Endoscopic Intervention for Anastomotic Leakage After Gastrectomy

Although endoscopic treatments, such as endoscopic submucosal resection or endoscopic submucosal dissection (ESD), are actively used to treat early gastric cancer, gastrectomy remains the standard treatment for early gastric cancer that does not meet the criteria for endoscopic resection. Retrospective studies indicate comparable outcomes between ESD and gastrectomy with lymph node dissection for specific early gastric cancer criteria: 1) tumor size >2 cm, mucosal cancer, and no ulcer; or 2) tumor size ≤3 cm, mucosal cancer, and ulcer. Gastrectomy remains a viable option, especially in challenging ESD cases or when regular follow-up is impractical. For poorly differentiated adenocarcinoma, endoscopic resection may be considered with a low nodal metastasis risk; however, confirmed risk factors may require additional gastrectomy. Treatment decisions should involve detailed discussions with patients about lymph node metastasis and potential complications. Surgical methods depend on factors like cancer size, depth, location, lymph node involvement, and pylorus preservation feasibility [1]. However, given its invasive nature, postoperative complications are inevitable and substantially impact patient’s clinical outcome.

Among postoperative complications, anastomosis site leaks and fistulas are major adverse events that play important roles in postoperative morbidity and mortality. Leakage is defined as disruption of a surgical anastomosis. If the leak persists, it can evolve into a fistula, which is characterized by abnormal communication between 2 epithelialized surfaces [2]. The rise in the occurrence of postoperative leaks can likely be attributed to the growing complexity of gastrointestinal (GI) surgeries. Reports indicate that postoperative leaks following oncologic surgery occur in 8%–26% of cases after distal esophagectomy and in 3%–12% of cases after total gastrectomy. In bariatric surgery, which is gaining significance in upper GI surgery due to rising obesity rates, leaks are reported at rates of 1%–2% after sleeve gastrectomy and 2%–8% following Roux-en-Y gastric bypass [3].

There is no definitive consensus regarding the classification of leaks. Onset after surgery, fluid collection, and location were major components by which leaks were classified. A review article on sleeve gastrectomy leaks classifies them into 2 types based on fluid collection: Type I for small subclinical leaks without fluid collection, and Type II for major clinical leaks with fluid collection. Leaks can also be categorized according to their onset after surgery as follows: acute (within 7 days), early (1–6 weeks), late (after 6 weeks), or chronic (after 12 weeks) [4].

Although anastomotic site leaks can sometimes be asymptomatic, they may be suspected when patients exhibit clinical symptoms, including abdominal pain, tachycardia, and fever, and in severe cases, septic shock. Radiological examinations, such as abdominal computed tomography (CT) and esophagography, along with endoscopy, can be performed to confirm leaks [5]. The treatment of anastomotic leaks includes conservative management, involving antibiotics, parenteral nutritional support, and percutaneous drainage. Surgical treatment is considered in cases of severe symptoms or hemodynamic instability [6]. With improvements in endoscopic treatment options, endoscopic approaches are considered the primary treatment option for relatively minor leaks with less severe symptoms [7]. Endoscopic treatment options include clipping, placing self-expandable metal stents (SEMS), internal drainage, endoscopic suturing, endoscopic negative pressure treatments like endoscopic vacuum therapy (EVT), and application of tissue sealants. Each method can be applied individually or in combination in many cases. This review aimed to explore various endoscopic methods for treating anastomotic leaks, with the goal of providing insights into each treatment option, including their effectiveness and limitations.

Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a systematic literature search to identify reliable studies focusing on endoscopic management of anastomotic leaks and fistulas after upper GI surgery, covering both surgical treatments for malignancy and bariatric procedures. The search was performed using the MEDLINE (PubMed), Embase, Cochrane Library, and Scopus databases between 2013 and September 2023. The search strategies used for each database are provided in the Appendix 1.

A total of 2,215 articles were extracted: 171 from PubMed, 196 from Embase, 87 from the Cochrane Library, and 1,761 from SCOPUS. To refine our search, we focused on clinical trials, randomized controlled trials (RCTs), cohort studies, and observational studies and excluded case reports or case series that lacked statistical analysis.

The initial sorting process involved organizing articles according to their titles and abstracts. Articles that did not provide full-text access, were duplicates, or not written in English language were excluded. Subsequently, full-text articles were assessed for eligibility based on the following inclusion criteria: 1) if the participants underwent surgical treatment for upper GI malignancy or bariatric surgery; 2) if the study investigated the endoscopic management of post-operative leaks or fistulas; and 3) if the article included statistical analysis as part of its findings.

