Tim Wheatley

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.

The implementation and effectiveness of an enhanced recovery programme after oesophago-gastrectomy: A prospective cohort study

BACKGROUND Oesophageal resection is notoriously complicated and produces a cohort of patients prone to postoperative complications. Maintaining quality care demands a systematic approach to patient management yet postoperative recovery after oesophagectomy is often needlessly inefficient, heterogeneous and governed by the idiosyncrasies of the operating surgeon. Enhanced recovery after surgery (ERAS) programmes are now well established in colorectal surgery and here we describe the implementation and effectiveness of an ERAS programme for the postoperative management of Ivor Lewis oesophago-gastrectomy (ILOG). METHODS An ERAS programme was devised and implemented with the support of a dedicated in-hospital task-force. Three consultant surgeons allocated consecutive patients to the programme (ERAS) and outcomes were compared to consecutive patients not on the ERAS programme (non-ERAS) and a pre-ERAS cohort (pre-ERAS). Principal outcome measures were total length of stay (TLOS), Accordion postoperative complication grade and 30-day readmission rate. RESULTS 75 patients were enrolled on the ERAS programme, 41 continued as a non-ERAS cohort and 80 consecutive pre-ERAS patients were identified. A significant improvement in median TLOS was observed in the ERAS group (10 days r.7-58) compared to pre-ERAS (13 days r. 8-57) (p = <0.001) and non-ERAS patients (13 days r.8-42) (p = <0.001). No significant difference in Accordion scores for postoperative complications or 30-day readmission rates were observed. DISCUSSION The introduction of an ERAS programme after ILOG can significantly reduce TLOS without jeopardising patient safety or clinical outcomes. The successful introduction of an ERAS programme requires full motivation and support from all team members including the patient.

Prospective cohort study of neoadjuvant therapy toxicity in the treatment of oesophageal adenocarcinoma

BACKGROUND Early studies investigating the benefits of neoadjuvant therapy in oesophageal cancer showed conflicting results, taking many years before a survival advantage was demonstrated in randomised trials. Gains are modest, limited by progressive disease and toxicity. This study aimed to investigate the relationship between neoadjuvant therapy-associated toxicity and clinical outcomes including survival in patients with potentially curable oesophageal adenocarcinoma. MATERIALS AND METHODS A cohort of 286 patients undergoing neoadjuvant therapy followed by surgical resection at a single institution was identified from a prospective database. Adverse events from neoadjuvant therapy were recorded and graded. Patients were divided into two groups according to whether they suffered toxicity or not. Clinical outcomes including whether patients completed the neoadjuvant course, whether they proceeded to resection and overall survival, were compared between the groups. RESULTS Neoadjuvant therapy-related toxicity was identified in 67/286 patients. 46 patients suffered severe, life-threatening or fatal adverse events. In patients with toxicity, 47% did not complete the chemotherapy course compared to 17% without toxicity, RR 2.7 (95%CI 1.7-4.4), (P < 0.001). In patients suffering toxicity, 17.9% failed to proceed to resection compared with 7.8% in those without toxicity, RR 2.3 (95%CI 1.2-4.6) P = 0.02. Median overall survival was shorter in patients suffering toxicity (20.7 months) compared to those without toxicity (37.8 months), P = 0.008. When patients failing to proceed to resection were excluded, median overall survival was shorter in patients suffering toxicity (26.2 months) compared with those without toxicity (47.8), P = 0.039. CONCLUSION Neoadjuvant therapy-related toxicity is common and can have serious consequences including failure to complete chemotherapy cycles, a higher risk of not proceeding to surgical resection and poorer overall survival. Efforts should be made to reduce toxicity and research should aim to identify responders and factors predictive of toxicity.

Loco-regional staging accuracy in oesophageal cancer—How good are we in the modern era?

INTRODUCTION Accuracy of locoregional staging in patients with oesophageal cancer is critical in determining operability and the need for neoadjuvant treatment. Imaging technology has advanced significantly in recent years but it is not known whether this translates to improved staging accuracy. This study investigates staging accuracy in relation to CT, EUS, PET-CT and final pre-operative stage. It specifically addresses the accuracy of staging with respect to the threshold for administering neoadjuvant therapies. MATERIALS AND METHODS Pre-operative staging according to CT, EUS, PET-CT and final pre-operative stage were compared to the postoperative histological staging in 133 patients undergoing potentially curative surgery (without neoadjuvant therapy) for oesophageal cancer between January 2010 and January 2015. T and N stage accuracies were reported separately for each imaging modality. Patients were also divided into two groups depending on whether the final pre-operative stage was below (≤T2, N0, early tumours) or above (≥T3 and/or ≥N1, locally advanced tumours) the threshold for offering neoadjuvant therapy. Accuracy of pre-operative staging was then analysed with respect to identification of patients below/above this threshold. The additional benefit offered by EUS for this purpose was investigated. RESULTS T stage accuracies were 72.6%, 76.7% and 79.3% for CT, EUS and final pre-operative stage respectively. N stage accuracies were 75.6%, 77.2%, 74.5% and 78.6% for CT, EUS, PET-CT and final pre-operative stage respectively. Staging accuracy with respect to threshold for neoadjuvant treatment showed 62.0% early tumours were correctly staged and 80.5% advanced tumours were correctly staged. Whether or not patients underwent EUS did not affect the staging accuracy with respect to neoadjuvant treatment threshold. CONCLUSIONS Staging accuracy with respect to the threshold for treatment with neoadjuvant therapy is poor, leading to potential over/under treatment. Predicting individual response to neoadjuvant therapy would provide a better way to determine which patients should receive this additional treatment.

