What is Missing Before Gastric Peroral Endoscopic Myotomy Can Go Mainstream for Treatment of Gastroparesis?

Abstract

Gastroparesis is a complex and heterogeneous motility disorder of the stomach. It is highly prevalent and etiologies include diabetes, surgery, and autoimmune, among others. Gastroparesis is a frustrating disease to patients and treating physicians. Medical therapy is limited for the most part to antiemetics and prokinetics, with suboptimal efficacy and nontrivial risk profile.1Camilleri M. Chedid V. Ford A.C. et al.Gastroparesis. Nat Rev Dis Primers. 2018; 4: 41Crossref PubMed Scopus (103) Google Scholar Pylorospasm has been implicated as a pathophysiologic mechanism in some patients.2Mearin F. Camilleri M. Malagelada J.R. Pyloric dysfunction in diabetics with recurrent nausea and vomiting.Gastroenterology. 1986; 90: 1919-1925Crossref PubMed Scopus (309) Google Scholar Surgical pyloroplasty and intrapyloric injection of botulinum toxin injection have been associated with positive outcomes in some studies, although robust data are lacking. With the availability of third-space endoscopy, the pylorus has become a readily and fully accessible target for endoscopic interventions. Gastric peroral endoscopic myotomy (G-POEM) results in complete endoscopic pyloromyotomy and is the endoscopic equivalent of surgical pyloroplasty, albeit being significantly less invasive.3Benias P.C. Khashab M.A. Gastric peroral endoscopic pyloromyotomy therapy for refractory gastroparesis.Curr Treat Options Gastroenterol. 2017; 15: 637-647Crossref PubMed Google Scholar We performed the first G-POEM procedure in 2013 on a patient with diabetic gastroparesis refractory to medical therapy with excellent outcomes.4Khashab M.A. Stein E. Clarke J.O. et al.Gastric peroral endoscopic myotomy for refractory gastroparesis: first human endoscopic pyloromyotomy (with video).Gastrointest Endosc. 2013; 78: 764-768Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar Since then, multiple studies have been conducted and suggested G-POEM as an efficacious and safe procedure.5Khashab M.A. Ngamruengphong S. Carr-Locke D. et al.Gastric per-oral endoscopic myotomy for refractory gastroparesis: results from the first multicenter study on endoscopic pyloromyotomy (with video).Gastrointest Endosc. 2017; 85: 123-128Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar Nonetheless, most studies have been small, single center, retrospective, and with major flaws in design and risk of bias.6Spadaccini M. Maselli R. Chandrasekar V.T. et al.Gastric peroral endoscopic pyloromyotomy for refractory gastroparesis: a systematic review of early outcomes with pooled analysis.Gastrointest Endosc. 2020; 91: 746-752Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Despite the limitations of the available literature, G-POEM seems safe. In a recent study including 216 patients who underwent G-POEM for gastroparesis, 31 (14%) adverse events (AEs) were encountered (mild, 24 [77%]; moderate, 5 [16%]; and severe, 2 [6%]).7Ichkhanian Y. Vosoughi K. Aghaie Meybodi M. et al.Comprehensive analysis of adverse events associated with gastric peroral endoscopic myotomy: an international multicenter study.Surg Endosc. 2020; Google Scholar Because most AEs occur or manifest intraprocedurally or during the early post-procedural period when patients are typically hospitalized, the reported rate of AEs is likely accurate. Significant AEs may include bowel perforation, delayed bleeding, and dumping syndrome. This latter complication seems uncommon and we have encountered it in 1 case after performing more than 100 G-POEM procedures. In terms of effectiveness, in a meta-analysis of 10 studies (8 retrospective, 2 prospective) including 292 patients,6Spadaccini M. Maselli R. Chandrasekar V.T. et al.Gastric peroral endoscopic pyloromyotomy for refractory gastroparesis: a systematic review of early outcomes with pooled analysis.Gastrointest Endosc. 2020; 91: 746-752Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar endoscopic pyloromyotomy was successful in all patients. Significant symptomatic improvement was achieved in 84% of cases and the overall AE rate was 6.8%. The current study by Abdelfatah et al8Abdelfatah M.N. Noll A. Kapil N. et al.Long-term outcome of gastric per oral endoscopic pyloromyotomy in treatment of gastroparesis.Clin Gastroenterol Hepatol. 2021; 19: 816-824Abstract Full Text Full Text PDF Scopus (10) Google Scholar is a welcome addition to the available literature despite being retrospective. Overall, 81% of patients (n = 97) experienced initial clinical response. Rate of recurrence was about 13% per year. The authors correctly addressed the major limitations of the study. Despite the widespread use of third-space endoscopy and high prevalence of gastroparesis, the uptake of G-POEM has been slow and definitely not as vigorous as the uptake of esophageal POEM. This is not necessary a negative statement; slow, judicious, and safe introduction of new techniques is always advisable for better care of patients. However, there are multiple shortcomings that have slowed progress in this field. These gaps need to be overcome to ensure G-POEM gets back on the right track. The current study defined clinical success as a decrease of at least 1 point in the average total gastroparesis cardinal symptom index score with more than 25% decrease in at least 2 subscales of cardinal symptoms. The same definition was used in other studies, but not all. This adds heterogeneity to the literature. In addition, this definition seems arbitrary and its clinical significance and validity remain questionable. Along the same lines, it is not clear if an increase in the gastroparesis cardinal symptom index score by 1 point signifies clinical recurrence. Formal definitions of these major patient-centered outcomes need to be agreed on and validated. POEM is now considered an accepted treatment option for patients with achalasia. There is a large body of literature examining the outcomes of esophageal POEM. This includes level 1 evidence through randomized controlled trails either comparing POEM with other treatment modalities (ie, pneumatic dilation and