Of the initial 171 PubMed results, 14 articles were selected based on their titles, 5 of which were found to be relevant. In the case of Embase, only 2 relevant articles were identified, primarily because of limited full-text access. In the Cochrane Library, none of the 87 articles met our inclusion criteria because of duplication, as they were previously identified in other databases. The Scopus database provided 1,761 documents, of which only 15 articles were considered relevant and included in our review. The references cited in these articles were also explored for additional analysis.

Among the various endoscopic treatment strategies, endoscopic clipping is one of the most commonly used method. There are 2 main types of endoclips: through-the scope clips (TTSC) and over-the-scope clips (OTSC) (Fig. 1). Through-the-scope clips are introduced through the operative channel of the endoscope, and are classified into 2 categories: reusable and single-use clips. The TTSC is known for its ease of use and adaptability to diverse clinical scenarios. In contrast, the OTSC is mounted on a cap affixed to the end of the endoscope, enabling full-thickness closure of GI defects of up to 2 cm in size [3].

Fig. 1
OTSC.
Note: Image of OTSC. SYNMED. Copyright 2023 by Syntetics Medical Ltd. (https://synecticsmedical.co.uk/product-category/over-the-scope-closure/).

OTSC = over-the-scope clips.

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A retrospective study conducted by the National Cancer Center in Korea analyzed the efficacy of endoscopic treatment for anastomotic leakage in patients who underwent endoscopic clipping and stent insertion. Of 85 patients, 62 underwent endoscopic clipping, resulting in a complete closure rate of 79%, which was not significantly different from that in the stent group that had a successful closure rate of 82.6% (P=0.89). Although the stent group required a significantly longer time to achieve complete closure of the leakage (median time: 26 vs. 13 days; P<0.001), the clipping group needed more than twice as many endoscopic sessions because the initial session did not result in complete closure [8]. A retrospective study assessed 45 patients who underwent OTSC procedures for various GI defects, such as perforations from endoscopic procedures and leaks or fistulas following abdominal surgery. Patients were divided into 2 groups: 15 in the acute setting, and 30 in the chronic setting. Although the study encompassed complications after colonic surgery and was not limited to post-gastric surgery cases, most patients with chronic fistulas had fistulas resulting from bariatric surgery. This study revealed a lower success rate in the chronic setting (36.6%) than that in the acute setting (100.0%). This suggests that OTSC may be less effective for long-standing GI defects, possibly because of tissue fibrosis and scarring in a chronic setting [9].

OTSC are generally considered safe, with a low rate of procedure-related complications. However, reported complications include deviation during the procedure due to tissue fibrosis, obstruction at the esophagogastric junction, fistula injury, microperforation of ulcers caused by OTSC claws, and additional damage to the perforated sites. A conservative approach is recommended to address these issues, limiting the number of clips applied, especially in narrow areas, such as the gastroesophageal junction and small intestine. The entire defect was gently suctioned before releasing the OTSC, to prevent further tearing of the exposed area. Furthermore, for precise clip placement, endoscopic dye staining with India ink injection into the target lesion can be an effective technique [10].

Endoscopic stenting is one of the mainstays of endoscopic therapy for postoperative leakage. Stent deployment can promote mucosal healing by closing a luminal gap and redirecting its contents. It also promotes early oral intake and reduces the risk of stricture formation. Stenting options consist of self-expandable plastic stents (SEPS) and SEMS, with the latter further categorized into fully covered SEMS (FCSEMS) and partially covered SEMS (PCSEMS) (Fig. 2) [3]. A systemic review evaluating the efficacy and safety of treating stent placement in the treatment of benign esophageal ruptures and anastomotic leaks has found that there is no significant difference in the clinical success rate among various stent types (SEPS 84%, FCSEMS 85%, and PCSEMS 86%; P=0.97). However, stent migration, a significant complication, occurred more frequently with SEPS (31%) and FCSEMS (26%) than with PCSEMS (12%; P≤0.001) [11].

Fig. 2
SEMS in anastomosis site fistula.
(A) EJ anastomosis site at UI 39 cm with 5 mm-sized fistula opening. (B, C) Guide wire insertion. (D) SEMS (full covered, 20×120 mm) insertion. (E) Clippings at proximal ends.

SEMS = self-expandable metal stents; EJ = esophagojejunal; UI = upper incisor.

