Endoscopic biliary drainage with self-expandable metallic stents (SEMS) is superior to plastic stents for unresectable malignant hilar biliary obstruction (UMHBO), with a life expectancy of > 3 months, because it is less invasive, has long-term stent patency and is more cost-effective.^1–4 No consensus has been reached on whether unilateral or bilateral drainage is optimal for UMHBO.^4–10 Liver volume and function are important factors for determining the drainage area in UMHBO. Drainage of more than 50% of the liver volume, which frequently requires bilateral stent placement, seems to be an important predictor of drainage effectiveness in UMHBO.^11,12 Bilateral drainage is also required for the treatment of segmental cholangitis or jaundice after unilateral biliary drainage. Unilateral drainage shows a significantly higher technical success rate and lower adverse event rate than bilateral drainage, which is technically difficult and requires multiple complex procedures. A recent randomized controlled trial comparing unilateral and bilateral SEMS placement revealed that endoscopic bilateral SEMS placement was more effective than unilateral SEMS placement in terms of stent patency and survival in advanced UMHBO.¹³

There are two methods for bilateral hilar SEMS placement for UMHBO: side-by-side (SBS) and stent-in-stent (SIS).¹³ Endoscopic bilateral SEMS placement is challenging, and sequential SBS has been performed previously.^7,12,14 However, recent developments in devices and techniques for endoscopic intervention allowed for endoscopic bilateral SEMS placement to be performed more commonly. SIS using laser-cut type stents and open-cell type stents showed higher technical success rates than previous types of SEMS.^15–17 Simultaneous SBS using a thin delivery system was also recently reported. Furthermore, SBS using covered SEMS (CSEMS) is another option for bilateral hilar SEMS placement. However, the optimal method for bilateral SEMS placement has been under debate. There is currently no consensus regarding whether SBS or SIS should be used in bilateral SEMS placement for UMHBO. Here, we review the current literature concerning SBS and SIS in endoscopic bilateral SEMS placement for UMHBO.

Sequential side-by-side method

The conventional sequential SBS technique involves the following steps. (a) Two guidewires are inserted into the targeted intrahepatic bile ducts. (b) The first SEMS is inserted into the targeted intrahepatic bile duct along the guidewire and deployed. (c) The second SEMS is inserted into a contralateral bile duct along the other guidewire and deployed. (d) The two SEMSs are parallel to each other in the common bile duct. The distal sides of the two SEMSs should be deployed at the same level as the common bile duct to facilitate endoscopic re-intervention for recurrent biliary obstruction (RBO) when the two SEMS are placed above the papilla (Fig. 1). The distal sides of the two SEMSs are more commonly located above rather than across the papilla. SBS above the papilla may be associated with longer time to RBO by reducing duodenobiliary reflux, and it decreases the risk of post-procedure pancreatitis compared to SBS across the papilla. On the contrary, re-intervention is technically easier in SBS across the papilla, and we can easily remove the occluded SEMS for re-intervention when we use fully covered SEMS (FCSEMS) across the papilla. However, there have been no comparative studies between SBS above the papilla and across the papilla. The most difficult step of the sequential SBS method is insertion of the second SEMS along the first SEMS. After deployment of the first SEMS in the common bile duct, delivery of the second SEMS could not pass beyond the distal edge of the first expanded SEMS in failure cases (Fig. 2). The technical success rates of sequential SBS vary from 73% to 97% (Table 1).^{14,15,17–23}

Uncovered SEMSs (USEMSs) with diameters of 8 mm or 10 mm are commonly used for UMHBO. Lee et al¹⁴ compared 8- and 10-mm diameter USEMSs in SBS and found that the functional success rate and successful endoscopic re-intervention rate did not differ; however, the 10-mm diameter SEMS tended to have a greater stent patency (median, 180 days vs 149 days; P = 0.117). There is no consensus on whether the 8- or 10-mm diameter SEMS should be used in SBS. We usually select the SEMS diameter based on the diameter of the common bile duct.

