Esophageal Stenting in Clinical Practice: an Overview

Esophageal stenting plays a role in the palliative treatment of patients with esophageal cancer or extrinsic compression on the esophageal lumen due to a malignancy (e.g., mediastinal metastases) [21••, 22]. Selection of the optimal palliative approach can be challenging and is dependent on patient- and disease-related factors. The optimal palliative approach is determined by the prognosis of the patient. Results from a RCT, comparing stent placement to palliative single-dose brachytherapy, showed that brachytherapy gave better long-term relief of dysphagia and was associated with fewer complications. Therefore, patients with mild dysphagia and a relatively long life expectancy are best treated with brachytherapy. Stent placement, as initial palliative approach, is reserved for patients with severe dysphagia and a short life expectancy. As a secondary palliative approach, stent placement can be considered for patients with persistent or recurrent tumor growth after brachytherapy [6••]. In 2005, Steyerberg et al. developed a simple prognostic score that may assist clinicians in identifying patients with a poor prognosis [7•]. Factors that predict the prognosis of inoperable esophageal cancer patients are age, gender, tumor length, presence of metastases, and the World Health Organization (WHO) performance score. Results from this study show that this prognostic tool performs well in identifying patients in whom stent placement is at least equivalent to or even better than brachytherapy. One retrospective cohort study shows that the selection of initial palliative management of patients with inoperable esophageal cancer varies widely in daily clinical practice. Moreover, this study shows that the selected palliative approach was not only associated with patient- and disease-related characteristics, but also with center-related factors [23]. This suggests that more therapeutic guidance is warranted in managing these patients, for example by a selected expert panel. A multidisciplinary tumor board meeting may aid in selecting the most optimal treatment modality, and it is currently recommended to discuss all patients with esophageal cancer that require management [24].

The limitations of stent placement for malignant dysphagia are important to consider when selecting stent placement. For example, the previously mentioned RCT [6••] showed a higher incidence of complications in the stent placement group when compared to brachytherapy, mainly due to hemorrhage. Esophageal hemorrhage is one of several complications that are associated with stent placement in general. Pain requiring analgesics after stent placement is the most frequently observed adverse event. One prospective cohort study reported significant pain during the first 2 weeks after stent placement in almost two-thirds of patients with malignant dysphagia [25]. Recently, a large cohort study reported early and late complications related to stent placement for malignant dysphagia in over a thousand patients, during a period of 23 years [10•]. An overview of the adverse events is shown in Table 2. Observed major complications included esophageal perforation (2%), hemorrhage (8%), pneumonia due to aspiration (5%), fever (5%), fistula formation (3%), and pressure necrosis (2%). Minor complications that were reported included post-procedural pain (30%) and gastroesophageal reflux (7%). Another reported complication after stent placement is recurrent dysphagia (in 31% of patients) due to stent migration (11%), tumor in- or overgrowth (14%), or food obstruction (7%). The results are consistent with those of a recently published systematic review [26].

The important question remains which type of stent clinicians should use. The latest ESGE guideline on esophageal stenting [21••] recommends to place a fully or partially covered self-expandable metal stents (fcSEMS, pcSEMS) for malignant dysphagia. RCTs have shown that both uncovered SEMSs and covered self-expandable plastic stents (SEPS) are inferior to covered SEMSs due to the higher risk of tumor ingrowth [27] and stent migration, respectively [28]. Recent RCTs have investigated the differences in recurrent dysphagia between pcSEMS and fcSEMS [29•, 30]. No significant differences were found in rates of recurrent dysphagia or any other adverse events after stent placement. However, a recognized disadvantage of a pcSEMS is its possible difficult endoscopic removal. For example, removal may be necessary in case of severe retrosternal pain after stent placement that cannot be relieved with analgesics Fig. 1. Hyperplastic tissue ingrowth at the uncovered stent mesh may lead to embedding into the esophageal mucosa, which prevents immediate endoscopic removal of the pcSEMS. Removal of an embedded pcSEMS can be achieved with the stent-in-stent method [31]. Using this technique, a similarly sized fcSEMS is placed inside the previously placed embedded stent. Over a period of 10 to 14 days, pressure necrosis of the hyperplastic tissue occurs as a result of friction. Hereafter, both stents can mostly easily be removed during a second endoscopic procedure. The stent-in-stent technique may also be applied in patients with recurrent malignant dysphagia due to tumor progression and overgrowth at the proximal or distal stent ends [32]. To treat tumor overgrowth, a second fcSEMS is placed through the first stent, adequately covering the site of tumor overgrowth. Both SEMSs are then left in place as long as sufficient palliation of dysphagia is achieved.

