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Success, complication, and mortality rates of initial biliary drainage in patients with unresectable perihilar cholangiocarcinoma

Open AccessPublished:August 18, 2022DOI:https://doi.org/10.1016/j.surg.2022.06.028

      Abstract

      Background

      The patients with unresectable perihilar cholangiocarcinoma require biliary drainage to relieve symptoms and allow for palliative systemic chemotherapy. The aim of this study was to establish the success, complication, and mortality rates of the initial biliary drainage in patients with unresectable perihilar cholangiocarcinoma at presentation.

      Methods

      In this retrospective multicenter study, patients with unresectable perihilar cholangiocarcinoma who underwent initial endoscopic or percutaneous transhepatic biliary drainage between 2002 and 2014 were included. The success of drainage was defined as a successful biliary stent or drain placement, no unscheduled reintervention within 14 days, and serum bilirubin levels <50 μmol/L (ie, 2.9 mg/dL) or a >50% decrease in serum bilirubin after 14 days. Severe complications, and 90-day mortality were recorded.

      Results

      Included were 186 patients: 161 (87%) underwent initial endoscopic biliary drainage and 25 (13%) underwent initial percutaneous transhepatic biliary drainage. The success of initial drainage was observed in 73 patients (45%) after endoscopic biliary drainage and 6 (24%) after percutaneous transhepatic biliary drainage. The reasons for an unsuccessful initial drainage were: the failure to place a drain or stent in 39 patients (21%), an unplanned reintervention within 14 days in 52 patients (28%), and the bilirubin level >50 μmol/L (or not halved) after 14 days of initial drainage in 16 patients (9%). Severe drainage-related complications occurred in 19 patients (12%) after endoscopic biliary drainage and in 3 (12%) after percutaneous transhepatic biliary drainage. Overall, 66 patients (36%) died within 90 days after initial biliary drainage.

      Conclusion

      Initial biliary drainage in patients with unresectable perihilar cholangiocarcinoma had a success rate of 45% and a 90-day mortality rate of 36%. Future studies for patients with perihilar cholangiocarcinoma should focus on improving biliary drainage.

