Original article
Self-expandable metallic stents vs. plastic stents for endoscopic biliary drainage in hepatocellular carcinoma
Authors
Kwang Hyun Chung1, Sang Hyub Lee1, Jin Myung Park1, 3, Jae Min Lee1, 4, Dong-Won Ahn2, Ji Kon Ryu1, Yong-Tae Kim1
Institutions
Institutions are listed at the end of article.
submitted 23. June 2014 accepted after revision 19. November 2014
Background and study aims: The patency of selfexpandable metallic stents (SEMS) is known to be better than plastic stents in the palliation of malignant biliary obstruction. However, data are scarce for obstructive jaundice caused by hepatocellular carcinoma (HCC). This study aimed to compare SEMSs and plastic stents for the palliation of obstructive jaundice in unresectable HCC. Patients and methods: A total of 96 patients who underwent endoscopic retrograde biliary drainage with SEMSs or plastic stents were included in this retrospective analysis. The rate of successful biliary drainage, adverse events, stent patency duration, and patient survival were compared between the SEMS (n = 36) and plastic stent (n = 60) groups.
Results: The rate of successful biliary drainage was similar between the SEMS and plastic stent groups (25/36 [69.4 %] vs. 39/60 [65.0 %]; P = 0.655). Adverse events occurred in 6 patients (16.7 %) in the SEMS group and 13 patients (21.7 %) in the plastic stent group (P = 0.552). The median patency duration was also similar between the two groups (60 vs. 68 days; P = 0.396). The median patient survival was longer in the plastic stent group than in the SEMS group (123 vs. 48 days; P = 0.005). Conclusions: SEMSs were not superior to plastic stents for the palliation of malignant biliary obstruction in HCC with regard to successful drainage, stent patency, and adverse events. Patient survival was better in the plastic stent group. Given the lower cost, plastic stents could be a favorable option for malignant biliary obstruction caused by HCC.
Introduction
in patients with HCC because of its low hemorrhagic risk and longer duration of patency [10, 11]. The biliary endoprostheses currently used in ERBD fall into two broad categories: plastic (Teflon, polyethylene, or polyurethane) and metallic (stainless steel or nickel-titanium alloy) stents. Self-expandable metallic stents (SEMS) have been shown to be superior to plastic stents with regard to patency and overall cost-effectiveness. Therefore, SEMSs are being used more frequently, especially for patients who are expected to survive for more than 6 months [12 – 15]. However, almost every study comparing plastic stents with SEMSs has been in patients with cholangiocarcinoma or periampullary tumors (e. g. pancreatic cancer). As such, these results cannot be applied to patients with HCC, because HCC has many important characteristics that distinguish it from cholangiocarcinoma or periampullary tumors, including hypervascularity, different bile duct involvement patterns, frequent biliary tumor thrombus and hemobilia, background liver conditions, treatment modality, and prognosis.
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1391304 Published online: 15.1.2015 Endoscopy 2015; 47: 508–516 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0013-726X Corresponding author Sang Hyub Lee, MD, PhD Department of Internal Medicine and Liver Research Institute Seoul National University Hospital Seoul National University College of Medicine 101, Daehak-ro, Jongno-gu 110-744, Seoul Republic of Korea Fax: +82-2-7629662 [email protected]
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Jaundice is present in 5 % – 44 % of patients with hepatocellular carcinoma (HCC) at the time of initial diagnosis, and usually occurs in the later stages of the disease [1 – 4]. However, jaundice related to malignant biliary obstruction is less common than that related to diffuse tumor infiltration of liver parenchyma or progressive terminal liver failure in HCC patients [5, 6]. Despite the fact that obstructive jaundice is infrequent in patients with HCC, distinguishing obstructive jaundice from jaundice due to liver parenchymal insufficiency is clinically important, in that biliary drainage may be beneficial in the former case [7, 8]. Effective biliary decompression can improve the quality of life by reducing the associated pruritus, malaise, and cholangitis, and liver function and survival can also be improved [8, 9]. Endoscopic retrograde biliary drainage (ERBD) rather than percutaneous transhepatic biliary drainage (PTBD) is accepted as the standard procedure for the palliation of obstructive jaundice
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508
The advantages of SEMSs may be diminished in HCC. Therefore, this study aimed to compare the clinical outcomes of SEMSs and plastic stents for ERBD in patients with HCC.
From 2004 to 2006, plastic stents were used most often, whereas both plastic stents and SEMSs were used equally from 2007 to 2009. Most recently (2010 – 2013), SEMSs have been the most commonly used stents.
Patients and methods
Definition of events and study outcome measurements
!
Malignant biliary obstruction was defined by radiological evidence of both focal bile duct stricture and dilatation of the proximal-to-stricture site, as well as elevation of the serum total bilirubin level to more than twice the upper normal value (1.2 mg/dL). The primary outcomes were short-term clinical outcomes, including the rate of successful drainage and procedure-related adverse events, such as post-ERCP pancreatitis, cholangitis, hemorrhage, biloma, or liver abscess. Successful biliary drainage was defined as the placement of the stent across the stricture with appropriate radiographic positioning, immediate biliary decompression, and at least a 30 % reduction of serum bilirubin level within 2 – 4 weeks [8, 18]. Drainage failure was considered when serum bilirubin level was not reduced by 30 % within 2 – 4 weeks, or when clinical signs and symptoms of cholangitis persisted after the procedure. When the cause of unsuccessful drainage was presumed to relate to undrained hepatic segments, an additional drainage procedure was attempted. However, when it was presumed to be related to hepatic parenchymal dysfunction, the additional procedure was not performed. Post-ERCP pancreatitis was diagnosed when two of the following three features were noted: persistent abdominal pain characteristic of acute pancreatitis for more than 24 hours after drainage; increased serum amylase and/or lipase levels to ≥ 3 times the upper limit of normal; and characteristic findings of acute pancreatitis on CT scan [19]. Post-ERCP cholangitis was defined as the presence of abdominal pain, leukocytosis, and fever (temperature ≥ 38oC) without any other infectious focus outside the hepatobiliary system and which required antibiotic treatment within 24 hours after a drainage procedure [20]. Significant bleeding was indicated by a decrease in the serum hemoglobin level of ≥ 2 mg/dL and a requirement for blood transfusion or a hemostatic procedure (including surgery) after the drainage procedure [21]. Procedure-related bowel perforation was defined as the presence of free air on radiography or CT scan of the abdominal cavity after a drainage procedure. The secondary outcomes were stent patency duration and patient survival. Stent dysfunction was diagnosed when a patient developed signs of cholangitis (fever and/or tenderness in the right upper quadrant) or when the total serum bilirubin level increased ≥ 2-fold above the baseline after ERBD, even without symptoms or signs of cholangitis. The stent patency duration was evaluated in those patients who had undergone successful biliary drainage, and the patency duration was calculated as the time between the stent insertion and stent occlusion. The overall survival rate was measured in all enrolled patients from the date of the ERBD procedure until 31 December 2013 or date of death.
Patients Patients who had been diagnosed with HCC at Seoul National University Hospital and who had undergone ERBD with SEMSs or plastic stents for malignant obstructive jaundice between January 2004 and June 2013 were included in this retrospective analysis. Patients with other intrahepatic cancers (e. g. metastatic tumor, cholangiocarcinoma), biliary obstruction due to causes other than HCC (e. g. common bile duct stones, benign stricture), patients who received PTBD prior to ERBD, and patients who underwent ERBD with both SEMSs and plastic stents were excluded. Using medical records, clinical data, including the Child–Pugh class, tumor-node-metastasis (TNM) classification [16], and the endoscopic and radiological findings were reviewed to compare the rate of successful biliary drainage, patency duration, adverse events, and patient survival in the SEMS and plastic stent groups. The type of obstruction was confirmed by direct cholangiography or computed tomography (CT), and was classified as being type 1 (intraluminal obstructions), type 2 (hemobilia), or type 3 (extraluminal obstructions) [3, 17]. The location of obstruction was classified as being extrahepatic, hilar, or intrahepatic. The study populations were followed until 31 December 2013 or patient death. The study was approved by the institutional review board of Seoul National University Hospital.
Procedure and techniques Endoscopic retrograde cholangiopancreatography (ERCP) was performed in order to identify and classify the biliary stricture site. Duodenoscopes (TJF-240, JF-240, TJF-200, and JF-200; Olympus Optical, Tokyo, Japan) were used for ERCP. All patients underwent endoscopic sphincterotomy during the procedure using pull-type sphincterotomes. A guidewire was then passed through the stricture site. In the case of difficult biliary cannulation, a needle-knife precut sphincterotomy was performed to promote biliary cannulation. The stricture length was measured using Tandem RX cannulas (Boston Scientific, Natick, Massachusetts, USA) or Tracer Metro guidewires (Cook Medical; WinstonSalem, North carolina, USA). The stent was placed after confirmation of the guidewire passage through the stricture site. Appropriate placement of the stent across the stricture was confirmed by fluoroscopy. Both plastic stents and SEMSs were placed across the papilla in order to make it easier to perform a secondary procedure in the event of stent occlusion. In the plastic stent group, Percuflex Amsterdam biliary stents (Boston Scientific) or Cotton – Leung (Amsterdam) biliary stents (Cook Medical) were used. The diameter of the plastic stent was 7 Fr or 10 Fr, and the length was 5 – 15 cm. For palliation of malignant biliary obstruction, the 10-Fr stent was preferred generally. A 7 Fr stent was placed when a duodenoscope with small-diameter working channels was used in cases of small body size or altered gastrointestinal anatomy. In the SEMS group, an uncovered Bonastent (Standard Sci-Tech, Seoul, Korea) or Niti-S biliary uncovered stent (Taewoong Medical, Seoul, Korea) was used. The diameter of the SEMS was 10 mm and the stent length was 5 – 10 cm.
