Feasibility of Duodenal Covered Self-Expandable Metal Stent Fixation: A Pilot Study (With Video)

Migration of duodenal covered self-expandable metal stents (C-SEMSs) is the main cause of stent dysfunction in patients with malignant gastric outlet obstruction (mGOO). Because endoscopic SEMS placement is frequently selected in patients with poor performance status, we concurrently focused on the safety of the treatment. This pilot study included 15 consecutive patients with mGOO who underwent duodenal C-SEMS placement with xation using an over-the-scope-clip (OTSC). Technical feasibility, clinical success for oral intake estimated by the Gastric Outlet Obstruction Scoring System (GOOSS) score, and adverse events including stent migration were assessed. All procedures were successful, and clinical success was achieved in 86.7% (13/15). Mean GOOSS scores were improved from 0.07 to 2.53 after the procedure (P < 0.001). Stent migration occurred in one case (6.7%) with no other adverse events. For xation using an OTSC, additional time required for the procedure was 8.9 ± 4.1 minutes. Poor performance status was associated with clinical success (P = 0.03), but we could provide the treatment safely and reduce mGOO symptoms even in patients with poor performance status. In conclusion, duodenal C-SEMS xation using an OTSC is feasible for preventing stent migration in patients with mGOO including those with poor performance status.


Introduction
The clinical syndrome of malignant gastric outlet obstruction (mGOO) occurs as a result of a narrowing in the region of the gastroduodenum. Two main etiologies for mGOO are pancreatic and gastric cancer. Several randomized controlled trials (RCTs) have evaluated endoscopic self-expandable metal stent (SEMS) placement and surgical gastrojejunostomy (GJ) for palliation of incurable mGOO 1,2 . No differences were observed in technical success, major adverse event rates, or postoperative mortality. Shorter time to resumption of oral intake and shorter recovery time with SEMS placement may decrease the time interval before palliative chemotherapy 3,4 . According to a recent published American Society for Gastrointestinal Endoscopy guideline 5 , although SEMS placement may offer short-term advantages, patients whose performance status is good and whose life expectancy is longer than 6 months may bene t more from surgical GJ than SEMS placement. A patient with poor performance status who would be unable to tolerate surgical GJ may be an appropriate candidate for endoscopic SEMS placement. Clinicians should evaluate treatment options carefully to optimize care for patients.
Endoscopic duodenal SEMS placement may be selected because it is minimally invasive. Uncovered SEMSs (U-SEMSs) and covered SEMSs (C-SEMSs) are available, and RCTs 6-10 have revealed their clinical features. The main cause of stent dysfunction with U-SEMSs is tumor ingrowth via the mesh of the stent, which occurs in 16-44% 6-9 of cases. Chemotherapy is reported as the only method to prevent tumor ingrowth 11,12 , but in actual clinical practice more than 70% of patients with mGOO are not eligible for chemotherapy due to disease progression 13 . C-SEMSs were designed to prevent tumor ingrowth, but the incidence of stent migration reportedly ranges from 6-32% 6-11, 14-24 . Chemotherapy that results in a decrease of tumor volume and reduction of alimentary tract compression is recognized as a major predictive factor for stent migration 11 . Improvements in the shape of the stent have been attempted to prevent C-SEMS migration, but the results have been controversial and unsatisfactory.
Anchoring of C-SEMSs with devices has been proposed as another countermeasure against C-SEMS migration 25,26 . We previously evaluated the safety and effectiveness of duodenal C-SEMS xation using suturing and an over-the-scope-clip (OTSC) device (Ovesco Endoscopy, Tübingen, Germany) in an experimental model 26 . However, to the best of our knowledge, no clinical trial has been conducted using these methods for duodenal SEMS xation. Endoscopic suturing device is not available for clinical use in our country; therefore, we conducted this pilot study to evaluate the feasibility and effectiveness of duodenal C-SEMS xation using OTSC in patients with mGOO. Table 1 lists the demographic and clinical characteristics of all patients. Patients included 10 males (66.7%), and the median age of all patients was 78 years (range 43−96). Pancreatic cancer (n = 9, 60.0%) and gastric cancer (n = 3, 20.0%) were the two main etiologies. Fourteen patients (93.3%) had no oral intake (GOOSS score 0), and 3 patients (20.0%) were unable to care for themselves (Group C; KPS score [0−40]). Table 2 lists treatment outcomes and adverse events. The technical success rate was 100.0% (15/15), and successful application of the OTSC for xation was accomplished in all patients. The mean procedure time required for OTSC placement was 8.9 ± 4.1 minutes, and no adverse events were related to the xation method. The total median procedure time for C-SEMS placement with xation was 32.1 ± 8.5 minutes. Clinical success was achieved in 13 patients (86.7%), and mean GOOSS scores were improved from 0.07 to 2.53 after C-SEMS placement with xation (P < 0.001). Eight patients (53.3%) were able to have full diets. The clinical success rate as estimated by the GOOSS score was signi cantly associated with KPS status (Groups A and B, 100.0% [12/12]; Group C, 33.3% [1/3]; P = 0.03). Chemotherapy was performed after SEMS placement in 4 patients (26.7%) as appropriate. All selected regimens were S-1 monotherapy. Median survival time was 84 days (range 15−192), and all patients died of their underlying carcinoma. Figure 3 presents the cumulative stent patency curve estimated by Kaplan-Meier analysis.

