Randomized controlled trial comparing the simplified and standard regimen for focal radiofrequency ablation

In the last three decades, the incidence of esophageal adenocarcinoma (EAC) has
increased six-fold, making it the most rapidly rising cancer in the Western
world.1 Presence of a Barrett*s esophagus (BE) is the most important risk
factor for developing EAC. In BE, the epithelium of the distal esophagus has
been replaced by columnar epithelium containing specialized intestinal
metaplasia, due to chronic gastro-esophageal reflux. Malignant transformation
of BE is thought to occur in a step-wise fashion from non-dysplastic intestinal
metaplasia (IM), to low-grade dysplasia (LGD) then high-grade dysplasia (HGD),
and eventually early cancer (EC).2,3
Radiofrequency ablation (RFA) is an established endoscopic technique for
eradication of Barrett*s esophagus which has been investigated in a variety of
study designs.4*8 Radiofrequency ablation is associated with an acceptable
safety profile, high rates of complete eradication of dysplasia and intestinal
metaplasia, durability of effect, and a significant relative risk reduction for
neoplastic progression.4*8 As a result, radiofrequency ablation is considered
standard of care for patients with high-grade dysplasia, as well as for
residual Barrett tissue after endoscopic resection of early cancer.9
RFA is usually performed primarily with a balloon based electrode for
circumferential ablation (Barrx 360-catheter), followed by focal ablation for
smaller areas of residual Barrett*s mucosa, such as residual BE islands, small
BE tongues or for treatment of the area just above the gastric folds (i.e.
neo-Z-line). In all European RFA studies, standard circumferential treatment of
the Z-line is performed during focal ablation procedures for islands or
tongues. In this area most recurrences occur and circumferential treatment with
the balloon based device may be suboptimal because of poor contact.4
The advised treatment regimen in Europe for focal ablation of Barrett*s
esophagus consists of two ablation passes at 15 J/cm2 with a cleaning phase in
between (2x2x15 J/cm2). These energy settings were derived from clinical dose
escalation studies which were conducted at the AMC Amsterdam in 2007.10,11 Most
US centers however use a regimen with two ablations at 12 J/cm2 (2x2x12 J/cm2),
which originates from a randomized controlled trial (AIM-dysplasia study).7 The
AIM-dysplasia study was initiated while the dosimetry studies at the AMC were
underway. As a result, the first dose-escalation from 2x12 J/cm2 to 2x2x12
J/cm2, which was evaluated at the AMC was included in the AIM-dysplasia trial
protocol, but the second step-up in energy dose (from 2x2x12 J/cm2 to 2x2x15
J/cm2) was not. Since then, all RFA studies from the US have used a 2x2x12
J/cm2 ablation protocol, while all European RFA studies have used 2x2x15 J/cm2.
Generally focal ablation is performed with the Barrx 90 catheter, which was the
first available catheter for focal ablation (previously: Halo 90).10 Ablation
with the Barrx90 catheter is relatively easy to perform. However, cleaning of
the ablation zone and removal of the catheter in order to clean the electrode,
followed by reintroduction for the second ablation pass are impractical and
uncomfortable for the patient. In a previous randomized study by our group, we
studied a simplified ablation regimen for focal ablation of residual Barrett*s
islands with the Barrx 90 device.12 In patients with pairs of islands, one
island was ablated with the standard 2x2x15 J/cm2 regimen (with cleaning of the
ablation zone and electrode) whereas the other island was treated with a
simplified 3x15 J/cm2 regimen without cleaning. The two settings were found to
be comparable for the eradication rate of the islands treated, however we could
not evaluate the outcome at a per patient level, as the remaining islands and
neo-Z-line were treated with the standard 2x2x15 J/cm2 regimen. Although the
3x15 J/cm2 regimen requires a reduced number of introductions and is therefore
easier to perform, in a prospective series we experienced that this regimen
seems to induce more scarring than the standard regimen.13 If patients undergo
the whole focal ablation procedure with this regimen (all islands and
circumferential treatment of the neo-Z-line) this may lead to a higher rate of
stenosis. Reducing the energy settings to 12 J/cm2 when using a triple regimen
may be the best compromise between efficacy and an acceptable stenosis
percentage. The current focal ablation regimen for squamous neoplasia consists
of triple applications at 12 J/cm2 with acceptable side effects.14 By setting
the energy dose to 12 J/cm2, the focal ablation regimen will be equalized
between the US and Europe, and will be comparable with treatment of squamous
cell neoplasia.

The aim of this study is the efficacy of a simplified triple regimen at an
energy setting of 12 J/cm2 instead of 2x2x15 J/cm2, without a cleaning phase in
between, and its effect on the rate of stenosis and overall complications when
using the Barrx 90 device in eradicating the residual Barrett*s segment and
neoplasia.

This is a prospective randomized study, comparing the standard ablation regimen
(2x2x15 J/cm2) against a simplified regimen (3x12 J/cm2 * no clean), using the
Barrx 90 device in the focal ablation treatment of Barrett*s neoplasia.
Patients are randomly assigned in 1:1 ratio to treatment with the standard
ablation regimen (standard group) vs. the simplified ablation regimen (simple
group). Randomization is performed according to a computer-generated sequence,
which is concealed from the researchers, using block randomization per center
(4 patients per block).
Randomization of eligible patients is performed on-site by the study
coordinator during the endoscopic procedure after eligibility of the patient is
confirmed, using ALEA software.

Radiofrequency ablation with the BARRX90-device using either the simple
regimen, or the standard regimen

Possible side-effects of RFA-treatment are pain after treatment (resolving
within a few days and fading away with pain medication), sore feeling in the
throat and a very small risk for a bleeding or a perforation. Also, a stenosis
can develop. We do not know yet if there will be more stenoses after treatment
with the simplified regimen. We do not expect the percentage of stenosis after
both regimen to be different.
Patients do not undergo additional endoscopies because of this study. They will
have to undergo RFA-treatment of their Barrett's esophagus with dysplasia
anyway.