Statistical analyses Data are shown as the number (%) for categorical variables, the mean (± SD) for continuous variables, and as median (interquartile range) for stent patency duration and patient survival. To compare the characteristics of the study groups, the chi-squared test or Fisher’s exact test was used for the categorical variables, and Student’s t test was used for the continuous variables, where appropriate. Binary logistic regression analysis was performed to estimate the significance of the association between these vari-
Chung Kwang Hyun et al. Stent comparison for biliary drainage in hepatocellular carcinoma … Endoscopy 2015; 47: 508–516
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Original article
Original article
Table 1
Baseline characteristics of patients with hepatocellular carcinoma who underwent endoscopic biliary drainage.
SEMS (n = 36)
Plastic stent (n = 60)
P value
Male sex, n (%)
28 (77.8)
50 (83.3)
0.500
Age, mean ± SD, years
57.9 ± 8.9
57.7 ± 12.1
Etiology of HCC, n (%) Nonviral
0.924 0.653
6 (16.7)
8 (13.3)
30 (83.3)
52 (86.7)
Type 1
16 (44.4)
32 (53.3)
Type 2
1 (2.8)
Type 3
19 (52.8)
20 (33.3)
Extrahepatic
13 (36.1)
23 (38.3)
Hilar
17 (47.2)
31 (51.7)
0.673
Intrahepatic
11 (30.6)
25 (41.7)
0.276
18.539 ± 9.468
14.983 ± 10.309
Viral Cholangiographic appearance, n (%)
0.077 8 (13.3)
Location of obstruction, n (%)
Total bilirubin, mean ± SD, mg/dL Child–Pugh class, n (%)
0.828
0.095 0.211
A
14 (38.9)
23 (38.3)
B
21 (58.3)
29 (48.3)
C
1 (2.8)
8 (13.3)
Stage I and II
6 (16.7)
18 (30.0)
Stage III
12 (33.3)
22 (36.7)
Stage IV
18 (50.0)
20 (33.3)
TNM stage, n (%)
0.197
Portal vein invasion
21 (58.3)
23 (38.3)
0.057
AFP, mean ± SD, ng/mL
5555.61 ± 19969.70
7499.97 ± 23583.37
0.680
TACE
29 (80.6)
45 (75.0)
0.531
PEIT
7 (19.4)
11 (18.3)
0.893
RFA
6 (16.7)
7 (11.7)
0.488
Systemic chemotherapy
4 (11.1)
7 (11.7)
1.000
Radiotherapy
3 (8.3)
2 (3.3)
0.360
Resection
2 (5.6)
9 (15.0)
0.200
Previous treatment, n (%)
SEMS, self-expandable metallic stents; HCC, hepatocellular carcinoma; TNM, tumor-node-metastasis; AFP, alpha-fetoprotein; TACE, transarterial chemoembolization; PEIT, percutaneous ethanol injection therapy; RFA, radiofrequency ablation.
ables and successful biliary drainage. To compare the patency duration of the stent and the patient survival rate, the Kaplan– Meier method and log-rank test were used. To identify the independent factors associated with these outcomes, a Cox proportional hazard model was used for the multivariate analysis. Twosided P values of < 0.05 were considered to be statistically significant. All analyses were performed using SPSS 21.0 (IBM Corp., Armont, New York, USA).
Results !
Patient characteristics A total 96 patients were enrolled. The baseline characteristics of " Table 1. Among these 96 all eligible patients are presented in ● patients, 36 received SEMSs and 60 received plastic stents. There were no significant differences in the demographic features, location of obstruction, cholangiographic appearance, total bilirubin level, liver function, HCC status (cancer stage, presence of portal vein invasion, and alpha-fetoprotein level), and previous treatment modality between these groups. Hemobilia seemed to be more common in the plastic stent group, and portal vein invasion seemed to be more frequent in the SEMS group, but these differences were not significant.
Primary outcomes The ERBD procedures were technically successful in all patients. Successful biliary drainage was achieved in 25 of 36 patients (69.4 %) in the SEMS group and in 39 of 60 patients (65.0 %) in the plastic stent group (P = 0.655). There was no significant difference in the frequency of procedure-related adverse events be" Table 2). Overall, successful biliary drainage tween the groups (● was achieved in 64 of 96 patients (66.7 %). Univariate analysis showed that the successful biliary drainage rate was significantly higher when the patient was at an earlier TNM stage [16], in a lower Child–Pugh class, had lower serum alpha-fetoprotein concentration, and in the absence of procedure-related adverse events. However, only the Child–Pugh class and procedure-related adverse events were significantly related to successful biliary drainage in the multivariate analysis " Table 3). Subsequently, 53.1 % (34/64) of patients with suc(● cessful biliary drainage and 25.0 % (8/32) of patients with unsuccessful biliary drainage received anticancer treatment.
Secondary outcomes The mean duration of follow-up was 165.6 days (97.4 ± 135.3 days for the SEMS group and 206.5 ± 317.6 days for the plastic stent group). The stent patency duration was evaluated in those patients who had successful biliary drainage. The median stent patency duration in the SEMS and plastic stent groups were not significantly different (68 days [range 34 – 116] vs. 60 days [range
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510
Original article
Table 2
511
Primary and secondary outcomes.
Successful biliary drainage, n (%)
SEMS
Plastic stent
n = 36
n = 60
P value
25/36 (69.4)
39/60 (65.0)
0.655
Total
6/36 (16.7)
13/60 (21.7)
Cholangitis
5 (13.9)
9 (15.0)
0.881
Biloma
0 (0)
1 (1.7)
1.000
Hemobilia
1 (2.8)
1 (1.7)
1.000
Liver abscess
0 (0)
2 (3.3)
0.526
0 (0)
N/A
Procedure-related adverse events, n (%)
Bowel perforation
0 (0)
0.552
Stent patency, median (IQR), days
60 (30 – 75)
68 (34 – 116)
0.396
Patient survival, median (IQR), days
48 (21 – 95)
123 (41 – 290)
0.005
Table 3
Factors related to successful biliary drainage.
Univariate analysis
n
Multivariate analysis
Success
Failure
64
32
P value
Hazard ratio [95 %CI]
P value
Male sex, n (%)
54 (84.4)
24 (75.0)
0.267
0.479 [0.134 – 1.710]
0.257
Age, mean ± SD, years
58.1 ± 11.7
57.0 ± 9.4
0.638
1.012 [0.961 – 1.065]
0.657
Etiology of HCC, n (%)
1.000
Nonviral
9 (64.3)
55 (67.1)
Viral
5 (35.7)
27 (32.9)
SEMS
25 (69.4)
11 (30.6)
Plastic stent
39 (65.0)
21 (35.0)
Stent type, n (%)
0.655
Cholangiographic appearances, n (%)
1.127 [0.375 – 3.391] 0.228
Type 1
29 (45.3)
Type 2
8 (12.5)
1 (3.1)
Type 3
27 (42.2)
12 (37.5)
15.009 ± 9.897
18.931 ± 10.148
Total bilirubin, mean ± SD, mg/dL
0.831 1
19 (59.4)
Child–Pugh Class, n (%)
0.073 0.010
0.049
A
25 (39.1)
12 (37.5)
B
37 (57.8)
13 (40.6)
2.185 [0.723 – 6.603]
C
2 (3.1)
7 (21.9)
0.187 [0.024 – 1.489]
Stage I and II
22 (34.4)
2 (6.3)
Stage III
19 (29.7)
15 (46.9)
Stage IV
23 (35.9)
15 (46.9)
Portal vein invasion, n (%)
25 (39.1)
19 (59.4)
AFP, mean ± SD, ng/dL
1865.8 ± 5793.8
16580.9 ± 35976.2
0.028
1.000 [1.000 – 1.000]
0.149
10 (31.3)
0.046
0.240 [0.071 – 0.816]
0.022
TNM stage, n (%)
1
0.010*
Procedure-related complications, n (%)
9 (14.1)
0.073 1 0.129 [0.022 – 0.747] 0.214 [0.037 – 1.223]
0.060
CI, confidence interval; HCC, hepatocellular carcinoma; SEMS, self-expandable metallic stents; TNM, tumor-node-metastasis; AFP, alpha-fetoprotein.
