, restaging undertaken, and the multidisciplinary team (MDT) of clinicians confirms that they will proceed to surgery. At this point eligible patients are informed about the trial and invited to have the method of their esophagectomy randomly selected from between open gastric mobilization and right thoracotomy, laparoscopic gastric mobilization and right thoracotomy, or (Bristol center only) totally minimally invasive surgery (Figure 1).
Inclusion criteria
Participants may enter the study if ALL of the following apply: (1) male or female patients, (2) over 18 years of age, (3) referred by the MDT for primary esophagectomy or esophagectomy following restaging after neoadjuvant chemotherapy (of any type including chemoradiotherapy), (4) confirmed histopathological evidence of esophageal or esophago-gastric junctional adenocarcinoma, squamous cell cancer, or high-grade dysplasia, (5) fit for preoperative anaesthesia and surgery, assessed by the MDT, (6) able to provide written informed consent, (7) endoscopic measurement before chemotherapy that the tumor starts more than 5 cm below the crico-pharyngeus, (8) endoscopic measurement before chemotherapy that the tumor involves less than 4 cm of the gastric wall, and (9) the final pretreatment tumor stage is between high-grade dysplasia and T4aN1M0.
Exclusion criteria
Participants may not enter the study if any of the following apply: (1) stage 4 disease, (2) type three tumors of the esophago-gastric junction that are scheduled for total gastrectomy, (3) patients with squamous cell cancer of the esophagus who the MDT recommends for, or who individually elect to undergo, definitive chemoradiotherapy, (4) evidence of previous complex thoracotomies or laparotomies, (5) evidence of previous or concomitant malignancy that would interfere with this treatment protocol, (6) pregnancy, (7) patients participating in other trials that would interfere with the implementation of this protocol at a particular study center.
Randomization
Internet-accessed randomization is conducted centrally at the Bristol Randomized Trials Collaboration (BRTC), a UK Clinical Research Collaboration registered Clinical Trials Unit hosted by the University of Bristol. Randomization within blocks of varying size is conducted separately for the two centers and further stratified by whether the patient has undergone neoadjuvant treatment or not. In Bristol, patients are randomly allocated in a 1:1:1 ratio to one of three arms: open esophagectomy (open gastric mobilization and right thoracotomy), laparoscopic-assisted esophagectomy (laparoscopic gastric mobilization and right thoracotomy) or totally minimally invasive surgery. In Plymouth, randomization is restricted to two of the study arms, open esophagectomy or laparoscopic-assisted esophagectomy (Figure 1), in a 1:1 ratio. Patients must be logged into the trial and issued with a unique study ID number prior to the treatment allocation being generated, so ensuring judgments about eligibility are made without knowledge of what the next allocation will be (allocation concealment).
Trial interventions
During the trial the surgical procedures are carried out under general anaesthesia with all patients receiving antibiotic and deep vein thrombosis (DVT) prophylaxis according to local hospital policies. The surgical procedures last between 5 and 8 hours. For the purposes of this pragmatic trial each intervention is allowed to be implemented according to the standard local policy, so long as there is consistency with the aspects of each intervention the study team currently consider as mandatory or prohibited for the particular method, as described below. This approach will be formalized in a process evaluation during this feasibility study leading to the production of an intervention manual and an assessment of the adequate standard of, and fidelity to, each procedure undertaken. The process evaluation will consider the surgical intervention itself and concomitant interventions.
Open esophagectomy
In the ROMIO feasibility study the operation consists of a two-phase esophagectomy (abdomen and right chest) with a two-field lymphadenectomy (abdomen and thorax) and involves two key steps or phases.
Abdominal phase
The incision (midline or subcostal) is at the surgeon’s discretion. Complete gastric mobilization will be performed based on the right gastroepiploic and right gastric arteries. Pyloroplasty, pyloromyotomy, or no drainage is at the surgeon’s discretion. Lymphadenectomies are performed along the common hepatic artery and the left gastric and splenic artery either en bloc or separately, and removal of sufficient crural fibres and a cuff of diaphragm performed if required for tumor clearance. The pericardial fat pad and strips of pleura are removed. Transection of the lesser curve may be undertaken or left to the thoracic phase of the operation. Placement of a feeding jejunostomy or naso-jejunal tube is at the surgeon’s discretion as are placement of intra-abdominal and intra-thoracic drains. Methods to close the abdomen are at the surgeon’s discretion.
Thoracic phase
The chest is opened through a right thoracotomy and the mediastinal pleura overlying the esophagus excised in continuity with the esophagus. The posterior limit of the dissection should be the antero-lateral wall of the aorta. The thoracic duct is mobilized en bloc or separately to the esophagus and periesophageal tissues. The thoracic duct is ligated and divided at the level of the diaphragm. The esophagus is mobilized to the level of at least the aortic arch or higher if required. The para-esophageal and diaphragmatic nodes are removed in continuity with the esophagus. The lymph nodes at the tracheal bifurcation and along the right and left main bronchi to the pulmonary hilus can be removed en bloc or separately at the surgeon’s discretion. The anastomotic technique and method of chest drainage is at the surgeon’s discretion. Methods to close the chest are at the surgeon’s discretion.