Results
One case (6.7%) had stent dysfunction related to C-SEMS migration at day 21, which was successfully treated by removal of the migrated C-SEMS using an enteroscope. No other adverse events, including perforation and tumor overgrowth, were observed during the remainder of the patients' lives.

Discussion
These results demonstrated that duodenal C-SEMS placement and xation with an OTSC for mGOO was successful in all cases and that 86.7% of the patients achieved clinical success. In particular, 53.3% of patients with mGOO could have full diets. The additional time required for the procedure was 8.9 ± 4.1 minutes, which may be within the permissible range. Moreover, no adverse events were related to the xation method. Poor performance status was associated with clinical success as estimated by the GOOSS score (P = 0.03). Stent migration occurred in one case (6.7%) with no other adverse events. No asymptomatic stent migration was observed on periodic abdominal X-ray imaging. Stent migration is a major adverse event of duodenal C-SEMSs. Kim et al. 6 reported that stent migration was signi cantly associated with chemotherapy after stent placement. Isayama et al. 17 recommended the use of longer stents to prevent stent occlusion caused by tumor in-or overgrowth at the uncovered portion. According to this recommendation, in this pilot study, we used the longest C-SEMS (120 mm) available in our country. We were fortunate to experience no cases of tumor in-or overgrowth. Once a duodenal C-SEMS has migrated into the jejunum, clinicians hope it will exit via the rectum or remain in the body without causing obstruction symptoms. Otherwise, with obstruction symptoms, surgical removal is required, and this exhausts patients with advanced cancer. In this study, we experienced one case with stent migration. Fortunately, we were able to remove the migrated C-SEMS using an enteroscope without surgery 27 . It is important to accommodate asymptomatic migration, which is not included in stent dysfunction. Although this event fortuitously may not cause symptoms related to gastrointestinal obstruction, it potentially results in intestinal obstruction. Table 3 lists some published articles about endoscopic duodenal covered metal stenting for mGOO 6-11, 14-24 . The literature review assessed more than 1000 cases of endoscopic duodenal C-SEMS stenting and found that chemotherapy was administered after C-SEMS placement in 41.2% (range 11.4-78.6%), and that stent migration occurred in 14.5% (range 6.0-32.3%) of cases. Not all of the clinical studies carried out periodic abdominal X-ray imaging or follow-up endoscopy, so the real rate of stent migration might be higher because asymptomatic stent migration could have been missed. Kim et al. 6 performed a routine 8-week follow-up endoscopy and found that 63% of cases with a distally migrating C-SEMS occurred in patients without any obstructive symptoms. Their prospective study con rmed stent migration in almost one-third of patients during total follow-up. Another important issue is that the rate of patients receiving chemotherapy varies in published articles. The chemotherapy regimen continues to change and evolve, and some prospective studies including RCTs excluded mGOO patients with poor performance status 10,17 . Patients with poor performance status tend to avoid receiving chemotherapy, so the rate of patients with mGOO receiving chemotherapy might be lower in real-world practice. We did not exclude patients with poor performance status, so 26.7% of patients in our study cohort received chemotherapy after the procedure. We found that poor performance status was associated with clinical success, de ned as relief of GOOSS score ≥ 2 within 1 week. Although the result could be due to underlying disease, symptoms related to mGOO were relieved in all cases (at least 1 GOOSS score improvement). Endoscopic duodenal C-SEMS placement with xation might be bene cial even in patients with poor performance status.