" Table 2, " Fig. 1). In the multivariate analy30 – 75]; P = 0.396) (● ● sis, the only factor significantly related to longer patency was the " Table 4). presence of anticancer treatment (● Of the 35 patients with stent occlusion in the plastic stent group, 17 underwent a secondary ERBD procedure (mostly stent exchange, 15/17), 6 underwent PTBD, and 12 received no further drainage procedures. Of the 17 patients with stent occlusion in the SEMS group, 3 underwent a secondary ERBD procedure (1 stent exchange, 2 additional plastic stents placed within the existing SEMS), 2 underwent PTBD, and 12 patients received no fur" Fig. e2, available online). After ther drainage procedures (see ● biliary occlusion, a secondary drainage procedure was attempted in 23 of 35 patients (65.7 %) in the plastic stent group and 5 of 17 patients (29.4 %) in the SEMS group.
The median overall survival of patients was significantly longer in the plastic stent group than in the SEMS group (123 vs. 48 days; " Fig. 3). The factors significantly related to longer paP = 0.005) (● tient survival were the use of plastic stents, lower total bilirubin level (< 15 mg/dL), higher Child–Pugh class, earlier TNM stage, absence of portal vein invasion, successful biliary drainage, and subsequent anticancer treatment. With regard to the type of biliary obstruction, patients with hemobilia survived longest followed by those with extraluminal biliary obstruction. Patients with intraluminal biliary obstruction had the shortest median survival, although the difference was not significant. However, in multivariate analysis, the factors that related significantly to longer survival were the use of plastic stents, lower total bilirubin level, earlier TNM stage, absence of portal vein invasion, suc-
Chung Kwang Hyun et al. Stent comparison for biliary drainage in hepatocellular carcinoma … Endoscopy 2015; 47: 508–516
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SEMS, self-expandable metallic stents; N/A, not available; IQR, interquartile range.
Original article
mal insufficiency. In such cases, no further drainage procedure was performed.
Stent patency 100
80
60
40
20
0 0
60
120
180
240
300
360
420
420
Time after biliary drainage (days) Plastic stent No. at risk 39 Patency SEMS No. at risk Patency
19
8
6
6
6
2
2
100% 50% 24.8% 18.6 % 18.6 % 18.6% 6.2% 6.2%
25
8
2
1
1
100% 46.1% 15.8% 7.9% 7.9%
1
1
7.9% 7.9%
0 0%
0
0
0%
0%
Fig. 1 Kaplan–Meier estimation of patency duration for self-expandable metallic stents (SEMS) and plastic stents. There was no significant difference between the two stent types (P = 0.396).
cessful biliary drainage, and subsequent anticancer treatment " Table 5). (●
Clinical courses of patients The mean length of hospital stay was 18.0 days (13.8 ± 11.8 days in the SEMS group and 20.5 ± 27.7 days in the plastic stent group). Subsequent anticancer treatment (e. g. transarterial chemoembolization or systemic chemotherapy) was performed in 51.7 % (31/60) of the plastic stent group and 30.6 % (11/36) of the SEMS group. Of the 21 patients with plastic stents in whom biliary drainage failed, 9 underwent an additional ERBD procedure (7 plastic stents and 2 SEMSs), 4 underwent PTBD, and 8 received no further drainage procedures. Of the 11 patients with failed biliary drainage in the SEMS group, one underwent an additional ERBD procedure with a plastic stent, one received endobiliary thrombus removal with stone retrieval basket, and 9 patients received no further drainage procedures. Of the 15 patients who underwent a secondary drainage procedure, 8 achieved successful biliary drainage (4 with additional ERBD with a plastic stent, 2 with PTBD, and 1 with SEMS). In the one patient who initially underwent ERBD using an SEMS, successful biliary drainage was achieved following two further ERBD procedures using plastic stents. For patients whose cholestasis was not improved despite patent and proper positioning of the stent, the presumed reason for the cholestasis was not a bile duct obstruction but hepatic parenchy-
Discussion !
SEMSs remain patent for longer than plastic stents in the case of ERBD in patients with cholangiocarcinoma and periampullary tumors [14, 22,23]. However, these results cannot be assumed to be the same for HCC, because HCCs are different from cholangiocarcinoma and periampullary tumors in terms of their hypervascular nature and mode of biliary obstruction. Furthermore, HCCs have a different tumor biology, and are commonly associated with liver cirrhosis and coagulopathies [7]. This study compared the efficacy of ERBD with SEMSs and plastic stents for the palliation of obstructive jaundice in patients with unresectable HCC. The rate of successful biliary drainage and the stent patency were not statistically different between the two stent types. The survival rate was significantly longer in the plastic stent group than in the SEMS group when patients with HCC underwent ERBD. The fact that the rates of successful biliary drainage and stent patency duration were not statistically significantly different between the two stents does not mean that they were similar. However, the given point estimation values of the study (difference of 4.5 % in successful biliary drainage rate and 6 days in median patency duration) may not be clinically significant either. Therefore, we consider that the nonsignificant results in rate of successful biliary drainage and stent patency duration may also be meaningful. One of the main causes of stent dysfunction in SEMSs is tumor ingrowth through the metal mesh. In plastic stents, bacterial colonization, biofilm, and sludge deposition are the main causes of stent dysfunction [24]. The use of a larger stent caliber has been suggested to be advantageous for prolonging stent patency, and has been suggested as the most important factor influencing the stent patency difference between SEMS and plastic stents. However, unlike cholangiocarcinoma or periampullary tumors, HCC generally obstructs the biliary tree not by the direct invasion of the bile duct but by extrinsic compressions, tumor thrombosis, and hemobilia [10]. Stent occlusion is also frequently caused by hemobilia or tumor thrombus. In such cases, using a larger stent caliber will have no major significance. Indeed, in the current study, both groups showed relatively short median stent patency duration (68 vs. 60 days). Moreover, a number of patients did not undergo secondary drainage procedures after drainage failure or stent occlusions because of worsened liver function and lowered performance status. This suggests that a large proportion of drainage failures and stent dysfunctions in patients with HCC are associated with liver failure. Stent occlusion related to stent clogging or bacterial colonization may be considerably less frequent in HCC, and this may nullify the advantage of SEMSs in terms of their larger stent caliber. Moreover, secondary biliary drainage was not attempted as frequently in patients with SEMSs compared with those with plastic stents, which might reflect worse hepatic function and performance status in the SEMS group than in the plastic stent group at the moment of stent dysfunction. With regard to patient survival, lower total bilirubin level, earlier TNM stage, absence of portal vein invasion, successful biliary drainage, and subsequent anticancer treatment were all related to longer survival. Here, the pre-procedural serum total bilirubin level and the TNM stage may both be related to a less aggressive
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Stent Plastic stent SEMS Cumulative patency rate of stents (%)
512
Original article
Factors related to stent patency duration.
n
Univariate analysis
Multivariate analysis
Median patency, days [95 %CI] Sex
P value
Hazard ratio [95 %CI]
0.279
Male
54
59 [34 – 106]
Female
10
100 [33 – 133]
Age, years
0.156 1 0.550 [0.241 – 1.257]
0.079
< 65
44
57 [36 – 106]
≥ 65
20
71 [32 – 342]
Stent type
0.223 1 0.637 [0.308 – 1.316]
0.396
SEMS
25
60 [30 – 75]
Plastic stent
39
68 [34 – 116]
Cholangiographic appearances
0.602 1 0.831 [0.415 – 1.666]
0.114
0.203
29
71 [34 – 125]
1
Type 2
8
41 [34 – 57]
2.255 [0.875 – 5.808]
Type 3
27
68 [32 – 106]
Type 1
Total bilirubin
0.998 [0.512 – 1.949] 0.565
< 15 mg/dL
37
68 [34 – 125]
≥ 15 mg/dL
27
57 [36 – 106]
25
57 [25 – 109]
Child–Pugh class A
P value
0.820
B
37
71 [34 – 106]
C
2
40 [N/A]
Stage I and II
22
59 [41 – 136]
Stage III
19
68 [35 – 84]
Stage IV
23
58 [25 – 109]
Absent
39
55 [34 – 136]
Present
25
68 [34 – 93]
< 200 ng/dL
37
71 [35 – 125]
≥ 200 ng/dL
27
50 [32 – 84]
TNM stage
0.902
Portal vein invasion
0.206
AFP
0.184
Subsequent anticancer treatment
0.267 1 1.419 [0.765 – 2.631]
0.080
0.037
No
30
41 [31 – 106]
1
Yes
34
75 [52 – 125]
0.494 [0.255 – 0.958]
CI, confidence interval; SEMS, self-expandable metallic stent; N/A, not applicable; TNM, tumor-node-metastasis; AFP, alpha-fetoprotein.
