Research Project AnnualReport

Lead investigator / Professor Andrew Renehan (Clinical Lead)
Lee Malcomson (Research Associate) / Institution / Institute of Cancer Sciences, University of Manchester & Department of Colorectal Surgery, The Christie NHS Foundation Trust
Project Title / Development of an IDEAL framework to standardise the complex intervention of cytoreductive surgery for colorectal peritoneal metastases: a necessary step to phase III trials
Start date / March 2016 / Finish date / March 2017
Lay Summary, including background, methods, results and conclusions to date
(max 1000 words) / Background
Cytoreduction surgery (CRS) followed by hyperthermic intraoperative peritoneal chemotherapy (HIPEC) is a relatively new intervention in selected patients with peritoneal metastases of colorectal origin (PMCR). Data from outside of trials suggest that CRS and HIPEC improve survival compared with the current standard care (chemotherapy). The big challenge is to do trials in this setting – as the intervention is complex, and there are wide variations in the process and recording of outcomes. If trials confirm findings from non‐randomised studies there are an estimated 1000 to 2000 patients who may benefit from this intervention in the UK each year.
There have only been two published randomised trials in this area. The first was published in 2003 and is now considered to be mainly historic. The results of a new trial were published in early 2016, but this terminated prematurely and had a major limitation in that there was no PCI staging used for the systemic arm. There are a small number of on-going trials, but these are small‐scale and have encountered various early problems (Table 1).

Table 1
There are potentially two broad sources of the variability summarised above:
(i) Wide variation in clinical practice
(ii) Poorly‐reproducible methods of recording key prognostic factors and outcomes
In addition to the two established reference centres at The Christie NHS FT and Hampshire Hospitals NHS FT, a ‘new wave’ of emerging peritoneal tumour treatment centres have started opening across the UK and Ireland. This will provide opportunities to integrate phase III trials into this clinical network.
The overarching aim of this project is to develop a robust and reproducible framework in which to undertake a phase III trial in patients with PMCR suitable for CRS with or without HIPEC.
Method
The study will be broken down into the following four stages:
Stage 1 – Documenting between-centre variability
To begin with,200 eligible patients will be identified from databases located at The Christie NHS Foundation Trust and Hampshire Hospitals NHS Foundation Trust.
Data Extraction
The Christie NHS Foundation Trust
The principal investigator will request the required data from the Peritoneal Tumour Service Data Manager who will extract the required data. This will be done by using data collected within the Peritoneal Tumour Service and Mortality and Morbidity databases stored at The Christie NHS FT.
Hampshire Hospitals NHS Foundation Trust
The Colorectal Peritoneal Malignancy Registry will be used with the assistance of the Colorectal Research Nurse based at Hampshire Hospitals NHS FT.
To document the between-centre variability we will collect the following 15 core variables from 100 patients from each trust:
Data Item
1 / Age at time of operation
2 / Gender
3 / WHO Performance Status
4 / Primary Vs Secondary Surgery
5 / Previous chemotherapy – If Yes – regimen, date and dose
6 / Nodal status at diagnosis and time or surgery
7 / HIPEC regimen used
8 / Primary Tumour Site
9 / Blood transfusion requirements
10 / Duration of operation
11 / Peritoneal cancer index (PCI Score)
12 / Cytoreduction completeness score
13 / Type of Stoma
14 / Highest complication grade
15 / Peri-operative 30-day mortality
Results: Between March and June 2016, 50 consecutive cases (25 from each centre) were evaluated as preliminary analyses. Within these modest numbers, differences emerged. For example, there was some variation in CC Score, stoma rates, age and, to some extent, PCI Score & the recording of complications.
Currently, this analysis is being extended to 100. These updated collections are near complete.
Stage 2 – Identifying sources of variability
The second stage will focus on reproducibility and explore within and between-observer sources of variability. We will mainly focus on the following three recordings:
(i) Intra-operative assessment of Completeness of Cytoreduction (CC Score)
(ii) Assessment of intra-operative disease staging [Peritoneal Cancer Index (PCI) score]
(iii) Reporting of post-operative complications
This will involve collecting intra-operative photographs and videos of intra-abdominal tumour deposits as below:
Photographs & videos at The Christie NHS Foundation Trust
Up to 25 eligible patients will be selected from The Christie NHS Foundation Trust. These operations will be photographed and video recorded at key points during the procedure by the Medical Illustration team based at the trust.
Photographs & videos at Hampshire Hospitals NHS Foundation Trust
If it is deemed feasible within the time frame, we may expand the study to include the photography and video recording of patients at Hampshire Hospitals NHS Foundation Trust. If so, the same procedure will be used as above.
Electronic survey
Once all the required photographs have been collected, they will be imported into a secure database and used to create an electronic survey for colorectal consultants at both trusts. Each consultant will thenview the set of images and videos and assess how they would score the PCI and CC score for each case. Once all consultants have completed the survey, the scores will be extracted and analysed for inter-observer variation.
Results: This work has started. Ethics approval was required. The study has been registered with the NCRN portfolio.
The initial ‘trialing’ of the video has had some challenges. We tested surgeon-operated videos (‘GroPro’ and camera within wearing glasses) but quality was poor. We are now collecting sets of cases by standard independent video operator, with better outputs.
Stage 3 – Development of trial manual to standardise variation
After the findings from stages 1 and 2 have been analysed, they will inform two face-to-face workshops which will result in the production of a ‘trial manual’. All members of the core research team and colorectal consultant teams from both trusts will be invited to the workshops.
Stage 4 – Testing of the trial manual
The final stage of the project will be to test the fidelity of the trial manual assembled in stage 3. The workshops that take place in stage 3 will involve a discussion of exactly which components of the trial manual are to be audited. This audit will take place during the final three months of the project and will use the same databases from the first stage of the study. We will also re-assess the scoring of PCI and CC scores using the same images captured in stage 2 of the study to see if there has been any standardisation in the scoring of PCI and CC scores since the manual was distributed.
Changes to protocol from proposed project / The primary change from the proposed project is the use of video instead of photography for the recording of intra-operative disease. It was decided that high definition video would allow surgeons to judge the disease spread much more accurately than still images. By working with the medical illustration department at The Christie NHS Foundation trust, we have been able to successfully capture the required videos for the first two patients recruited into the study.
Additionally, for the first stage of the project, it was decided to analyse the data from a total of 100 patients from each site instead of the original 50. This was to give ourselves a better idea of the variation between the two sites after the initial analysis was completed. As this is a purely exploratory stage of the study, with no hypothesis made, changing the sample size at this point was deemed acceptable. This did require a substantial amendment to be submitted to HRA and go through further REC approval. This has been submitted and we are currently awaiting final confirmation before we can proceed with the analysis of the additional data.
Aims of project / The overarching aim of this project is to develop a robust and reproducible framework in which to undertake a phase III trial in patients with PMCR suitable for CRS with or without HIPEC. In order to do this, this study will result in the creation of a trial manual to distribute amongst all relevant sites.
Progress made to date / The funding for this study commenced on the 11th of March 2016. The project was initially registered with the HRA and granted full REC approval. In addition, we successfully applied for the study to be adopted on the NIHR Clinical Research Network Portfolio of studies.
After all the required registrations were completed, work commenced on stage one of the study. By working with the Data Manger at the Christie NHS FT and thePeritoneal Malignancy Research CNS at Hampshire Hospital NHS FT we were able to collect the specified data from 50 patients from each site. This data was them analysed with several significant differences found between the two sites.
An oral presentation on the study was given at The 3rd UK Peritoneal Malignancy Conference in Birmingham. This lead to a very useful discussion amongst the attendees, one outcome of which was that it would be beneficial to try and collect data from 100 patients from each trust to clarify and confirm the initial findings. It was decided to go ahead with this change and so a substantial amendment request was placed with the HRA (currently awaiting final approval).
Work then started on the second stage of the project to capture images and videos of patients’ intra-operative disease and clearance. To date,two patients have been recruited into the study. We initially trialled photographs and SunnyCam video recording glasses (pictured), howeverneither option provided sufficiently high quality images/videos to use for the study. After further discussions with the Medication Illustrations department at the Christie, we decided on using a HD video camera – which provided excellent video quality and is to be used for all future participants.
Additionally, work has been carried out on the assessment tool that will be distributed once a sufficient number of cases have been filmed. A sample screenshot of which is shown below:

