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Peroral endoscopic myotomy vs laparoscopic myotomy and partial fundoplication for esophageal achalasia: A single-center randomized controlled trial

BACKGROUND Achalasia is a rare benign esophageal motor disorder characterized by incomplete relaxation of the lower esophageal sphincter (LES). The treatment of achalasia is not curative, but rather is aimed at reducing LES pressure. In patients who have failed noninvasive therapy, surgery should be considered. Myotomy with partial fundoplication has been considered the first-line treatment for non-advanced achalasia. Recently, peroral endoscopic myotomy (POEM), a technique that employs the principles of submucosal endoscopy to perform the equivalent of a surgical myotomy, has emerged as a promising minimally invasive technique for the management of this condition. AIM To compare POEM and laparoscopic myotomy and partial fundoplication (LM-PF) regarding their efficacy and outcomes for the treatment of achalasia. METHODS Forty treatment-naive adult patients who had been diagnosed with achalasia based on clinical and manometric criteria (dysphagia score ≥ II and Eckardt score > 3) were randomized to undergo either LM-PF or POEM. The outcome measures were anesthesia time, procedure time, symptom improvement, reflux esophagitis (as determined with the Gastroesophageal Reflux Disease Questionnaire), barium column height at 1 and 5 min (on a barium esophagogram), pressure at the LES, the occurrence of adverse events (AEs), length of stay (LOS), and quality of life (QoL). RESULTS There were no statistically significant differences between the LM-PF and POEM groups regarding symptom improvement at 1, 6, and 12 mo of follow-up (P = 0.192, P = 0.242, and P = 0.242, respectively). However, the rates of reflux esophagitis at 1, 6, and 12 mo of follow-up were significantly higher in the POEM group (P = 0.014, P < 0.001, and P = 0.002, respectively). There were also no statistical differences regarding the manometry values, the occurrence of AEs, or LOS. Anesthesia time and procedure time were significantly shorter in the POEM group than in the LM-PF group (185.00 ± 56.89 and 95.70 ± 30.47 min vs 296.75 ± 56.13 and 218.75 ± 50.88 min, respectively; P = 0.001 for both). In the POEM group, there were improvements in all domains of the QoL questionnaire, whereas there were improvements in only three domains in the LM-PF group. CONCLUSION POEM and LM-PF appear to be equally effective in controlling the symptoms of achalasia, shortening LOS, and minimizing AEs. Nevertheless, POEM has the advantage of improving all domains of QoL, and shortening anesthesia and procedure times but with a significantly higher rate of gastroesophageal reflux.


INTRODUCTION
Achalasia is a rare benign esophageal motor disorder characterized by incomplete relaxation of the lower esophageal sphincter (LES) [1][2][3]. For primary or idiopathic achalasia, the underlying etiology has yet to be clearly defined; secondary achalasia results from any one of several systemic diseases including infectious, autoimmune, and drug-induced disorders [4][5][6]. In both cases, the most common symptoms are progressive dysphagia, regurgitation, and weight loss. The symptom intensity and treatment response can be assessed with validated scales such as the Eckardt score [2,7,8]. The diagnosis requires the proper integration between reported symptoms and the interpretation of diagnostic tests such as a barium esophagogram, esophagogastroduodenoscopy (EGD), and manometry-either conventional esophageal manometry (EM) or high-resolution manometry (HRM) [9][10][11][12].
The treatment of achalasia is not curative but rather is aimed at reducing LES pressure [13][14][15][16][17]. In patients who have failed noninvasive therapy, surgery should be considered [18]. Myotomy with partial fundoplication has been considered the first-line treatment for non-advanced achalasia [19].
Recently, peroral endoscopic myotomy (POEM), a technique that employs the principles of submucosal endoscopy to perform the equivalent of a surgical myotomy, has emerged as a promising minimally invasive technique for the management of this condition [20]. This technique was first described in 1980 and subsequently modified to create what is now POEM [21,22].
This randomized controlled trial (RCT) compared the efficacy and outcomes of laparoscopic myotomy and partial fundoplication (LM-PF) with those of POEM for the treatment of patients with achalasia of any etiology. We also compared the two procedures in terms of the incidence of reflux esophagitis.