cancer and greater residual liver function, and this may be the reason for their association with longer patient survival, as has been shown in previous studies [16, 25]. Portal vein invasion is also known to be an independent factor related to shorter survival, and this tendency was reproduced in the current study [26]. The beneficial effect of biliary drainage for the survival of HCC patients with obstructive jaundice has already been proven [8, 9, 25], and anticancer treatments including percutaneous ethanol injection therapy, radiofrequency ablation, and transcatheter arterial chemoembolization, also improve patient survival [27 – 30]. Previous studies have reported no significant overall survival differences between SEMSs and plastic stents in patients with periampullary tumors and cholangiocarcinoma [12, 14, 15]. However, in the current study, biliary drainage with plastic stents rather than SEMSs was a significant factor related to longer survival, despite similar patency. This difference in survival could have resulted from the better overall liver function, more favorable biliary obstruction type (e. g. type 2), and cancer stage classification in the plastic stent group. In fact, the SEMS group had more patients at stage IV and with portal vein thrombosis, and fewer patients with type 2 obstruction, although these differences were not statistically significant. However, the tendency toward better survival in the plastic stent group was also significant in
the multivariate analysis. Considering the fact that survival of patients with HCC has improved in recent years, it is very interesting that the SEMS group showed shorter survival despite most of the patients in the SEMS group undergoing biliary drainage in the later period of the study. Plastic stents can be easily removed by an endoscopic procedure, and in the case of stent dysfunction, stent exchange is much easier. In the current study, a greater number of patients in the plastic stent group were able to undergo a secondary biliary drainage procedure compared with patients in the SEMS group, where this often could not be attempted. Another possible reason for fewer patients in the SEMS group undergoing a secondary biliary drainage procedure is that SEMS patients had worse hepatic function or performance status at the time of stent failure; however, it is unclear whether this was due to the metallic stent itself or baseline characteristics of the patients in this group. The fact that more patients in the plastic stent group underwent secondary biliary drainage could have affected the better survival outcome in this group, in that most of these secondary procedures involved the removal of a stent occluded by tumor thrombus or hemobilia, and stent exchange. Moreover, SEMSs have a much larger lumen than plastic stents and, theoretically, SEMSs may be more predisposed to duodenal biliary reflux and ascending
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Table 4
513
Original article
Overall survival 100 Stent Plastic stent SEMS
Fig. 3 Kaplan–Meier estimation of the overall survival in the self-expandable metallic stent (SEMS) and plastic stent groups. The median overall survival of patients was significantly longer in the plastic stent group than in the SEMS group (123 vs. 48 days; P = 0.005).
80
60
40
20
0 0 Plastic stent No. at risk Survival SEMS No. at risk Patency
300
1200 1500 600 900 Time after biliary drainage (days)
1800
60
14
6
3
2
1
1
100%
30.3 %
17.0 %
10.7 %
17.1%
3.6 %
3.6%
36
3
1
0
0
0
0
100%
12.2 %
4.1%
0%
0%
0%
0%
cholangitis than plastic stents. It is possible that more frequent ascending cholangitis in the SEMS group was a factor that affected the worse survival outcome in the SEMS group. The mean length of hospital stay was quite long compared with a previous study conducted at our institution, which compared the efficacy of metallic stents and plastic stents for malignant biliary obstruction [23]. We speculate that the higher prevalence of hepatic dysfunction and higher rate of biliary drainage failure in HCC patients compared with patients with cholangiocarcinoma or periampullary tumors might have contributed to the longer hospital stay in the current study. The patients in whom biliary drainage failed tended to stay longer in hospital than patients in whom biliary drainage was successful (25.91 vs. 13.98 days). Moreover, in patients with successful biliary drainage, those with worse hepatic function stayed longer in hospital (Child– Pugh class A: 9.92 vs. Child–Pugh class B and C: 16.59 days). The limitations of the current study are that that it was conducted retrospectively, with a relatively small number of patients. It is possible that the differences in adverse events and median patency duration between the two groups were not detected because of the small sample size of the study. Stent selection was not randomized, and therefore the selection of stent type could have been influenced by the preference of the attending physician. Possibly the differences in the baseline characteristics of patients may have influenced the success rate of biliary drainage or the patency, although the baseline characteristics of both groups were not significantly different. This study is significant for several reasons. First, it was performed solely in patients with HCC in order to compare the rela-
2100
tive efficacy of SEMS and plastic stents. There was no significant difference between SEMSs and plastic stents in terms of the drainage success rate, procedure-related adverse events, and patency in patients with malignant biliary obstruction related to HCC. Second, this study indicated which factors were related to successful drainage and better survival in patients with HCC. Although the plastic stent was not superior in terms of patency, the use of this type of stent was a significant factor related to longer survival. In conclusion, the use of a plastic stent may be a better option for the palliation of malignant biliary occlusion due to unresectable HCC, given its impact on longer patient survival and its lower cost compared with the use of an SEMS. Competing interests: None Institutions 1 Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea 2 Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea 3 Department of Internal Medicine, Kangwon National University School of Medicine, Kangwon National University Hospital, Chuncheon, Republic of Korea. 4 Department of Internal Medicine, Myongji Hospital, Goyang, Republic of Korea
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Cumulative survival (%)
514
Original article
Table 5
515
Factors related to patient survival.
Univariate analysis
Multivariate analysis
n Median survival, days [95 %CI]
Hazard ratio [95 %CI]
0.246
Male
78
78 [33 – 223]
Female
18
46 [28 – 247]
Age, years 69
71 [33 – 211]
≥ 65
27
95 [32 – 410]
Stent type
1 1.041 [0.558 – 1.942] 0.769 1 1.097 [0.590 – 2.041] 0.005
SEMS
36
48 [21 – 95]
Plastic stent
60
123 [41 – 290]
Cholangiographic appearances
0.007 1 0.472 [0.274 – 0.814]
0.204 48
66 [31 – 275]
Type 2
9
277 [123 – 832]
Type 3
39
72 [41 – 147]
Total bilirubin
0.221 1 0.409 [0.142 – 1.177] 0.787 [0.466 – 1.329]
0.001
< 15 mg/dL
48
123 [51 – 351]
≥ 15 mg/dL
48
45 [20 – 139]
Child–Pugh class
0.023 1 1.790 [1.083 – 2.958]
0.004
0.295
A
37
95 [52 – 223]
B
50
90 [30 – 257]
0.893 [0.522 – 1.527]
C
9
20 [13 – 45]
1.878 [0.750 – 4.704]
Stage I and II
24
257 [95 – 459]
Stage III
34
46 [20 – 106]
Stage IV
38
52 [33 – 151]
TNM stage
1
0.004
Portal vein invasion
0.027 1 1.171 [0.538 – 2.547] 2.227 [1.076 – 4.611]
< 0.001
Absent
52
141 [45 – 410]
Present
44
48 [20 – 106]
AFP
0.049 1 1.791 [1.003 – 3.198]
0.076
< 200 ng/dL
49
111 [34 – 410]
≥ 200 ng/dL
47
55 [26 – 193]
Drainage
0.201 1 1.413 [0.831 – 2.402]
< 0.001
Fail
32
23 [18 – 48]
Success
64
139 [55 – 351]
Subsequent anticancer treatment
0.008 1 0.460 [0.258 – 0.819]
< 0.001
No
54
34 [20 – 75]
Yes
42
211 [95 – 490]
P value 0.899
0.726
< 65
Type 1
P value
< 0.001 1 0.208 [0.109 – 0.396]
CI, confidence interval; SEMS, self-expandable metallic stent; TNM, tumor-node-metastasis; AFP, alpha-fetoprotein.
Acknowledgment !
We appreciate the statistical advice provided by the Medical Research Collaborating Center at the Seoul National University College of Medicine and the Seoul National University Hospital.
