A Randomised Trial comparing Surveillance with Radio-Frequency Ablation of Barrett*s Esophagus with Low-Grade Dysplasia; the SURF-study

Patients with low-grade dysplasia (LGD) in their Barrett esophagus are
considered to have a significantly increased risk for development of esophageal
cancer (i.e. synchronous cancer). The reported risk varies between 16% to 28%
for patients in whom two or more pathologists have agreed on the diagnosis of
low grade dysplasia. In addition, the presence of LGD is also a risk factor for
the presence of more advanced lesions elsewhere in the Barrett segment that may
have been overlooked at the initial endoscopy.
Patients with LGD are therefore kept under more close observation and/or
undergo more frequent endoscopic surveillance (every 6 to 12 months).
Endoscopic ablation therapy is used for treatment of selected patients with
high-grade dysplasia (HGD) and early cancer in a Barrett*s esophagus. In
addition, several groups have also treated LGD-patients with different ablation
techniques in the past. After PDT and APC, a substantial number of patients
have residual Barrett*s epithelium and small areas of intestinal metaplasia
and/or dysplasia may remain hidden underneath neosquamous mucosa. Anecdotal
reports of submucosal cancers that occurred during follow-up after PDT and APC
have been reported.Radiofrequency ablation (RFA) is a new promising endoscopic
ablation technique that may overcome some of the aforementioned drawbacks of
PDT and APC.
In RFA, the Barrett*s segment is ablated by radiofrequency ablation through a
specially designed balloon which contains a spindle shaped electrode on its
outer surface. Balloons with different diameters and lengths of electrodes are
available. The instrument has been developed by BARRx Inc, California, USA and
FDA approval is pending for ablation of non-dysplastic Barrett*s mucosa.
Studies have shown that RFA allows for quick, simple and effective superficial
ablation of the esophageal mucosa. Compared to PDT and APC, RFA seems to be
more easy to use and requires two or three treatment session with * in theory-
less esophageal scarring and a lower chance of for developing esophageal
stenosis

The purpose of this project is to perform a randomized trial comparing BARRX
ablation with endoscopic surveillance for patients with a Barrett*s esophagus
containing low-grade dysplasia. This study will also assess the effect of RFA
ablation in eradication of genetic oncogenic abnormalities at the epithelial
level.

This study will be performed as a follow-up study on a multi-centre imaging
study in Barrett*s patients with LGD in the Amsterdam region. For this study
120 Barrett*s patients with LGD will be identified from the regional Barrett*s
registration project. This imaging study is a randomized trial comparing high
resolution endoscopy with high resolution endoscopy using autofluorescence
endoscopy and narrow band imaging and includes patients that have had a
consensus diagnosis of low-grade dysplasia after review of all their biopsies
by an expert panel of pathologists.
Patients selection Pilot study I
Inclusion criteria:
- Patients in the age of 18-85 years with LGD in a Barrett*s esophagus.
- LGD in biopsies obtained from the Barrett*s esophagus in the preceding 12
months and after revision of the pathology slides by at least one of the study
pathologists.
- Informed written consent.
Exclusion criteria:
- Patients with a Barrett*s segment >12 centimeters.
- Any endoscopic visual abnormality detected by high-resolution white light
endoscopy.
- High-grade dysplasia or invasive cancer in any of the biopsies obtained at
prior endoscopies.
- Any prior endoscopic treatment of Barrett*s neoplasia.
- Patients unable to give informed consent.



Schedule
Pre assessment
- At least one high-resolution endoscopy with biopsies according to the Seattle
protocol (at least 6 months prior to randomisation) and cyto-brushes.
- Revision of histopathology by two expert pathologists.
Study: in case randomized to RFA
- T=0 months: first RFA-treatment (HALO-360 RFA balloon).
- T=2 months: endoscopy ± RFA. For isolated islands with a maximum length of 2
cm and less than 50% of the circumference RFA will be performed with the
HALO-90 RFA device. For larger areas of residual Barrett*s mucosa, RFA will be
performed using the HALO-360 RFA balloon. It is expected that the majority of
patients will require some form of additional RFA.
- T=4 months: endoscopy ± RFA. For isolated islands with a maximum length of 2
cm and less than 50% of the circumference RFA will be performed with the
HALO-90 RFA device. For larger areas of residual Barrett*s mucosa, RFA will be
performed using the HALO-360 RFA balloon. It is expected that the minority of
patients will require some form of additional RFA and that this mainly will be
done using HALO-90 RFA device.
- T=6 months: high-resolution endoscopy with lugol staining and biopsies from
neosquamous epithelium (4QBx/2 cm, standard biopsy forceps). In case biopsies
are obtained from areas with visible Barrett*s mucosa, additional treatment
using the catheter based RFA device is allowed.
- T=12 months: endoscopy with lugol staining and biopsies from neosquamous
epithelium (4QBx/2 cm, standard biopsy forceps) and cyto-brushes.
- From the second year: annual endoscopy with lugol staining and biopsies from
neosquamous (4QBx/2 cm, standard biopsy forceps) and cyto-brushes.
Study: in case randomized to surveillance
- T=0 months: endoscopic surveillance using high-resolution endoscopy with
biopsies according to the Seattle protocol (4QBx/2 cm, standard biopsy forceps)
and cyto-brushes.
- T=6 months: endoscopic surveillance using high-resolution endoscopy with
biopsies according to the Seattle protocol (4QBx/2 cm, standard biopsy forceps).
- T=12 months: endoscopic surveillance using high-resolution endoscopy with
biopsies according to the Seattle protocol (4QBx/2 cm, standard biopsy forceps)
and cyto-brushes.
- From the second year: annual endoscopic surveillance using high-resolution
endoscopy with biopsies according to the Seattle protocol (4QBx/2 cm, standard
biopsy forceps) and cyto-brushes

Patients, who are randomized for radiofrequency ablation will be treated for
low-grade dysplasia in Barrett's esophagus with radiofrequency ablation.

25% of patients with low grade dysplasia may be expected to develop high-grade
dysplasia or early cancer during two years of follow-up.
For patients in the RFA group this rate is expected to be less than 5%.
In addition, we anticipate a 5%rate of acute complications and a 5% rate of
late stenosis due to esophageal scarring.