Study design and participants
This was a single-center RCT in which we evaluated 40 treatment-naive patients with esophageal achalasia. We included patients ≥ 18 years of age who had been diagnosed with achalasia based on clinical and manometric criteria (dysphagia score ≥ II and Eckardt score > 3) and who provided informed consent. Patients who had previously undergone endoscopic or surgical procedures involving the esophagogastric junction (EGJ) were excluded, as were those with liver cirrhosis, esophageal varices, Barrett's esophagus, esophageal strictures, premalignant or malignant EGJ lesions, coagulopathies, pseudoachalasia, esophageal diverticulum, severe cardiopulmonary diseases, or severe systemic diseases, as well as those who were at high surgical risk and those who were pregnant or lactating.

Randomization strategy
An investigator who was unaffiliated with the trial created the randomization list. Specific software ( www.randomizer.org) was used, and participants were randomly allocated at a 1:1 ratio to the experimental (POEM) group or the comparison (LM-PF) group.

Sample size calculation
The sample size was calculated to identify statistical significance between LM-PF and POEM regarding reflux esophagitis rates, which were assumed to be 5% and 40% after LM-PF and POEM, respectively [23]. To achieve a power of 80% with an alpha of 0.05, we estimated the minimum sample size to be 38 (19 patients in each group). Taking potential losses into consideration, we chose to include a total of 40 patients.

Techniques
POEM: All POEM procedures were performed by a single operator with extensive experience in the technique. Prophylactic intravenous antibiotics and a proton pump inhibitor (PPI) were administered 30 min before intubation and general anesthesia.
After the gastroscope was introduced, the esophageal lumen and mucosa were thoroughly cleaned. This was followed by submucosal injection of 10 mL of 0.5% indigo carmine. An incision was made into the mucosa of the posterior wall, between 5 and 6 o'clock, at 10 cm above the EGJ. The incision was made with a dual-function submucosal dissection knife (HybridKnife; Erbe, Tübingen, Germany) in Endocut Q mode (effect 2, width 3, and interval 5). Subsequently, spray coagulation (effect 2 at 40 W) was used to create a submucosal tunnel extending 3-4 cm beyond the EGJ into the proximal stomach. In all patients, full-thickness myotomy-including the circular and longitudinal muscle layers-was performed in Endocut Q mode. The myotomy was initiated 2 cm distal from the mucosal entry point and extended 3-4 cm into the proximal stomach. The mucosal incision was closed by using through-thescope clips ( Supplementary Figures 1 and 2).
A barium esophagogram was obtained on postoperative day 1. In the absence of complications, the patient was started on a clear liquid diet and subsequently advanced to a full liquid diet for 14 d.

LM-PF:
All LM-PF procedures were performed by members of the foregut surgery group. After pneumoperitoneum had been established, five trocars were positioned, after which the left hepatic lobe was retracted to access the EGJ (Supplementary Figure 3). That was followed by division of the phrenoesophageal ligament, dissection, and isolation of the distal esophagus from adjacent structures; and anterolateral dislocation of the distal esophagus. The anterior gastric adipose tissue and the anterior vagus nerve were dissected and separated from the esophagus and stomach, after which myotomy of the circular and longitudinal muscle layers was performed, extending from 5-6 cm above the EGJ to 2-3 cm below the EGJ. Partial fundoplication between the esophagus and stomach was then performed by placing sutures in three planes: Posterior-two to three sutures; left lateral-four to five sutures (on the left side); and right anterior-a line of sutures covering the myotomy, thus interposed with the gastric fundus on the right. In the absence of complications, patients were started on a clear liquid diet on the morning following the procedure and maintained on a mechanical soft diet for 14 d after discharge.

Diagnosis and follow-up
Clinical assessments: Although achalasia subtyping is defined based on HRM, in this study, the achalasia subtype was evaluated according to the degree of esophageal dilation on the barium esophagogram and esophageal motor activity on EM or HRM. Given that Chagas disease, which often involves the esophagus, is common in Brazil, all patients were screened for anti-Trypanosoma cruzi antibodies by enzyme-linked immunosorbent assay and indirect immunofluorescence. Weight loss, dysphagia, and pain were assessed before the procedure, as well as at 6 and 12 mo after the procedure, by using the Eckardt score. Patients with an Eckardt score ≥ 3 were categorized as symptomatic. The clinical evaluation of gastroesophageal reflux (GER) and the diagnosis of GER disease (GERD) was based on the application of the GER Disease Questionnaire (GerdQ)[24] (Supplementary Figure 4).