In summary, based on the literature and our expert opinion, the preferred choice is to place fcSEMSs for malignant dysphagia as a first- or second-line palliative treatment.

In contrast to malignant strictures, the mainstay in therapeutic management of BES is repeated EBD. The dilating effect of EBD is applied for a short period of time during the endoscopic procedure. It should be recognized that EBD for malignant strictures is associated with a higher risk of esophageal perforation and therefore should be performed cautiously in these patients [33]. When repeated EBD fails to achieve satisfactory relief of benign dysphagia, other endoscopic treatment modalities are available. For example, 4-quadrant corticosteroid injections may be performed in peptic strictures [34] and needle-knife incisions in esophagogastric anastomotic strictures [35]. Esophageal stent placement is considered the last endoscopic treatment option in the management algorithm for RBES [15]. As opposed to EBD, a temporary stent acts as a dilator that is kept in place for a substantially longer time of several weeks. Notorious etiologies of BES, associated with a high risk of becoming refractory to repeated EBD are caustic, radiation-induced, and esophagogastric anastomotic strictures [36‐39]. A rising incidence of post-endoscopic strictures is expected as a consequence of new endoscopic interventional treatment modalities in daily clinical practice. For example, in recent guidelines, endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), and radiofrequency ablation (RFA) are recommended to treat premalignant stages and early-stage malignancies in Barrett’s esophagus [40], all carrying a risk of stricture formation [36].

In the past decade, clinical success of temporary stent placement for RBES has been investigated in mainly non-randomized and uncontrolled observational cohort studies. Not so long ago, two systematic reviews were published [41, 42], reporting and comparing all studies that investigated esophageal stents in RBES. Three stent types investigated in predominantly retrospective studies included SEPS, fcSEMS, and most recently biodegradable (BD) stents. In terms of clinical success, defined as the resolution of dysphagia without needing any further intervention at the end of follow-up, all stent types showed similar results and the overall clinical success rate was approximately 40%. In terms of migration rate and risk for other adverse events, no significant differences were observed between the stent types. In general, the average migration rate was 29% and the adverse event rate was 21% for all stent types [42]. An overview of the adverse events related to stent placement for RBES are shown in Table 2. Remarkably, these adverse event rates are comparable to the rates that were observed in stenting of patients with malignant dysphagia. The Polyflex SEPS (Boston Scientific, Natick, Massachusetts) is the only FDA-approved esophageal stent for RBES. In several studies, the Polyflex was proven to be effective for treatment of RBES [43‐45], but due to the high risk of stent migration [44] and other adverse events [45], the production of the Polyflex has been terminated.

As for malignant dysphagia, but without formal FDA approval, fcSEMS have also been investigated in clinical trials treating RBES [46‐48]. The clinical success rates of fcSEMS are likely to be comparable and not significantly different from SEPS and BDS [42], although this has never been investigated in head-to-head RCTs. Furthermore, temporary placement of a pcSEMS is not recommended because of the higher risk of hyperplastic tissue ingrowth [49]. It is assumed that a longer stent indwell time is associated with a risk of stent embedment. However, different periods of esophageal stenting for RBES have not been compared in studies. The ESGE guideline on esophageal stenting [21] recommends placing a fcSEMS and to keep it in place for at least 6–8 weeks and no more than 12 weeks, to achieve optimal treatment response and reduce the risk of stent embedding. In addition, one retrospective cohort study, investigating the safety of esophageal stenting in RBES patients, found no association between indwell time and risk of adverse events [50].