Simultaneous side-by-side method

Recently, a thinner delivery system (6-Fr) was developed that enabled two SEMSs to be simultaneously inserted and deployed through the accessory channel of a therapeutic duodenoscope after SEMS.^15–17 This new bilateral stenting method enabled us to accomplish simultaneous SBS placement. The simultaneous SBS technique involves the following steps (Fig. 3). (a) Two guide-wires are inserted into the targeted intrahepatic bile ducts. (b) Two SEMSs are then simultaneously inserted into the targeted intrahepatic bile ducts along each guidewire through the working channel. (c) The two SEMSs are then simultaneously or sequentially deployed. (d) The two SEMSs are parallel to each other in the common bile duct. Theoretically, simultaneous SBS can avoid failure of insertion of the second SEMS in sequential SBS after the two guidewires are inserted into the targeted intrahepatic bile ducts. The technical success rate of simultaneous SBS (85%–100%) is higher than that of sequential SBS (73%–91%) (Table 1).^{14,15,17–23} Inoue et al²² retrospectively compared sequential SBS and simultaneous SBS using a novel SEMS with a 5.7-Fr ultra-thin delivery system. The technical success rate was significantly higher in the simultaneous than sequential SBS group (100% vs 71%; P = 0.045). The median procedure time was significantly shorter in the simultaneous than sequential SBS group (22 minutes vs 52 minutes; P = 0.017). Therefore, the simultaneous SBS method might be a good option for bilateral hilar SEMS placement because it has a higher success rate and shorter procedure time than sequential SBS.

Side-by-side method with CSEMS

USEMS is typically used for drainage of the UMHBO, because the membrane in CSEMS might occlude the side branch of the intrahepatic bile duct. One disadvantage of USEMS is that it cannot prevent tumor ingrowth. Another disadvantage is that removal of USEMS is usually difficult during re-intervention after RBO. To reduce the occurrence of tumor ingrowth, ensure that the CSEMS can be easily removed during intervention after RBO, and reduce the risk of intrahepatic bile duct obstruction, a 6-mm diameter CSEMS was developed. Three retrospective studies examining the use of 6-mm diameter CSEMSs have been reported to date.^21,23,24 When 6-mm diameter CSEMSs were used, the time to RBO ranged from 2.6 to 7 months, which is shorter than the time associated with the use of 8- or 10-mm diameter USEMS. Tumor ingrowth was not observed with the use of 6-mm diameter CSEMS, and the causes of RBO were sludge formation and tumor overgrowth. Kanno et al²⁵ reported that soft surface irregularity of the perihilar malignancy in cholangiography was a significant risk factor for a shorter time to RBO in multiple SEMS placement. Most of the RBO cases were associated with tumor ingrowth in their study. Therefore, we consider the presence of this type of tumor to be an indication for CSEMS. The success rate of FCSEMS removal for re-intervention after RBO was 100%, respectively.^21,24 On the other hand, the success rate of partially covered SEMS (PCSEMS) removal was 60.0% (6 out of 10 patients) because tumor ingrowth involved the uncovered part of PCSEMS.²³ The success rate of SEMS removal for re-intervention after RBO may be higher when a 6-mm diameter CSEMS is used instead of USEMS. FCSEMS might be better than PCSEMS from the viewpoint of stent removal during re-intervention among CSEMS.

A concerning disadvantage of CSEMS is that intrahepatic bile duct occlusion can occur with the use of CSEMS for UMHBO. Inoue et al²⁴ reported that liver abscesses occurred in 2 out of 17 cases (11.8%) when 6-mm FCSEMSs were used. The posterior bile ducts were occluded because these two cases were classified as Bismuth type III or IV, and FCSEMSs were placed across the posterior bifurcation. Yoshida et al²¹ reported that liver abscesses occurred in 2 out of 32 cases (6.3%) when 6-mm FCSEMSs were used. However, the site of the abscess was apart from the inserted stent, and it is unclear if the abscess occurred due to obstruction of a side branch by the CSEMS, or due to other causes such as reflux of intestinal bacteria (which can occur with USEMS or plastic stents). The indications for FCSEMS should be considered carefully in patients who require placement across the intrahepatic bile duct bifurcation.

