PROGRESSIVE ESOPHAGEAL DILATION FOR BENIGN STRICTURES: A RANDOMIZED CONTROLLED TRIAL

A benign esophageal stricture is a narrowing of the esophagus that causes
difficulty to swallow, and endoscopically is defined by the inability to cross
it with an endoscope of 9 mm of diameter. Clinical symptoms may be dysphagia,
odynophagia, weight loss and regurgitation of food.

Benign esophageal strictures are relatively common in clinical practice. In the
past, peptic stricture secondary to gastroesophageal reflux, were the most
frequent, whereas at present are mainly secondary to caustic ingestion and
radiotherapy (1). In recent years they have also been described as a result of
advanced endoscopic therapy in the esophagus: endoscopic mucosal resection
(EMR) and submucosal dissection (ESD).

Generally, most benign strictures respond well to endoscopic dilation, but in
25-35% of cases, multiple sessions of dilation are necessary.2 Postsurgical
stenosis secondary to ingestion of caustic, and those caused by radiation
treatments, have a low response rate to endoscopic treatment, where over 40% of
cases tend to recur. Additionally, a hypopharyngeal location of a stenosis,
regardless of the cause, is usually refractory to endoscopic dilation.

Endoscopic dilation therapy
The aims of dilation are to alleviate dysphagia, reduce the risk of pulmonary
aspiration, maintain oral nutrition, and facilitate passage of endoscopes.3
Adverse events (AEs) of dilation include perforation, bleeding, pulmonary
aspiration, and fistula formation. Perforation occurs in 0.1% to 2.6% of
procedures and is the most feared AE with a mortality rate as high as 20%4,5.
Risk factors for dilation-induced perforation include eosinophilic esophagitis,
complex strictures, and malignant stenoses.4,6
Balloon and bougie dilators are used to perform dilation. As opposed to radial
forces incurred by balloon dilators, bougie dilators also generate longitudinal
forces. This difference has never been proven to have any effect on the rate of
AEs or clinical outcome between Savary (bougie) and through-the-scope (TTS)
balloon dilators.7-10 Theoretically, more dilation sessions are needed with
bougie dilators because the rule of 3 may limit the number of sessions. The
rule of 3 states that no more than 3 dilators of progressively increasing
diameter should be passed after moderate resistance is encountered. This rule
is applicable to bougienage alone and was intended to preclude overaggressive
dilation and consequent perforation. Although the rule of 3 makes common sense,
it is not evidence based. One study suggests that dilation using larger
incremental diameters may be safe for simple strictures.11
One retrospective cohort study assesses a high volume of esophageal dilations
and the association between the rule of 3 and non-adherence to the rule of 3 to
AEs during esophageal bougienage and balloon dilation. Results demonstrate that
adherence to the rule of 3 does not appear to reduce the risk of AEs, including
esophageal perforation, after esophageal dilation with bougie or balloon
dilators. Malignant structures are associated with an increased risk of AEs and
perforations.12

This clinical trial is designed to investigate prospectively, in a randomized
controlled setting, the efficacy of non-adherence to the rule of 3 in benign
esophageal strictures with the use of the Savary bougie dilator. The proposed
alternative to the rule of 3 is the rule of > 3 esophageal dilation strategy.
Advantages of this more progressive dilation strategy is less esophageal
dilation sessions in total and thus less risks of AEs during esophageal
dilation and lower costs. This is hypothesised to result in an accelerated
response to dilation treatment for dysphagia due to severe benign esophageal
strictures.

The main objective is to compare the efficacy and safety of esophageal dilation
with the balloon the Savary bougie dilator according to the rule-of-3 to
rule-of > 3 strategy during 6 months in patients with a severe benign
esophageal stricture.

Secondary objectives are to compare safety, quality of life and technical
success of dilation with the Savary bougie dilator.