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Studies have reported clinical success rates of 64.6%, 74.3%, 82.6%, 87.5%, and 100.0% for the treatment of anastomotic leakage with stents (Table 1) [5, 8, 12, 13, 14, 15]. The reported success rates vary, depending on the location and site of the anastomotic leaks. In a retrospective observational study conducted after bariatric surgery, treatment was successful in 85.7% of laparoscopic sleeve gastrectomy patients, although it was 60% in laparoscopic gastric bypass surgery [16]. In a retrospective study focusing on endoscopic treatment for anastomotic leakage following gastrectomy in gastric cancer patients, the comparison included both clipping and stent insertion. The results indicated that complete closure rates for leakage were as follows: 86.1% for esophagojejunostomy or esophagogastrostomy sites, 94.1% for gastroduodenostomy, gastrojejunostomy, or gastrogastrostomy sites, and 60.1% for duodenal or jejunal stump sites [8]. The average stent placement duration in patients with leaks varied across studies, ranging from approximately 26–28 days in most studies to 55 days in one study [5, 8, 12, 14, 17, 18].

Table 1
Published data on stent insertion for the management of anastomotic leaks

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Primary concerns related to stent placement include the risk of stent migration and patient intolerance. In a multicenter study on managing complications of bariatric procedures with endoscopic stents, it was found that migration occurred in 19.5% of patients who underwent stent placement, and 3.4% were unable to complete treatment due to stent intolerance [17]. However, a different retrospective analysis, focusing on endoscopic interventions for anastomotic leakage after bariatric surgery, reported a notably higher stent migration rate (66.7%) [16]. In some cases, endoscopic suture anchoring was performed due to the potential for stent migration, which can result in further complications, such as perforation and luminal obstruction. As a result, a retrospective study demonstrated a significant reduction in migration rate [19]. Although FCSEMS is known to be more prone to migration, removing PCSEMS can be challenging, primarily because of its propensity for tissue ingrowth [20]. Additional complications linked to stent placement include issues, such as tissue hyperplasia, stricture formation, perforation, the development of fistulas, and minor discomforts, such as chest pain, mucosal erosions, food impaction, and bleeding [21].

Although SEMS and endoclips have been the mainstream endoscopic treatments for anastomotic leaks, EID has recently gained popularity as a treatment option [22]. Many studies emphasize the importance of infection control in cases of leakage. Fluid drainage through surgery, radiology, or endoscopy is crucial. However, to reduce the risk of reoperation or gastrocutaneous fistula formation along a radiological drainage path, the endoscopic approach is preferred whenever possible [4, 23]. The underlying principle of EID involves the placement of ≥1 pigtail plastic stents to facilitate the internal drainage of fluid accumulation into the digestive system, with the ultimate goal of sealing the leak opening [24]. The pigtail stent may also function as a foreign body that promotes defect re-epithelialization [25].

Endoscopic internal drainage has shown promising results in the treatment of anastomotic leaks. In a single-center retrospective study, double pigtail stent placement achieved an 85% success rate in treating anastomotic leaks, with an average follow-up of 15.9±12.2 months after EID completion [22]. Another retrospective study that compared EID to endoscopic closure using stent and/or endoclip reported an overall success rate of 86% for EID and 63% for endoscopic closure. However, healing duration was longer in an EID group, with a mean time of 12.2±15.8 months, compared to 6.7±9.6 months in a closure group [23]. A single-center retrospective study that evaluated 617 patients undergoing EID as a first-line treatment for leaks, fistulae, and collections demonstrated slightly varying clinical outcomes for EID. Although a statistical comparison was not conducted, the overall success rate was 84.7%, with clinical success rates of 89.5% for leaks, 78.5% for fistulae, and 90% for collections [26]. In many studies, EID showed a higher rate of treatment success, although it often requires a longer duration to achieve effective treatment.

One advantage of EID is that it enables early enteral feeding. In a retrospective analysis conducted on patients who had a double pigtail tube inserted for internal drainage of an anastomotic leak after upper GI surgery in 2 tertiary upper GI centers, the findings revealed that majority of patients were permitted oral fluids within 1 week and a soft diet in the second week [27]. Providing early nutritional support and effectively managing sepsis through drainage are crucial components of treatment of anastomotic leakage. Endoscopic internal drainage can improve patient mobility and potentially shorten hospital stay, reducing the risk of complications, such as deep vein thrombosis and hospital-acquired pneumonia that can result from extended hospitalization [27]. The incidence of adverse events associated with EID typically falls within the range of 4%–15%, with most cases amenable to conservative management. However, severe adverse events have been reported, including instances of double-pigtail stent migration into the perigastric cavity, and more critically, into the splenic artery or spleen [22].

Endoscopic suturing is another technique used for endoscopic management of post-anastomotic leaks. Endoscopic suturing can be beneficial, owing to its potential precision. However, this requires additional training and expertise because performing such a procedure in a tight endoluminal space or at tilted sites can be demanding [28].

