Toward a Tailored Treatment of Achalasia: An Evidence-Based Approach

Abstract

Background:

The treatment options in achalasia patients aim to improve symptoms by reducing the functional obstruction at the level of the gastroesophageal junction. Available treatment modalities are endoscopic botulinum toxin injection (EBTI), pneumatic dilatation (PD), laparoscopic Heller myotomy (LHM), and peroral endoscopic myotomy (POEM). We provide an evidence-based review of current indications, limitations, and future perspectives of these options for the treatment of achalasia.

Methods:

The PubMed/Medline electronic databases and the Cochrane Library were searched. Quality of evidence was assessed according to the GRADE system.

Results:

Functional outcomes after EBTI are significantly worse than those after PD or LHM. LHM with partial fundoplication is associated with low complication rates and provides excellent long-term results with lower need for additional treatment of recurrent dysphagia than PD. POEM is a new promising treatment option with good short-term outcomes and low morbidity in experienced hands.

Conclusions:

LHM should be considered the procedure of choice for the treatment of achalasia in patients who are fit for surgery. Large randomized controlled trials with long follow-up are needed to validate the role of POEM.

Introduction

The treatment options in achalasia patients aim to improve symptoms by reducing the functional obstruction at the level of the gastroesophageal junction. Current treatment options include endoscopic botulinum toxin injection (EBTI), pneumatic dilatation (PD), laparoscopic Heller myotomy (LHM), and peroral endoscopic myotomy (POEM).

The aims of this article were to critically review the outcomes of these treatment options and provide an evidence-based algorithm for the management of achalasia patients.

Literature search

The critical appraisal of the literature was performed searching the electronic PubMed/Medline databases and the Cochrane Library for articles published between January 1975 and January 2016 using the following medical subject headings (MeSH) and free text words alone or in combination: “achalasia,” “endoscopic botulinum toxin injection,” “pneumatic dilatation,” laparoscopic Heller myotomy,” “fundoplication,” “POEM,” “dysphagia,” “reflux,” and “recurrent dysphagia.” We limited the literature search to articles published in English language. Reference lists from the included articles were manually checked, and additional studies were included when appropriate. When multiple publications on the same data from a single institution were retrieved, the most recent study was considered.

Evaluation of evidence and recommendation

Quality of evidence and strength of recommendation are evaluated according to the GRADE system (www.gradeworkinggroup.org/index.htm).^1,2

Endoscopic botulinum toxin injection

EBTI into the lower esophageal sphincter (LES) blocks acetylcholine release at the level of the cholinergic synapses, thus decreasing the LES pressure. Several studies have investigated the functional results of EBTI in achalasia patients.^3–11 EBTI is a safe treatment option that leads to relief or improvement of dysphagia in about 80% of patients at 1 month after the procedure. However, the clinical benefits progressively decline over time: About 40% patients only are free of symptoms at 12 months, and repeated EBTIs are necessary in more than 50% of cases.¹²

There are a few studies that have evaluated the optimal dose of botulinum toxin. For instance, Annese et al.¹³ randomized 118 achalasia patients to receive 50 U (n = 40), 100 U (n = 38), and 200 U (n = 40) of botulinum toxin in a single injection. Responsive patients who were treated with 100 U were reinjected with an identical dose after 30 days. Clinical and manometric evaluation was performed preoperatively, 30 days after the first EBTI, and at the end of follow-up. At 30 days, 82% of patients showed symptom improvement. However, only 19% of patients who received two injections of 100 U compared with 47% and 43% in the 50 and 200 U groups complained recurrence of symptoms at the end of follow-up (mean: 12 months; range: 7–24 months).

Based on the promising results of this study and the increasing popularity that the laparoscopic approach was gaining at that time, Zaninotto et al.¹⁴ conducted a few years later a randomized controlled trial (RCT) aiming to compare the outcomes in patients undergoing EBTI (100 U twice a month apart in responders) (n = 40) or LHM plus Dor or Nissen fundoplication (n = 40) for achalasia. There was no perioperative mortality. After 24 months after surgery, 66% of EBTI patients complained recurrence of symptoms compared to 12.5% of patients treated surgically (P < .05).

