Barrett&Apos;s Intervention for Dysplasia by Endoscopy
Condition: Barretts Esophagus; Esophageal High-Grade Intraepithelial Neoplasia; Esophageal Cancer Stage I
MeSH terms: Barrett Esophagus
Study type: Interventional

Summary: 
      LAY SUMMARY

      A type of gullet cancer (oesophageal adenocarcinoma) has become the 5th commonest UK cause of
      cancer death. Unfortunately, by the time patients have symptoms, the cancer is often
      incurable. People with Barrett's oesophagus (change of gullet lining occurring in some with
      acid reflux) at risk of this cancer can have regular check-ups, involving examination through
      an endoscope (an instrument inserted by mouth, under mild sedation if required). A small
      proportion of people with Barrett's develop further changes (which might become cancer) in
      the gullet lining; if they do, it is important to remove the affected tissue before cancer
      develops, or when it is at an early stage.

      There are several ways of removing this tissue but the investigators do not know which is
      best. The standard treatment is surgery, but there is a small risk of dying from the
      operation, and patients often suffer complications affecting them for a year or more
      afterwards. Two endoscopic treatments do not involve surgery. Both involve removing visible
      abnormalities by a technique called endoscopic resection, followed by cauterising the
      remaining Barrett's gullet lining by 1 of 2 techniques. One is recommended by the National
      Institute for Health and Clinical Excellence, but it is expensive and less widely available
      than the second. No-one has compared these treatments with each other, nor with surgery, in
      randomised trials (the most reliable way of deciding which is best). Patient groups say they
      would prefer to avoid surgery if the alternative works, and have encouraged us to do trials.

      This feasibility study is a vital step towards two trials: (a) a trial to compare the two
      non-surgical techniques and (b) a trial comparing surgery with endoscopic treatment. It will
      help us find out whether it will be possible to enroll and retain enough patients by using
      several centres, and to identify/resolve any other potential barriers to recruitment and
      retention, including exploring viewpoints of patients and surgeons.
    

Detailed description: 
      The study will comprise 2 parts:

      Firstly, randomising up to 100 suitable patients over a 1 year period, identified at the
      upper gastrointestinal cancer specialist multidisciplinary team meeting in 6 expert English
      centres. Patients will have either high grade dysplasia (HGD) or early cancer in Barrett's
      oesophagus (BE) and will be randomised to two curative endoscopic non-surgical therapies
      (endoscopic resection [ER] and argon plasma photocoagulation [APC] versus ER and
      radiofrequency ablation [RFA]). All techniques are used in current clinical practice, but
      have never been directly compared.

      Secondly, 2 qualitative studies in which we will examine clinicians' and surgeon's attitudes
      towards a trial of oesophageal surgery compared to endoscopic treatment (ER and ablation) by
      questionnaire. Qualitative interviews with a purposive sample of patients will explore their
      views of randomisation, recruitment and participation to help identify and pre-empt problems
      in subsequent planned trials of endoscopic treatments compared to each other and to surgical
      removal of all or part of the gullet.

      Participants will be randomised to the ER plus RFA or ER plus APC group at enrollment. The
      randomisation schedule will be managed by the University of Leicester Clinical Trials Unit,
      using a computer generated random assignment.

      Randomisation will be stratified for length of Barrett's epithelium (< 5; 5-10; > 10 cm).

      DETAILS OF SAMPLE SIZE

      Currently available estimates of eradication rates have poor precision, being derived from
      small case series. Consequently the sample size has been chosen to allow estimation of the
      quantities of interest whilst not exposing too many patients to trial procedures.

      10- -15 new cases per million population per year are treated. Each participating centre is
      based on an upper gastrointestinal cancer treatment centre serving 1.5- - 2 million people.

      Since each centre would expect to see 15- - 20 new patients a year, we aim recruit up to 100
      patients over 1 year from 6 UK centres.

      ENDOSCOPIC INTERVENTIONS

      ER, RFA and APC are all techniques used in current practice, with which all investigators are
      familiar. We will ensure that all investigators are using the same techniques and that
      histological assessment is scrutinised by an an external expert pathology panel (see quality
      control below).