OverStitch (Appollo Endosurgery, Austin, TX, USA) has become a primary endoscopic suturing system [28]. The OverStitch system is a disposable, single-use endoscopic suturing device that enables the placement of either permanent or absorbable sutures through full-thickness tissue. In some cases, it is necessary to de-epithelialize the fistula tract using methods, such as argon plasma coagulation before performing endoscopic closure [29].

This single-center, retrospective, observational study was conducted at a tertiary medical center to analyze 20 patients who underwent endoscopic suturing for the management of post-surgical wall defects, primarily intermediate and chronic defects with fistula or leak formation. The patients were divided into 3 groups: group A received pure endoscopic direct suture; group B received combined therapy with endoscopic direct suture, FCSEMS, and anchoring; and group C received FCSEMS and anchoring. The overall long-term clinical success rate was 80%, with success rates of 77%, 85%, and 75% in groups A, B, and C, respectively. This study suggests that suturing is an effective method for leak management, although the placement of FCSEMS can yield good results in cases where suturing is not feasible. Additionally, this study noted that long-term clinical success was more likely when dealing with acute defects [28]. Although this study has demonstrated a relatively high long-term success rate, others have reported a decreased rate of long-term success. A large multicenter series that retrospectively reviewed patients treated with an endoscopic suturing system for fistula closure reported an immediate success rate of 100%. However, at follow-up, approximately 40% of the patients maintained closure with endoscopic therapy. Notably, despite multiple endoscopic attempts, fistulas in many patients failed to close [30].

Endoscopic suturing can be an effective treatment option for postoperative leaks and fistulas by achieving full-thickness closure of defects. However, various study results underscore the importance of a tailored approach that considers the nature and duration of defects to achieve the best patient outcomes. Combining endoscopic suturing with other endoscopic methods, such as SEMS and EID, can be considered based on specific lesion characteristics.

Endoscopic vacuum therapy has recently emerged as an endoscopic approach for managing anastomotic leakage after upper GI surgery (Fig. 3). However, EVT or endoscopic negative pressure therapy employs an open-pore polyurethane sponge drain that can seal a leak, as well as provide continuous drainage of fluid collection, which can encourage faster ingrowth of granulation tissue, thereby promoting rapid defect closure [13]. The sponges need to be replaced every 3–7 days until wound healing is completed [3].

Fig. 3
EVT in anastomotic leak.
(A) EJ anastomosis site at UI 40 cm with a hole at 2 o’clock. (B) Anastomosis stricture. (C) Insertion of a sponge at the tip of the L-tube. (D) Sponge tip positioned at UI 40 cm.

EVT = endoscopic vacuum therapy; EJ = esophagojejunal; UI = upper incisor.

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Although EVT was originally introduced to treat anastomotic leakage after colorectal surgery, it has now become one of the primary treatment options for anastomotic leakage following upper GI surgery [31]. The clinical outcomes observed so far have shown a promising success rate in the management of leaks (Table 2). A single-center study that assessed patients treated with EVT for anastomotic leakage following upper GI surgery reported a success rate of 74% (95% confidence interval, 57%–87%) [32]. Another single-center study reported the outcomes of 6 consecutive patients treated with EVT for early postoperative leaks in close proximity to the esophagogastric junction following bariatric surgery. The study found a 100% success rate in managing the leaks, with a median treatment duration of 23.5 days [33]. Although not specific to postoperative leak management, a systematic review of EVT for various upper GI tract conditions reported an overall success rate of EVT for anastomotic leakage after esophagogastric surgery or esophageal perforation, with a rate of 90% (range, 70%–100%) observed across >200 patients [34]. The clinical success of EVT can be influenced by various factors. A multicenter retrospective study of patients who underwent EVT for upper GI perforation or leak at 4 tertiary hospitals in South Korea explored the success and failure of EVT, as well as factors associated with its efficacy. A sponge was placed in the cavity when the defect was sufficiently large and intraluminally otherwise. The results showed that clinical failure was significantly associated with neoadjuvant treatment (P=0.007), with more frequent clinical failures observed with the intraluminal method than with the intracavitary method (P=0.006). Neoadjuvant treatments, such as radiotherapy, can cause tissue remodeling and potentially lead to EVT failure. Better clinical results with the intracavitary method suggest that precise positioning of the sponge can better achieve more effective drainage, leading to a higher success rate of defect closure [35].