EBTI is not only inferior to LHM in treating achalasia patients but also associated with higher risk of intraoperative complications and poorer outcomes in patients undergoing subsequent Heller myotomy, mainly secondary to the development of transmural inflammation and fibrosis at the level of the gastroesophageal junction.^15–17

Finally, several RCTs^18–24 have compared the outcomes in patients undergoing EBTI or PD, showing higher symptom recurrence rates and a greater need for additional treatment after EBTI. For instance, Vaezi et al.¹⁹ randomized symptomatic achalasia patients to EBTI (22 patients) or PD (20 patients). They found that only 32% of EBTI patients were in symptom remission compared to 70% of PD patients at 12 months (P = .017).

In conclusion, functional outcomes after EBTI are significantly worse than those after PD or LHM. Therefore, EBTI should be restricted only to frail patients who are not fit for PD and LHM (quality of evidence: HIGH; strength of recommendation: STRONG).

Pneumatic dilatation

PD using controlled pneumatic pressure devices (30, 35, and 40 mm in diameter) is the most effective nonsurgical treatment for achalasia.²⁵ Esophageal perforation is the most serious complication after PD, with an overall rate reported in the literature of 2% (range: 0%–8%).²⁶ A surgical repair is needed in 50% of patients. The clinical response in terms of dysphagia relief to a single PD session is 85% at 1 month, 66% at 12 months, 50% at 5 years, and 25% at 10 years. A strategy based on multiple PDs is commonly used in these patients to treat recurrent dysphagia; however, less than 60% of patients and only 36% of patients are free of symptoms at 3 and 10 years, respectively.^12,27 Significant predictors of poor long-term outcomes in patients undergoing PD are young age (less than 40 years) and a post-PD LES pressure higher than 10 mmHg. Repeated PDs are not associated with better outcomes at 10 years after the first PD.²⁷ Therefore, young patients (<40 years) and those who do not experience symptom relief after a single PD should be referred for surgery.

Pathologic gastroesophageal reflux is objectively detected by 24-hour pH monitoring in up to one third of patients.^28–30

Laparoscopic Heller myotomy

The development of the laparoscopic approach to achalasia is the result of the evolution of minimally invasive techniques that started in 1991 when Pellegrini et al. performed the first thoracoscopic Heller myotomy.³¹ In the early 1990s, the thoracoscopic Heller myotomy was the minimally invasive approach of choice for the surgical treatment of achalasia since the construction of a fundoplication was not deemed necessary.³¹ Later in the 1990s, it became clear that a longer myotomy extending onto the stomach and the construction of a fundoplication performed laparoscopically were associated with better dysphagia relief and lower incidence of pathologic gastroesophageal reflux than the thoracoscopic myotomy alone,^32–46 thus leading to a progressive switch to the laparoscopic approach.

LHM is a safe procedure with a negligible mortality rate (0.1%). The most common complication is the inadvertent perforation of the esophagus (6.9%) that is most frequently recognized intraoperatively. Postoperative sequelae of esophageal perforation are uncommon (less than 1%).¹²

Several nonrandomized studies comparing transabdominal open and LHM with partial anterior fundoplication have been conducted in the second half of the 1990s,^47–52 showing better short-term outcomes in patients treated laparoscopically and equivalent functional outcomes between the two approaches. This evidence led to a progressive increase in the number of patients referred for surgery rather than PD, with a subsequent decrease in the number of patients surgically treated after one or more endoscopic treatments.