      Best practice is to perform ER of all visible lesions. We will therefore aim for complete
      resection of all visible lesions initially and ablate residual flat Barrett's mucosa at
      subsequent treatment sessions (at 2 monthly intervals up to 8 months after the initial
      treatment by ER).

      The treatment phase of the trial terminates at 8 months. At T= 12 months, diagnostic high
      resolution endoscopy is performed with targeted biopsies of any abnormal areas as well as 4
      quadrant biopsies at 2 cm intervals of the area containing or previously containing the BE.
      The biopsies are in order to identify 'buried' Barrett's glands under the new squamous
      epithelium. The clinical endpoint is at 1 year when recurrent or persistent HGD or cancer
      will be assessed. Any residual BE (not containing HGD or cancer) will be assessed and
      recorded.

      QUALITATIVE STUDIES

      A purposive sub-sample of patients (sampling strategy designed to include a wide range of
      views and experiences, including patients from each centre) will be interviewed by telephone
      after being invited to take part in the feasibility trial, using a topic guide (developed
      collaboratively with lay representatives, with an emphasis on encouraging patients to
      describe their own perspectives freely - a preliminary topic guide has been developed and is
      included with this application), exploring views on being invited to participate in research
      in which they are randomised to different treatment options. The interview would also invite
      views on conducting a trial of endotherapy versus surgery. Interviews will be audio-recorded
      with separate consent and transcribed verbatim by transcribers working to professional
      standards of confidentiality.

      Analysis of Qualitative Data

      Analysis of the interview transcripts will be based on the constant comparative approach and
      managed by NVivo software. The findings will thus include a set of issues that are important
      from a patient perspective, that can help/hinder recruitment and retention, to inform
      subsequent trials.

      Surgeon/clinician Questionnaires

      A purposive sample of surgeons and clinicians at expert centres will receive questionnaires
      to explore views to endotherapy and surgery for the treatment of Barrett's oesophagus with
      HGD or early cancer and on the proposed trials (including 'free text' options inviting views
      on randomization to a trial comparing surgery to endoscopic treatment). Questionnaires will
      be distributed to up to 100 oesophagogastric surgeons and clinicians (lead MDT
      gastroenterologists or expert endoscopists) from the participating centres and other centres
      in the UK as advised by our surgical lead. The questionnaires will be administered by e mail.
      A second e mail will follow after a month in the case of non-response, but those who chose
      not to respond thereafter will not be further contacted.

      Quality of life assessments and healthcare cost assessment

      Quality of Life will be assessed at baseline and at the 6 and 12 months visits, using the
      EORTC Quality of Life Questionnaire version 3.0 (EORTC QLQ-C30) and module QLQ-OES18 to
      assess specific relevant aspects of quality of life related to oesophageal disease. General
      quality of life will also be assessed using EQ-5D. Additional data on healthcare utilisation
      will be collected at baseline, 6 and 12 months using a questionnaire we have developed which
      patients will be asked to complete at these scheduled visits for endoscopy.

      The perspective of the economic analysis will be that of the NHS and personal social service.
      Costs to be obtained will include the costs of endoscopic treatment and continued endoscopic
      surveillance in both groups, as well as any additional intervention after the initial 8-
      month therapeutic phase of the trial. The costs of any salvage treatment at any stage will be
      included. We will test the validity and feasibility of administering the economic evaluation
      questionnaire (patient healthcare utilisation questionnaire and EQ-5D), examining the
      response rate achieved and levels of missing data. EORTC QLQ- C30 will also be tested to
      directly estimate QALYs using EORTC- 8D. Both EQ-5D and EORTC will be used to obtain the
      appropriate information for cost per QALY analysis in future economic evaluation. The
      economic analysis will inform sample size calculation and other necessary information to
      calculate the cost savings for future economic evaluation.
    

Intervention name(s): ER plus RFA; ER plus APC
Intervention type(s): Procedure; Procedure
Intervention description(s): 2 litres/minute, 70 watts
Other intervention name(s): Barrx HALO 360; Barrx HALO 90; Erbe APC 'forward fire' endoscopic catheter
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Health Services Research