Abstract
Objective
The treatment result of the uncovered metallic stent (uncovered MS) and covered metallic stent (covered MS) for unresectable malignant distal biliary obstruction is controversial. This time, we conducted this study to compare the efficacies and complication rates of uncovered MS and covered MS in unresectable malignant distal biliary obstructions at a prospective randomized multicenter trial.
Materials and methods
From April 2014 to September 2018, patients with unresectable malignant distal biliary obstruction were randomly assigned to 2 groups: the uncovered MS group and the covered MS group.
Results
92 treatment results patients were discussed. 48 patients were assigned to the uncovered MS group and 44 cases were assigned to the covered MS group. Both groups showed a drainage effect. No significant difference was found in the drainage effect between the 2 groups. The number of stent occlusion was significantly greater (p = .0467) in uncovered MS (43.8%) comparing with those in covered MS (22.7%). As the cause of stent occlusion, tumor ingrowth was significantly greater (p < .001) in the uncovered MS group (35.4%) than in the covered MS group (2.3%). The median stent patency period was significantly longer (p = .0112) in the covered MS group (455 days) than that of the uncovered MS group (301 days). A significant difference in the median survival period was not found between the 2 groups.
Conclusions
Covered MS showed the possibility of extending the stent patency period by suppressing tumor ingrowth more than uncovered MS does. The UMIN Clinical Trial Registry number is UMIN000015093.
Introduction
The clinical practice guideline of biliary cancer recommends drainage for unresectable malignant distal biliary obstruction wherever possible, in consideration of the patient’s quality of life (QOL) [Citation1]. Endoscopic, percutaneous transhepatic, and surgical drainages are available. Of these, endoscopic drainage is recommended by the guideline because of its low invasiveness, high success rate, and easiness of internal drainage [Citation1]. Thus, endoscopic drainage for unresectable malignant distal biliary obstruction and internal drainage by stenting should be employed as basic therapeutic strategies.
Stents include plastic stents (PS) and metallic stents (MS). Randomized controlled trials (RCTs) comparing PS and MS placement for unresectable malignant distal biliary obstruction recommend MS because of their longer patency periods attained [Citation2–6] and low costs, in view of hospitalization and retreatment due to obstruction, as compared with PS [Citation2]. MS includes uncovered MS type and covered MS type. Covered MS is the stent developed to prevent tumor ingrowth which is the weak point of uncovered MS [Citation7]. Comparing with uncovered MS, covered MS showed great superiority during the stent patency period in the period when the effect of chemotherapy was hardly confirmed [Citation8]. However, in recent days, chemotherapy is advancing and the types of available stents are increasing and various results also have been reported in RCT [Citation9–14]. Considering these situations, it is considered to be necessary to reevaluate them as the prospective study along with the change of times. This time, we conducted this study to compare the efficacies and complication rates of uncovered MS and covered MS in unresectable malignant distal biliary obstructions at RCT.