Patients undergoing LHM after previous endoscopic treatments are at higher risk of esophageal perforation and less predictable long-term outcomes.^16,17,53,54 For instance, Smith et al.¹⁷ reported the outcomes in 209 achalasia patients undergoing Heller myotomy: 100 patients had 100 PD, 33 had EBTI, and 21 had both treatments. Overall, intraoperative complication rate was significantly higher among the patients who had a previous endoscopic treatment (9.7% versus 3.6%). While gastric perforation occurred in both groups, esophageal perforation was experienced only by patients who had undergone surgery after prior endoscopic treatment. Pulmonary complications were more common after endoscopic treatment (10.4% versus 5.4%). Persistent or recurrent severe dysphagia requiring additional therapy, including redo myotomy or esophagectomy, was higher in the endoscopically treated group (19.5% versus 10.1%). Snyder et al.⁵⁴ published in 2009 a study comparing achalasia patients undergoing LHM with none or one preoperative endoscopic treatment and patients undergoing LHM after two or more endoscopic procedures. A total of 134 patients were included; 88 (66%) had zero to one preoperative intervention. The need for reintervention for recurrent or persistent symptoms was 7% in the zero to one intervention group and 28% in the more than one intervention group (P < .01), with a median duration of follow-up of 11.2 months (interquartile range: 1.4–24.6 months). The logistic regression modeling showed that more than one endoscopic intervention was a significant predictor of surgical failure.

The mean success rate in terms of symptom relief after LHM is 89% after a mean follow-up of 35 months (range: 8–83 months).¹² Even it seems that the efficacy of LHM might decrease over time,^55,56 several studies show excellent clinical outcomes even in patients followed for more than 5 years after LHM.^57–61 Costantini et al.⁵⁷ evaluated 71 consecutive patients with a minimum 6-year follow-up after LHM and documented a success rate of 81.7%. Zaninotto et al.⁵⁸ reported no or occasional dysphagia in 93% of patients at a median follow-up of 18.3 months (range: 2–26 months). Similar results were reported by Cowgill et al.⁶⁰ in 33 patients with a follow-up longer than 10 years: Symptom control was good to excellent in 92% of patients.

The length of the myotomy is key in reducing the risk of recurrent dysphagia: It has been clearly demonstrated that a 3-cm myotomy carried out below the gastroesophageal junction is associated with durable dysphagia relief after surgery.^39,62

The occurrence of pathologic reflux after LHM is reported significantly less frequently if a fundoplication is added to the LHM: 14.5% versus 41.5%.¹² The rates of reflux after LHM with fundoplication are lower than those after PD.¹² A prospective randomized trial aimed to objectively evaluate the esophageal function after LHM alone or LHM with fundoplication.⁶³ A total of 21 patients treated by LHM alone and 22 patients undergoing LHM and Dor fundoplication were enrolled. At 6-month follow-up, pathologic gastroesophageal reflux was recorded in 47.6% (10/21) of patients who had LHM alone and in 9.1% (2/22) of patients who had LHM with Dor (P = .005). No significant differences were observed in postoperative LES pressure and dysphagia score between the two groups.

Even though a total fundoplication achieves the best reflux control, it is associated with higher rates of postoperative dysphagia than a partial fundoplication. An RCT including 138 achalasia patients found a significantly higher dysphagia rate in patients undergoing LHM with a total fundoplication than an anterior partial fundoplication at a mean follow-up of 125 months (15% versus 2.8%; P < .001). No significant differences in reflux control were observed.⁶⁴

Partial anterior and partial posterior fundoplications are equally effective in controlling reflux after LHM. A multicenter, prospective, RCT showed similar reflux scores and total acid exposure between achalasia patients undergoing LHM with partial anterior or partial posterior fundoplication at 1 year after surgery.⁶⁵

