Hybrid argon plasma coagulation for the treatment of Barrett’s esophagus: A prospective, multicenter study

Abstract

BACKGROUND

The incidence of Barrett’s esophagus (BE) in China is lower compared to the Western populations. Hence, studies conducted in the Chinese population has been limited. The current treatment options available for BE treatment includes argon plasma coagulation (APC), radiofrequency ablation and cryoablation, all with varying degrees of success.

AIM

To determine the efficacy and safety of HybridAPC in the treatment of BE.

METHODS

The study cohort consisted of patients with BE who underwent HybridAPC ablation treatment. These procedures were performed by seven endoscopists from different tertiary hospitals. The duration of the procedure, curative rate, complications and recurrent rate by 1-year follow-up were recorded.

RESULTS

Eighty individuals were enrolled for treatment from July 2017 to June 2020, comprising of 39 males and 41 females with a median age of 54 years (range, 30 to 83 years). The technical success rate of HybridAPC was 100% and the overall curative rate was 98.15%. No severe complications occurred during the operation. BE cases were classified as short-segment BE and long-segment BE. Patients with short-segment BE were all considered cured without complications. Thirty-six patients completed the one-year follow-up without recurrence. Twenty-four percent had mild dysplasia which were all resolved with one post-procedural treatment. The mean duration of the procedure was 10.94 ± 6.52 min.

CONCLUSION

Treatment of BE with HybridAPC was found to be a simple and quick procedure that is safe and effective during the short-term follow-up, especially in cases of short-segment BE. This technique could be considered as a feasible alternative ablation therapy for BE.

Key Words: Barrett’s esophagus, Hybrid argon plasma coagulation, Ablation treatment, Prospective study, Multicenter study

Core Tip: Among the ablation therapies, radiofrequency ablation (RFA) and Argon plasma coagulation (APC) have been the preferred method. However, there is no method that can 100% complete ablation success. Cryotherapy has become a rescue technique for patients with failed RFA. Meanwhile, the techniques used and resulting success rates have been variable. Hybrid APC technology combines injection and APC ablation technology, which may become an easier to use alternative method and may be used more widely. A prospective, multicenter study was undertaken to assess the feasibility and safety of ablation treatment, using HybridAPC, in the treatment of Barrett’s esophagus patients in China.

INTRODUCTION

Barrett’s esophagus (BE) is characterized by the replacement of normal squamous epithelium with columnar epithelium, with the latter potentially evolving into esophageal adenocarcinoma. The prevalence of BE in Asia is between 0.06% and 5% which is much lower than that of the United States and Western European countries[1]. However, the prevalence of BE in Asia is increasing, and the incidence of adenocarcinoma is in the ranges of 0.26%-1.2%[1,2]. The risk of esophageal adenocarcinoma in individuals with BE is approximately 30 times higher than that for healthy individuals[3]. Therefore, the elimination of BE constitutes a means by which esophageal adenocarcinoma can be prevented[4,5]. Currently, data obtained from western countries is used to guide diagnosis and management of BE patients in China[6,7].

There are a variety of treatment options available for BE, with varying levels of success[8]. Radiofrequency ablation (RFA) and Argon plasma coagulation (APC) have been the preferred method used to treat BE[9,10]. However, these techniques do not confer 100% complete ablation success. So, cryotherapy has become a rescue technique for patients with failed RFA[11]. HybridAPC^® is a device combining a high pressure needle-free injection, which creates a protective saline cushion to protect the underlying muscle layer, with APC ablation technology. With this device, it may become an feasible alternative for the treatment of BE[8].

So, the aim of this prospective, multicenter study was to assess the feasibility and safety of HybridAPC, in the treatment of BE patients in China.