Materials and methods
The study period included the enrolment period between April 2014 and September 2018 which prospectively included the cases and the follow-up period 1 year after last enrollment, which was September 2019. Six institutions participated in this RCT (Chiba University Hospital, Tokai University Hospital, Kameda Medical Center, Niigata Prefectural Shibata Hospital, Niigata Cancer Center Hospital, St. Marianna University Hospital). Inclusion criteria were (i) the patients with unresectable malignant distal biliary obstruction and eligible for endoscopic retrograde cholangiopancreatography (ERCP); (ii) the patients who are eligible for endoscopic sphincterotomy (EST) or drainage and have provided the consent to these treatment; (iii) the patients with confirmed diagnosis of malignant tumor after performing pathological search (cytology class IV or V, or confirmed cancer by endoscopic bile duct biopsy or endoscopic ultrasound-guided fine needle aspiration), or the patients who are clinically diagnosed as malignant by image diagnosis or blood test if malignant diagnosis is difficult even if pathological search was performed; (iv) the patients whose World Health Organization performance status is between 0 and 2; (v) the patients who are 20 years old or older at the time of consent; (vi) the patients who received the first drainage treatment within 30 days; (vii) the patients who understood the study well and have given the consent after receiving enough explanation for participating in this clinical study; (viii) the patients who are hospitalized or will be hospitalized in other hospital after receiving treatment. Exclusion criteria were (i) the patients with bile duct stricture from the hilum to the liver; (ii) the patients with an extremely poor general condition; (iii) the patients with obstruction at 3rd portion of the duodenum; (iv) the patients who cannot provide consent to ERCP and EST; (v) the patients who have an allergy to metals; (vi) the patients with a history of MS placement; (vii) the patients whose prognosis is considered to be less than 30 days; (viii) the patients whom the study doctor considered to be ineligible as the subject. The primary endpoint was a comparison of the MS patency period. The secondary endpoints were (i) comparison of the rate of occlusion of MS; (ii) comparison of drainage effect; (iii) comparison of the success rate of MS placement; (iv) comparison of occurrence of an accidental event during MS placement; (v) comparison of survival period. The patients with the withdrawal of consents and the cases whom the study doctor determined as ineligible after consents were not included in the analysis. Regular medical follow up were performed monthly after MS insertion. Blood tests, US and CT were performed as appropriate. MS obstruction was considered to have caused acute cholangitis during the observation time. Acute cholangitis was diagnosed using Tokyo Guideline 2013 [Citation15]. This study was performed based on the approval of the ethical committee of each institution (IRB number G25035) and registered at UMIN Clinical Trial Registry (UMIN000015093).
Randomization
Considering that 1-year follow-up period is for 1 year from the last enrolment date, based on the study results of Isayama et al. [Citation8], if the superiority study design was used to detect if the patency rate of covered MS (assumed to be 74%) is 22% higher, assuming that the patency rate of uncovered MS is 52% in 1 year, the number of qualified subjects is calculated using the Lakatos method [Citation16] with two-sided α of 5% and detection rate of 80%; as a result, the number of cases per group is 46 and the total is 92. Based on the above ad the study results of Isayama et al. [Citation8], the expected number of subjects to be enrolled were 49 per group and 98 for both groups, estimating that 5% will become untraceable. The patients were assigned to each group by central registration method. When the doctor determined that the case was appropriate, the doctor reported it to a coordinating center that had nothing to do with the study sites where the study is being conducted, and the patient was assigned by computer based on age, sex, and background disease. All the treatment procedures were performed after obtaining informed consent in writing from the patients. The incident relating to ERCP was evaluated using Cotton’s criteria [Citation17].
Stent insertion
The endoscopes used were JF240, JF260V, or TJF260V (Olympus Corp), a backward side-viewing endoscope. WallFlex uncovered MS and WallFlex partially covered MS were used as MS (Boston Scientific Japan, Tokyo, Japan) (). WallFlex partially covered MS has uncovered a flare structure at 5 mm of both sides. As the Delivery system, 8 Fr. is used for uncovered MS and 8.5 Fr. is used for covered MS. MS is the product for which platina is cored to nitinol. ERCP was performed and EST was performed after bile duct cannulation. After confirming the stricture site and stricture length by cholangiography, MS was placed following inserting the guidewire. A 0.025-inch or 0.035-inch guidewire (Jagwire: Microvasive, Boston Scientific Corp., Natick, MA; Revo Wave: PIOLAX, or VisiGlide: Olympus Corp., Tokyo, Japan) was used. ERCP was conducted by the doctors who were accredited as specialists by the Japan Gastroenterological Endoscopy Society.
Figure 1. WallFlex biliary metallic stents (WallFlex biliary MSs). Upper is the uncovered MS and below is the covered MS. MS is nitinol type with cored platinum. Covered MS has uncovered flare structure at 5 mm of both sides. The film used for the cover is silicon.
Statistical analysis
Person’s Chi-squared test with Yates correction and Fisher’s exact test, when appropriate, were used for statistical analysis of categorical variables. Stent patency and patient survival period were estimated using the Kaplan–Meier method, and the log-rank test was used to access differences between the groups. Data were analyzed using SPSS software version 17 (SPSS, Chicago, IL). Differences with a p-value of <.05 were considered statistically significant.