Most patients who are 75 years or older are untreated or referred for PD⁶⁶ even though (1) the likelihood of further treatments to treat dysphagia is higher after PD than surgery, (2) in the elderly, the probability of esophageal perforation is higher after PD than LHM,⁶⁷ and (3) there is increasing evidence that both short-term and functional long-term outcomes after LHM are not adversely affected by increased age. For instance Kilic et al.⁶⁸ reported the outcomes in 57 patients who were 70 years or older after laparoscopic (n = 55) or thoracoscopic (n = 2) Heller myotomy for achalasia. There was no perioperative mortality, and median hospital stay was 3 days. Conversion rate to open surgery was 5.3%, secondary to adhesions and concern regarding the viability of the myotomy following repair of a small perforation. Complication rate was 19.3%, including three (5.3%) intraoperative esophageal perforations. With a mean follow-up of 23.5 months, mean dysphagia score decreased from 3.38 preoperatively to 1.36 (P < .0001). A total of 4 (7%) patients required a reoperation for recurrent dysphagia. Salvador et al.⁶⁹ stratified 571 achalasia patients undergoing LHM and Dor fundoplication according to their age: group A (≤45 years), group B (45–70 years), and group C (≥70 years). The three groups did not differ for esophageal perforation, such as the treatment failure rate (10.1% in group A, 8.4% in group B, and 7.5% in group C) (P = .80).

In addition, the esophageal diameter does not appear to be a factor affecting the outcomes of LHM. Sweet et al.⁷⁰ reported similar results in 113 achalasia patients regardless of the maximal diameter of the esophageal lumen and the shape of the esophagus: group A, diameter <4.0 cm; group B, esophageal diameter 4.0–6.0 cm; group C, diameter >6.0 cm and straight axis; and group D, diameter >6.0 cm and the sigmoid-shaped esophagus. No patients required an esophagectomy.

In conclusion, laparoscopy is the preferred surgical approach to achalasia patients in most centers in Europe and the United States (quality of evidence: HIGH; strength of recommendation: STRONG). A long myotomy and the construction of a partial fundoplication lead to durable symptom relief and low occurrence of gastroesophageal reflux in most patients (quality of evidence: HIGH; strength of recommendation: STRONG).

PD versus LHM

During the past 30 years, we have witnessed a progressive shift from PD to surgery for the treatment of achalasia, mainly secondary to the wide diffusion of minimally invasive surgery.^32,71

To date, three RCTs compared PD and LHM in newly diagnosed achalasia patients.^67,72,73 PDs were performed in all studies using 30-, 35-, and 40-mm balloons. Kostic et al.⁷² randomized 26 patients to PD and 25 patients to LHM. PDs were performed using 30-, 35-, and 40-mm balloons. At 12 months, more treatment failures were observed among PD patients (30.8% versus 4%; P = .04). Esophageal perforation requiring emergent surgery occurred in 2 patients allocated to PD. No major complications were recorded after LHM.

Novais et al.⁷³ randomized 94 untreated patients with achalasia to PD (n = 47) or LHM with partial anterior fundoplication (n = 47). Clinical, manometric, and 24-hour pH monitoring results were compared. PDs were performed with 30-, 35-, and 40-mm balloons. At 3 months after surgery, clinical success rates were 73.8% among PD patients and 88.3% in the LHM group (P = .08). Pathologic reflux was detected in 31% of patients after PD and 4.7% after LHM (P = .001).

More recently, Boeckxstaens et al. published the short-term results of a randomized, multicenter, European trial.⁶⁷ The authors found no significant difference in the symptom relief rate at 2-year follow-up between 95 achalasia patients randomized to PD and 106 randomized to LHM: PD 86% versus LHM 90%. In addition, LES pressure, esophageal emptying, and quality of life were similar in the two groups.

A systematic review and meta-analysis of these three RCTs⁷⁴ have shown (1) a significantly lower rate of complications requiring medical or surgical interventions among patients surgically treated and (2) a significantly higher symptom remission rate after LHM than PD at 1 year of follow-up (86% versus 75.6%). These results confirm the findings of a meta-regression analysis of 15 PD studies (1065 patients) and 39 LHM studies (3086 patients) published between 1975 and 2006 that showed better symptom improvement after surgery at 3-year follow-up (89% versus 58%).¹²

To date, very few comparative studies have reported long-term outcomes after PD or LHM. The long-term results of the multicenter randomized controlled European achalasia trial⁷⁵ showed no differences in the success rate between PD (82%) and LHM (84%) patients at 5-year follow-up. Better results were observed after LHM than PD in the subgroup of patients younger than 40 years. Even though the authors concluded that PD and LHM achieve similar long-term outcomes, it must stress that 25% of PD patients required further endoscopic dilatations and 7 patients refused a redilatation; in addition, some flaws in the design of the study⁷⁶ might bias the interpretation of the results.