EGD:
We performed EGD before the procedure, as well as at 6 and 12 mo after. Esophagitis was graded according to the Los Angeles classification system [25]. We performed chromoendoscopy with narrowband imaging and 2.5% Lugol's solution to screen for esophageal cancer. Suspicious lesions were biopsied.
Barium esophagogram: To assess esophageal emptying before and 12 mo after the procedure, we used a timed barium esophagogram, as previously described [26]. The degree of esophageal emptying is qualitatively estimated by comparing 1-and 5-min images or by measuring the height and width (in centimeters) of the barium column at both times, calculating the approximate area, and determining the percentage change in the area.

EM:
Conventional EM was performed before and 12 mo after the procedure. It should be noted that HRM technology was not available in Brazil when the trial began. To perform conventional EM, we used an eight-channel computerized polygraph under pneumohydraulic capillary infusion at a flow rate of 0.6 mL/min/channel. Preparation was required with a 12-h fast and suspension of medications that alter esophageal motility. The technique consists of passing a probe through the nostril and checking the position in the stomach through deep inspiration. With the patient in the supine position, the probe is pulled centimeter by centimeter to measure the mean respiratory pressure and pressure inversion point, and then one of the channels is positioned distal to 3 cm from the upper edge of the LES and the other channels are distant 5 cm apart. Finally, the catheter is pulled up to the upper esophageal sphincter. Through the average of the four distal radial channels of the conventional manometry catheter, the maximum expiratory pressure (MEP) was identified, which best represents the LES pressure itself.

Quality of life:
To evaluate the quality of life (QoL), we used the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) [27,28]. The SF-36 comprises 36 questions covering eight domains: Physical functioning, role-physical, bodily pain, general health, vitality, social functioning, roleemotional, and mental health.
Adverse events: Among the adverse events (AEs) recorded, pneumoperitoneum requiring drainage or puncture was categorized as a minor AE, as was minor mucosal damage requiring endoscopic closure. Major AEs were defined as pneumoperitoneum leading to hemodynamic instability and premature interruption of the procedure; bleeding requiring a blood transfusion and accompanied by hemodynamic instability or requiring an additional intervention; major mucosal damage requiring endoscopic closure or increasing the length of stay (LOS); or fistula/dehiscence of the incision with signs of fever or infection associated with hemodynamic instability. For AEs occurring in the LM-PF group, we used the Clavien-Dindo classification [29].

Outcome measures and data collection
For POEM and LM-PF, the following outcome measures were evaluated: Operative time; length of the myotomy in the esophagus and stomach; myotomy site; complications; and LOS. Patient data were collected on the Research Electronic Data Capture platform.

Follow-up
At 1, 6, and 12 mo after the interventions, the Eckardt score was determined, the SF-36 was applied, EGD was performed, and timed barium esophagograms were obtained. Conventional EM was performed at 6 and 12 mo. Patients received the maximum dose of PPI for the first 30 d postprocedure, and those who presented with erosive esophagitis at follow-up endoscopy were maintained on PPI treatment for 8 wk. Treatment success was defined as symptom improvement (≤ 3-point reduction in the Eckardt score), an LES pressure < 15 mmHg [30][31][32], and a > 50% reduction in the height of the barium column at 1 min. Treatment failure was defined as symptom persistence in patients with an Eckardt score ≥ 3.

Statistical analysis
We performed descriptive analyses of all study variables. Quantitative variables were expressed as means with standard deviations or as medians with interquartile ranges. Qualitative variables are expressed as absolute and relative frequencies. For the comparison of means between the two groups, the Student's t-test was used. When the assumption of normality was rejected, the nonparametric Mann-Whitney test was used. To test the homogeneity between proportions, the chi-square test or Fisher's exact test was used. Repeated-measures analysis of variance was used to compare the groups over the course of the study. When the assumption of normality was rejected, the nonparametric Mann-Whitney test and Friedman test were used. The data were processed with the SPSS Statistics software package, version 17.0 for Windows (SPSS Inc., Chicago, IL, United States). P < 0.05 was considered statistically significant.