      Introduction

      Perihilar cholangiocarcinoma (pCCA) is the most common malignancy of the bile duct. It arises from the epithelial cells at or near the biliary confluence.
      • Jarnagin W.R.
      • Fong Y.
      • DeMatteo R.P.
      • et al.
      Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma.
      Patients with pCCA typically present with painless jaundice due to biliary obstruction caused by the tumor. Relief of biliary obstruction through biliary drainage can resolve jaundice and liver dysfunction as well as improve the wellbeing of patients.
      • George C.
      • Byass O.R.
      • Cast J.E.
      Interventional radiology in the management of malignant biliary obstruction.
      Endoscopic retrograde biliary drainage (EBD) and percutaneous transhepatic biliary drainage (PTBD) are the 2 approaches most frequently used for biliary drainage.
      The majority of patients with pCCA have unresectable disease (ie, locally advanced or metastatic) on imaging at the time of presentation.
      • Jarnagin W.R.
      • Fong Y.
      • DeMatteo R.P.
      • et al.
      Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma.
      ,
      • Chaiteerakij R.
      • Harmsen W.S.
      • Marrero C.R.
      • et al.
      A new clinically based staging system for perihilar cholangiocarcinoma.
      The median overall survival (OS) of patients with unresectable disease is about 6 months.
      • Almadi M.A.
      • Barkun A.
      • Martel M.
      Plastic vs. Self-expandable metal stents for palliation in malignant biliary obstruction: a series of meta-analyses.
      Most patients with pCCA die from cholangitis or liver failure due to progressive biliary obstruction rather than widespread metastatic disease.
      • Anderson C.D.
      • Pinson C.W.
      • Berlin J.
      • Chari R.S.
      Diagnosis and treatment of cholangiocarcinoma.
      Palliative chemotherapy with gemcitabine plus cisplatin may improve median OS with about 3 months.
      • Valle J.
      • Wasan H.
      • Palmer D.H.
      • et al.
      Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer.
      However, patients are only eligible for systemic chemotherapy with bilirubin below 50 μmol/L (ie, 2.9 mg/dL), which may require drainage.
      • Cho M.S.
      • Kim S.H.
      • Park S.W.
      • et al.
      Surgical outcomes and predicting factors of curative resection in patients with hilar cholangiocarcinoma: 10-year single-institution experience.
      Most studies have focused on the outcomes of preoperative biliary drainage in patients with resectable pCCA.
      • Kloek J.J.
      • van der Gaag N.A.
      • Aziz Y.
      • et al.
      Endoscopic and percutaneous preoperative biliary drainage in patients with suspected hilar cholangiocarcinoma.
      • Kim K.M.
      • Park J.W.
      • Lee J.K.
      • Lee K.H.
      • Lee K.T.
      • Shim S.G.
      A comparison of preoperative biliary drainage methods for perihilar cholangiocarcinoma: endoscopic versus percutaneous transhepatic biliary drainage.
      • Wiggers J.K.
      • Coelen R.J.
      • Rauws E.A.
      • et al.
      Preoperative endoscopic versus percutaneous transhepatic biliary drainage in potentially resectable perihilar cholangiocarcinoma (DRAINAGE trial): design and rationale of a randomized controlled trial.
      Biliary drainage is even more challenging in patients with unresectable pCCA because of progressive isolation of segmental bile ducts.
      • Boulay B.R.
      • Birg A.
      Malignant biliary obstruction: from palliation to treatment.
      Patients often have complications after initial biliary drainage (eg, cholangitis), and reinterventions are frequently needed because of inadequate biliary drainage. The goal of initial biliary drainage is to avoid complications and reinterventions, as well as allow for early initiation of systemic chemotherapy. The aim of this study was to evaluate the success, severe complication, and mortality rates of initial palliative biliary drainage in patients with unresectable pCCA.

      Methods

      Study population and data acquisition

      Consecutive patients with unresectable pCCA who underwent initial biliary drainage procedure between 2002 and 2014 were retrospectively identified in 2 tertiary referral centers in The Netherlands: Erasmus MC, University Medical Center in Rotterdam, and Amsterdam University Medical Center (AUMC) in Amsterdam. All of the patients were discussed at a multidisciplinary meeting at the tertiary referral center. Initial drainage procedure was performed in one of the tertiary referral centers or in referring hospitals. The patients were considered to have unresectable disease in the event of locally advanced or metastatic pCCA on imaging at the time of presentation or when they were physically unfit for surgery.
      • Jarnagin W.R.
      • Fong Y.
      • DeMatteo R.P.
      • et al.
      Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma.
      Metastatic pCCA (ie, AJCC stage IV) was defined as the presence of distant metastases or lymph node metastases beyond the hepatoduodenal ligament (AJCC staging, seventh edition).
      • Edge S.B.
      • Compton C.C.
      The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM.
      If no pathological confirmation of suspicious lymph nodes was obtained, positive lymph node metastases were defined on imaging as nodes >1 cm in short-axis diameter, nodes with central necrosis, or an irregular border or hyper-attenuation compared with portal phase liver parenchyma.
      • Lee H.Y.
      • Kim S.H.
      • Lee J.M.
      • et al.
      Preoperative assessment of resectability of hepatic hilar cholangiocarcinoma: combined CT and cholangiography with revised criteria.
      ,
      • Coelen R.J.S.
      • Gaspersz M.P.
      • Labeur T.A.
      • et al.
      Validation of the Mayo Clinic staging system in determining prognoses of patients with perihilar cholangiocarcinoma.
      Locally advanced disease was defined as invasion of surrounding organs or vascular and biliary involvement that precluded an R0 resection with an adequate future liver remnant.
      • Chaiteerakij R.
      • Harmsen W.S.
      • Marrero C.R.
      • et al.
      A new clinically based staging system for perihilar cholangiocarcinoma.
      The patients with primary sclerosing cholangitis (PSC) were excluded as these patients often undergo biliary drainage procedures before pCCA develops. They were also excluded if a detailed report of the initial drainage procedure was not available.