In conclusion, even though one RCT shows similar long-term functional outcomes after PD and LHM, several large case series report significantly better results after surgery. In addition, PD is associated with a larger need for additional treatment for recurrent dysphagia than LHM. Therefore, LHM should be recommended as the initial therapeutic option in patients fit for surgery (quality of evidence: HIGH; strength of recommendation: STRONG).

Peroral endoscopic myotomy

POEM is an innovative endoscopic procedure that has been recently introduced as an alternative to LHM. Briefly, a 2-cm longitudinal incision is performed on the mucosal surface of the esophagus about 15 cm proximal to the gastroesophageal junction. The submucosa is entered, and a tunnel extending down onto the proximal stomach is created. The circular muscular fibers are then sectioned beginning 2–3 cm distal to the mucosal entry and extending about 3 cm on the stomach. The mucosal entry is closed using hemostatic clips.

Following the first report of POEM by Inoue et al. in 2010,⁷⁷ several case series of achalasia patients treated with POEM have been published reporting controversial results.

In 2015, three systematic reviews and meta-analyses of studies aiming to evaluate the efficacy and adverse outcomes after POEM were published.^78–80 Patel et al.⁸⁰ included both case series and studies comparing POEM and LHM that were published between 2010 and January 2015. They found a total of 22 studies including 1122 POEM patients (19 case series and 3 retrospective comparative studies). Overall mediastinal leak and bleeding rates were 0.3% and 1.1%, respectively. There was only one death (0.09%). Mean follow-up was 10 months. There was a significant decrease in LES pressure and timed barium esophagram column height. Symptoms improved after POEM, with mean Eckardt score decreasing from 6.8 preoperatively to 1.2 postoperatively. Post-POEM reflux symptoms rate was 33%, with a pathologic esophageal acid exposure at 24-hour pH monitoring in 43% of patients. The incidence of esophagitis after POEM was 19%. The pooled analysis of the three comparative studies reported no significant differences in total adverse events, perforation rates, and operative time. The occurrence of postoperative pathologic reflux was similar. A nonsignificant trend toward a reduced length of postoperative hospital stay after POEM was observed.

Recently, the results of a multicenter retrospective study comparing 49 patients treated with POEM and 26 patients undergoing LHM for type III achalasia have been published.⁸¹ Mean operative time was significantly shorter in the POEM group (102 versus 264 minutes). Duration of hospital stay was similar (3.3 versus 3.2 days). Complication rates were lower after POEM (6% versus 27%). The authors reported better symptom relief among POEM patients (98% versus 80.8%); however, the duration of follow-up was significantly shorter in this group (8.6 versus 21.5 months).

Even though the current evidence shows encouraging results after POEM in expert centers, with limited morbidity and excellent outcomes in the short term, there are still several concerns that need to be addressed:

(1) the quality of the studies may bias the interpretation of these data: Most studies are retrospective with high heterogeneity in variable definitions and reporting adverse effects; there is no RCT comparing POEM and LHM;

(2) there are very limited long-term data⁸²;

(3) POEM is a very demanding procedure requiring superior endoscopic skills, with better results reported in high volume and expertise centers⁸³; and

(4) the incidence of pathologic acid exposure of the esophagus is high.

In conclusion, POEM should not be considered an alternative to LHM in the routine clinical practice until more robust data from RCTs will be available (quality of evidence: MODERATE; strength of recommendation: STRONG).

Recurrent dysphagia: Which are the therapeutic options?