Laparoscopically assisted esophagectomy
This operation consists of identical steps as described for the open esophagectomy, but access to the abdominal cavity is achieved with four or five 10 or 5 mm incisions and surgery performed laparoscopically. Placement of a feeding jejunostomy is at the surgeon’s discretion and may be performed laparoscopically or by extending a port site to an 8 cm abdominal incision. The thoracic part of the operation is performed as described for the open esophagectomy.
Totally minimally invasive esophagectomy
This consists of performing the steps of the abdominal and chest phases of the operation as described for the open esophagectomy. These are performed with abdominal and chest ports positioned by the surgeon at their discretion. Within the ROMIO feasibility study it is also possible to perform a three phase procedure (undertaking the anastomosis with a left cervical incision). Surgeons in Bristol undertaking the totally minimally invasive procedure are recording variations to this outlined approach, with reasons, during this feasibility study to inform the design and interventions to be evaluated in the main trial.
Concomitant interventions and the enhanced recovery protocol
Concomitant interventions are defined as naturally accompanying or associated elements of the surgical intervention itself, and can be divided into preoperative, perioperative and postoperative components. Concomitant interventions to be considered as part of the process evaluation during the pilot trial include the anaesthetic and other perioperative procedures, immediate postoperative care (including intensive care management), and patient rehabilitation, input from allied health professionals such as physiotherapists and dieticians, which may or may not be encompassed into a formal enhanced recovery program. During the ROMIO feasibility study standard protocols for follow-up care after both procedures will be developed to minimize the risk of performance bias arising from carers differentially providing co-interventions in the main trial.
This work will inform development of an enhanced recovery pathway or manual to be used in the main trial to provide the minimum standard of care permitted. Together with the surgical intervention itself, concomitant interventions will be considered during the process evaluation and incorporated into the manual if identified as important.
Outcome measures
The primary outcome for the main trial is currently planned to be patient-reported physical fatigue, as measured by the Multidimensional Fatigue Inventory MFI-20 [32, 33] measuring fatigue at several time points during the first three months post-surgery; the speed of recovery of each patient will be captured.
During the pilot trial we are asking participants to complete a range of measures which are being considered as secondary outcome measures for the main trial [34–36]. These are listed below. In addition, post-surgery morbidity will be classified according to both the Accordian and Clavien-Dindo schemes [37, 38].
List of pilot trial secondary outcome measures
Date and cause of death
Disease recurrence with date
Lung function
Patient completed visual analogue scale assessment of pain
Patient completed questionnaires on generic HRQL: EuroQoL EQ-5D-5 L
Patient completed questionnaires on disease-specific HRQL: European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) and the esophageal specific module (QLQ-OES18)
Development of a core clinical outcome set for esophageal cancer surgery
The ROMIO feasibility study provides the opportunity to develop a core outcome set for esophageal cancer surgery [39, 40]. A core outcome set is a standardized set of clinical outcomes that represents the minimum that should be measured and reported in all clinical trials [40]. A relatively long list of potential outcomes will be generated by surveying patients and clinicians, which will be reduced to those considered crucial and distinctive through a Delphi exercise. This work will link with 'COMET' (Core Outcome Measures in Effectiveness Trials), funded by the Medical Research Council ConDuCT (Collaboration and innovation in difficult randomized controlled trials) Hub for Trials Methodology Research and North West Hubs for trials methodology research [40]. The final core set of outcomes for esophageal cancer surgery is expected to be less than 10 items.
Development of resource use data collection
During the ROMIO study best methods for capturing cost and resource use in relation to the interventions and follow-up in secondary care are being established. Questionnaires are also being developed in order to collect information about the use of primary NHS services and social services and direct and indirect costs incurred by patient and carers. The average costs for all the different categories will be compared by study arm to enable the main cost drivers of the interventions to be established and compared. Any areas where obtaining accurate estimates of costs is problematic will also be identified. This will allow a more focused collection of resource use data and a more accurate estimate of cost-effectiveness in the main trial.
Data collection
Socioeconomic details and height are measured when the patient is seen for a pre-surgery assessment only. Lung function measurements and assessments of pain are taken pre-surgery, during the first week post-surgery, and at days three and six as a minimum. HRQL is assessed using standardized questionnaires pre-surgery and at 6, 42, 90, and 185 days; questionnaires are posted with a stamped addressed envelope when necessary. Resource use is assessed through medical records review and interviews with patients.