Successes with the project in the last year / 1. REC & HRA approval granted
2. Adoptionon the NIHR Clinical Research Network Portfolio of Studies
3. Successful collaboration between two trusts (The Christie NHS Foundation Trust & Hampshire Hospitals NHS Foundation Trust) forthe collection and analysis of data requiredfor the first stage of the study
4. Development of a suitable technique to collect the required intra-operative video/images and to ensure they are of a sufficient quality
5. Successful recruitment of first two patients for the second stage of the study
6. Well received presentation given at the 3rd UK Peritoneal Malignancy Conference in Birmingham.
Difficulties with the project in the last year / The main difficulty that we have encountered over the past 6 months has been due to the length of time required for the study to be fully registered with the Health Research Authority (HRA). Due a major change over within the HRA Department, there were severe delays with acquiring approval for the study. While the approval process would normally take up to two weeks, due to this changeover, the process took in excess of six weeks. Fortunately, we submitted all the required documents in advance of starting the study, so were not too badly impeded by this delay.
We did encounter some difficulty in acquiring intra-operative images of a suitable quality for the study. We initially tried photographs as well as SunnyCam video recording glasses, but neither option provided particularly good results. After working with the medical illustration department, we then used a HD video camera, which provided us with the desired high quality video.
Timescales and milestones for the project in the next year / Please see below for a timeline indicating the key timescales and milestones for the project:

In summary, the next steps for the project are as follows:
•Video recording of Cyto & HIPEC for PMCR – Approx. 8 cases to film over next 3 months
•Distribution of the PCI & CC Score Assessment Tool – Later this year
•Workshops x 2 – January/February 2017
•Creation & Testing of Trial Manual – Early 2017
Publications and presentations to date / Presentations:
June 2016 - The 3rd UK Peritoneal Malignancy Conference, Sutton Colefield, Birmingham:
“Development of an IDEAL framework to standardise the complex intervention of
cytoreductive surgery for colorectal peritoneal metastases: a necessary step to phase III trials”(25 minute oral presentation about the study to open the conference)
Publications:
None as yet.