Even though a major improvement in esophageal emptying and symptom relief is reported in the vast majority of patients, some patients, however, experience symptom recurrence over time (the so-called recurrent dysphagia).⁸⁴

The most common causes are (1) scarring of the distal edge of the myotomy,^85–87 (2) the construction of a total fundoplication, (3) the occurrence of reflux in patients who are often asymptomatic,⁸⁴ (4) previous endoscopic treatments,^15,17,54,86 and (5) esophageal cancer.⁶¹

Treatment modalities include (1) pneumatic balloon dilatation that is associated with very low risk of perforation,^70,86 (2) redo surgery if the patient does not experience dysphagia relief after dilatations: This strategy is associated with dysphagia improvement in about 80% of patients at 5-year myotomy^88–91, and (3) esophagectomy that should be reserved to patients with end-stage achalasia and dilated and the sigmoid-shaped esophagus who have already undergone a Heller myotomy and sometimes a redo Heller myotomy since it is burdened by a mortality rate ranging between 2% and 4% and high morbidity rates.^92,93 Furthermore, dysphagia secondary to an anastomotic stricture requiring dilatation, regurgitation, and dumping syndrome is complained in up to 50% of patients.

More recently, POEM has been proposed as a minimally invasive alternative in selected patients. For instance, Fumagalli et al.⁹⁴ reported the outcomes in 15 patients with recurrent dysphagia after a previous myotomy. A total of 9 patients underwent a surgical redo myotomy, while 6 underwent POEM. No postoperative complications occurred in either group. Median postoperative stay was 3 and 2.5 days in the surgical and POEM groups, respectively. In the surgical group, Eckardt score was <3 in 7 of 9 patients after a mean follow-up of 19 months and in all 6 patients treated with POEM after a mean follow-up of 5 months. Similar results have been reported in other small case series.^95,96

In conclusion, there are several modalities for the treatment of recurrent dysphagia after Heller myotomy. Esophagectomy should be considered in highly selected cases when previous treatments fail. POEM appears to be a promising treatment option (quality of evidence: LOW; strength of recommendation: WEAK).

Conclusions

According to the current evidence, we recommend a tailored approach to achalasia patients (Fig. 1). LHM should be proposed to patients at low surgical risk, while PD should be performed in poor surgical candidates or in those who refuse surgery. POEM might be proposed as the first treatment modality in highly expert centers or as a rescue therapy for recurrent dysphagia after LHM (Table 1).

FIG. 1.

Esophageal achalasia: treatment algorithm. EBTI, endoscopic botulinum toxin injection; LHM, laparoscopic Heller myotomy; POEM, peroral endoscopic myotomy.

Table 1.

Treatment for Achalasia: The Current Evidence

Statement	Quality of evidence	Strength of recommendations
EBTI should be restricted only to frail patients who are not fit for PD and LHM	High	Strong
LHM is the preferred surgical approach since it achieves better results than thoracoscopic or open Heller myotomy	High	Strong
LHM should be the preferred treatment option since long-term outcomes after surgery are better than PD	High	Strong
PD requires more additional treatment for recurrent dysphagia than LMH	High	Strong
Previous endoscopic treatments make LHM more challenging and long-term outcomes less predictable	Moderate	Strong
The construction of a fundoplication during LHM reduces the risk of postoperative reflux	High	Strong
LHM plus total fundoplication are associated with higher rates of postoperative dysphagia than partial fundoplication	High	Strong
Partial anterior or posterior fundoplications are equivalent in symptom relief and reflux control	High	Strong
Age and esophageal diameter do not affect the outcomes after LHM	Moderate	Strong
POEM as first treatment is an effective procedure in very experienced hands	Moderate	Weak
POEM is a promising treatment option in patients with failure of LHM	Low	Weak

EBTI, endoscopic botulinum toxin injection; LHM, laparoscopic Heller myotomy; PD, pneumatic dilatation; POEM, peroral endoscopic myotomy.

Footnotes

Disclosure Statement

No competing financial interests exist.

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