Population characteristics
Between March 2017 and February 2018, 40 patients diagnosed with achalasia were enrolled and randomized to undergo LM-PF (n = 20) or POEM (n = 20), as detailed in Figure 1. Nine (22.5%) of the forty patients (five in the POEM group and four in the LM-PF group) tested positive for anti-T. cruzi antibodies, indicating exposure to Chagas disease. At baseline, there was no statistical difference between the two groups in terms of sex, age, etiology, grade, symptom duration, weight, body mass index, or Eckardt score ( Table 1). The study was terminated after all patients had been followed for at least 12 mo.

Treatment outcomes
Eckardt scores at 1, 6, and 12 mo were lower than the baseline scores in both groups-1.0, 0.5, and 0.50, respectively, vs 8.0, in the POEM group; and 0.0, 0.0, and 0.0, respectively, vs 8.5, in the LM-PF group-and the differences were statistically significant (P < 0.001; Table 2). There were no statistical differences between the two groups for the Eckardt scores at 1, 6, and 12 mo of follow-up (P = 0.192, P = 0.242, and P = 0.242, respectively).
In the POEM group, treatment success was confirmed at 1 mo in all 20 patients, at 6 mo in 18 of the patients (90%), and at 12 mo in 19 (95%). In the LM-PF group, treatment success was confirmed at 1 mo and was maintained at 6 and 12 mo in all 20 patients. As shown in Table 3, there was no statistical difference between the two groups regarding treatment success at 1, 6, or 12 mo (P = 0.487 and P = 1.000 for 6 and 12 mo, respectively).
In both groups, there were significant postprocedural improvements in dysphagia, although the differences were not significant at 1, 6, or 12 mo (P = 0.602; P = 0.565, and P = 0.547, respectively). However, statistically significant improvements in weight loss, chest pain, and regurgitation were observed in both groups (Supplementary Tables 1 and 2). The postprocedure rate of GER, as assessed with the GerdQ, was higher in the POEM group than in the LM-PF group (64.6% vs 11.1%; P < 0.02).

Endoscopic findings
At 1, 6, and 12 mo, only 20, 18, and 18 POEM group patients, respectively, underwent EGD, as did only 17, 16, and 17 LM-PF group patients, respectively. The remaining patients declined to undergo EGD because they were asymptomatic. The rates of esophagitis were significantly higher in the POEM group than in the LM-PF group at 1, 6, and 12 mo of follow-up (P = 0.014, P < 0.001, and P = 0.002, respectively). In the LM-PF group, 1 patient had esophagitis (classified as grade A) at 6 mo and 2 patients had esophagitis (classified as grades B and C, respectively) at 12 mo. In the POEM group, esophagitis was observed at 1 mo in 5 patients (being classified as grade A in one, grade B in three, and grade C in one), at 6 mo in 10 patients (being classified as grade A in three, grade B in two, and grade C in five), and at 12 mo in 11 patients (being classified as grade A in five, grade C in four, and grade D in two). At 1, 6, and 12 mo, the rates of esophagitis were 0.0%, 5.6%, and 11.1%, respectively, in the LM-PF group and 29.4%, 62.5%, and 64.6%, respectively, in the POEM group (Table 4). Table 5 shows the results of the barium esophagogram. In both groups, the heights of the barium column at 1 and 5 min were significantly lower at 1, 6, and 12 mo than at baseline (P < 0.001). There was no statistical difference between the two groups regarding the barium column height values at 1 and 5 min in the follow-up periods (intent-to-treat analysis: P = 0.429 and 0.773; per-protocol analysis: P =

EM
In both groups, the MEP values were significantly lower at 6 and 12 mo than at baseline (Table 6). There was no statistical difference between the two groups at either of those time points (intention-to-treat analysis: P = 0.848).    Data are presented as mean ± SD. LM-PF: Laparoscopic myotomy and partial fundoplication; POEM: Peroral endoscopic myotomy.  Table 8 shows the results obtained with the SF-36. In the POEM group, there were postprocedural improvements in all SF-36 domains, whereas there were improvements in only three domains (physical functioning, energy/fatigue, and general health) in the LM-PF group.