In two studies, 6-mm CSEMSs were placed across the duodenum papilla in 24 patients and 17 patients.^21,23 A concern in bilateral SEMS placement across the duodenum papilla is the occurrence of acute pancreatitis after SEMS placement. However, acute pancreatitis was not observed in these two studies. Therefore, we presume that the risk of acute pancreatitis is low in patients with 6-mm diameter bilateral CSEMS placement across the duodenum papilla.

Outcomes of the side-by-side method

Previous studies that used the SBS method are summarized in Table 1.^{14,15,17–23} The technical success rate of SBS was 73% to 100%, being higher in simultaneous SBS than sequential SBS. The functional success rate of SBS was 82% to 100%. The incidence rate of RBO was 3% to 47% and the time to RBO was 4.7 to 15.6 months in USEMS. On the other hand, the incidence rate of RBO was 61% to 71% and the time to RBO was 2.6 to 3.2 months in 6-mm CSEMS. The incidence rate of RBO was higher, and the time to RBO was shorter in 6-mm CSEMS than USEMS. The incidence rate of adverse events other than RBO was 3% to 44%. One study revealed a high incidence of cholecystitis (16%), which might have been associated with occlusion of the cystic duct caused by excessive expansion of the biliary duct in the region of overlapping SEMSs²⁰; however, the incidence of cholecystitis ranged from 0% to 3% in other previous studies. Previous studies that examined re-intervention for RBO are shown in Table 2.^{14,16,20,26–29} The success rate of endoscopic re-intervention for SBS was 75% to 100%, and that of endoscopic bilateral re-intervention was 50% to 75%. The success rate of FCSEMS removal for re-intervention was 100% in two studies,^21,24 but that of PCSEMS was 60.0% (6/10) and 66.7% (4/6), respectively.^21,23 The success rate of SEMS removal for re-intervention was higher in 6-mm-diameter FCSEMS than PCSEMS, because tumor ingrowth involving the uncovered part of the partial CSEMS occurred with PCSEM.

The SIS technique involves the following steps. (a) Two guide-wires are inserted into the targeted intrahepatic bile ducts. (b) The first SEMS is inserted into the targeted intrahepatic bile duct along the guidewire and deployed. (c) A new guidewire is inserted into the contralateral bile duct through the mesh of the first deployed SEMS. (d) The second SEMS is inserted into the contralateral bile duct along the new guidewire through the mesh of the first SEMS. (e) The second SEMS is deployed through the mesh of the first SEMS. (f) The two SEMSs are overlapped in the common bile duct (Fig. 4). Endoscopic sphincterotomy (EST) is commonly performed to reduce the risk of post-procedure pancreatitis because we generally need long procedure time for the diagnosis and treatment of malignant hilar biliary obstruction. Theoretically, EST is associated with reflux cholangitis because it causes a permanent reduction in biliary sphincter function. Therefore, EST might increase the incidence of RBO and time to RBO by sludge occlusion or non-occlusion cholangitis. However, there have been no previous studies comparing the outcome with and without EST before this procedure.

Insertion of the guidewire and delivery of the second SEMS through the mesh of the first SEMS are the most challenging steps in SIS. Newly designed SEMSs that are suitable for SIS were developed to overcome these challenges. Lee et al³⁰ reported a high technical success rate (8 out of 10 patients; 80.0%) with the use of these newly designed SEMS with a central wide-open mesh (Bonastent M-Hilar; Standard Sci Tech Inc., Seoul, Korea). In a prospective multicenter study using M-Hilar,³¹ the success rate of a single session of SIS was 81.8% (27/33). The final technical and functional success rates were 94.3% (33/35) and 100% (33/33), respectively. Kogure et al³² reported a high technical success rate (12 out of 12 patients; 100%) of SIS using a Niti-S large cell D-type biliary stent (LCD; Taewoong Corp., Seoul, Korea). In a prospective multicenter study using the LCD,³³ the success rate of a single session of SIS was 96.2% (25/26). The final technical and functional success rates were 100% and 89%, respectively.