Results
A total of 99 patients were included. 50 patients were assigned to the uncovered MS group and 49 were assigned to the covered MS group by randomization. 1 patient who withdrew consent and 1 patient whom the study doctor considered to be ineligible after consent in the uncovered MS group, and 1 patient who withdrew consent and 4 patients whom the study doctor considered to be ineligible after consent were excluded from the analysis. 92 patients were included in an analysis finally. It was possible to follow up all 92 patients analyzed during the observation period for prognosis.
All stents used had a diameter of 10 mm and a length of 6 cm. The background of patients are shown (). No significant difference was found in age, sex, or diseases. The results of MS placement are shown in . Drainage effect due to MS can be found both in uncovered MS group and covered MS group. Comparing with the time of admission, significant improvement was found in blood test findings after 2 weeks of MS placement (p < .001). No significant difference was found in drainage effect between the uncovered MS group and the covered MS group. Stent occlusion rate was significantly higher in uncovered MS group, which was found in 21 (43.8%), comparing with covered MS group which was found in 10 (22.7%) (p = .0467). As the cause of stent occlusion, tumor ingrowth was significantly found in the uncovered MS group comparing with the covered MS group (p < .001); 17 patients had tumor ingrowth in the uncovered MS group (35.4%) and one patient in the covered MS group (2.3%). Stent occlusion due to sludge was not found in the uncovered MS group but found in 6 patients in the covered MS group (13.6%), which was significantly different (p < .001). For other reasons of stent occlusion, there were no significant differences between both MS. The median stent patency period was 301 days in the uncovered MS group (95% confidence interval [CI], 188–421 days) and 455 days in the covered MS group (95% CI, 312–568 days); the stent patency period was significantly longer in the covered MS group (p = .0112) (). The median survival period was 223 days in the uncovered MS group (95% CI, (101–338 days), and was 213 days in the covered MS group (95% CI, 111–323 days); there were no significant differences between them (p = .238) (). The median (range) of the total follow-up period was 212.3 days (16–1089) in the uncovered MS group, and was 201.2 days (21–1089) in the covered MS group; there were no significant differences between them (p = .296). Complications after ERCP was 7 (7.6%) overall. In the uncovered MS group, 4 overall (8.3%) complications including 2 cases of pancreatitis (mild; 4.2%) and 2 cases of cholangitis (mild, 4.2%) were confirmed. In the covered MS group, 3 overall (6.8%) complications including 2 cases of cholangitis (mild; 4.5%) and 1 case of cholecystitis (moderate; 2.3%) were confirmed. Cholecystitis that developed due to the covered MS placement was not recovered by conservative treatment but was recovered by percutaneous transhepatic gallbladder drainage. All other cases were mild and conservatively recovered. No significant difference was found in complications of ERCP between the 2 groups (p = .549) ().
Figure 2. Kaplan–Meier graph showing cumulative stent patency time. Cumulative stent patency was significantly higher in covered metallic stent (MS) than in uncovered MS (log-rank test; p = .0112). Median stent patency period was 301 days in the uncovered MS group (95% CI, 188–421 days) and 455 days in the covered MS group (95% CI, 312–568 days).
Figure 3. Kaplan–Meier graph showing survival time. No significant difference was observed between the uncovered metallic stent (MS) and covered MS (log-rank test; p = .238). The median survival period was 223 days in the uncovered MS group (95% CI, (101–338 days), and was 213 days in the covered MS group (95% CI, 111–323 days).
Table 1. Background of patients.
Table 2. Outcome of randomized patients based on stent type.
Table 3. Complications after ERCP.