DISCUSSION
In this single-center RCT comparing POEM and LM-PF in treatment-naive patients with achalasia, a significant proportion of the patients evaluated had achalasia attributed to Chagas disease. In a study by Farias et al [33], no statistical difference was observed between idiopathic and Chagas disease-associated achalasia regarding treatment success and AEs with POEM. For years, LM-PF has been considered the gold-standard treatment for achalasia [34], because it provides good clinical results, has a low reintervention rate, and has adequate reproducibility. In the first study involving the use of endoscopic myotomy[21], conducted in 1980, all 17 of the patients in the sample showed symptom improvement. Although, technical improvements proposed by Inoue et al [22] in 2010 and several cohort studies comparing POEM and LM-PF [35][36][37][38][39][40][41][42][43][44][45] over the last decade have proved its safety and efficacy in the management of achalasia, the POEM technique is still not fully standardized [22].
The first RCT comparing the two techniques in the treatment of idiopathic achalasia [46], including 221 patients, demonstrated clinical success rates at 1 year and 2 years of follow-up of 84.8% and 83.0%, respectively, in the POEM group, comparable to the 83.5% and 81.7%, respectively, observed for the LM-PF group. In our study, the clinical success rate at the end of the 1 st year was 95% in the POEM group and 100% in the LM-PF group, with no statistical difference between the two techniques. This discrepancy between our results and those of the earlier trial may be related to the fact that approximately 35% of the patients evaluated in that trial had previously received some type of treatment, which could have increased the degree of technical difficulty in dissection secondary to submucosal fibrosis. We observed no statistical differences between the two techniques concerning Eckardt scores for dysphagia, regurgitation, chest pain, and weight loss, at 1, 6, and 12 mo of follow-up, which demonstrates the noninferiority of POEM to the LM-PF.
Immediate postprocedural complications occurred in 10% of the 40 patients evaluated in the present study. There were no cases of death in our sample, and the rate of AEs did not differ significantly between the two techniques. In our study, all POEM procedures involved a full-thickness myotomy, which made pneumoperitoneum an expected event. Pneumoperitoneum is a common finding after POEM and is not indicative of an unfavorable outcome for the patient. We categorized pneumoperitoneum as an AE only if abdominal decompression was required.
Anesthesia and procedure times were shorter for POEM than for LM-PF. That can be explained by the fact that the POEM involved full-thickness myotomy and did not involve fundoplication. There was no difference between the two procedures in terms of LOS and QoL.
We found that POEM and LM-PF both resulted in significant decreases in the 1-and 5-min barium column heights at 1, 6, and 12 mo after the procedures, demonstrating a clear decrease in resistance to the passage of contrast at the level of the EGJ. Sanagapalli et al [47] showed an association of significant improvement in symptoms when there is a mean reduction in the residual barium column height by about 53%. The LES pressure (MEP) on conventional EM was significantly lower throughout the followup period than at baseline, and there was no significant difference between the two groups.
In this study, the rates of treatment success were comparable between surgical and endoscopic myotomy, both providing symptom improvement, as well as objective improvement in radiological and manometric parameters, at 1, 6, and 12 mo. A recent systematic review and meta-analysis demonstrated that the incidence of GER is higher after POEM than after laparoscopic Heller myotomy [48]. That is in agreement with our findings. The evaluation of GER in our study was based on the typical clinical manifestations of GERD or the identification of erosive esophagitis by EGD. All patients with symptoms and suggestive endoscopic findings of GER received PPI treatment with suspension or maintenance according to the clinical and endoscopic response. A significant limitation of our study was the absence of pHmetry evaluation, which is the main method for GERD evaluation. Prior to our study, we considered that the pHmetry evaluation would be compromised because patients with esophageal achalasia present retention of food residues in the esophageal mucosa and the fermentation of those residues can decrease the intraluminal pH and thus be a confounding factor in the diagnosis of GERD. However, Smart et al [49] showed that such fermentation would affect only pre-procedure pHmetry, September 7, 2022 Volume 28 Issue 33 without much influence on the post-procedure pHmetry. Erosive esophagitis, especially grade C or D, is considered indicative of GER after endoscopy in patients without a history of the condition [50]. We consider that patients undergoing POEM have a wider esophagogastric transition that favors a higher rate of GER compared to LM-PF, despite similar LES pressures between the groups. Werner et al [46] also showed more GER in patients undergoing POEM despite no differences in manometry compared to LM-PF.
