June 2016 – Report from the Upper GI Surgical Specialty Lead
Professor Jane Blazeby,
Upper GI Speciality Research Lead
Why randomised trials?
Historically, surgical research studies have been mainly case series. These reports (usually single centre and often single surgeon) are limited in their scientific strength In case series it is usually unclear which patients were included (and whether any were excluded). Most series lack a comparison group and, follow-up and outcome assessment is usually performed by the surgeon who undertook the procedure (or their team). These design features in surgical case series mean that results are at high risk of (at least) selection and ascertainment bias. There is also a risk of publication bias because series with “good” results are more likely to be published than those where poor outcomes were observed. The overall effect is that published data are not valid or reliable.
Multiple reasons explain why surgical case series have traditionally been published. They relate to methodological challenges with surgical trials in recruiting to randomised studies, binding staff to treatment allocation and intervention standardisation. these challenges are compounded by issues related to surgical hierarchy when there is an uncollaborative spirit (so multi-centre studies fail because of a lack of teamwork). The Royal College Trials initiative is changing this. randomised trials in surgery are increasing and studies are recruiting well and on target.
What is selection bias?
Whilst surgical cases are permeated with methodological problems, the biggest problem is the lack of randomised comparative data. Randomisation is absolutely critical to create high quality evidence for the effectiveness of new interventions or to compare standard treatments head to head. for a surgeon to randomise patients there is a need for them to explain and and balance treatment options. In trials that are randomised properly the participants have an equal probability of being allocated to any of the groups being compared. Thus we expect to end up with groups that are on average similar to each other in all respects other than the treatment(s) under investigation.
Randomisation doesn’t ensure that groups are the same, rather it ensures, when conducted properly, that any differences between the groups in their measured or unmeasured characteristics at baseline are due to chance. Randomisation itself involves two key stages. The first is generation of an unpredictable random allocation sequence. This is usually done using computer-generated random numbers. The second is concealment of the allocation sequence from the investigators enrolling patients into the study (this makes it impossible for the person undertaking the randomisation to ‘guess’ what is coming next). This is usually achieved using an automated telephone or web-based randomisation service
Knowledge of the allocation sequence in advance could result in investigators allocating certain patients to receive either the new or control treatment based on their age, sex, disease severity or any other prognostic variable. When randomisation’s performed properly this reduces the risk of selection bias.
Randomisation: purpose and process. For patients to be able to give informed consent for participation in an RCT it is necessary for them to understand the purpose and process of randomisation. This means developing language and communication skills to explain, i) the uncertainty and rationale for the study and ii) why randomisation is needed (to create similar groups to allow a fair comparison of outcomes) and iii) what will happen to them if they take part. In many surgical trials (e.g. comparing surgical and nonsurgical interventions) can be conducted.
February 2016 – Report from the Upper GI Surgical Specialty Lead
The purpose of the Royal College of Surgeons Research Lead in Upper GI Surgery is to facilitate collaboration between surgeons and triallists to design and deliver high quality surgical trials. Historically, surgical research has involved some engagement with trials in oncology (eg OEO5), but there is a paucity of true surgical trials.
Surgical trials compare different operations (eg minimal access versus open surgery), parts of an operation (eg different types of anastomotic techniques) or surgical and non-surgical interventions (e.g. surgery vs. definitive chemoradiotherapy). All types of trials in surgery are challenging to develop and conduct. There is a need for us to learn how to recruit patients and communicate clinical equipoise and there is a need for quality assurance of the surgical interventions in the trial. We also need to learn to collaborate to ensure that sufficient numbers of patients are recruited across centres to answer pragmatic research questions of importance to the NHS.
Despite the challenges associated with surgical research, progress is being made! The culture is changing and more and better trials are being conducted. The investment from the Royal College of Surgeons and the appointments of the research leads is having a huge impact. In upper GI surgery there are now four open ‘surgical trials’ and four more under way (either in design, submitted for funding or awaiting final funding approvals following amendments).
The four open trials are generally recruiting well. This is a tribute to the hard work of the clinical trials units running the trials and to participating centres. In addition, two new ‘difficult-to-recruit into’ trials will open in 2016 or early 2017. One will compare thermal ablation versus surgery for patients with colorectal liver metastases led by Professor Brian Davidson (University College London) and the other will compare surgery and conservative management for patients with simple gallstone disease (awaiting funding approval) led by Mr Irfan Ahmed and Prof Craig Ramsay, Aberdeen.
Opportunities to share and develop new ideas for RCTs
There will be an opportunity for surgeons across all sub-specialities represented at AUGIS to submit new ideas for RCTs to be presented at the ‘Dragon’s Den meets Shark Tank and Methodology Queens and Kings’ event to be held in Leeds at AUGIS in 2016. Details soon to be advertised on the website.
In addition to the above, there have been meetings held to discuss new trials around gallbladder disease (antibiotics vs. no antibiotics for laparoscopic cholecystectomy and a trial of imaging strategies for patients with abnormal liver function tests and symptomatic gall stones). It is hoped to discuss these in more detail at the forth coming GBIHPBA Meeting. If you wish to discuss ideas in advance of the AUGIS submission date or explore other trials please email Professor Jane M Blazeby (firstname.lastname@example.org)
August 2015 – Over the past year the number of funded and open randomised controlled trials (RCTs) in UGI surgery continues to increase. Multi-centre funded studies are described below.