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.

The impact of a two or three-group RCT design on blinding of patients

In RCTs using subjective outcomes, blinding of patients to treatment allocation is recommended. It is unknown whether two or three-group trial designs influence blinding success. We examined the success of blinding patients within a three or two-group pilot RCT in surgery. Cancer centres randomised patients to a three or two-group trial comparing: (i) standard open surgery; (ii) combination open and keyhole surgery, or (in one centre); (iii) totally keyhole surgery. Feasibility of blinding patients for seven days post-surgery to minimise bias in pain assessments was explored by using identical wound dressings covering all incisions. On days two and six, patients completed the Bang Blinding Index (BBI). This measures blinding success by asking patients to guess their treatment allocation. Scores range from -1 (more wrong guesses than expected) to 1 (more correct guesses), with 0 indicating perfect blinding (random guessing). Results were compared between the three and two-group studies. The study recruited 70 patients (42 and 28 three and two-group respectively). Data indicated successful blinding in the three-group study, with fewer patients than expected guessing correctly (day two BBI scores by group (i)0.00, (ii)0.14, (iii)-0.13; day six: (i)-0.13, (ii)0.38, (iii)0.04). In the two-group study, slightly more patients became unblinded, with more than expected guessing they had combination surgery (day two: (i) -0.73, (ii) 0.35; day six: (i) - 0.25, (ii) 0.57). This pilot study successfully blinded patients in a three-group study. However, in the two-group study more patients had become unblinded. This suggests that blinding is more successful in multi-arm studies.

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.

PWE-157 Reducing anastomotic leak rate in ivor lewis oesophagectomy – testing a change from mechanical to semi-mechanical anastomosis

Introduction The reduction in mortality after oesophagectomy seen over the last decade has not been matched by a reduction in anastomotic leaks with a leak rate of 5–10% accepted as a standard of care. Leaks increase postoperative mortality, morbidity and length of stay and reduce cancer survival. We present the results of a modified semi-mechanical intrathoracic anastomotic technique (SM) originally described by Orringer et al 1for the cervical anastomosis. Method Centralisation of oesophagogastric cancer surgery took place in our region in January 2010, bringing together five surgeons from three surgical units. For consistency, all five surgeons used a standard circular stapled anastomotic technique (CS) from 2010, but the leak rate was deemed too high. As a result, three of the five surgeons (A, B, and C) changed to a modified SM technique (surgeon A changed in November 2011, surgeon B in December 2011 and surgeon C in May 2013). This anastomosis joins the obliquely cut end of the oesophagus to the side of the proximal gastric conduit with a single 25 mm firing of a 45 mm linear stapler posteriorly (ATS45, Blue cartridge, Ethicon), the remainder of the anastomosis being completed with single layer inverting interrupted 3/0 PDS. The other two surgeons (D and E) continued to use the CS technique. Anastomotic leak rates, mortality and length of stay were evaluated to test this change in technique. Results Between Jan 2010 and February 2015 inclusive 376 patients underwent curative intent, 2-stage Ivor Lewis oesophagectomy for cancer. One patient died in hospital (0.27% mortality). The anastomotic leak rate Surgeons A, B and C using CS was 16.8%(15/92) and SM 0.8%(1/127) for surgeons D and E the rate was 10.2%(16/157). The median post-operative length of stay between groups was 11(7–56), 10(6–58) and 12(7–51) respectively.Abstract PWE-157 Figure 1 Conclusion There was a profound reduction in anastomotic leak rate for all three surgeons who changed from circular to semi-mechanical anastomosis. Disclosure of interest None Declared. Reference Orringer MB, et al. Eliminating the cervical esophagogastric anastomotic leak rate with a side to side stapled anastomosis. J Thorac Cardiovasc Surg. 2000 Feb;119(2):277-88