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14 Prat F, Chapat O, Ducot B et al. A randomized trial of endoscopic drainage methods for inoperable malignant strictures of the common bile duct. Gastrointest Endosc 1998; 47: 1 – 7 15 Kaassis M, Boyer J, Dumas R et al. Plastic or metal stents for malignant stricture of the common bile duct? Results of a randomized prospective study Gastrointest Endosc 2003; 57: 178 – 182 16 Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010; 17: 1471 – 1474 17 Lau WY. Management of hepatocellular carcinoma. J Royal Coll Surg Edinburgh 2002; 47: 389 – 399 18 Hong HP, Kim SK, Seo TS. Percutaneous metallic stents in patients with obstructive jaundice due to hepatocellular carcinoma. J Vasc Interv Radiol 2008; 19: 748 – 754 19 Banks PA, Freeman ML. Practice Parameters Committee of the American College of G. Practice guidelines in acute pancreatitis. Am J Gastroenterol 2006; 101: 2379 – 2400 20 Kapral C, Duller C, Wewalka F et al. Case volume and outcome of endoscopic retrograde cholangiopancreatography: results of a nationwide Austrian benchmarking project. Endoscopy 2008; 40: 625 – 630 21 Cote GA, Sherman S. Advances in pancreatobiliary endoscopy. Curr Opin Gastroenterol 2010; 26: 429 – 435 22 Soderlund C, Linder S. Covered metal versus plastic stents for malignant common bile duct stenosis: a prospective, randomized, controlled trial. Gastrointest Endosc 2006; 63: 986 – 995
23 Yoon WJ, Ryu JK, Yang KY et al. A comparison of metal and plastic stents for the relief of jaundice in unresectable malignant biliary obstruction in Korea: an emphasis on cost-effectiveness in a country with a low ERCP cost. Gastrointest Endosc 2009; 70: 284 – 289 24 Levy MJ, Baron TH, Gostout CJ et al. Palliation of malignant extrahepatic biliary obstruction with plastic versus expandable metal stents: an evidence-based approach. Clin Gastroenterol Hepatol 2004; 2: 273 – 285 25 Choi J, Shim JH, Park do H et al. Clinical usefulness of endoscopic palliation in patients with biliary obstruction caused by hepatocellular carcinoma. Digestion 2013; 88: 87 – 94 26 Cabibbo G, Enea M, Attanasio M et al. A meta-analysis of survival rates of untreated patients in randomized clinical trials of hepatocellular carcinoma. Hepatology 2010; 51: 1274 – 1283 27 Shiina S, Teratani T, Obi S et al. A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology 2005; 129: 122 – 130 28 Lin SM, Lin CJ, Lin CC et al. Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma < or = 4 cm Gastroenterology 2004; 127: 1714 – 1723 29 Livraghi T, Giorgio A, Marin G et al. Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection. Radiology 1995; 197: 101 – 108 30 Bruix J, Sala M, Llovet JM. Chemoembolization for hepatocellular carcinoma. Gastroenterology 2004; 127: 179 – 188
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Self-expandable metallic stents vs. plastic stents for endoscopic biliary drainage in hepatocellular carcinoma
Authors
Kwang Hyun Chung1, Sang Hyub Lee1, Jin Myung Park1, 3, Jae Min Lee1, 4, Dong-Won Ahn2, Ji Kon Ryu1, Yong-Tae Kim1
Institutions
Institutions are listed at the end of article.
submitted 23. June 2014 accepted after revision 19. November 2014
Background and study aims: The patency of selfexpandable metallic stents (SEMS) is known to be better than plastic stents in the palliation of malignant biliary obstruction. However, data are scarce for obstructive jaundice caused by hepatocellular carcinoma (HCC). This study aimed to compare SEMSs and plastic stents for the palliation of obstructive jaundice in unresectable HCC. Patients and methods: A total of 96 patients who underwent endoscopic retrograde biliary drainage with SEMSs or plastic stents were included in this retrospective analysis. The rate of successful biliary drainage, adverse events, stent patency duration, and patient survival were compared between the SEMS (n = 36) and plastic stent (n = 60) groups.
Results: The rate of successful biliary drainage was similar between the SEMS and plastic stent groups (25/36 [69.4 %] vs. 39/60 [65.0 %]; P = 0.655). Adverse events occurred in 6 patients (16.7 %) in the SEMS group and 13 patients (21.7 %) in the plastic stent group (P = 0.552). The median patency duration was also similar between the two groups (60 vs. 68 days; P = 0.396). The median patient survival was longer in the plastic stent group than in the SEMS group (123 vs. 48 days; P = 0.005). Conclusions: SEMSs were not superior to plastic stents for the palliation of malignant biliary obstruction in HCC with regard to successful drainage, stent patency, and adverse events. Patient survival was better in the plastic stent group. Given the lower cost, plastic stents could be a favorable option for malignant biliary obstruction caused by HCC.
Introduction
in patients with HCC because of its low hemorrhagic risk and longer duration of patency [10, 11]. The biliary endoprostheses currently used in ERBD fall into two broad categories: plastic (Teflon, polyethylene, or polyurethane) and metallic (stainless steel or nickel-titanium alloy) stents. Self-expandable metallic stents (SEMS) have been shown to be superior to plastic stents with regard to patency and overall cost-effectiveness. Therefore, SEMSs are being used more frequently, especially for patients who are expected to survive for more than 6 months [12 – 15]. However, almost every study comparing plastic stents with SEMSs has been in patients with cholangiocarcinoma or periampullary tumors (e. g. pancreatic cancer). As such, these results cannot be applied to patients with HCC, because HCC has many important characteristics that distinguish it from cholangiocarcinoma or periampullary tumors, including hypervascularity, different bile duct involvement patterns, frequent biliary tumor thrombus and hemobilia, background liver conditions, treatment modality, and prognosis.
Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1391304 Published online: 15.1.2015 Endoscopy 2015; 47: 508–516 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0013-726X Corresponding author Sang Hyub Lee, MD, PhD Department of Internal Medicine and Liver Research Institute Seoul National University Hospital Seoul National University College of Medicine 101, Daehak-ro, Jongno-gu 110-744, Seoul Republic of Korea Fax: +82-2-7629662 [email protected]
!
Jaundice is present in 5 % – 44 % of patients with hepatocellular carcinoma (HCC) at the time of initial diagnosis, and usually occurs in the later stages of the disease [1 – 4]. However, jaundice related to malignant biliary obstruction is less common than that related to diffuse tumor infiltration of liver parenchyma or progressive terminal liver failure in HCC patients [5, 6]. Despite the fact that obstructive jaundice is infrequent in patients with HCC, distinguishing obstructive jaundice from jaundice due to liver parenchymal insufficiency is clinically important, in that biliary drainage may be beneficial in the former case [7, 8]. Effective biliary decompression can improve the quality of life by reducing the associated pruritus, malaise, and cholangitis, and liver function and survival can also be improved [8, 9]. Endoscopic retrograde biliary drainage (ERBD) rather than percutaneous transhepatic biliary drainage (PTBD) is accepted as the standard procedure for the palliation of obstructive jaundice
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508
The advantages of SEMSs may be diminished in HCC. Therefore, this study aimed to compare the clinical outcomes of SEMSs and plastic stents for ERBD in patients with HCC.
From 2004 to 2006, plastic stents were used most often, whereas both plastic stents and SEMSs were used equally from 2007 to 2009. Most recently (2010 – 2013), SEMSs have been the most commonly used stents.
Patients and methods
Definition of events and study outcome measurements
!
Malignant biliary obstruction was defined by radiological evidence of both focal bile duct stricture and dilatation of the proximal-to-stricture site, as well as elevation of the serum total bilirubin level to more than twice the upper normal value (1.2 mg/dL). The primary outcomes were short-term clinical outcomes, including the rate of successful drainage and procedure-related adverse events, such as post-ERCP pancreatitis, cholangitis, hemorrhage, biloma, or liver abscess. Successful biliary drainage was defined as the placement of the stent across the stricture with appropriate radiographic positioning, immediate biliary decompression, and at least a 30 % reduction of serum bilirubin level within 2 – 4 weeks [8, 18]. Drainage failure was considered when serum bilirubin level was not reduced by 30 % within 2 – 4 weeks, or when clinical signs and symptoms of cholangitis persisted after the procedure. When the cause of unsuccessful drainage was presumed to relate to undrained hepatic segments, an additional drainage procedure was attempted. However, when it was presumed to be related to hepatic parenchymal dysfunction, the additional procedure was not performed. Post-ERCP pancreatitis was diagnosed when two of the following three features were noted: persistent abdominal pain characteristic of acute pancreatitis for more than 24 hours after drainage; increased serum amylase and/or lipase levels to ≥ 3 times the upper limit of normal; and characteristic findings of acute pancreatitis on CT scan [19]. Post-ERCP cholangitis was defined as the presence of abdominal pain, leukocytosis, and fever (temperature ≥ 38oC) without any other infectious focus outside the hepatobiliary system and which required antibiotic treatment within 24 hours after a drainage procedure [20]. Significant bleeding was indicated by a decrease in the serum hemoglobin level of ≥ 2 mg/dL and a requirement for blood transfusion or a hemostatic procedure (including surgery) after the drainage procedure [21]. Procedure-related bowel perforation was defined as the presence of free air on radiography or CT scan of the abdominal cavity after a drainage procedure. The secondary outcomes were stent patency duration and patient survival. Stent dysfunction was diagnosed when a patient developed signs of cholangitis (fever and/or tenderness in the right upper quadrant) or when the total serum bilirubin level increased ≥ 2-fold above the baseline after ERBD, even without symptoms or signs of cholangitis. The stent patency duration was evaluated in those patients who had undergone successful biliary drainage, and the patency duration was calculated as the time between the stent insertion and stent occlusion. The overall survival rate was measured in all enrolled patients from the date of the ERBD procedure until 31 December 2013 or date of death.
Patients Patients who had been diagnosed with HCC at Seoul National University Hospital and who had undergone ERBD with SEMSs or plastic stents for malignant obstructive jaundice between January 2004 and June 2013 were included in this retrospective analysis. Patients with other intrahepatic cancers (e. g. metastatic tumor, cholangiocarcinoma), biliary obstruction due to causes other than HCC (e. g. common bile duct stones, benign stricture), patients who received PTBD prior to ERBD, and patients who underwent ERBD with both SEMSs and plastic stents were excluded. Using medical records, clinical data, including the Child–Pugh class, tumor-node-metastasis (TNM) classification [16], and the endoscopic and radiological findings were reviewed to compare the rate of successful biliary drainage, patency duration, adverse events, and patient survival in the SEMS and plastic stent groups. The type of obstruction was confirmed by direct cholangiography or computed tomography (CT), and was classified as being type 1 (intraluminal obstructions), type 2 (hemobilia), or type 3 (extraluminal obstructions) [3, 17]. The location of obstruction was classified as being extrahepatic, hilar, or intrahepatic. The study populations were followed until 31 December 2013 or patient death. The study was approved by the institutional review board of Seoul National University Hospital.