      Outcomes and definitions

      The primary outcome consisted of 3 determinants of successful drainage: successful biliary stent or catheter placement, absence of unscheduled reintervention within 14 days, and serum bilirubin levels <50 μmol/L (ie, 2.9 mg/dL) or a >50% decrease in serum bilirubin after 14 days. A decrease of >50% of serum bilirubin after 14 days was also considered to be successful drainage because the absolute amount of bilirubin after stenting also depends on the serum bilirubin before drainage.
      • Weston B.R.
      • Ross W.A.
      • Wolff R.A.
      • et al.
      Rate of bilirubin regression after stenting in malignant biliary obstruction for the initiation of chemotherapy: how soon should we repeat endoscopic retrograde cholangiopancreatography?.
      A planned reintervention within 14 days (eg, initial external percutaneous biliary drainage followed by stent placement 3 days later, or a plastic stent replaced by a metal stent) was not considered a failure of initial biliary drainage.
      The secondary outcomes included drainage related complications, reinterventions, and an OS at 90 days after initial drainage. Drainage-related complications included cholangitis, acute cholecystitis, acute pancreatitis, bile duct injury (perforation and bleeding), duodenal perforation, and cardiopulmonary complications. Cholangitis was defined as both fever (ie, body temperature >38.5°C) and leukocytosis (ie, ≥10 ×109/L) requiring a reintervention, without clinical or radiological evidence of acute cholecystitis.
      • Wiggers J.K.
      • Coelen R.J.
      • Rauws E.A.
      • et al.
      Preoperative endoscopic versus percutaneous transhepatic biliary drainage in potentially resectable perihilar cholangiocarcinoma (DRAINAGE trial): design and rationale of a randomized controlled trial.
      ,
      • van der Gaag N.A.
      • Rauws E.A.
      • van Eijck C.H.
      • et al.
      Preoperative biliary drainage for cancer of the head of the pancreas.
      ,
      • Wiggers J.K.
      • Groot Koerkamp B.
      • Cieslak K.P.
      • et al.
      Postoperative mortality after liver resection for perihilar cholangiocarcinoma: development of a risk score and importance of biliary drainage of the future liver remnant.
      Acute cholecystitis was defined as radiologic diagnosis of cholecystitis, in combination with fever and leukocytosis (ie, ≥10 ×109/L), requiring percutaneous drainage, cholecystectomy, or antibiotics. Acute pancreatitis was defined by abdominal pain and a serum concentration of pancreatic enzymes (amylase or lipase) ≥3 times the upper limit of normal requiring at least one night of hospitalization.
      • van der Gaag N.A.
      • Rauws E.A.
      • van Eijck C.H.
      • et al.
      Preoperative biliary drainage for cancer of the head of the pancreas.
      The OS was defined as the time between initial drainage procedure and date of death or date of last follow-up. The primary and secondary outcomes were compared between EBD and PTBD.
      The data on initial biliary drainage were collected from medical records until 90 days after drainage, including the indication for drainage, bilirubin serum levels before and after initial drainage, drainage approach (PTBD or EBD), type of stent (metal or plastic), drainage-related complications, and survival. If the initial drainage procedure was not performed in one of the tertiary referral centers, data were collected at the referring hospital where initial drainage procedure was performed.
      Experienced abdominal radiologists revised the contrast-enhanced computed tomography (CT) and/or magnetic resonance imaging (MRI) performed at the time of presentation. The parameters reassessed on imaging were tumor diameter, Bismuth-Corlette classification,
      • Bismuth H.
      • Corlette M.B.
      Intrahepatic cholangioenteric anastomosis in carcinoma of the hilus of the liver.
      presence of suspected lymph nodes, distant metastases, lobar atrophy, and vascular involvement. The Institutional Review Boards of both centers approved the study, and the need for informed consent was waived.