Previously, because there were no designated duodenal C-SEMSs, clinicians applied esophageal C-SEMSs for relief of mGOO symptoms 16 . Due to the bended anatomy of the duodenum, stent fracture and gastrointestinal perforation became a serious problem. Recently, SEMSs with low axial force 28 (i.e., those that follow the gastrointestinal tract) have been preferred and widely used. As shown in Figs. 1C and 2D, a SEMS with low axial force resulting from the devised knit pattern easily follows the gastrointestinal tract. Both ends of the uncovered portion were designed to stick to the tumor to prevent migration. Furthermore, the range of proximal are was widened (Fig. 1A). Even with these ingenious improvements, previous studies using the C-SEMS ( ared-ComVi stent) 10 24 used a 40-mm diameter funnel shape. Those stents could prevent distal migration (no cases in both studies), but proximal migration occurred in 11.1% and 16.7% of cases, respectively. Thus, stent migration is still a challenging problem, but our xation method that anchors C-SEMSs to the gastrointestinal tract may contribute to approaching the ideal endoscopic SEMS placement.
Not enough is known about the role of anchoring of duodenal C-SEMSs in preventing migration. One previous study 25 reported the usefulness of endoscopic clips generally used for closing perforations or controlling bleeding to prevent C-SEMS migration. We previously practiced this technique, but still encountered cases of C-SEMS migration, and even without stent migration the clips were often out of place as assessed by routinely performed abdominal X-rays. Therefore, we evaluated the feasibility and safety of anchoring methods using experimental models 26 . The OTSC and suturing system had a signi cantly higher gripping force compared with the clipping system (OTSC vs. clip: 13.2 vs. 1.0 Newtons [N], P < 0.001; suture vs. clip: 8.5 vs. 1.0 N, P < 0.001). Based on pathological ndings in a porcine model, OTSC compressed the submucosal layer but not the muscle layer, and we concluded that the method may be safe even for preventive use. The results revealed that SEMS xation with an OTSC and suturing method is feasible compared with the clipping method. Because an endoscopic suturing device is not available for daily clinical use in our country, we conducted duodenal C-SEMS xation using OTSC in patients with mGOO. In this pilot study, we did not observe adverse events, such as gastrointestinal perforation, related to OTSC placement. We also con rmed that the position of C-SEMSs and OTSCs was unchanged until the last follow-up in 93.3% of cases. Further largescale research using our xation method will be required to establish higher quality evidence. The one problem with this xation method is the additional cost (79,800 Japanese yen; approximately 770 US dollars) for an OTSC. Further studies should be planned considering medical costs.
This study had some limitations. First, it was a pilot study with a limited number of cases, and was conducted at a single institution. Further large-scale multicenter prospective research will be required to verify the superiority of our method over other conventional treatments and assess medical costs. Second, we selected an OTSC for xation to anchor the C-SEMS; other methods such as an endoscopic suturing system should be evaluated. Currently, this system is not available in our country; we hope it will be accepted as a daily clinical procedure in the future.
In conclusion, an OTSC used for xation of duodenal C-SEMSs was safe and feasible for preventing stent migration in patients with mGOO. The treatment may bring bene ts even for patients with poor performance status. We believe our efforts will contribute to establishing an anti-migratory method for duodenal C-SEMSs.

Patients
Fifteen consecutive patients underwent duodenal C-SEMS placement and xation with an OTSC for mGOO at Nagoya City University Graduate School of Medical Sciences between October 2018 and April 2020. Procedural and clinical data were collected and analyzed retrospectively from a prospectively maintained endoscopy database. The inclusion criteria were obstruction of the stomach or duodenum causing nausea, vomiting that reduced oral intake, or weight loss; and unresectable malignant pyloroduodenal obstruction, as shown by endoscopic or radiographic ndings. The exclusion criteria were multiple gastrointestinal tract stenoses; previous treatment of GOO or transpapillary biliary stricture; and refusal to participate in the study. All patients provided written informed consent before the procedure in accordance with the Helsinki Declaration, and the study was approved by the Institutional Review Board of the Nagoya City University Graduate School of Medical Sciences (approval no. 46-18-0009) (clinical trial registration number: UMIN000034510, date of registration: 15/10/2018).