The POEM technique has undergone numerous changes since its initial description by Inoue et al [22]. It has been shown that short-to medium-term efficacy is comparable between myotomy of the circular muscle layer only and full-thickness myotomy, as well as that the latter, despite significantly reducing the duration of POEM, may increase the risk of GERD [51,52]. Likewise, there is uncertainty about whether myotomy should be performed in the anterior or posterior wall, the latter technique being associated with a higher incidence of GER [53,54], although other studies have failed to demonstrate that [55,56]. In the present study, we chose a long posterior full-thickness myotomy, because of the greater technical ease [43,57,58].
The results obtained in our study corroborate those of a previous study demonstrating the noninferiority of POEM to LM-PF for symptom control in patients with achalasia, except for postprocedure GER [46]. That raises the question of which technical changes we should study. Therefore, it is valid to perform in-depth analyses of oblique fiber preservation techniques [59], as well as the use of POEM with fundoplication [60,61]. One study [58] demonstrated that preservation of the oblique muscle, using the two penetrating vessels as an anatomical landmark, can significantly reduce the frequency of post-POEM GER, although that should be interpreted with caution because it was a retrospective cohort study, without strict methodological criteria, and with limited reproducibility. In the present study, we employed the conventional POEM technique as previously described [62], and the preservation of the two penetrating vessels was not standardized. The postprocedural occurrence of GERD symptoms in our sample was > 50%, similar to what has been reported by other authors. Despite not including patients undergoing POEM, a recent study [63] showed that achalasia patients with post-treatment reflux symptoms demonstrate esophageal hypersensitivity to chemical and mechanical stimuli, which may determine symptom generation.
Another strategy proposed to minimize the occurrence of GER after POEM is performing transoral incisionless fundoplication. In one pilot study [60], that procedure was reported to have a 100% success rate in terms of symptom control, acid exposure time, and the need for antisecretory drugs. In another pilot study [61], standard POEM combined with endoscopic fundoplication (POEM-F) was employed, and no complications were observed. A recent retrospective study followed patients for 12 mo after POEM-F [64], and showed that the incidence of postprocedural GER was only 11.1%. Albeit attractive, POEM-F has several potential limitations [65]. First, it is necessary to perform POEM in the anterior wall, contrary to the current trend of using a posterior wall approach. Second, it may not be possible to perform POEM-F in patients who have previously undergone anterior myotomy and experience symptom recurrence due to submucosal fibrosis. Third, the long-term durability of this type of fundoplication is still unknown.
In our opinion, it will take some time for the literature to reveal whether endoscopic or surgical myotomy is the best long-term option for the treatment of achalasia. Two crucial points that weigh unfavorably on the POEM procedure, in terms of the possibility that it will come to be widely indicated for the treatment of achalasia [66,67]. The first is the paucity of high-quality (randomized) technical studies comparing POEM with the well-established techniques of pneumatic dilatation of the cardia and laparoscopic myotomy with fundoplication, which could show, at least, the noninferiority of POEM. The second is the lack of studies with long (> 5 years) follow-up periods, which could demonstrate the true reintervention rate, based on the identification of serious late complications, including GER requiring fundoplication and dysphagia resulting from an inadequate myotomy [68]. Currently, the results at 2-3 years are similar between the endoscopic and surgical myotomy techniques concerning the clinical parameters, except for the greater occurrence of GER after the endoscopic technique, which typically responds well to antisecretory drug treatment. However, those data are accompanied by uncertainties that will only be resolved over time.

CONCLUSION
Our results allow us to conclude that LM-PF and POEM are equally effective in controlling the clinical symptoms of achalasia at 1, 6, and 12 mo. Although the use of the POEM technique results in a significantly higher rate of postprocedure GER, it also shortens anesthesia and procedure times. We found no differences between the two methods regarding LOS, the occurrence of AEs, or QoL. In the POEM group, there was an improvement in all domains of QoL.