      Statistical analysis

      The continuous variables were presented as means with SD if normally distributed or as median with IQR if not normally distributed. The categorical parameters are reported as counts and percentages. The categorical variables were compared with Fisher exact test, whereas continuous variables were compared with Mann-Whitney U test. Univariable analyses were performed using logistic regression analyses. The variables with a P < .20 in univariable analyses were included in multivariable analysis for mortality. Kaplan-Meier method with log-rank test was used for survival outcomes. The survival status was retrieved from the municipal records. All of the analyses were conducted using IBM SPSS Statistics for Windows (version 21.0; IBM Corp, Armonk, NY).

      Results

      Patient characteristics

      A total of 186 drainage naïve patients with unresectable pCCA underwent initial biliary drainage; EBD in 161 patients (87%) and PTBD in 25 patients (13%). Table I presents the baseline patient characteristics, which did not differ between approaches. Thirteen patients (9%) received palliative systemic chemotherapy. Two patients (3%) underwent palliative radiotherapy, and 1 patient (2%) photodynamic therapy. Endoscopic stent placement during initial biliary drainage was most frequently performed with plastic stents in both tertiary referral centers, although the use of metal stents has increased since 2010.
      Table IBaseline patient characteristics (n = 186)
      Demographics, exam, and laboratory valuesTotal cohort (% or IQR)EBD (% or IQR) N = 161PTBD (% or IQR) N = 25P value
      Age at first presentation, y72 (62–77)72 (62–78)71 (62–75).303
      ≥75 y73 (39)65 (40)8 (32).512
      Sex, males105 (57)90 (56)15 (60).829
      BMI, kg/m225 (23–27)25 (23–27)24 (21–28).193
      WHO performance status.923
      067 (36)58 (37)9 (39)
      167 (36)57 (37)10 (44)
      225 (13)23 (15)2 (9)
      319 (10)17 (11)2 (9)
      41 (1)1 (1)
      CA 19.9 (U/ml)324 (105–2172)299 (100–2377)454 (195–1871).660
      ≥1,000 U/ml33 (17.7)28 (34.1)5 (45.5).512
      Highest bilirubin predrainage, median248 (138–377)232 (138–375)284 (203–384).379
      <50 μmol/L6 (4.6)5 (4.6)1 (4.5)1.000
      Tumor characteristics on imaging at presentation
      Tumor size, cm3.0 (2.3–3.9)3 (2.3–3.9)2.6 (2.4–4.1).880
      Size >3 cm81 (44)70 (44)11 (44).669
      Suspicious lymph nodes on imaging§,ǁ.842
      N093 (54)80 (54)13 (52)
      N140 (23)33 (22)7 (28)
      N240 (23)35 (24)5 (20)
      Suspected distant metastases on imaging27 (15)24 (16)3 (12).772
      Any vascular involvement
      Defined as ≥180° tumor involvementon imaging.
      129 (69)110 (77)18 (75).799
      PV involvement107 (58)92 (64)16 (62)1.000
      Unilateral60 (32)52 (36)8 (33)1.000
      Main/Bilateral47 (25)40 (28)7 (29)
      HA involvement105 (57)91 (65)14 (54).647
      Unilateral72 (39)61 (43)11 (46).654
      Main/Bilateral33 (18)30 (21)3 (13)
      Lobar atrophy on imaging.736
      None124 (72)106 (72)18 (72)
      Left9 (5)7 (5)2 (8)
      Right40 (21)35 (24)5 (20)
      Bismuth classification [18]
      Nodes along the cystic duct, common bile, duct, hepatic artery, and portal vein were classified as N1 and periaortic, pericaval, SMA, and celiac nodes as N2.12
      .760
      I11 (7)11 (8)
      II23 (14)20 (14)3 (13)
      IIIA34 (21)28 (20)6 (25)
      IIIB28 (17)24 (17)4 (17)
      IV71 (42)59 (42)11 (45)
      Data missing for: 7 patients, 93 patients, 55 patients, 13 patients§, 7 patients, 19 patients††, 21 patients‡‡, 13 patients§§, 20 patients.
      Nodes along the cystic duct, common bile, duct, hepatic artery, and portal vein were classified as N1 and periaortic, pericaval, SMA, and celiac nodes as N2.12
      EBD, endoscopic retrograde biliary drainage; BMI, body mass index; CA 19.9, carbohydrate antigen 19.9; HA, hepatic artery; PTBD, percutaneous transhepatic biliary drainage; PV, portal vein; WHO, World Health Organization.
      ǁǁ Nodes along the cystic duct, common bile, duct, hepatic artery, and portal vein were classified as N1 and periaortic, pericaval, SMA, and celiac nodes as N2.
      • Edge S.B.
      • Compton C.C.
      The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM.
      ∗∗ Defined as ≥180° tumor involvementon imaging.