Devices
All C-SEMSs used in this study were ared-ComVi stents (Taewoong Medical, Seoul, Korea), 20 mm in diameter and 120 mm long. The stents had an uncovered are (15 mm long) at both ends. The proximal uncovered are was 25 mm in diameter and was expected to prevent stent migration (Fig. 1A). The type of OTSC was 12/6 t, which has an OTSC cap diameter of 17.5 mm and clip width of 10 mm (Fig. 1B). Figure 1C presents an ex vivo image of C-SEMS placement with xation using an OTSC.

Stent placement and xation technique with an OTSC
All procedures were performed with patients under deep sedation using midazolam (5−10 mg) and pethidine hydrochloride (17.5−35 mg). Duodenal stent placement was performed using a direct-viewing scope (CF-HQ290ZI; Olympus Medical Systems, Tokyo, Japan) or a side-viewing duodenoscope (TJF260V; Olympus Medical Systems, Tokyo, Japan). The endoscope was rst positioned close to the gastric or duodenal stenosis site, and the GOO was evaluated endoscopically ( Fig. 2A). Contrast medium was injected under uoroscopic guidance to identify the site and length of the obstruction. The obstruction was negotiated using a 0.025-inch standard biliary guidewire and an endoscopic retrograde cholangiopancreatography (ERCP) catheter. After con rming the position of the stenosis with the ERCP catheter, we deployed the C-SEMS and placed it under endoscopic and uoroscopic guidance (Fig. 2B).
Subsequently, the OTSC system for xation was loaded onto the scope (PCF-Q260AI; Olympus Medical Systems, Tokyo, Japan), and part of the upper rim of the SEMS was suctioned into the transparent cap before releasing the OTSC, grasping both the SEMS and the gastric or duodenal wall. One OTSC was placed per patient ( Fig. 2C and D).

Data analysis and follow-up
The baseline information collected included age, gender, diagnosis, site of obstruction, Karnofsky performance status (KPS) score 29 , Gastric Outlet Obstruction Scoring System (GOOSS) 30 score, presence of ascites/liver metastasis/peritoneal dissemination, and chemotherapy after SEMS placement. The KPS is an assessment administered by a healthcare provider to assign a patient to one of 11 categories (ranging from 0 [dead] to 100 [normal activity, no evidence of disease]). According to the assessment results, patients are divided into three groups; Group A (80−100) can independently perform daily activities, Group B (50−70) can perform daily activities with help, and Group C (0−40) requires continuous assistance and progressively approaches death. The GOOSS is a scoring system to classify a patient's level of oral intake as follows: 0, no oral intake; 1, liquids only; 2, soft solids; 3, low-residue or full diet 30 . The presence of ascites/liver metastasis/peritoneal dissemination was evaluated by computed tomography before the procedure.
The primary endpoint was technical success. The secondary endpoints were clinical success, changes in GOOSS score from before SEMS placement to 1 week after SEMS placement, and adverse events including SEMS migration. Technical success was de ned as satisfactory SEMS placement and precise positioning at the obstruction site, and ability to deploy the OTSC for SEMS xation. Clinical success was de ned as a GOOSS score of ≥ 2 and relief of GOO symptoms within 1 week after SEMS insertion. Procedure time for OTSC placement was calculated from inserting the endoscope that loaded the OTSC to endoscope removal after OTSC placement. Stent migration was de ned as movement out of the stricture, which was diagnosed on endoscopy and radiography. We routinely perform abdominal X-rays on days 1, 3, 7, and 14 and every 2 weeks after the procedure to detect symptomatic and asymptomatic stent migration until the patient's death.

Statistical analysis
Values are reported as medians with ranges. Categorical data were compared using Fisher's exact test. Procedure time and changes in GOOSS scores are expressed as mean (± standard deviation) and were analyzed using Wilcoxon's signed rank test. Differences were considered to be signi cant at P < 0.05. The cumulative time to stent dysfunction was evaluated using Kaplan-Meier analysis. All statistical analyses were performed using SPSS software (version 19; IBM Corporation, USA).  A 60-year-old female with pancreatic cancer. The third portion of the duodenum was obstructed by the tumor (A), and a covered self-expandable metal stent (C-SEMS) was deployed (B). The over-the-scope-clip (OTSC) system was loaded onto the endoscope, and part of the upper rim of the metal stent was suctioned into the transparent cap. The OTSC was released to grasp both the metal stent and duodenal wall (C). A uoroscopic image after OTSC and C-SEMS placement (D).