Lastly, BD stents have been introduced as treatment option in patients with RBES. The Ella BD stent (Ella CS, Hradec Králové, Czech Republic) has been investigated in several clinical studies. An important advantage of BD stents is that no stent removal is indicated due to its biodegradable feature, making it a potentially more cost-effective and patient-friendly treatment option. After 4 months, the BD stent appears to be dissolved in most patients, but the stent increasingly loses radial force after a couple of weeks due to the degradation process. Since the first study in 2010 with the BD stents [51], a few more studies have been performed assessing safety and efficacy [42, 52], all concluding that the BD stent is safe for use in RBES. In addition, the only RCT with BD stents was performed in 2014 in the UK, but was terminated prematurely due to recruitment issues [53]. One prospective cohort study was performed that compared BD stents with other types of esophageal stents, i.e., SEPS and fcSEMS [54]. The authors concluded that placement of BD stents and fcSEMS may lead to long-term relief of dysphagia in 30 and 40% of patients, respectively. The use of a sequential BD stents in patients with RBES was reported by Hirdes et al. [55]. A total of 59 BD stents were placed in 28 patients. Unfortunately, this strategy proved to be effective in only a small proportion of patients. After 6 months, only 15% of patients, who had recurrent dysphagia after the first BD stent placement, were still dysphagia-free after placement of a second BD stent.

In summary, based on the literature and our expert opinion, it seems preferably to place fcSEMS for treatment of RBES, after repeated EBD and other endoscopic treatment modalities have failed to achieve long-term relieve of dysphagia. If available, BD stents may be considered as an effective, patient-friendly alternative for fcSEMS placement, as stent removal is avoided.

The formation of fistula connecting the esophageal lumen to surrounding tissue may be the result of predominantly esophageal cancer and less frequently extrinsically growing cancer. End-stage malignant disease for which palliative management is indicated is seen in the majority of patients. Furthermore, when an esophageal fistula is present, concomitant metastatic disease is found in approximately 90% of patients [56]. Fistula formation may also be the result of tumor necrosis induced by CRT.

The management of malignant fistula always includes conservative and may include endoscopic treatment modalities. Conservative management may consist of ‘nil by mouth’, duodenal tube feeding, intravenous antibiotics, and adequate drainage of contaminated cavities surrounding the fistula. Endoscopic management with a pcSEMS or fcSEMS to seal esophageal fistula and palliate concomitant dysphagia has been shown to be feasible and effective. In recent studies, few retrospective case series have been published of patients treated with esophageal stents for malignant fistula [57‐59••]. One prospective cohort study included 15 patients that were treated with pcSEMS or fcSEMS for esophageal fistula [60•]. The authors demonstrated successful restoring of luminal patency in all patients. The fistulae were successfully sealed off in all but one patient (93%) Fig. 2. In four patients, stent migration was observed and subsequently sealed off with placement of a second stent.

Until now, no randomized studies have compared pcSEMS or fcSEMS for sealing off esophageal fistula. Based on available literature and the high risk of concomitant malignant dysphagia, a fcSEMS seems the preferred palliative choice for endoscopic management of malignant fistula.

Benign esophageal perforations (BEP) can be subdivided into spontaneous esophageal perforations, also known as Boerhaave’s syndrome (BS) and iatrogenic esophageal perforations (IEP).

BS is associated with excessive vomiting leading to a barogenic trauma in the distal esophagus. Patients with BS typically present with vomiting followed by pain, dyspnea, and septic shock [17]. Early diagnosis, within 24 h, is crucial for successful outcome and can be challenging in patients with BS because the symptom onset usually sets off in an out of hospital setting [18, 61]. Esophageal stent placement to treat BS has been shown to be feasible and may have a role in the treatment algorithm [62, 63].

IEP induced by instrumentation during endoscopy is an emerging entity, as more invasive endoscopic treatment options (e.g., EMR and ESD) are being performed [64‐66]. EBD for esophageal narrowing and pneumatic dilation for achalasia is associated with a relatively high risk of perforation [67, 68]. IEP is managed according to a similar treatment algorithm as in patients with BS [17], but associated with a better prognosis because of in-hospital symptom onset, likely resulting in an early diagnosis within 24 h.