MATERIALS AND METHODS

Participants

Participants were patients with GE from Changhai Hospital (Shanghai, China), the First Affiliated Hospital of Zhejiang University (Zhejiang Province, China), Zhongshan Hospital, Fudan University (Shanghai, China), Tongji Hospital of Tongji University (Shanghai, China), Taizhou Hospital of Zhejiang Province, the Affiliated Hospital of Medical School, Ningbo University (Zhejiang Province, China), and the First Affiliated Hospital of Soochow University (Jiangsu Province, China). Enrolled patients met diagnostic criteria as described[7] and had signed informed consent before participating. The exclusion criteria included: (1) Severe cardiopulmonary dysfunction and intolerance of endoscopy; (2) severe bleeding tendencies; (3) poor compliance as judged by the investigator; (4) unstable vital signs with less that a two-year life expectancy; (5) esophageal varices or venous tumors and inability to prevent bleeding; (6) severe esophageal stenosis; (7) pregnancy; and (8) a lesion located in or spreading to the esophageal diverticulum. The study was approved by Institutional Review Board (IRB) and registered in clinical trials.gov (NCT03418584).

Treatment methods

Patients underwent complete routine blood and coagulation tests, and liver and kidney function tests before undergoing the HybridAPC procedure. Under intravenous anesthesia, the patients were subjected to the following specific procedures: (1) The lesion(s) was/were displayed in narrow band imaging (NBI) mode, and the lesion margin was marked with APC at low power; (2) Submucosal injection was performed by injecting 0.9% NaCl, using the ERBEJET^® 2 hydrosurgery system in HybridAPC^® (ERBE, Tubingen, Germany), to form a fluid cushion underneath the lesion area; and (3) APC ablation was performed on the raised mucosa surface until it turned white or yellow in color.

Research indicators

The primary endpoint of the study was the technical success rate of HybridAPC. The curative rate was determined at the 3-month follow-up endoscopic review with either NBI or blue-laser imaging and/or histopathological proof after biopsy executed at the original treatment site. A BE patient was considered ‘cured’ if there was no columnar epithelium or cancer in the mucosa. The secondary endpoints of the study were: (1) Recurrence rate, defined as the presence of columnar epithelium at the original lesion area, or the recurrence of cancer at the 12-month follow-up visit; (2) complication rate (bleeding, esophageal stenosis, perforation, pain), complication severity and treatment administered; (3) duration of the procedure, defined as the time interval between the insertion of the HybridAPC probe and its removal from the esophagus; and (4) the endoscopists’ level of experience.

Statistical analysis

Statistical analysis was performed using SPSS22.0 software package (IBM, Armonk, NY, United States). The measurement data are presented as mean ± SD, and the counting data are presented as number of cases (%). We analyzed measurement data by two-tail t test (i.e., an independent sample t test), and counting data by corrected Chi-squared test. P < 0.05 was considered to constitute a significant difference.

RESULTS

Baseline characteristics of the patients

Eighty individuals with BE (39 males and 41 females) were enrolled between July 2017 and June 2020. Their demographic characteristics are listed in Table 1. Their mean age was 55.26 ± 11.17 years, with a median age of 54 years (range, 30 to 83 years). Six patients were presented with circumferential columnar epithelium, 38 patients with tongue-like epithelium, 28 patients with island-like epithelium, and eight patients with tongue combined with island epithelium. 61 patients were found to have short-segment BE (< 3 cm in length) while 19 patients had long-segment BE (≥ 3 cm in length). 61 patients had intestinal metaplasia (76.25%), while 19 patients were presented with mild dysplasia (24%).

Table 1 Cohort demographics.

Parameter	Research particpants, number of cases (%), n = 80
Age
≤ 50 yr	26 (32.5)
> 50 yr	54 (67.5)
Sex
Male	39 (48.75)
Female	41 (51.25)
Morphology of BE under endoscopy
Circumferential columnar epithelium	6 (7.5)
Tongue-like epithelium	38 (47.5)
Island-like epithelium	28 (35)
Other	8 (10)
Length of esophageal columnar epithelium
Short-segment BE (< 3 cm)	61 (76.25)
Long-segment BE (≥ 3 cm)	19 (23.75)
Accompanied by intestinal metaplasia
Yes	31 (39)
No	49 (61)

BE: Barrett’s esophagus.