Table 2
Published data on endoscopic vacuum therapy for the management of anastomotic leaks

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Studies have reported significant advantages of EVT over SEMS placement. A retrospective study comparing EVT and SEMS for postsurgical gastroesophageal leakage treatment reported a 100% success rate in an EVT group compared with 63.6% in a stenting group. Thus, EVT had a shorter median time to success (19.5 days for EVT vs. 27.0 days for SEMS) and significantly lower complication rate (0.0% for EVT vs. 54.5% for SEMS, P=0.042) [14]. The study had limitations due to the small number of cases and retrospective single-center nature of the study, making it challenging to make a statistically significant statement. However, the results were consistent with the overall trend of higher success rates with EVT treatment than those with SEMS treatment in other studies. In another study comparing EVT and SEMS for postgastrectomy, EVT had a 100.0% success rate, while SEMS showed 2 (7.1%) patients that failed to heal, with no statistically significant difference. Post-procedural complications, such as anastomotic stricture, occurred in 1 (9.1%) patient in an EVT group, and in 4 (14.3%) patients in an SEMS group within 1 year. The median treatment duration for EVT was shorter than that for SEMS placement (15 vs. 36 days, P<0.001). Most studies that compared EVT and sent implantation in upper GI defects reported a higher clinical success rate with a lower mortality rate for EVT compared to that for stent placement [14]. The reported advantage of EVT may be attributed to its treatment mechanism, where SEMS simply blocks the leak site, while EVT has the added benefit of draining necrotic debris and pus, which, in turn, can prevent the spread of inflammation and promote tissue healing [5]. Although both studies yielded consistent results, their limited sample size emphasized the need for further research through larger RCTs.

According to the literature, EVT is not associated with procedure-related complications. Most studies reported bleeding as a complication associated with EVT treatment, and in a few cases, anastomosis site stricture after its removal [5, 36, 37]. One of the studies reported 2 severe adverse events, including a tracheoesophageal fistula occurring during sponge exchange using an overtube and an esophageal ulcer due to a suction catheter [32].

Owing to its high effectiveness and low incidence of adverse events, EVT has emerged as a promising treatment for post-gastric surgery leakage. However, the existing body of literature predominantly comprises studies with relatively small patient cohorts. Consequently, there is a need for more extensive investigations involving larger sample sizes to validate the safety and efficacy of EVT.

Tissue sealants, such as fibrin glue and cyanoacrylate, have emerged as effective solutions for managing anastomotic leaks [3]. Fibrin tissue adhesive is composed of highly concentrated fibrinogen, which transforms into a stable fibrin polymer upon the addition of thrombin, factor 13, iodine calcium, and aprotinin [38]. Fibrin sealants exhibit versatility in their applications, including hemostasis promotion, wound closure, and tissue sealing. Their key advantage lies in their excellent tolerability, as they do not induce inflammation, foreign body reactions, tissue necrosis, or excessive fibrosis tissue formation [39]. In contrast, cyanoacrylate glue is a potential adhesive that polymerizes upon contact with moisture, which can induce a foreign body reaction in the tissue, fostering tissue healing [40].

Although not limited to the upper GI tract, a study that reported the use of tissue sealants in both the upper and lower GI tracts demonstrated a high success rate of 96.7%. The study also noted that tissue sealants are highly effective in reducing treatment duration. Nevertheless, in many cases, repeated sessions and large volumes of sealants are necessary [40].

Despite the promise of tissue sealants for managing anastomotic leaks following gastric surgery, there is a notable gap in the dedicated analysis of their application in post-gastric anastomosis surgery. Consequently, further studies are imperative to conduct a thorough assessment of their effectiveness in managing anastomotic leaks specific to post-gastric surgery.

The management of anastomotic leaks and fistulas following upper GI surgeries is of great importance because of their potential to cause significant morbidity and mortality. As these surgeries become increasingly complex, the incidence of postoperative leakage also increases, necessitating the development of effective treatment strategies. Endoscopic approaches, including clipping, SEMS, internal drainage, endoscopic negative-pressure treatment, and tissue sealants, have emerged as primary choices for addressing these challenges. Each approach has unique advantages and limitations, and the selection of the most suitable method should be guided by the patient’s clinical presentation and specific characteristics of the leak. In many cases, a combination of these methods is used to achieve the most effective treatment outcomes (Table 3).

Table 3
Summary

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By providing insights into the effectiveness and constraints of a range of endoscopic treatments, this review aimed to be a valuable resource for clinicians and researchers committed to enhancing outcomes in patients with anastomotic leaks and fistulas. The need for further studies and ongoing advancements in endoscopic techniques cannot be overemphasized, as they are essential for enhancing the management of these challenging complications in the field of upper GI surgery.