Abstract
Peptic oesophageal stricture can be considered as the end result of prolonged gastro-oesophageal reflux. The ‘gold standard’ treatment for peptic stricture is endoscopic dilatation with balloon or bougie. It is predicted that up to 40% of patients remain symptomatic with dysphagia due to refractory (resistant to treatment) or recurrent strictures, needing frequent interventions at short intervals. Such patients have poor nutritional status due to the primary disease and are susceptible to complications related to repeated endoscopic dilatation such as bleeding and perforation. This general review aims to analyse existing published evidence and address the role of biodegradable stents in resistant peptic strictures as an alternative treatment to provide long-term dysphagia-free intervals.
The Problem of Resistant Peptic Stricture
Peptic oesophageal stricture is the end result of long-term gastro-oesophageal reflux disease (GORD). A competent lower oesophageal sphincter and active peristalsis, clearing small amounts of oesophageal refluxate, normally protects oesophageal mucous membrane. Breakdown of this mechanism along with prolonged mucosal exposure to irritant gastric acid, bile, or pancreatic enzymes leads to erosive changes with inflammation, ulcers, healing by fibrosis, and finally stricture formation 1 (defined as oesophageal diameter <13 mm, restricting passage of food and or fluids). A stricture results in dysphagia, traditionally scored by 5-point Mellow and Pinkas (score 0-4) scoring system. 2 A variable but significant proportion of patients with long-term GORD progress to develop oesophageal strictures. Although most of these are simple strictures allowing easy passage of an endoscope through them, some may have a complex nature (>2 cm, tortuous and narrow enough not to allow endoscope passage). It is the latter variety that has a higher recurrence rate and is more difficult to treat. 3 For most obvious reasons, peptic strictures start at the squamo-columnar junction and progress proximally.4-6 Endoscopic dilatation is a standard treatment offered to these patients. 7 However, up to 33% of patients need repeated dilatations, sometimes as frequently as twice every month.8,9 A varied proportion of these patients would present with ‘refractory’ or treatment-resistant stenosis (inability to achieve a diameter of at least 14 mm by dilatation over 5 sessions performed at 2-weekly intervals) or as ‘recurrent’ stenosis (failure to maintain a luminal diameter of 14 mm for a minimum of 4 weeks, even after this has been achieved once).7,10,11 Strictures that are longer than 2 cm, have a narrower diameter, and are tortuous have greater propensity towards being recurrent or refractory. Unsurprisingly, patients with long-term strictures have poor nutritional status and weight loss, 12 they may require repeated dilatation with a small (up to 0.4%) but significant risk of oesophageal perforation. Needless to say, frequent endoscopic procedures have a huge financial burden on current health care systems.13–15
Current guidance (2018) from the British Society of Gastroenterology (BSG) acknowledges the challenge of managing refractory strictures, calling for further studies to help clarify the role and outcomes of stent use in this cohort. Although the BSG recommends the use of self-expanding metal stents (SEMS) for selected patients with refractory disease, their use is limited by associated complications. Biodegradable stents (BDS) have emerged in the past few years as an attractive alternative and may also reduce the frequency of serial dilatation 7 ; however, it is not clear whether they provide long-term symptom relief and whether the benefits achieved in these situations outweigh the risks associated with BDS. This review aims to analyse contemporary evidence for the role of BDS in managing refractory peptic oesophageal strictures.