Procedure and techniques Endoscopic retrograde cholangiopancreatography (ERCP) was performed in order to identify and classify the biliary stricture site. Duodenoscopes (TJF-240, JF-240, TJF-200, and JF-200; Olympus Optical, Tokyo, Japan) were used for ERCP. All patients underwent endoscopic sphincterotomy during the procedure using pull-type sphincterotomes. A guidewire was then passed through the stricture site. In the case of difficult biliary cannulation, a needle-knife precut sphincterotomy was performed to promote biliary cannulation. The stricture length was measured using Tandem RX cannulas (Boston Scientific, Natick, Massachusetts, USA) or Tracer Metro guidewires (Cook Medical; WinstonSalem, North carolina, USA). The stent was placed after confirmation of the guidewire passage through the stricture site. Appropriate placement of the stent across the stricture was confirmed by fluoroscopy. Both plastic stents and SEMSs were placed across the papilla in order to make it easier to perform a secondary procedure in the event of stent occlusion. In the plastic stent group, Percuflex Amsterdam biliary stents (Boston Scientific) or Cotton – Leung (Amsterdam) biliary stents (Cook Medical) were used. The diameter of the plastic stent was 7 Fr or 10 Fr, and the length was 5 – 15 cm. For palliation of malignant biliary obstruction, the 10-Fr stent was preferred generally. A 7 Fr stent was placed when a duodenoscope with small-diameter working channels was used in cases of small body size or altered gastrointestinal anatomy. In the SEMS group, an uncovered Bonastent (Standard Sci-Tech, Seoul, Korea) or Niti-S biliary uncovered stent (Taewoong Medical, Seoul, Korea) was used. The diameter of the SEMS was 10 mm and the stent length was 5 – 10 cm.
Statistical analyses Data are shown as the number (%) for categorical variables, the mean (± SD) for continuous variables, and as median (interquartile range) for stent patency duration and patient survival. To compare the characteristics of the study groups, the chi-squared test or Fisher’s exact test was used for the categorical variables, and Student’s t test was used for the continuous variables, where appropriate. Binary logistic regression analysis was performed to estimate the significance of the association between these vari-
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Original article
Original article
Table 1
Baseline characteristics of patients with hepatocellular carcinoma who underwent endoscopic biliary drainage.
SEMS (n = 36)
Plastic stent (n = 60)
P value
Male sex, n (%)
28 (77.8)
50 (83.3)
0.500
Age, mean ± SD, years
57.9 ± 8.9
57.7 ± 12.1
Etiology of HCC, n (%) Nonviral
0.924 0.653
6 (16.7)
8 (13.3)
30 (83.3)
52 (86.7)
Type 1
16 (44.4)
32 (53.3)
Type 2
1 (2.8)
Type 3
19 (52.8)
20 (33.3)
Extrahepatic
13 (36.1)
23 (38.3)
Hilar
17 (47.2)
31 (51.7)
0.673
Intrahepatic
11 (30.6)
25 (41.7)
0.276
18.539 ± 9.468
14.983 ± 10.309
Viral Cholangiographic appearance, n (%)
0.077 8 (13.3)
Location of obstruction, n (%)
Total bilirubin, mean ± SD, mg/dL Child–Pugh class, n (%)
0.828
0.095 0.211
A
14 (38.9)
23 (38.3)
B
21 (58.3)
29 (48.3)
C
1 (2.8)
8 (13.3)
Stage I and II
6 (16.7)
18 (30.0)
Stage III
12 (33.3)
22 (36.7)
Stage IV
18 (50.0)
20 (33.3)
TNM stage, n (%)
0.197
Portal vein invasion
21 (58.3)
23 (38.3)
0.057
AFP, mean ± SD, ng/mL
5555.61 ± 19969.70
7499.97 ± 23583.37
0.680
TACE
29 (80.6)
45 (75.0)
0.531
PEIT
7 (19.4)
11 (18.3)
0.893
RFA
6 (16.7)
7 (11.7)
0.488
Systemic chemotherapy
4 (11.1)
7 (11.7)
1.000
Radiotherapy
3 (8.3)
2 (3.3)
0.360
Resection
2 (5.6)
9 (15.0)
0.200
Previous treatment, n (%)
SEMS, self-expandable metallic stents; HCC, hepatocellular carcinoma; TNM, tumor-node-metastasis; AFP, alpha-fetoprotein; TACE, transarterial chemoembolization; PEIT, percutaneous ethanol injection therapy; RFA, radiofrequency ablation.
ables and successful biliary drainage. To compare the patency duration of the stent and the patient survival rate, the Kaplan– Meier method and log-rank test were used. To identify the independent factors associated with these outcomes, a Cox proportional hazard model was used for the multivariate analysis. Twosided P values of < 0.05 were considered to be statistically significant. All analyses were performed using SPSS 21.0 (IBM Corp., Armont, New York, USA).
Results !
Patient characteristics A total 96 patients were enrolled. The baseline characteristics of " Table 1. Among these 96 all eligible patients are presented in ● patients, 36 received SEMSs and 60 received plastic stents. There were no significant differences in the demographic features, location of obstruction, cholangiographic appearance, total bilirubin level, liver function, HCC status (cancer stage, presence of portal vein invasion, and alpha-fetoprotein level), and previous treatment modality between these groups. Hemobilia seemed to be more common in the plastic stent group, and portal vein invasion seemed to be more frequent in the SEMS group, but these differences were not significant.
Primary outcomes The ERBD procedures were technically successful in all patients. Successful biliary drainage was achieved in 25 of 36 patients (69.4 %) in the SEMS group and in 39 of 60 patients (65.0 %) in the plastic stent group (P = 0.655). There was no significant difference in the frequency of procedure-related adverse events be" Table 2). Overall, successful biliary drainage tween the groups (● was achieved in 64 of 96 patients (66.7 %). Univariate analysis showed that the successful biliary drainage rate was significantly higher when the patient was at an earlier TNM stage [16], in a lower Child–Pugh class, had lower serum alpha-fetoprotein concentration, and in the absence of procedure-related adverse events. However, only the Child–Pugh class and procedure-related adverse events were significantly related to successful biliary drainage in the multivariate analysis " Table 3). Subsequently, 53.1 % (34/64) of patients with suc(● cessful biliary drainage and 25.0 % (8/32) of patients with unsuccessful biliary drainage received anticancer treatment.
Secondary outcomes The mean duration of follow-up was 165.6 days (97.4 ± 135.3 days for the SEMS group and 206.5 ± 317.6 days for the plastic stent group). The stent patency duration was evaluated in those patients who had successful biliary drainage. The median stent patency duration in the SEMS and plastic stent groups were not significantly different (68 days [range 34 – 116] vs. 60 days [range
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510
Original article
Table 2
511
Primary and secondary outcomes.
Successful biliary drainage, n (%)
SEMS
Plastic stent
n = 36
n = 60
P value
25/36 (69.4)
39/60 (65.0)
0.655
Total
6/36 (16.7)
13/60 (21.7)
Cholangitis
5 (13.9)
9 (15.0)
0.881
Biloma
0 (0)
1 (1.7)
1.000
Hemobilia
1 (2.8)
1 (1.7)
1.000
Liver abscess
0 (0)
2 (3.3)
0.526
0 (0)
N/A
Procedure-related adverse events, n (%)
Bowel perforation
0 (0)
0.552
Stent patency, median (IQR), days
60 (30 – 75)
68 (34 – 116)
0.396
Patient survival, median (IQR), days
48 (21 – 95)
123 (41 – 290)
0.005
Table 3
Factors related to successful biliary drainage.