      Initial biliary drainage procedure

      In 125 patients (67%) the initial drainage procedure was performed in a tertiary referral center, and in 61 patients (33%) in the referring hospital (Table II). The median serum bilirubin level before initial drainage procedure was 248 (IQR 138–377) μmol/L (ie, 15.1 (IQR 8.1–22.1) mg/dL). Cholangitis was diagnosed in 13 (7%) patients before initial biliary drainage. During initial EBD (n = 161), one or more stents were placed in 124 patients (77%), which were plastic stents in 109 patients (68%) and metal stents in 15 patients (9%). There was no association between Bismuth stage and type of stent used (P = .760). During initial PTBD procedure (n = 25), a drain was placed in 23 patients (92%): an internal-external drain in 20 patients (80%) and an external drain in 3 patients (12%). A plastic stent was placed during 1 initial PTBD (4%).
      Table IIInitial biliary drainage characteristics (N = 186)
      Total cohort

      N = 186
      EBD n = 161PTBD n = 25P value
      Hospital of initial drainage
      Tertiary referral hospital125 (67)106 (66)19 (76).367
      Referring hospital61 (33)55 (34)6 (24)
      Cholangitis before drainage procedure13 (7)10 (7)3 (12).386
      Drain placed at initial PTBD, yes23 (12)23 (92)
      Internal-external20 (11)20 (80)
      External only3 (2)3 (12)
      Papillotomy performed at initial EBD74 (57)74 (58)
      Stent placed at initial drainage:125 (67)124 (77)1 (4)< .001
      Plastic110 (59)109 (68)1 (4)
      Metal stent15 (8)15 (9)0
      Lowest bilirubin within 4 wk after initial drainage104 (46.5–287)99 (44–273)233 (119–393).026
      Success of initial drainage
      Unsuccessful drainage
      No drain or stent placed39 (21)37 (23)2 (8).114
      Unplanned reintervention52 (28)38 (24)14 (56).002
      Inadequate bilirubin decrease
      Serum bilirubin levels >50 μmol/L or a <50% decrease in serum bilirubin within 14 days.
      53 (53)43 (50)10 (71).160
      Severe drainage-related complications
      Severe complications were recorded for 90 days after initial drainage.
      22 (12)19 (12)3 (12)1.000
      Acute cholecystitis
      Acute cholecystitis was defined as radiologic diagnosis of cholecystitis, in combination with fever and leukocytosis, requiring percutaneous drainage or cholecystectomy.
      000
      (Worsening of) cholangitis <48 h
      Cholangitis was defined as an elevation in temperature >38.5°C and leukocytosis ≥10 × 109/L, thought to have a biliary cause, without concomitant evidence of acute cholecystitis, requiring invasive intervention.10,16,17
      11 (6)9 (6)2 (8)
      Acute pancreatitis
      Acute pancreatitis were abdominal pain and a serum concentration of pancreatic enzymes (amylase or lipase) ≥3 times the upper limit of normal that requires ≥1 night of hospitalization.
      5 (3)5 (3)0
      Bile duct injury3 (2)2 (1)1 (4)
      Duodenal perforation1 (1)1 (1)0
      Cardiopulmonary complications2 (1)2 (1)0
      Total number of drainage procedures per patient, median (IQR)3 (2–6)3 (2–6)4 (3–7).162
      Data missing for: 13 patients, 33 patients, 86 patients.
      EBD, endoscopic retrograde biliary drainage; PTBD, percutaneous transhepatic biliary drainage.
      § Serum bilirubin levels >50 μmol/L or a <50% decrease in serum bilirubin within 14 days.
      Ι Severe complications were recorded for 90 days after initial drainage.
      Acute cholecystitis was defined as radiologic diagnosis of cholecystitis, in combination with fever and leukocytosis, requiring percutaneous drainage or cholecystectomy.
      ∗∗ Cholangitis was defined as an elevation in temperature >38.5°C and leukocytosis ≥10 × 109/L, thought to have a biliary cause, without concomitant evidence of acute cholecystitis, requiring invasive intervention.
      • Wiggers J.K.
      • Coelen R.J.
      • Rauws E.A.
      • et al.
      Preoperative endoscopic versus percutaneous transhepatic biliary drainage in potentially resectable perihilar cholangiocarcinoma (DRAINAGE trial): design and rationale of a randomized controlled trial.
      ,
      • van der Gaag N.A.
      • Rauws E.A.
      • van Eijck C.H.
      • et al.
      Preoperative biliary drainage for cancer of the head of the pancreas.
      ,
      • Wiggers J.K.
      • Groot Koerkamp B.
      • Cieslak K.P.
      • et al.
      Postoperative mortality after liver resection for perihilar cholangiocarcinoma: development of a risk score and importance of biliary drainage of the future liver remnant.
      †† Acute pancreatitis were abdominal pain and a serum concentration of pancreatic enzymes (amylase or lipase) ≥3 times the upper limit of normal that requires ≥1 night of hospitalization.