A randomized controlled clinical trial, in a single center (Radboudumc), is
designed to compare the efficacy of esophageal dilation with the Savary bougie
dilator according to the rule-of-3 to rule-of > 3 strategy during 6 months in
patients with a severe benign esophageal stricture.
After dilation to 16-18mm, the patient will be monitored for 6 months

Dilation is carried out with the Savary bougie dilator in both groups. The
stricture will be dilated to a diameter of 16-18mm, according to the preference
of the endoscopist. As a general rule in daily practice (rule of 3) a minimum
of 3 dilation sessions are required to reach a diameter of 16-18mm when a
severe stricture is present. The maximum diameter should be reached within a
maximum of 3 weeks time. A severe stricture is defined as a stricture with no
patency for a standard endoscope (9-10mm diameter).
In the scenario where dilation is done progressively (rule of > 3) a minimum
of 2 dilation sessions are required to reach a diameter of 16-18mm in severe
strictures. The maximum diameter should be reached within a maximum of 2 weeks
time. Endoscopy is performed immediately after the dilation session to check
for potential complications and to confirm efficacy of the dilation.

Rule of 3 (standard of care )
One group consists of dilation according to the rule of 3. The rule of 3 is
defined by the American Society for Gastrointestinal Endoscopy (ASGE)
guideline13 on esophageal dilation: no more than 3 consecutive dilations in
increments of 1 mm should be passed in a single dilation session.

Examples:
Patient presented with a severe stricture of 9mm diameter.
- first dilation session: 9 - 10 - 11mm
- second dilation session: (11) - 12 - 13 - 14mm
- third dilation session: (14) - 15 - 16 - 17mm

Patient presented with a severe stricture of 10mm diameter.
- first dilation session: 10 - 11 - 12mm
- second dilation session: (12) - 13 - 14 - 15mm
- third dilation session: (15) - 16 - 17 - 18mm

Rule of > 3 (intervention)
The rule of > 3 is defined as: no more than 6 consecutive dilations in
increments of 1 mm should be passed in a single dilation session.

Example:
Patient presented with a severe stricture of 9mm diameter.
- first dilation session: 9 - 10 - 11 - 12 - 13mm
- second dilation session: (13) - 14 - 15 - 16 - 17mm

Patient presented with a severe stricture of 10mm diameter.
- first dilation session: 10 - 11 - 12 - 13mm
- second dilation session: (13) - 14 - 15 - 16 - 17 - 18mm

As of today no literature is available investigating the effect of a less
conservative dilation strategy. In theory, the expected benefits for patients
that are dilated according to the rule of > 3 are:
- A smaller number of sessions required to achieve response to treatment. The
patient has to undergo less sessions of esophageal dilation to achieve relief
of their dysphagia, resulting in less risk of AEs and less hospital visits.
- Response to treatment is reached at an earlier stage of treatment due to the
extended effect of the dilation increments. Thus, the patient has relief of
their dysphagia at an earlier stage of disease, resulting in a potential
quality of life improvement.

In terms of safety, Grooteman et al12. reported that non-adherence to the rule
of 3 was not associated with a higher risk of major AEs in patients with benign
esophageal strictures. Non-adherence to the rule of 3 was defined as a
esophageal dilation with increments higher than 1 mm per dilation and >= 3
dilations in a single session. In the non-adherence group 0.5% vs. 1.6% AEs in
rule of 3-dilations was reported, with no significant difference (P = .18). For
perforations, the most feared complication of dilation, 0% in the non-adherence
group vs. 0.7% in rule of 3-dilations was reported, with no significant
difference (P = .18)

Participation in the study does not cause any additional charge to patients.
The esohpageal dilations and follow-up are not different from the usual in
clinical practice.

The main advantage of esophageal dilation according to the rule of > 3 is that
is possible less interventions required. Moreover, another advantage is that
it can be more effective in solving the benign stricture at an earlier stage of
disease.

The risk classification is determined as negligible based on the guideline of
the *Nederlandse Federatie van Universitair Medische Centra*. The risks
associated with the participation in the study are similar to the risks of
treatment with conservative dilation, and not different from the complications
arising from dilation according to the rule of 3.