PTU-140 Neoadjuvant therapy toxicity and efficacy in oesophago-gastric cancer

Introduction The advantages of neoadjuvant therapy (NAT) in oesophago-gastric (OG) cancer have been proven in randomised trials. Benefits are modest and likely to be restricted to patients who respond well to therapy. The risks may outweigh benefits in earlier stages of disease. This study explores the risks associated with NAT, analyses which patients benefit and investigates whether there is a need for a change in NAT treatment strategy. Method All patients planned for surgical resection of OG cancer in this unit between 01/2010 and 12/2014 were identified. Part a) patients were divided according to pre-operative stage. Within each stage, survival was compared in patients undergoing NAT and those undergoing surgery alone. Similar comparisons were made with the NAT group further divided into histological responders and non-responders. Part b) from the cohort, patients undergoing NAT were identified. Adverse effects (AE) were recorded and graded according to the Common Terminology Criteria for Adverse Events v3.0. The relationships between the presence of AE and a range of variables were investigated along with survival. Survival analyses were undertaken by plotting Kaplan-Meier curves. Groups were compared using the Log Rank (Mantel-Cox) test. Results 587 patients were identified from the database. Part a) only stage III patients had improved survival with NAT vs. surgery alone (P = 0.02). Those in stage II with a histological response to treatment showed a trend towards better survival vs. surgery alone (P = 0.058). In all patients above the threshold for offering NAT (≥stage II), survival was no different in non-responders vs. those having surgery alone. Age and performance status were lower in the NAT group vs. the surgery only group and were both associated inversely with survival. This could mean NAT effects are overestimated and true survival in non-responders to NAT may be poorer than in patients having surgery alone. Part b) 376 patients received NAT and 88 (23.4%) suffered AE. 69% of these were severe, life-threatening or fatal. NAT course completion rate was lower in patients suffering AE vs. those not (P = 0.003). 20.5% patients with AE did not proceed to resection vs. 6.4% without AE (P = 0.001). Survival was better in patients without AE vs. with AE (P = 0.02) and was better in those undergoing resection (P < 0.001) but was no different in patients completing the course vs. not completing (P = 0.861). Conclusion Efficacy of NAT is dependent on cancer stage and histological response to NAT. AE are common, often severe and associated with a reduced resection rate and survival. Identifying a means of predicting response to NAT is of great importance and should be used to guide treatment alongside/instead of disease stage. Disclosure of interest None Declared.

PTU-139 Re-defining response to neoadjuvant therapy in patients with oesophago-gastric cancer

Introduction Response to neoadjuvant therapy in oesophago-gastric (OG) cancer can be measured using a range of radiological and histological measures. However, there is no agreed definition of what constitutes a beneficial response. An accurate definition is critical for standardisation of outcome reporting and will be necessary if predicting response can be used to provide personalised treatment. This study re-defines response to neoadjuvant therapy in OG cancer. Method A literature search was performed to identify potential measures for accurately defining response the neoadjuvant therapy. All patients undergoing surgical resection for OG cancer at this Unit between January 2010 and December 2014 were identified from a database. Part a) Patients meeting the threshold for offering neoadjuvant therapy (≥T3 and/or ≥N1) were identified and divided according to whether they were TRG responders, non-responders or had surgery only. These groups were then compared with respect to the apparent T- and N-down-staging (defined as a reduction in stage between pre-operative staging and post-operative pathological staging) in order to assess the validity of down-staging for use in defining response. Part b) Patients undergoing neoadjuvant therapy were identified and potentially valid measures of response were then analysed with respect to overall survival in order to determine and validate a definition of response. Results The literature review identified methods using histopathological regression as the most promising measures of response with the Becker and Mandard scoring systems validated for use in OG cancer. T and N down-staging offer the potential to identify partial responders. 587 patients were identified from the database. Part a) In 419 patients above the neoadjuvant therapy threshold, the rate of apparent T down-staging was 62.8% in TRG responders, 15.7% in non-responders and 21.4% in the surgery only patients. The rate of apparent N down-staging was 35.9% in responders, 13.0% in non-responders and 12.9% in the surgery only patients. Part b) In 376 patients undergoing neoadjuvant therapy, patients with a Mandard TRG score of 1–3 had longer survival than those with TRG 4–5, mean survival 49.5 months vs. 35.7 months respectively (P = 0.001, Log Rank Mantel-Cox). Conclusion Histopathological regression scores correlate well with survival and represent the most accurate measure of response to neoadjuvant therapy in OG cancer. Survival in TRG1–3 patients (Mandard Score) is better than in TRG 4–5 patients. Apparent T and N down-staging were no higher in the TRG non-responder group than the surgery only group suggesting this represents clinical over-estimation of stage rather than a true therapy effect and is not valid for use in the definition of response to therapy. Disclosure of interest None Declared.