      Success of initial biliary drainage

      The success of initial drainage was achieved in 79 patients (43%), 73 patients (45%) after EBD and 6 patients (24%) after PTBD (Figure 1). Reasons for unsuccessful initial drainage were: failure to place a drain or stent in 39 patients (21%), unplanned reintervention within 14 days in 52 patients (28%), and bilirubin level above 50 μmol/L (ie, 2.9 mg/dL) (or not halved) after 14 days in 16 patients (9%) despite drain or stent placement (Figure 1). Irrespective of the reason for failure, 53 patients in the entire cohort (53%) did not reach bilirubin levels <50 μmol/L (ie, 2.9 mg/dL) (or not halved) within 14 days. The time period was not associated with outcomes: success of biliary drainage before 2008 was 39% (19/49) compared to 47% (65/137) after 2008 (P = .295).
      Figure thumbnail gr1
      Figure 1Flowchart success of initial drainage (n = 186). EBD, endoscopic retrograde biliary drainage; PHC, perihilar cholangiocarcinoma; PTBD, percutaneous transhepatic biliary drainage.
      At initial EBD, no drain or stent was placed (ie, CBD not cannulated or biliary stricture not passed) in 37 patients (23%), 38 patients (24%) needed an unplanned reintervention within 14 days, and another 13 patients (8%) had bilirubin levels >50 μmol/L (ie, 2.9 mg/dL) (or not halved) after 14 days despite stent placement. Irrespective of the reason for failure, a total of 43 patients (50%) in the EBD group did not reach bilirubin levels <50 μmol/L (ie, 2.9 mg/dL) (or not halved) within 14 days.
      After initial PTBD, success of drainage was observed in 6 (24%) patients; in 2 patients (8%) no drain or stent was placed, 14 patients (56%) needed an unplanned reintervention within 14 days, and 3 patients (12%) had bilirubin levels >50 μmol/L (ie, 2.9 mg/dL) (or not halved) after 14 days despite successful drain placement. Irrespective of the reason for failure, a total of 10 patients (71%) in the PTBD group did not reach bilirubin levels <50 μmol/L (ie, 2.9 mg/dL) (or not halved) within 14 days. Out of the 25 patients that initially underwent PTBD, 4 patients had an EBD as a second biliary drainage.
      Two factors associated with an unplanned reintervention were found; PTBD (OR 4.12, 95% CI: 1.73–9.83, P = .001) and portal vein involvement (OR 2.58, 95% CI: 1.12–5.97, P = .027; Supplementary Table S1). No factors associated with inadequate drainage (ie, bilirubin levels above 50 μmol/L (ie, 2.9 mg/dL) or not halved) were found. In total, 26 patients (14%) had continued hyperbilirubinemia (median 307, IQR 206–454) but did not undergo a reintervention within 14 days. Twenty-three out of these 26 patients eventually had a second drainage procedure after 14 days at a median of 29 days (IQR 17.5–30). The remaining 3 patients did not undergo a biliary reintervention.

