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

Background:

In the last three decades the incidence of esophageal adenocarcinoma (EAC) has increased almost fourfold, making it the most rapidly rising cancer in the Western world. EAC carries a poor prognosis when diagnosed in symptomatic patients. The most important risk factor for developing EAC is the presence of a Barrett esophagus (BE), a condition in which, due to chronic gastro-esophageal reflux, the epithelium of the distal esophagus has been replaced by columnar epithelium containing specialized intestinal metaplasia. Patients with a BE are kept under endoscopic surveillance to detect malignant progression in their esophagus at an early and curable stage.

Patients with low-grade intestinal neoplasia (LGIN) in their Barrett esophagus are considered to have a significantly increased risk for development of esophageal cancer (i.e. synchronous cancer). Patients with LGIN 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 intraepithelial neoplasia (HGIN) and early cancer in a Barrett’s esophagus. Radiofrequency ablation (RFA) is a new promising endoscopic ablation technique. In RFA, the Barrett’s segment is ablated by radiofrequency ablation through a specially designed balloon or electrode-cap. Balloons with different diameters and lengths of electrodes are available.




Aim:

to perform a randomized trial comparing RFA with endoscopic surveillance for patients with a Barrett’s esophagus containing low-grade intraepithelial neoplasia. This study will also progression and development of genetic oncogenetic abnormalities.


Hypothesis:

RFA will lead to permanent and complete eradication of Barrett's epithelium. This will prevent development of HGIN or early carcinoma and may eliminate the need for endoscopic surveillance.




Patients and methods:

Patients are eligible if they have LGIN 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. At inclusion, patients are randomized to RFA or standard endoscopic surveillance. Patients randomized to RFA will have complete removal of all Barrett epithelium in one or multiple treatment sessions. RFA will be performed using the HALO-360 balloon. For additional RFA-treatment the HALO-90 device will be used. After complete eradication of BE, patients will are scheduled for endoscopic surveillance annually. Patients randomized to standard surveillance will undergo upper endoscopies every 6 months the first year and annually from the second year. In the surveillance arm, cyto-brushes will be performed at all endoscopies for analysis of genetic oncogenetic alterations using FISH.
Primary outcome parameter is the rate of high-grade intraepithelial neoplasia and early cancer during two year follow-up. Quality of life will be compared in the two groups using questionnaires.
A sample size of 120 patients will allow detection of a difference between the groups, assuming that 25% of these patients may be expected to develop high-grade intraepithelial neoplasia or early cancer during two years of follow-up.

Radiofrequency ablation (RFA) will lead to permanent and complete eradication of Barrett's epithelium. This will prevent development of high grade intraepithelial neoplasia (HGIN) or early carcinoma and may eliminate the need for endoscopic surveillance.

Study: in case randomized to RFA (t= number of months after first RFA-treatment).

1. T=0 months: first RFA-treatment (HALO-360 RFA balloon).

2. 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.

3. 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.

4. 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.

5. T=12 months: endoscopy with lugol staining and biopsies from neosquamous epithelium (4QBx/2 cm, standard biopsy forceps). From the second year: annual endoscopy with lugol staining and biopsies from neosquamous (4QBx/2 cm, standard biopsy forceps).




Study: in case randomized to surveillance (t=number of months after last endoscopy prior to inclusion)

1. T=6 months: endoscopic surveillance using high-resolution endoscopy with biopsies according to the Seattle protocol (4QBx/2 cm, standard biopsy forceps) and cyto-brushes.

2. 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.

3. T=24 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.




Study: quality of life (t= number of months after randomization).

In both groups quality of life questionnaires (QoLq) will be completed at parallel time points: T= before randomization: QoLq1, T=2 months after randomization when the RFA-group will have been treated with RFA one time: QoLq2, T=9 months after randomization when the control-group will have had the first surveillance endoscopy within the study and the RFA-group will have been treated multiple times QoLq3, T=14 months after randomization when the surveillance group will have had the second surveillance endoscopy within the study: QoLq4, T=26 months after randomization during the time interval between control endoscopies in both groups: QoLq5, T=38 months after randomization as final measurement: QoLq6.

Radiofrequency ablation of the Barrett’s segment.