Braided type SEMS or laser-cut type SEMS are commonly used in SIS. Kawakubo et al³⁴ reported that the technical success rate was higher when a laser-cut type SEMS with a large mesh and thin delivery system was used, compared to use of a braided type SEMS with a small mesh and thick delivery system, in SIS for UMHBO. Therefore, they concluded that the laser-cut type SEMS with a large mesh and thin delivery system might be preferable for the SIS procedure. Lee et al³⁵ compared the clinical outcomes of SIS between small cell-sized stents (SCS) (Bonastent M-Hilar; cell size 1.6 mm, delivery 7-Fr) and large cell-sized stents (LCS) (Niti-S large-cell D-type biliary stent; 6-mm cell size, delivery 8-Fr). There were no significant differences between the two groups in terms of the technical or functional success rate (SCS vs LCS, 100% vs 100%, respectively), or in the incidence of early adverse events (38.1% vs 18.2%), late adverse events (14.3% vs 22.7%) or stent occlusion (42.9% vs 45.5%). The time to RBO and overall survival were not significantly different between SCS and LCS (P = 0.086 and P = 0.320, respectively). Sugimoto et al³⁶ compared the technical success and failure groups to clarify the factors predictive of SIS failure. They found that the type of the first SEMS (SCS or LCS) was not predictive of SIS failure (P = 0.26), and the area of the first SEMS cell was not significantly different between the technical success and failure groups. Therefore, at the present time, it is difficult to conclude whether the SCS or LCS type of SEMS is superior for SIS.

Several studies have been conducted to identify the risk factors for technical failure of SIS for UMHBO. Kawakubo et al³⁴ revealed that metastatic disease was a significant risk factor for technical failure of SIS (odds ratio, 9.63; 95% confidence interval, 1.11–105.5). Park et al³⁷ reported that the technical success rate was significantly higher in patients without masses obstructing the biliary confluence (MOCs) than patients with MOCs in SIS, using large cell type SEMS (95.2% vs 60.0%; P = 0.03). Furthermore, the incidence of adverse events tended to be higher in patients with MOCs than without (50.0% vs 19.0%; P = 0.11). They concluded that the risk of technical failure increased in patients with MOCs; therefore, caution is needed to prevent adverse events in these patients. Sugimoto et al³⁶ revealed that the angle between the target biliary duct stricture and the first deployed SEMS was significantly larger in the failure group than the success group. There were significantly fewer guidewires or dilation devices (endoscopic retrograde cholangiopancreatography catheter, dilator, or balloon catheter) that passed the first SEMS cell in the failure group than in the success group. They concluded that a large angle was predictive of SIS failure.

Either an 8- or 10-mm diameter SEMS is commonly used for UMHBO. Theoretically, a 10-mm diameter SEMS should result in a longer time to RBO than an 8-mm diameter SEMS. However, the diameter of SEMS may influence the adverse event rate. Naitoh et al²⁸ retrospectively compared clinical outcomes between 8- and 10-mm diameter SEMS in SIS for UMHBO. There were no significant differences between 10- and 8-mm diameter SEMS in terms of technical success (8-mm vs 10-mm group, both 100%), functional success (96% vs 100%), or early (5% vs 9%) and late (19% vs 14%) adverse event rates (other than RBO), respectively. However, the success rate of endoscopic bilateral revisionary stent insertion for RBO after SIS was significantly higher in the 10- than 8-mm diameter SEMS group (68% vs 31%; P = 0.044). They concluded that 10-mm diameter SEMS is more suitable than 8-mm diameter SEMS from the viewpoint of endoscopic re-intervention after SIS.

Outcomes of stent-in-stent method

Previous studies regarding SIS with more than 20 cases are shown in Table 3.^{20,27,31,33,34,37–40} The technical success rate was 82% to 100% and the functional success rate was 77% to 100%. The incidence of RBO was 6% to 42% and the time to RBO was 3.9 to 7.9 months. The incidence rate of adverse events other than RBO was 0% to 29%. The success rate of endoscopic re-intervention for SIS was 60% to 100%, and the success rate of endoscopic bilateral re-intervention was 30% to 83% (Table 2).^{14,16,20,26–29}