Oesophageal Stents: Pros and Cons
Stents used to treat benign oesophageal stenoses are of metal, plastic, or biodegradable variants. Self-expanding metal stents are made of shaped memory alloys and may be ‘fully covered’ (with silicone or polytetra-fluoro-ethylene), ‘partially covered’, or ‘uncovered’ (bare).16–18 Given the mechanical irritation produced by the stent, partially covered and uncovered metal stents can embed in oesophageal mucosa because of tissue ingrowth 1 to 4 weeks after placement. This ingrowth is mostly granulation tissue, but with time, fibrosis leads to new onset stricture formation making removal of the stent difficult. Apart from this, migration, bleeding, pain, fistula, and worsening reflux may occur following SEMS insertion.3,19,20 Fully covered SEMS show resistance to tissue ingrowth, especially when used for shorter periods. However, migration rates remain high when compared with partially covered stents (36% versus 12%).15,21 Current BSG guidelines dissuade use of uncovered or partially covered SEMS. They recommend fully covered SEMS as second-line for resistant strictures ahead of other stent subtypes. 7 In practice, SEMS are employed in the palliative setting or temporarily for benign conditions, especially for patients with short life expectancy, where previous stents have failed or repeated procedures are not feasible. When used for refractory benign conditions as second-line treatment, their removal is recommended after a period of 3 months and no sooner than 6 weeks to achieve maximum benefit, on one hand, and to prevent tissue ingrowth, on the other.22,23
Self-expanding plastic stents (SEPS) are used temporarily in several benign conditions including peptic strictures and are cheaper than their metal counterpart and are easily deployed. The Polyflex (Boston Scientific Corp., Natick, MA, USA, made of polyester in silicone membrane) is licensed for this but has shown poor outcomes and is difficult to place in a complex stricture due to a wider delivery system of 39 to 42 F; sometimes requiring pre-stenting dilatation. A major drawback of the plastic stent is their high frequency of migration, occurring in almost 80% of cases. They are also more traumatic to remove (due to absence of a purse string). These factors are responsible for associated poor long-term outcome.11,15,24–27
Biodegradable stents are made of degradable synthetic material, and disintegrate by random hydrolysis, and therefore do not need removal. They potentially cause mechanical irritation of tissues too, but this is time-limited by their dissolution. SX-ELLA Stent Esophageal Degradable BD – BD Stent (Hradec Kralove, Czech Republic), made of PDX/polydioxanone monofilament, is currently marketed and is indicated in resistant cases of benign oesophageal strictures and inoperable achalasia which has not responded to conventional therapy. Radial force is maintained for up to 6 weeks and the stent disintegrates gradually about 12 weeks after placement by hydrolysis, a process that is accelerated by increased acid exposure. Breakdown products are inert and are largely excreted through bowel. This stent has flared ends designed to reduce migration.28,29 Again, distal migration into stomach enhances stent disintegration by increased exposure to gastric acid, causing stent hydrolysis. This prevents distal bowel injury or obstruction-related complications and potential morbidity. 30
Resistant Peptic Stricture: Options Available
Endoscopic dilatation and steroid injection
Endoscopic dilatation with balloon or bougie remains the ‘gold standard’ treatment offered to patients with peptic oesophageal stricture. 7 No significant differences were found between the success, recurrence, or complication rates of these 2 techniques.31,32 However, based on the current evidence, it is predicted that up to 40% of patients will need ongoing dilatation for recurrent symptoms of dysphagia because of refractory or recurrent stenosis.33–35 Investigations are ongoing to find ways to reduce the recurrent or resistant stenoses and establish more viable alternatives to repeated endoscopic dilatation. Dilatation combined with steroid injection has been shown to have some added benefit over dilatation alone in this respect. A randomised trial compared the effects of dilatation with added 4-quadrant triamcinolone injection against dilatation alone in a cohort of 30 patients with peptic oesophageal stricture (15 patients in each arm), all of whom had at least 1 failed dilatation in the past 18 months. The authors reported significant decrease in need for repeated dilatation episodes (13% versus 60%; P = .01) and significant increase in symptom-free period in the steroid arm added with acid suppression therapy. 36 In a similar randomised study involving a smaller cohort (n = 21 patients) with oesophageal strictures from different causes (peptic, caustic, anastomotic, and postradiotherapy; only 29% patients in this cohort had peptic strictures), the effects of intra-lesional steroid injection was assessed with or without bougie dilatation. Although this study dealt with a small group of patients and did not specifically look at peptic strictures, the mean symptom-free period in the steroid arm was found to be significantly longer (24 ± 12.75 months versus 5.18 ± 5.06 months; P < .001) with fewer number of dilatations (significantly lower periodic dilatation index, defined as the ratio of number of dilatation episodes and follow-up duration in months; P < .05). However, there was no statistically significant difference between the 2 groups in achieving sufficient postdilatation oesophageal diameter (P = .28). 37 Benefit of adding steroid injections with dilatations was demonstrated in other non-randomised studies in peptic strictures.38,39 Non-peptic strictures, however, were found to be more resistant to this technique.40,41 In addition, no definite dose of injected steroid has been optimised and has been largely empirical in different studies, hence still in experimental phase. 42 Steroids are known to decelerate the inflammatory process and reduce fibroblast action. This may be the mechanism of action. However, a major downside of using steroids is a possibility of delayed perforation. 43 In summary, although marginal benefit has been demonstrated by combining steroid injections with dilatations, the studies were limited either by their cohort size or were non-randomised, had heterogeneous cohorts with strictures from several causes, and sometimes had conflicting results; hence, no robust evidence is available to routinely support this treatment.