Discussion
Regarding MS placement for unresectable malignant distal biliary obstruction, it is considered that the longer the stent patency period is, the better the patients’ QOL and the less medical cost get [Citation8]. In the case that uncovered MS and covered MS were placed for unresectable malignant distal biliary obstruction, covered MS was reported to significantly suppress tumor ingrowth and extend the stent patency period on RCT by Isayama et al. [Citation8]. However, there are some reports that deny the superiority of the stent patency period of covered MS due to the advancement of chemotherapy and the improvement of MS in recent years [Citation9,Citation10,Citation12–14]. At first, regarding the chemotherapy, the response rate in the period when 5-FU was used for the unresectable pancreatic cancer was 0% and the median overall survival was 4.4 months [Citation18]. After that, the response rate became 9.4–48% and the median overall survival became 5.9–12.2 months by using gemcitabine or molecular target drugs [Citation19–22], which shows that they can suppress tumor ingrowth which was the weak point of uncovered MS at a certain level. In addition, the same can be said for unresectable biliary cancer; the prognosis has been improved by therapeutic agents such as gemcitabine and S-1 [Citation23]. For MS, both uncovered MS and covered MS have been improved by innovative technology. MS used in RCT for the report by Isayama et al. [Citation8] is Diamond stent. The cell of Diamond uncovered MS is extremely large and has a structure that is easy to tumor ingrowth. The WallFlex that we used this time is the nitinol braided type MS in which platinum is cored [Citation24,Citation25]. Although this is the uncovered MS, the cell is small and tumor ingrowth is difficult as the structure (). WallFlex is the stent that improved Wallstent. Comparing with Wallstent, axial force [Citation26] is reduced and the structure is difficult to kink stent. Therefore, both uncovered MS and covered MS are successfully and significantly extend the stent patency period reducing incidents [Citation24,Citation27]. Other than that, many MS are launched in the market and MS themselves are on a way of improvement.
Therefore, the stent patency period may vary depending on the type of MS. The reported RCT as of today which placed the same types of uncovered MS and covered MS used for unresectable malignant distal biliary obstruction by the endoscopic transpapillary insertion are shown (). In these reports including our reports, 3 reports show that the stent patency period is significantly longer in the covered MS group than in the uncovered MS group [Citation8,Citation11], 1 report shows that the stent patency period is significantly longer in the uncovered MS group than in covered MS group [Citation14], and 4 reports show that there is no significant difference in the stent patency period [Citation9,Citation10,Citation12,Citation13]. The current meta-analysis shows that there is no significant difference in the stent patency period [Citation28]. In several meta-analyses, tumor ingrowth is significantly higher in the uncovered MS group and migration is significantly higher in the covered MS group [Citation28–30]; however, other than these are controversial. In our study this time, covered MS showed significantly longer stent patency period extension. In our study, approximately 60% of cases are under chemotherapy treatment, and not all cases respond to chemotherapy treatment. Therefore, since a higher percentage of the cases which did not receive chemotherapy or which did not respond to chemotherapy developed tumor ingrowth with uncovered MS, the stent patency period was considered to be shortened. Covered MS suppresses tumor ingrowth while many migrations are reported [Citation28–30]. Therefore, it is important for covered MS to reduce migration to extend the stent patency period. WallFlex partially covered MS is the MS that prevents migration with the uncovered flare structure at 5 mm of both sides [Citation11,Citation24,Citation25] (). With this structure, the migration percentage is reduced to extend the stent patency period. In our study this time, migration was found only in 1 case (2.3%), and this can be considered to extend the stent patency period of the covered MS significantly. In the report of Kitano et al. [Citation11], which studied with the same MS, the migration rate of covered MS is 0% and it extended the stent patency period of covered MS significantly comparing with that of uncovered MS. Above all, the possibility was shown that the stent patency period of covered MS may be extended if the anti-migration system is solid. In the future, we hope that further improved MS becomes available and incident due to MS placement is reduced, as well as extending stent patency period. Covered MS showed that it may extend the stent patency period more than uncovered MS in unresectable malignant distal biliary obstruction.
Table 4. Uncovered versus covered metallic stents for the management of unresectable malignant distal biliary obstruction by the endoscopic transpapillary insertion – results of randomized controlled trial.
Conclusion
Metallic stents are useful for drainage of unresectable malignant distal biliary obstruction. Covered MS showed that it may extend the stent patency period more than uncovered MS by suppressing tumor ingrowth.
Acknowledgements
The authors thank Drs. Akiko Tsujimoto, Kentaro Sudo and Masashi Ijima for supporting this study.
Disclosure statement
No potential conflict of interest was reported by the author(s).
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