Analysis of the overall effectiveness and safety

The technical success rate of HybridAPC was 100% and the mean duration of the procedure was 10.94 ± 6.52 min. The overall curative rate was 98.15% at the 3-month follow up. One patient with circumferential columnar epithelium was treated twice and showed no recurrence at one year. No serious complications occurred during the operation. There was one case of mild postoperative esophageal stenosis (1.25%) that was treated with dilatation and one case of postoperative hematochezia (1.25%) that healed spontaneously. In China, the definition of BE does not entail the presence or lack of intestinal metaplasia[7]. One of the 17 patients with intestinal metaplasia was not cured. Thirty-six patients completed the one-year follow-up without recurrence. Twenty-four percent manifested mild dysplasia which was resolved in all at one post-procedure.

Exploratory analysis

BE cases were classified as short-segment and long-segment. The two patients with long-segment BE experienced the mild esophageal stenosis and hematochezia, respectively. In addition, one patient with long-segment BE was not cured. Patients with short-segment BE were all cured without complications. The duration of HybridAPC varied significantly in the two groups (P = 0.013). In 28 cases the procedure was performed by the attending endoscopist, while the chief physician/associate chief physician performed the procedure in the remainder. Analysis of the duration of the procedure after regrouping the patients based on the seniority of the endoscopists showed no significant difference between the two groups (P = 0.3222). Two patients with postoperative complications had the procedure performed by the attending endoscopist, and one patient in each of the two groups (the attending-endoscopist group and chief physician/associate chief physician group) was not cured. However, after correction of the Chi-squared test, we found that postoperative complications, cure rate, and recurrences were not related to age, seniority of the endoscopist, length of columnar mucosa, BE morphology, or presence of dysplasia, that may be due to limited sample size. Tables 2 and 3 summarize the data.

Table 2 Correlation analysis between the length of esophageal columnar epithelium and therapeutic efficacy of ERBE argon plasma coagulation.

	Short-segment BE (n = 61)	Long-segment BE (n = 19)	P value
Duration of the procedure (min)	9.93 ± 5.46	14.16 ± 8.56	0.013
Complications	0% (0/61)	10.53% (2/19)	1.000
Curative rate of BE	100% (39/39)	87.50% (14/16)	0.186

BE: Barrett’s esophagus.

Table 3 Correlation analysis between clinical expertise (years performing endoscopy) of endoscopists and therapeutic efficacy of ERBE argon plasma coagulation.

	Attending physician (n = 28)	Senior physician (n = 52)	P value
Duration of the procedure (min)	11.93 ± 7.81	10.40 ± 5.73	0.322
Complications	7.12% (2/28)	0% (0/52)	0.230
Curative rate of BE	95.45% (21/22)	96.97% (32/33)	1.000

BE: Barrett’s esophagus.

DISCUSSION

Esophageal adenocarcinoma evolves from BE and proceeds from nondysplastic BE (ND), low-grade dysplasia (BE with low-grade dysplasia, LGD), high BE with high-grade dysplasia (HGD), and intramucosal carcinoma (IMC)[7]. Active treatment methods for HGD-BE and IMC were adopted worldwide. However, whether to perform endoscopic treatment for ND-BE and LGF-BE remains controversial. Due to the relatively low progression rate of ND-BE and LGD-BE, endoscopic monitoring of both is recommended by some endoscopists[12]. BE accompanied by metaplasia is a risk factor for cancer. Endoscopic ablation for LGD-BE and HGD-BE with intestinal metaplasia is recommended in the United States guideline[13]. Data supports this, as cancer rates after endoscopic RFA was 1.5%; while that after endoscopic monitoring group was 26.5%[9,14]. As well, that clinical symptoms and psychological burden of LGD-BE were alleviated after RFA[15].