In clinical practice, therapeutic management of BS and IEP is comparable, as available treatment strategies are conservative, endoscopic, or surgical in both groups [61, 69]. High-quality evidence from RCTs on therapeutic management is lacking due to the rarity of BEP in daily practice [70]. Therefore, evidence on treatment decisions is solely based on retrospective data. In 2009, Abbas et al. developed a clinical tool, the Pittsburgh perforation severity score (PSS), to predict patients’ prognosis following BEP [71]. After validation, the PSS proved a reliable tool to stratify patients into risk groups with differential morbidity and mortality outcomes [72•]. However, further prospective research is warranted to evaluate utility of this tool in clinical decision-making. With respect to the incidence of BEP, a nation-wide or international prospective registry seems the most appropriate study design to generate evidence for the optimal therapeutic management of BEP.

In the past decade, a rise in esophageal stent placement to manage BEP is observed. In the USA, the use of esophageal stents for BEP has increased from 7% in 2007 to 30% in 2014 [73]. In the UK, a similar trend is observed in a nation-wide cohort analysis [70]. In a newly proposed BEP treatment algorithm, based on the PSS, stenting is incorporated [72•]. According to this treatment algorithm, esophageal stents may have role in patients stratified in the low and medium risk groups. In these patients, BEP is accompanied by a non-contained leak into the surrounding structures. A covered stent, followed by adequate drainage of the fluid collections, is expected to cease further contamination by sealing off the leak.

The clinical success of stent placement for BEP, defined as successful closure of the perforation after single of sequential stent placement, varies widely from 50 to 86% [41, 62, 74]. Very recently, Van Halsema et al. developed a prediction rule for successful stent placement for esophageal anastomotic leakage, perforations, and fistula [59••]. The prediction rule consisted of four clinical predictors: etiology, location and size of the leak, and CRP level at diagnosis. After validation in a different patient cohort, the rule was found to significantly discriminate between failure and success of stent placement in patients with a predicted low (≤ 50%) or high (≥ 70%) clinical success. Therefore, this clinical tool may be supportive in clinical decision-making and informing patients with various types of benign perforations, leakage, and fistula.

The selection of the right stent design in treatment of BEP also remains a challenge, as no high-quality evidence is available. In a pooled meta-analysis of several case series investigating stent placement for BEP, stent migration was reported in around 20% of patients [41]. An overview of most prevalent adverse events related to stent placement for BEP is shown in Table 2. In BEP, the consequence of stent migration may have a higher impact on the clinical outcome due to inadequate sealing of the defect, leading to further contamination of the surrounding tissue. Prevention of stent migration is therefore of major importance. Covered stent designs with a wider diameter may result in fewer stent migrations. One retrospective case series investigated a large diameter (stent body: 24 mm, flares: 32 mm) fcSEMS in 34 patients with BEP, anastomotic leakage, and fistula [57]. Disappointingly, stent migration was observed in 41% of patients.

In summary, prediction rules may aid in careful selection of patients that could benefit from stent placement. Based on the literature and our expert opinion, it seems preferable to place a pcSEMS or fcSEMS in selected patients. Furthermore, we hypothesize that placing a pcSEMS may contribute to even better sealing of the perforation and reducing the risk of stent migration, as a result of stent embedding of the uncovered stent mesh ends in the esophageal mucosa.

Ever since the use of esophageal stents in clinical practice, the most important drawback of stenting remains stent migration, occurring in approximately one-third of all patients [10•, 29•, 42]. In the past few years, various attempts were done to investigate methods to prevent stent migration by anchoring the stent to the esophageal wall. An interesting method to anchor the stent is the placement of through-the-scope (TTS) clips [75] or over-the-scope (OTS) clipping devices [76]. The clip is placed over the proximal stent mesh end, into the esophageal wall. Retrospective case series show promising results, particularly for OTS clipping, but are still reporting migration ranging from 13 to 17% [20, 75, 77].

Another promising method of anchoring is endoscopic suturing with the novel, FDA-approved, endoscopic suturing device [78]. A systematic review and meta-analysis was performed to analyze retrospective case series (n = 14), investigating endoscopic suture fixation of esophageal covered SEMS [79•]. Results from some case series look promising, but pooled data analysis revealed that stent migration occurred in still 1 of 6 patients after suture fixation. Needless to say that high-quality evidence provided by comparative RCTs is required.