Through medical records review, routine clinical measures are also captured whenever they are taken as part of the patient’s care during the six month study period. Clinical report forms designed for the study are used to formalize this data collection. Measures of the surgical process (for example blood loss or duration of surgery) and pathological assessment of the tumor and lymph nodes are included in this collection.
Sample size calculation and statistical analysis
In the feasibility study recruitment is occurring initially over a 12-month period, with 72 potentially eligible patients expected during that time. This will allow a true 50% recruitment rate to be estimated with a 95% confidence interval of approximately 38 to 62%. If 11 patients are randomly allocated to each surgical procedure this will allow a true difference of 1.25 standard deviations between two procedures on a continuous measure of early outcome to be detected with 80% power at the 5% significance level. Hence the pilot trial will provide an acceptably precise estimate of the recruitment rate to inform plans for the main trial, and may provide evidence suggesting that a particular method may be achieving relatively poorer short-term outcomes and may need to be refined before proceeding to the main study.
Summary statistics that will inform plans for the main trial will be presented, including (in a CONSORT chart format) the number of potentially eligible and confirmed patients per month per center and the percentage of patients agreeing to randomization and completing outcome measurements. Mean scores on short-term outcome measures will be presented for each study arm, with P values and 95% confidence intervals presented for treatment comparisons where at least 10 patients have been randomized to each study arm. No conclusions about the relative clinical effectiveness of the three interventions will be drawn from these results; they will purely inform the refinement of the interventions prior to proceeding to the main trial. Additional summary statistics will arise from the pilot work, for example, mean scores on the blinding scale achieved by different blinding procedures.
Quality control of surgery and development of the surgical manual
Only surgeons or trainees under direct supervision perform the procedures. A sample of procedures is being video recorded for analysis by the research team at Imperial College London. This will inform the development of the following resources for the main trial: (1) a surgical manual to define the framework for the steps of each trial intervention and describe acceptable and prohibited (unacceptable) protocol deviations; (2) an esophageal competency-assessment tool (O-CAT) based on the Observational Clinical Human Reliability Assessment (OCHRA) techniques to assess the level of competency for technical surgical performance [41], including adherence to procedural steps, protocol deviations, errors, and near miss events; and (3) a manual to describe details of concomitant interventions, such as type of anaesthesia, pre- and postoperative rehabilitation, and key elements of enhanced recovery pathways which are important in fulfilling the CONSORT criteria for reporting evaluations of complex interventions [30].
Pathological specimens are processed in an agreed uniform manner in both centers and dissection of lymph nodes from the main specimen and lymphadenectomy specimens follow a pro forma. These processes are reviewed regularly in both centers and standardized techniques for sampling lymph nodes are adopted so that the maximum yield can be obtained from all cases. Involvement of the surgical resection margin is assessed both microscopically and macroscopically.
Blinding patients
Methods to achieve blinding of patients and outcome assessors to the type of surgery during the initial post-surgery period are being piloted. In the first seven days post-surgery patients are blinded by using large adhesive dressings that are positioned similarly on all trial patients regardless of the type of surgery (covering the abdominal, thoracic, and cervical incisions). Patients are asked to turn their head away during dressing changes and on days two and six they are asked to complete the Bang Blinding Index, which assesses blinding success by asking patients to guess their arm allocation [42]. The Bang Blinding Index is administered by ward or nursing staff not routinely involved in the patient’s care. Patients’ experiences of blinding and experiences of ward staff and nurses involved with these processes are being further explored in qualitative interviews described below.
Recruitment investigation
The ROMIO trial compares different surgical procedures that are in common use in specialist centers, and therefore the trial is likely to face a number of recruitment challenges. Based on previous works by de Salis et al. and Donovan et al.[43–49], a key component of the pilot trial is an integrated qualitative study which is exploring these challenges to inform the design of the main ROMIO trial. Interviews with members of the trial management group, principal investigators and active recruiters explore their own views about the trial including their knowledge of the evidence and equipoise, and any recruitment challenges expected or experienced. The patient pathway is mapped through recruitment and appointments are audio recorded to scrutinize information provision and identify issues potentially affecting trial recruitment along that pathway. This will inform the development of information and training programs for the main trial. Finally, interviews with a sample of eligible patients will explore patient perspectives of surgery, previous experiences with treatments, views about surgery, and the acceptability of randomization between the procedures.
Emerging issues related to trial design and conduct that may be hindering recruitment are discussed between the trial team and a plan to improve recruitment during the pilot trial will be introduced if necessary. This may include reconsideration of eligibility criteria, study information, advice about presenting the study, discussions about equipoise or evidence, issues with patient pathways, and logistical issues in particular centers. These may be addressed by changes to study information or the protocol, or training for recruiters.
Ethical approval and informed consent
Ethical approval was granted by the South West - Frenchay Research Ethics Committee (12/SW/0161). Informed consent is obtained from each participant in the ROMIO study.