In the present study, the majority of patients had ND-BE and LGD-BE. There are several probable reasons for this. First, the incidence of BE in China is extremely low, and second endoscopic resection is a common treatment for HGD-BE and IMC in China. In the present cohort, 35% demonstrated island-like epithelium, 47.5% tongue-like epithelium, and 76.25% short-segment BE. These findings are consistent with other data from China[6]. Endoscopic resection of such lesions is associated with stenosis in 9% of participants[16]. To reduce APC-associated stenosis, submucosal injection before ablation to create a water cushion between the submucosa and the muscle layer was instituted[17,18]. In animal test (porcine), the thermal damage of HybridAPC under different levels of power (50W and 70W) was approximately half that of standard APC (468 ± 136 µm vs 1096 ± 320 µm, P = 0.003)[19]. Further, with HybridAPC no muscle damage was observed. In 50 BE patients with a ≥ 1 cm length of columnar mucosa in the esophagus who underwent HybridAPC, 78% had complete cure demonstrated by pathology, and only one (2%) showed stenosis[20]. Still, HybridAPC is mostly used for ablation of residual island-like epithelium after radical treatment of HEG-BE[20,21]. Recently, HybridAPC (pulsed APC, effect 2, 40-60W) to treat BE in a series of patients in Russia[22]. Eleven of 120 BE patients had LGD and HGD, five underwent endoscopic mucosal resection (EMR) before ablation and all achieved complete ablation with an average of 1.6 operations (ranging from 1 to 3). One patient receiving HybridAPC treatment developed esophageal stenosis three months later. Of note, this patient also underwent EMR prior to HybridAPC. The stenosis was treated with balloon dilatation. All patients were followed-up for an average of 2.5 years (ranging 10 to 46 months) and experienced no recurrence of metaplasia. Similar to our study, the results suggest that HybridAPC is a safe and effective for the treatment of BE and that certain individuals can be treated with HybridAPC alone.

Injection and APC ablation techniques have been mastered by most endoscopists for a long time, so the need for training may be reduced. Feedback from endoscopists indicates that HybridAPC is easy to perform and takes little time. Indeed, HybridAPC was quickly mastered by our endoscopists despite having different qualifications. The system enables water injection to form a water cushion for ablation to protect adjacent tissues from thermal injury. Parenthetically, in our study, a number of patients with stomach polys received HybridAPC for these lesions. In applying HybridAPC, pulse APC and effect 2, 60W is recommended in the publications[20]. Rather than adherence to a fixed energy range, this study employed as a guide ablated tissue color changes (white or yellow). In addition, the factors associated with lesion recurrence, especially intestinal metaplasia remain incompletely determined. In this regard, advanced patient age and longer length of the columnar mucosa were independently corelated with the recurrence of BE[23]. Others noted that recurrence of BE was related to dysplasia, long-segment BE, and limited experience in RFA[24]. The two individuals who were not cured both possessed long-segment BE lesions although this association was not found statistically significant. One of the two patients refused further treatment and the other was lost to follow-up after repeated ablation. The loss to follow-up was relatively high in the present study. It is interesting to speculate if the coronavirus disease 2019 pandemic played a part in this.

The present study still has several limitations. First, the study was a single-arm study. Thus, comparisons between HybridAPC and other treatments are not possible. Second, the duration of follow-up was short. Long-term follow-up is needed to verify the clinical efficacy of HybridAPC. Third, study cohort did not manifest those factors known to be related to disease recurrence. The results were different from previous studies[7,12,23,24], possibly due to the limited sample size.

CONCLUSION

In summary, this prospective multicenter study is, to the best of our knowledge, the first to assess the outcomes of HybridAPC alone in the treatment of BE in China. The data showed that HybridAPC was technically straightforward with short operative times, safe and with reasonable rates of complications. This technique could be considered as an alternative ablation therapies for BE. Based on this, large multi-center studies with long-term follow-up are warranted.