Heller myotomy) or examining variations of POEM techniques (eg, partial vs full thickness myotomy and anterior vs posterior POEM). Reliable and scientifically sound evidence aids in the dissemination and uptake of procedures and techniques. This unfortunately has not been the case with G-POEM. There is a great need for multicentric prospective studies and randomized trials that evaluate the effectiveness and safety of G-POEM for management of gastroparesis. Otherwise, we suspect this field will come to a standstill. Sham-controlled randomized trials are difficult to conduct at this stage because of lack of knowledge on proper patient selection. Multicenter prospective studies are crucial in identifying patient and clinical variables that are predictive of clinical outcomes. Pyloric dysfunction or spasm is believed to play a pivotal role in a subset of patients with gastroparesis. Plausibly, G-POEM only benefits such patients. Offering G-POEM to all patients with gastroparesis without determining the physiologic status of the pyloric sphincter is not reasonable. However, definitive and commercially available methods for the diagnosis of pylorospasm are currently lacking. Antroduodenal manometry and electromyography are not routinely used for this purpose. Dynamic gastric magnetic resonance imaging and scintigraphy may play an increasing role by providing pathophysiologic data of the antrum and the pylorus. We and others have studied the use of the endoluminal functional luminal imaging probe (EndoFLIP, Crospon, Galway, Ireland) for the assessment of the pylorus before G-POEM and other pylorus-directed therapies. In a recent trial,9Vosoughi K. Ichkhanian Y. Jacques J. et al.Role of endoscopic functional luminal imaging probe in predicting the outcome of gastric peroral endoscopic pyloromyotomy (with video).Gastrointest Endosc. 2020; 91: 1289-1299Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar we demonstrated that EndoFLIP reflected the improvement of the physiologic characteristics of the pylorus after G-POEM. However, although the increase of pylorus distensibility and cross-sectional area after G-POEM predicted clinical outcomes, pre-G-POEM pylorospasm did not correlate with clinical response. However, other studies have shown that preprocedure EndoFLIP assessment was able to predict short-term clinical response to G-POEM10Jacques J. Pagnon L. Hure F. et al.Peroral endoscopic pyloromyotomy is efficacious and safe for refractory gastroparesis: prospective trial with assessment of pyloric function.Endoscopy. 2019; 51: 40-49Crossref PubMed Scopus (53) Google Scholar and intrapyloric botulinum toxin injection.11Desprez C. Melchior C. Wuestenberghs F. et al.Pyloric distensibility measurement predicts symptomatic response to intrapyloric botulinum toxin injection.Gastrointest Endosc. 2019; 90: 754-760Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar Overall, currently available data suggest that endoFLIP is helpful in identifying patients who are unlikely to respond to G-POEM (those with pyloric distensibility index >8–10 mm2/mm Hg). However, a low distensibility index (ie, spastic pylorus) does not necessarily predict response. It is likely that other factors, such as antral motor activity, play a major role in whether patients would improve after G-POEM. Anecdotally, patients with gastroparesis with poorly controlled diabetes, major psychiatric comorbidities, significant abdominal pain component, and those on opioids respond poorly to G-POEM. However, clinical reasoning alone may not be enough and has to be accompanied with proper assessment of antropyloric motility. Only then can one properly identify candidates who have a high likelihood of response to G-POEM. In a recent editorial, Katzka and Camilleri12Katzka D.A. Camilleri M. Treating the pylorus in gastroparesis: the new riddle wrapped in the ultimate enigma?.Gastrointest Endosc. 2020; 91: 1300-1302Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar elegantly addressed some missing links related to the use of G-POEM for the treatment of refractory gastroparesis. They mentioned “the studies conducted in patients who have undergone G-POEM to date provide no information on antral postprandial motor activity; therefore, it is unclear what additional pathophysiologic mechanisms might affect the outcome from G-POEM.” They added “if there is not enough propulsive force to first triturate and then propel the chime into the duodenum, pyloric diameter may not be critical.”12Katzka D.A. Camilleri M. Treating the pylorus in gastroparesis: the new riddle wrapped in the ultimate enigma?.Gastrointest Endosc. 2020; 91: 1300-1302Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar It seems as prudent to study antral motility as it is to study the pyloric physiology for optimal patient selection before G-POEM. Close collaboration between gastric motility specialists and endoscopists is needed to conduct proper preprocedural motility work-up. It is likely that new-generation antrodudoenal manometry catheters, electromyography, and endoFLIP will play a crucial role in patient selection. In conclusion, there is a potential large demand for G-POEM for the treatment of gastroparesis in view of the high disease prevalence and lack of available drugs that are safe and effective. Major deterrents to scaling the procedure are detailed here. Collaboration and communication between motility and endoscopy specialists is paramount for proper patient selection. Identifying and addressing the missing links (validating clinical scores, conducting prospective trials, identifying patient factors that may impact outcomes, and studying antropyloric motility and physiologic parameters) (Figure 1) are needed before G-POEM becomes mainstream. Long-term Outcome of Gastric Per-Oral Endoscopic Pyloromyotomy in Treatment of GastroparesisClinical Gastroenterology and HepatologyVol. 19Issue 4PreviewGastric per oral endoscopic pyloromyotomy (GPOEM) is a promising treatment for gastroparesis. There are few data on the long-term outcomes of this procedure. We investigated long-term outcomes of GPOEM treatment of patients with refractory gastroparesis. Full-Text PDF