There is no consensus on whether SBS or SIS is optimal for bilateral hilar SEMS placement. Three retrospective studies compared the clinical outcomes between SIS and SBS (Table 4).^16,20,41 Naitoh et al²⁰ reported that there were no significant differences between SBS and SIS in terms of technical success (SBS vs SIS, 89% vs 100%), functional success (96% vs 100%), early adverse events (11% vs 4%), late complications (32% vs 8%) or incidence of RBO (20% vs 42%). The incidence of adverse events was significantly higher in SBS than SIS (44% vs 13%; P = 0.016). The adverse events include cholecystitis and cholangitis. We hypothesized that these adverse events were associated with excessive expansion of the biliary duct and portal vein occlusion. In contrast, the time to RBO was significantly better for SBS than SIS (log-rank, P = 0.047). There is controversy regarding whether the incidence of adverse events and time to RBO can be used to determine if SBS or SIS is optimal. Kim et al⁴¹ reported that there were no significant differences between SBS and SIS in terms of functional success (SBS vs SIS, 79% vs 82%), the incidence of early adverse events (32% vs 23%) or the incidence of late adverse events (37% vs 50%). The time to RBO and survival curves did not differ significantly between SBS and SIS (P = 0.771 and P = 0.769). Law and Baron¹⁶ compared SIS and SBS stenting using a Zilver biliary SEMS with a 6-Fr delivery system. They revealed that there were no significant differences with respect to the technical success rate (SBS vs SIS, 81% vs 100%), need for re-intervention (43% vs 53%; P = 0.31), successful re-intervention (75% vs 100%; P = 0.60), or procedure time (63.9 minutes vs 65.5 minutes; P = 0.89). There were no significant differences in clinical outcomes between SBS and SIS according to these three retrospective studies.

We compared the technical success rate, functional success rate, incidence of RBO, time to RBO, incidence of adverse events other than RBO and incidence of re-intervention for RBO between SIS and SBS according to previous studies. The technical success rate was similar between SBS and SIS (SBS, 73%–100%; SIS, 82%–100%), but it might have been higher in simultaneous SBS than SIS. The functional success rate was similar between SBS and SIS (SBS, 82%–100%; SIS, 77%–100%). The incidence of RBO was similar between SBS with USEMS and SIS (SBS, 3%–47%; SIS, 6%–43%), but was higher in SBS with 6-mm diameter CSEMS than SIS. The time to RBO was similar between SBS with USEMS and SIS (SBS, 4.7–15.6 months; SIS, 3.9–7.9 months), but varied widely in SBS with USEMS. The incidence rate of adverse events other than RBO was similar between SBS with USEMS and SIS (SBS, 3%–44%; SIS, 0%–29%), but varied widely in SBS with USEMS. The incidences of cholecystitis were similar between SBS and SIS (SBS, 0%–16%; SIS, 0%–15%), although we presumed it might have been higher in SBS because of excessive expansion of the biliary duct in the region of the overlapping SEMSs. The success rate of endoscopic re-intervention was similar between SBS and SIS (SBS, 75%–100%; SIS, 60%–100%). The success rate of bilateral endoscopic re-intervention was similar between SBS and SIS (SBS, 50%–75%; SIS, 30%–67%). Inoue et al⁴² compared the success rate of revisionary stent insertion after bilateral SEMS placement between initial SEMS using SBS or SIS, but there was no difference between SBS and SIS. According to previous studies, there were no significant differences between SBS and SIS in terms of technical success rate, functional success rate, incidence of RBO, time to RBO, incidence of adverse events other than RBO, and re-intervention for RBO. The outcomes varied widely in the previous studies because the kind and diameter of SEMS, and the devices available for these procedures, were different. Therefore, we cannot conclude whether SBS or SIS is optimal. The development of new devices and techniques for stent deployment, and further randomized controlled trials, are warranted to resolve these issues.

We reviewed the current status of SBS and SIS in endoscopic bilateral SEMS placement for UMHBO. No consensus has been reached on the optimal drainage area (unilateral or bilateral) for UMHBO. Recent developments in devices and techniques have allowed us to conduct endoscopic bilateral SEMS placement, although it is technically challenging. The optimal deployment method (SBS or SIS) for bilateral SEMS placement is debatable. We should be aware of features of SBS and SIS, and the techniques and devices used to conduct each method.

No potential conflict of interest relevant to this article was reported.