Univariate analysis
n
Multivariate analysis
Success
Failure
64
32
P value
Hazard ratio [95 %CI]
P value
Male sex, n (%)
54 (84.4)
24 (75.0)
0.267
0.479 [0.134 – 1.710]
0.257
Age, mean ± SD, years
58.1 ± 11.7
57.0 ± 9.4
0.638
1.012 [0.961 – 1.065]
0.657
Etiology of HCC, n (%)
1.000
Nonviral
9 (64.3)
55 (67.1)
Viral
5 (35.7)
27 (32.9)
SEMS
25 (69.4)
11 (30.6)
Plastic stent
39 (65.0)
21 (35.0)
Stent type, n (%)
0.655
Cholangiographic appearances, n (%)
1.127 [0.375 – 3.391] 0.228
Type 1
29 (45.3)
Type 2
8 (12.5)
1 (3.1)
Type 3
27 (42.2)
12 (37.5)
15.009 ± 9.897
18.931 ± 10.148
Total bilirubin, mean ± SD, mg/dL
0.831 1
19 (59.4)
Child–Pugh Class, n (%)
0.073 0.010
0.049
A
25 (39.1)
12 (37.5)
B
37 (57.8)
13 (40.6)
2.185 [0.723 – 6.603]
C
2 (3.1)
7 (21.9)
0.187 [0.024 – 1.489]
Stage I and II
22 (34.4)
2 (6.3)
Stage III
19 (29.7)
15 (46.9)
Stage IV
23 (35.9)
15 (46.9)
Portal vein invasion, n (%)
25 (39.1)
19 (59.4)
AFP, mean ± SD, ng/dL
1865.8 ± 5793.8
16580.9 ± 35976.2
0.028
1.000 [1.000 – 1.000]
0.149
10 (31.3)
0.046
0.240 [0.071 – 0.816]
0.022
TNM stage, n (%)
1
0.010*
Procedure-related complications, n (%)
9 (14.1)
0.073 1 0.129 [0.022 – 0.747] 0.214 [0.037 – 1.223]
0.060
CI, confidence interval; HCC, hepatocellular carcinoma; SEMS, self-expandable metallic stents; TNM, tumor-node-metastasis; AFP, alpha-fetoprotein.
" Table 2, " Fig. 1). In the multivariate analy30 – 75]; P = 0.396) (● ● sis, the only factor significantly related to longer patency was the " Table 4). presence of anticancer treatment (● Of the 35 patients with stent occlusion in the plastic stent group, 17 underwent a secondary ERBD procedure (mostly stent exchange, 15/17), 6 underwent PTBD, and 12 received no further drainage procedures. Of the 17 patients with stent occlusion in the SEMS group, 3 underwent a secondary ERBD procedure (1 stent exchange, 2 additional plastic stents placed within the existing SEMS), 2 underwent PTBD, and 12 patients received no fur" Fig. e2, available online). After ther drainage procedures (see ● biliary occlusion, a secondary drainage procedure was attempted in 23 of 35 patients (65.7 %) in the plastic stent group and 5 of 17 patients (29.4 %) in the SEMS group.
The median overall survival of patients was significantly longer in the plastic stent group than in the SEMS group (123 vs. 48 days; " Fig. 3). The factors significantly related to longer paP = 0.005) (● tient survival were the use of plastic stents, lower total bilirubin level (< 15 mg/dL), higher Child–Pugh class, earlier TNM stage, absence of portal vein invasion, successful biliary drainage, and subsequent anticancer treatment. With regard to the type of biliary obstruction, patients with hemobilia survived longest followed by those with extraluminal biliary obstruction. Patients with intraluminal biliary obstruction had the shortest median survival, although the difference was not significant. However, in multivariate analysis, the factors that related significantly to longer survival were the use of plastic stents, lower total bilirubin level, earlier TNM stage, absence of portal vein invasion, suc-
Chung Kwang Hyun et al. Stent comparison for biliary drainage in hepatocellular carcinoma … Endoscopy 2015; 47: 508–516
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SEMS, self-expandable metallic stents; N/A, not available; IQR, interquartile range.
Original article
mal insufficiency. In such cases, no further drainage procedure was performed.
Stent patency 100
80
60
40
20
0 0
60
120
180
240
300
360
420
420
Time after biliary drainage (days) Plastic stent No. at risk 39 Patency SEMS No. at risk Patency
19
8
6
6
6
2
2
100% 50% 24.8% 18.6 % 18.6 % 18.6% 6.2% 6.2%
25
8
2
1
1
100% 46.1% 15.8% 7.9% 7.9%
1
1
7.9% 7.9%
0 0%
0
0
0%
0%
Fig. 1 Kaplan–Meier estimation of patency duration for self-expandable metallic stents (SEMS) and plastic stents. There was no significant difference between the two stent types (P = 0.396).
cessful biliary drainage, and subsequent anticancer treatment " Table 5). (●
Clinical courses of patients The mean length of hospital stay was 18.0 days (13.8 ± 11.8 days in the SEMS group and 20.5 ± 27.7 days in the plastic stent group). Subsequent anticancer treatment (e. g. transarterial chemoembolization or systemic chemotherapy) was performed in 51.7 % (31/60) of the plastic stent group and 30.6 % (11/36) of the SEMS group. Of the 21 patients with plastic stents in whom biliary drainage failed, 9 underwent an additional ERBD procedure (7 plastic stents and 2 SEMSs), 4 underwent PTBD, and 8 received no further drainage procedures. Of the 11 patients with failed biliary drainage in the SEMS group, one underwent an additional ERBD procedure with a plastic stent, one received endobiliary thrombus removal with stone retrieval basket, and 9 patients received no further drainage procedures. Of the 15 patients who underwent a secondary drainage procedure, 8 achieved successful biliary drainage (4 with additional ERBD with a plastic stent, 2 with PTBD, and 1 with SEMS). In the one patient who initially underwent ERBD using an SEMS, successful biliary drainage was achieved following two further ERBD procedures using plastic stents. For patients whose cholestasis was not improved despite patent and proper positioning of the stent, the presumed reason for the cholestasis was not a bile duct obstruction but hepatic parenchy-
Discussion !
SEMSs remain patent for longer than plastic stents in the case of ERBD in patients with cholangiocarcinoma and periampullary tumors [14, 22,23]. However, these results cannot be assumed to be the same for HCC, because HCCs are different from cholangiocarcinoma and periampullary tumors in terms of their hypervascular nature and mode of biliary obstruction. Furthermore, HCCs have a different tumor biology, and are commonly associated with liver cirrhosis and coagulopathies [7]. This study compared the efficacy of ERBD with SEMSs and plastic stents for the palliation of obstructive jaundice in patients with unresectable HCC. The rate of successful biliary drainage and the stent patency were not statistically different between the two stent types. The survival rate was significantly longer in the plastic stent group than in the SEMS group when patients with HCC underwent ERBD. The fact that the rates of successful biliary drainage and stent patency duration were not statistically significantly different between the two stents does not mean that they were similar. However, the given point estimation values of the study (difference of 4.5 % in successful biliary drainage rate and 6 days in median patency duration) may not be clinically significant either. Therefore, we consider that the nonsignificant results in rate of successful biliary drainage and stent patency duration may also be meaningful. One of the main causes of stent dysfunction in SEMSs is tumor ingrowth through the metal mesh. In plastic stents, bacterial colonization, biofilm, and sludge deposition are the main causes of stent dysfunction [24]. The use of a larger stent caliber has been suggested to be advantageous for prolonging stent patency, and has been suggested as the most important factor influencing the stent patency difference between SEMS and plastic stents. However, unlike cholangiocarcinoma or periampullary tumors, HCC generally obstructs the biliary tree not by the direct invasion of the bile duct but by extrinsic compressions, tumor thrombosis, and hemobilia [10]. Stent occlusion is also frequently caused by hemobilia or tumor thrombus. In such cases, using a larger stent caliber will have no major significance. Indeed, in the current study, both groups showed relatively short median stent patency duration (68 vs. 60 days). Moreover, a number of patients did not undergo secondary drainage procedures after drainage failure or stent occlusions because of worsened liver function and lowered performance status. This suggests that a large proportion of drainage failures and stent dysfunctions in patients with HCC are associated with liver failure. Stent occlusion related to stent clogging or bacterial colonization may be considerably less frequent in HCC, and this may nullify the advantage of SEMSs in terms of their larger stent caliber. Moreover, secondary biliary drainage was not attempted as frequently in patients with SEMSs compared with those with plastic stents, which might reflect worse hepatic function and performance status in the SEMS group than in the plastic stent group at the moment of stent dysfunction. With regard to patient survival, lower total bilirubin level, earlier TNM stage, absence of portal vein invasion, successful biliary drainage, and subsequent anticancer treatment were all related to longer survival. Here, the pre-procedural serum total bilirubin level and the TNM stage may both be related to a less aggressive
Chung Kwang Hyun et al. Stent comparison for biliary drainage in hepatocellular carcinoma … Endoscopy 2015; 47: 508–516
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Stent Plastic stent SEMS Cumulative patency rate of stents (%)
512
Original article
Factors related to stent patency duration.