Metal (SEMS) and plastic (SEPS) stents
Stents (SEMS, SEPS, and BDS) have been used in resistant cases of peptic oesophageal stenosis as a second-line treatment. Self-expanding metal stents have several drawbacks, including tissue ingrowth causing embedding of the stent with the chance of fibrosis and more resistant stenosis. Fully covered SEMS are preferred over partially covered or bare-stents for this reason. 7 Studies using covered SEMS have demonstrated good success with complete relief of dysphagia in 40% 44 ; however, migration remains problematic with high rates of 30% 44 and recurrence occurring in 69% following SEMS removal. 45 Partially covered SEMS have a place in ‘stent in stent technique’, used as a salvage procedure in situations, whereas fully covered SEMS are inserted in the lumen of a pre-existing embedded stent. The new internal stent is slightly longer and has a slightly bigger diameter than the embedded outer stent. Due to pressure necrosis of the hyperplastic tissue ingrowth caused by the inner stent in 10 to 14 days, both stents can be removed.44,46,47 The Polyflex (SEPS) stent has FDA (Food and Drug Administration) approval for use in benign oesophageal stricture. Although it performed well in malignant oesophageal stenosis in 90% of cases (major complications were dysphagia due to migration of stent, embedding, and impacted food bolus), results in benign disease were variable. 48 Effects of expandable polyester silicone covered plastic stent placed temporarily for 6 weeks were studied in a small cohort of 15 patients with resistant benign oesophageal stricture. After removal of stents, relief of dysphagia (assessed by pre- and post-treatment dysphagia scores) was found to be statistically significant (P < .0005). Long-term resolution of stricture was reported in 80% cases in this cohort. 49 A retrospective study by Holm et al reported 98.8% success from SEPS placement in a mixed group of benign oesophageal conditions (stenosis from reflux, ischaemia, idiopathic, radiation, anastomotic stricture, and oesophageal fistula/leak). Nearly 80% of stents placed in benign strictures in this study were found to have migrated, and only 6% of cases experienced long-term improvement after stents were removed. 26 A meta-analysis from 2010 assessed 10 studies and 128 patients who underwent SEPS insertion with a variety of benign oesophageal strictures at different levels, of which only 12% of patients had peptic strictures. Although this study does not comment about the success rate in peptic strictures in particular, the overall success in relieving dysphagia was 52% at a median follow-up period of 13 months. Early migration rates (defined in this study as migration in less than 4 weeks) and major complication rates were low (24% and 9%, respectively). The limitations of this meta-analysis are quite apparent. First, given most of the analysed studies were retrospective with small sample size and reporting bias, possibility of further magnification of this bias cannot be excluded. Second, given the median follow-up of 13 months is very small, long-term success rates with SEPS are still unclear. Finally, this meta-analysis reports the success rates in a heterogeneous group of benign strictures (from several causes: peptic, post-surgical, corrosive, radiation), previous evidence points towards the fact that strictures from different pathologies (reflux versus other pathologies) react differently to different forms of treatment. 50 The relationship between cause of stricture and clinical success rate of treatment used was further strengthened by a meta-analysis. 51 In summary, the current evidence points towards moderate success rates of plastic stents in benign stenosis in general with complications mostly related to migration, but not specifically in peptic oesophageal stricture. As most of the current evidence is from heterogeneous cohort and with varying results, rationale for using SEPS to achieve long-term relief of dysphagia in peptic stricture is still weak.
Biodegradable stents
Biodegradable stents have shown some promising results in animal models.52,53 Initial clinical experience in treatment of benign oesophageal strictures involved the use of PLLA (poly-
Outcome of stents in different studies.