Thermal ablation versus surgery for patients with colorectal liver metastases
A new multicentre, open, pragmatic parallel randomised controlled trial design with internal has been funded to compare thermal ablation versus surgery for patients with colorectal liver metastases. It will open in 2016. The primary outcome is disease free survival (DFS) at 2 years. The team to be led by Professor Brian Davidson (University College London) is to be congratulated on this major achievement. It is funded by the National Institute for Health Research (NIHR).
The ORANGE-II PLUS trial
The ORANGE-II PLUS Trial is an international multicentre study that will provide evidence on the merits of laparoscopic surgery in patients undergoing a left or right hemihepatectomy and participating in an enhanced recovery programme. It is single blind and in the UK it is led by Professor John Primrose, University of Southampton. Currently it is recruiting patients from University Hospital, Ghent, University Hospital Southampton NHS Foundation Trust, Academisch Medisch Centrum – Universiteit van Amsterdam, Plymouth Hospitals NHS Trust, Royal Free Hospital NHS Foundation Trust and University Hospital Birmingham. It is funded by Cancer Research UK
The ROMIO study
The Randomised Oesophagectomy: Minimally Invasive versus Open surgery (ROMIO) pilot study has shown it is possible to recruit successfully. It is therefore hoped to continue and extend this directly into a main trial (grant application under review). The pilot is open in Plymouth Hospitals NHS Trust and Bristol Hospitals NHS Foundation Trust. It is funded by the NIHR.
The PANasta trial
PANasta is designed to compare two methods of pancreatico-jejunostomy, the Cattell Warren and Blumgart techniques following pancreato-duodenectomy for presumed malignancy of the head of pancreas. The pilot phase has just opened to recruitment. It is being led by Chris Halloran and the University of Liverpool. It is funded by Cancer Research UK
The By-Band-Sleeve Study
The original By-Band study was designed to compare the effectiveness and cost-effectiveness of adjustable gastric band with Roux-en-y gastric bypass for patients with severe and complex obesity. Following successful completion of the internal pilot phase the study has expanded and received additional support to include a third group (sleeve gastrectomy). Currently it is open in six centres (Musgrove Park Hospital, Taunton, Southampton NHS Foundation Trust, Southampton, Royal Bournemouth Hospital, Bournemouth, Leeds, Sunderland and Truro). Six more centres will open over the summer. It is funded by the NIHR.
Developing ideas for new RCTs in upper GI surgery
Over the past year meetings to identify priority areas for an RCT in gallbladder disease have been held including a meeting attended by 12 patients in Liverpool in May 2015. Currently the areas suggested for possible RCT design include those recommended in the NICE guidance, i) EUS vs. MRCP for the preoperative management of bile duct stones, ii) timing of laparoscopic cholecystectomy after ERCP clearance of ductal stones and iii) surgery versus conservative management for simple gall stone disease.
There have also been meetings to discuss a possible trial of surgical versus non-surgical treatment for locally advanced oesophago-gastric cancer (lead Dr Was Mansoor). Feasibility work to establish current practice and understand the evidence base is being undertaken to inform an external randomised pilot study.
Anyone interested in designing new trials or joining the work on gall bladder disease or advanced oesophago gastric cancer are welcome to get in touch (email@example.com).
January 2015 – Raising awareness and interest in RCTs in upper GI surgery
The Brighton AUGIS conference was preceded by a rather less orthodox take on research in the shape of a surgical Dragons’ Den. Audience members were invited to hear ambitious teams present their research ideas for surgical RCTs to the ‘Dragons’, in a bid to win support for the development of their proposal into a fundable project.
I chaired the session which was supported by members of the Bristol Surgical Trials Centre. The event was the culmination of a rigorous selection procedure. Eighteen abstracts were submitted for consideration by an expert surgical and methodological panel; Ms Sally Norton, North Bristol NHS Trust, Mr Shaun Preston, The Royal Surrey County Hospital, Guildford, Mr Mark Taylor, Belfast, Dr Jonathan Cook, University of Oxford and Dr Sara Brookes, University of Bristol. A final four RCTs were chosen to present on the day. Prior to presentation, the successful teams were offered in-house mentoring by experienced researchers within the Trials Centre (Mr Angus McNair, Dr Barry Main and Dr Sean Strong) in preparation for the anticipated grilling.
The expected interrogation and incisive comments from the Dragons pushed presenters to their limits, igniting discussion and encouraging additional questions from a receptive and engaged audience especially appreciative of emerging educative aspects such as the translation of research concepts outside of clinical expertise. Tension was dispelled by some light-hearted interjections and notably so by one team whose members, truly throwing themselves at the mercy of the Dragons, presented two proposals following a last-minute retraction by a selected squad. In the event, their somewhat irreverent inclusions were rewarded when one of their ideas came in as winner of the populist vote which was taken before the judges delivered their final verdict.
Ultimately, the RCT proposal ‘EMT2’ (a multi-centre Phase 3 RCT of the omega-3 polyunsaturated fatty acid eicosapentaenoic acid for secondary prevention of colorectal cancer liver metastases) triumphed. Judges praised its presenter, Mr Andrew Cockbain – a Leeds-based ST5 in General Surgery – for his succinct and polished delivery and the project itself for its transparency, clarity and conception. And, finally, all presenting teams were congratulated on their effort, commitment and enthusiasm and, unlike the television blueprint, none found themselves speedily despatched via black cab…
This was our first attempt to raise the profile of surgical RCTs at AUGIS and to encourage surgeons to submit ideas for new trials. We hope to do this again in the future. In the meantime we are working closely with the newly formed AUGIS RCT research committee to develop ideas for trials in upper GI surgery and invitations to collaborate in this work will be circulated in due course.