n
Univariate analysis
Multivariate analysis
Median patency, days [95 %CI] Sex
P value
Hazard ratio [95 %CI]
0.279
Male
54
59 [34 – 106]
Female
10
100 [33 – 133]
Age, years
0.156 1 0.550 [0.241 – 1.257]
0.079
< 65
44
57 [36 – 106]
≥ 65
20
71 [32 – 342]
Stent type
0.223 1 0.637 [0.308 – 1.316]
0.396
SEMS
25
60 [30 – 75]
Plastic stent
39
68 [34 – 116]
Cholangiographic appearances
0.602 1 0.831 [0.415 – 1.666]
0.114
0.203
29
71 [34 – 125]
1
Type 2
8
41 [34 – 57]
2.255 [0.875 – 5.808]
Type 3
27
68 [32 – 106]
Type 1
Total bilirubin
0.998 [0.512 – 1.949] 0.565
< 15 mg/dL
37
68 [34 – 125]
≥ 15 mg/dL
27
57 [36 – 106]
25
57 [25 – 109]
Child–Pugh class A
P value
0.820
B
37
71 [34 – 106]
C
2
40 [N/A]
Stage I and II
22
59 [41 – 136]
Stage III
19
68 [35 – 84]
Stage IV
23
58 [25 – 109]
Absent
39
55 [34 – 136]
Present
25
68 [34 – 93]
< 200 ng/dL
37
71 [35 – 125]
≥ 200 ng/dL
27
50 [32 – 84]
TNM stage
0.902
Portal vein invasion
0.206
AFP
0.184
Subsequent anticancer treatment
0.267 1 1.419 [0.765 – 2.631]
0.080
0.037
No
30
41 [31 – 106]
1
Yes
34
75 [52 – 125]
0.494 [0.255 – 0.958]
CI, confidence interval; SEMS, self-expandable metallic stent; N/A, not applicable; TNM, tumor-node-metastasis; AFP, alpha-fetoprotein.
cancer and greater residual liver function, and this may be the reason for their association with longer patient survival, as has been shown in previous studies [16, 25]. Portal vein invasion is also known to be an independent factor related to shorter survival, and this tendency was reproduced in the current study [26]. The beneficial effect of biliary drainage for the survival of HCC patients with obstructive jaundice has already been proven [8, 9, 25], and anticancer treatments including percutaneous ethanol injection therapy, radiofrequency ablation, and transcatheter arterial chemoembolization, also improve patient survival [27 – 30]. Previous studies have reported no significant overall survival differences between SEMSs and plastic stents in patients with periampullary tumors and cholangiocarcinoma [12, 14, 15]. However, in the current study, biliary drainage with plastic stents rather than SEMSs was a significant factor related to longer survival, despite similar patency. This difference in survival could have resulted from the better overall liver function, more favorable biliary obstruction type (e. g. type 2), and cancer stage classification in the plastic stent group. In fact, the SEMS group had more patients at stage IV and with portal vein thrombosis, and fewer patients with type 2 obstruction, although these differences were not statistically significant. However, the tendency toward better survival in the plastic stent group was also significant in
the multivariate analysis. Considering the fact that survival of patients with HCC has improved in recent years, it is very interesting that the SEMS group showed shorter survival despite most of the patients in the SEMS group undergoing biliary drainage in the later period of the study. Plastic stents can be easily removed by an endoscopic procedure, and in the case of stent dysfunction, stent exchange is much easier. In the current study, a greater number of patients in the plastic stent group were able to undergo a secondary biliary drainage procedure compared with patients in the SEMS group, where this often could not be attempted. Another possible reason for fewer patients in the SEMS group undergoing a secondary biliary drainage procedure is that SEMS patients had worse hepatic function or performance status at the time of stent failure; however, it is unclear whether this was due to the metallic stent itself or baseline characteristics of the patients in this group. The fact that more patients in the plastic stent group underwent secondary biliary drainage could have affected the better survival outcome in this group, in that most of these secondary procedures involved the removal of a stent occluded by tumor thrombus or hemobilia, and stent exchange. Moreover, SEMSs have a much larger lumen than plastic stents and, theoretically, SEMSs may be more predisposed to duodenal biliary reflux and ascending
Chung Kwang Hyun et al. Stent comparison for biliary drainage in hepatocellular carcinoma … Endoscopy 2015; 47: 508–516
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Table 4
513
Original article
Overall survival 100 Stent Plastic stent SEMS
Fig. 3 Kaplan–Meier estimation of the overall survival in the self-expandable metallic stent (SEMS) and plastic stent groups. The median overall survival of patients was significantly longer in the plastic stent group than in the SEMS group (123 vs. 48 days; P = 0.005).
80
60
40
20
0 0 Plastic stent No. at risk Survival SEMS No. at risk Patency
300
1200 1500 600 900 Time after biliary drainage (days)
1800
60
14
6
3
2
1
1
100%
30.3 %
17.0 %
10.7 %
17.1%
3.6 %
3.6%
36
3
1
0
0
0
0
100%
12.2 %
4.1%
0%
0%
0%
0%
cholangitis than plastic stents. It is possible that more frequent ascending cholangitis in the SEMS group was a factor that affected the worse survival outcome in the SEMS group. The mean length of hospital stay was quite long compared with a previous study conducted at our institution, which compared the efficacy of metallic stents and plastic stents for malignant biliary obstruction [23]. We speculate that the higher prevalence of hepatic dysfunction and higher rate of biliary drainage failure in HCC patients compared with patients with cholangiocarcinoma or periampullary tumors might have contributed to the longer hospital stay in the current study. The patients in whom biliary drainage failed tended to stay longer in hospital than patients in whom biliary drainage was successful (25.91 vs. 13.98 days). Moreover, in patients with successful biliary drainage, those with worse hepatic function stayed longer in hospital (Child– Pugh class A: 9.92 vs. Child–Pugh class B and C: 16.59 days). The limitations of the current study are that that it was conducted retrospectively, with a relatively small number of patients. It is possible that the differences in adverse events and median patency duration between the two groups were not detected because of the small sample size of the study. Stent selection was not randomized, and therefore the selection of stent type could have been influenced by the preference of the attending physician. Possibly the differences in the baseline characteristics of patients may have influenced the success rate of biliary drainage or the patency, although the baseline characteristics of both groups were not significantly different. This study is significant for several reasons. First, it was performed solely in patients with HCC in order to compare the rela-
2100
tive efficacy of SEMS and plastic stents. There was no significant difference between SEMSs and plastic stents in terms of the drainage success rate, procedure-related adverse events, and patency in patients with malignant biliary obstruction related to HCC. Second, this study indicated which factors were related to successful drainage and better survival in patients with HCC. Although the plastic stent was not superior in terms of patency, the use of this type of stent was a significant factor related to longer survival. In conclusion, the use of a plastic stent may be a better option for the palliation of malignant biliary occlusion due to unresectable HCC, given its impact on longer patient survival and its lower cost compared with the use of an SEMS. Competing interests: None Institutions 1 Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea 2 Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea 3 Department of Internal Medicine, Kangwon National University School of Medicine, Kangwon National University Hospital, Chuncheon, Republic of Korea. 4 Department of Internal Medicine, Myongji Hospital, Goyang, Republic of Korea
Chung Kwang Hyun et al. Stent comparison for biliary drainage in hepatocellular carcinoma … Endoscopy 2015; 47: 508–516
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Cumulative survival (%)
514
Original article
Table 5
515
Factors related to patient survival.
Univariate analysis
Multivariate analysis
n Median survival, days [95 %CI]
Hazard ratio [95 %CI]
0.246
Male
78
78 [33 – 223]
Female
18
46 [28 – 247]
Age, years 69
71 [33 – 211]
≥ 65
27
95 [32 – 410]
Stent type
1 1.041 [0.558 – 1.942] 0.769 1 1.097 [0.590 – 2.041] 0.005
SEMS
36
48 [21 – 95]
Plastic stent
60
123 [41 – 290]
Cholangiographic appearances
0.007 1 0.472 [0.274 – 0.814]
0.204 48
66 [31 – 275]
Type 2
9
277 [123 – 832]
Type 3
39
72 [41 – 147]
Total bilirubin
0.221 1 0.409 [0.142 – 1.177] 0.787 [0.466 – 1.329]
0.001
< 15 mg/dL
48
123 [51 – 351]
≥ 15 mg/dL
48
45 [20 – 139]
Child–Pugh class
0.023 1 1.790 [1.083 – 2.958]
0.004
0.295
A
37
95 [52 – 223]
B
50
90 [30 – 257]
0.893 [0.522 – 1.527]
C
9
20 [13 – 45]
1.878 [0.750 – 4.704]
Stage I and II
24
257 [95 – 459]
Stage III
34
46 [20 – 106]
Stage IV
38
52 [33 – 151]
TNM stage
1
0.004
Portal vein invasion
0.027 1 1.171 [0.538 – 2.547] 2.227 [1.076 – 4.611]
< 0.001
Absent
52
141 [45 – 410]
Present
44
48 [20 – 106]
AFP
0.049 1 1.791 [1.003 – 3.198]
0.076
< 200 ng/dL
49
111 [34 – 410]
≥ 200 ng/dL
47
55 [26 – 193]
Drainage
0.201 1 1.413 [0.831 – 2.402]
< 0.001
Fail
32
23 [18 – 48]
Success
64
139 [55 – 351]
Subsequent anticancer treatment
0.008 1 0.460 [0.258 – 0.819]
< 0.001
No
54
34 [20 – 75]
Yes
42
211 [95 – 490]
P value 0.899
0.726
< 65
Type 1
P value
< 0.001 1 0.208 [0.109 – 0.396]
CI, confidence interval; SEMS, self-expandable metallic stent; TNM, tumor-node-metastasis; AFP, alpha-fetoprotein.
Acknowledgment !
We appreciate the statistical advice provided by the Medical Research Collaborating Center at the Seoul National University College of Medicine and the Seoul National University Hospital.
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