Discussion
Primary recommended treatment for benign peptic stricture of oesophagus is endoscopic dilatation with balloon or bougie in specialist centres under the care of experienced endoscopists. In cases where the stricture is severe enough not to allow passage of the endoscope (<10 mm luminal diameter), endoscopic dilatation should be performed. This should be graded; the initial dilatation restricted to a diameter of 10 to 12 mm (30-36 F) only. Use of fluoroscopic guidance and carbon dioxide insufflation, as opposed to simple wire-guided dilatation, blind bougie dilatation, and air insufflation, respectively, adds to the safety of this procedure. It is recommended that 3 or less diameter increments should be targeted in each dilatation session to decrease chances of perforation which has been reported to be approximately 1% in peptic strictures. The BSG guidelines recommend weekly or twice monthly dilatations until 15 mm luminal oesophageal diameter is achieved with symptomatic improvement of dysphagia, following which intervals may be increased accordingly. Intensive follow-up is advised for these high-risk patients. There is poor evidence regarding role of surgery in treating benign strictures. 7 Patients, who fail to respond to endoscopic dilatations with refractory or recurrent stenosis as defined above, pose a serious challenge to the clinician. These patients are mostly in their extremis and malnourished, prone to complications from factors both related and unrelated to interventions.12-15 Hence possible alternative or secondary treatments which reduce number of invasive interventions or increase their intervals are worth exploring. In quest for this, investigators have tried steroid injection with endoscopic stretching and stents of different varieties including BDS. Endoscopic steroid injection to the stricture site was reported initially as a better option over endoscopic dilatation alone, however, in absence of a specified dose of injection, set regime and added risk of delayed perforation36-39,43 are still under review.
Following several initial reports of complications and low success rates in benign setting with metal and plastic stents (embedding, migration, and need for re-intervention),15,26,67-71 BDS came forward as a more viable alternative. However, studies failed to show success rates of more than 55% with BDS (Table 1). Most of these studies were non-randomised, prospective, or retrospective, with small cohorts and affected by several types of bias. Moreover, most used heterogeneous cohort comprising strictures from different causes (peptic strictures ranging from 0% to 80% of the cohort size in different studies), although a meta-analysis 51 suggested association between cause and outcome of treatment in benign strictures. Different follow-up periods were used to define clinical success in these studies, ranging from 3 to 264 weeks (median follow-up ranging from 20 to 94 weeks in different studies). Thus, inferences drawn about success rates were difficult to compare between reports.
Furthermore, a randomised trial 64 reported inferior performance of BDS with respect to mean number of adverse outcomes, post-intervention dysphagia score at 6 and 12 months as compared with endoscopic dilatation alone, in benign setting. This was in clear contradiction to reports from non-randomised studies claiming superiority of BDS in providing greater dysphagia-free intervals. 65 The cumulative risk reduction in perforation achieved using BDS, with not having multiple dilatations (up to 6 per patient and each adding 0.4% risk of perforation), needs to be considered here.14,15 A recent meta-analysis, 51 after analysing results from 444 patients and 18 studies, reported no significant difference between results from SEMS, SEPS, and BDS in benign strictures. The authors warned about high levels of heterogeneity in participant studies, especially those involving plastic and metal stents. There was also the obvious risk of amplification of bias from several participant studies which were largely non-randomised. Again, stents may be liable to cause more strictures at its ends for reasons not entirely clear to us. A possible mechanism is direct mechanical irritation by keeping the gastro-oesophageal junction open promoting continued reflux. This may result in proximal migration and increased length of strictures with poorer prognosis and progressively shorter dysphagia-free interval along with need for sequential stenting.63,72
Therefore, on one hand, after comparing several secondary treatments (SEMS versus SEPS versus BDS) in patients where primary treatment of endoscopic dilatation has failed, BDS emerges with marginal benefit only. But, on the other hand, it may also be argued that in patients with failure of primary treatment, a success rate of 45% may be acceptable and should be considered after careful discussion of associated risks and benefits. Although based on very weak evidence and classed as ‘low level’ recommendation, this later view has been reflected in the recent BSG guidelines. 7
In summary, although several studies have reported advantages in obtaining longer dysphagia-free intervals with BDS in peptic strictures, many refute the notion. Success rates differ widely, so do complication rates, making these reports contradict each other. In the light of this, routine use of BDS as first choice in resistant peptic stricture is not yet an established option. It may only be considered in a small subset of patients unfit for regular frequent endoscopic interventions and poor life expectancy. Furthermore, its routine use in benign conditions as a secondary treatment modality needs further investigation through targeted studies with larger, non-heterogeneous cohorts, longer follow-up periods, and more robust evidence base.
Footnotes
Funding:
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests:
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Author Contributions
SB, TR and GN compiled evidences and wrote the main manuscript. NR and HS completed an extensive review of this manuscript and contributed towards updating manuscript in lines with reviewers’ queries. SB was the team lead in this project.