      Severe drainage-related complications after initial biliary drainage

      Severe drainage-related complications after initial EBD were observed in 19 patients (12%); 9 patients (6%) developed new onset cholangitis, 5 (3%) acute pancreatitis, 2 (1%) bile duct injury, 1 (1%) duodenal perforation, and 2 (1%) cardiopulmonary complications (Table II). Of the 2 patients with bile duct injuries, 1 patient underwent a reintervention under general anesthesia and the other patient developed sepsis and died. Severe drainage-related complications after initial PTBD were observed in 3 patients (12%); 2 patients (8%) developed cholangitis and 1 patient (4%) a biliary injury.

      Mortality after initial biliary drainage

      At the time of last follow-up, 182 patients (98%) had died. No patient was lost to follow-up. The median OS of the entire cohort was 6.7 months (95% CI: 4.9–8.5; Figure 2). Figure 3 shows the survival curves after initial EBD or PTBD. The 30-day mortality rate after initial drainage for the entire cohort was 11% (n = 20) with a 90-day mortality rate of 36% (n = 66). The majority of patients with 90-day mortality (77%) had no evidence of metastatic disease. Of the patients with 90-day mortality, 21 patients (32%) had distant metastasis (M1 disease), 8 patients (12%) had main/bilateral involvement of the hepatic artery, 4 patients (6%) had a WHO performance status of 3 or 4, and 20 patients (30%) were ≥75 years old. However, no statistically significant poor prognostic factors for 90-day mortality were identified in univariate and multivariable analysis (Supplementary Table S2). In particular, no difference in 90-day mortality was found between the initial EBD and PTBD, or whether EBD patients received a plastic or a metal stent.
      Figure thumbnail gr2
      Figure 2Survival after biliary drainage for unresectable perihilar cholangiocarcinoma (n = 186).
      Figure thumbnail gr3
      Figure 3Survival after initial endoscopic retrograde biliary drainage and percutaneous transhepatic biliary drainage for unresectable perihilar cholangiocarcinoma. EBD, endoscopic retrograde biliary drainage; PTBD, percutaneous transhepatic biliary drainage.

      Subsequent biliary drainage procedures

      After initial EBD, a second drainage procedure was performed in 125 (78%) patients at some point during palliative care (Supplementary Figure S1); 107 patients (84%) underwent a second EBD and 21 (16%) underwent a PTBD as a second drainage procedure. After initial PTBD, a second drainage procedure was performed in 24 (96%) patients; 20 patients (83%) underwent another PTBD, and 4 patients (17%) underwent an EBD as a second drainage procedure. The median period between the initial and second drainage procedure was 10 (5–28) days. The median number of drainage procedures during the entire palliative period was 3 (IQR 2–6), and 66 patients (36%) underwent 5 or more drainage procedures.

      Discussion

      In the present study, we found a success rate of 43% for initial biliary drainage in 186 drainage-naïve patients with unresectable pCCA. The most common reasons for unsuccessful initial drainage were failure to place a drain or stent in 21% and unplanned reinterventions in 28%. Inadequate decrease of bilirubin (ie, below 50 μmol/L [2.9 mg/dL] within 14 days or not halved) was observed in 53% of all treated patients. Observed 90-day mortality was 36%.
      These high failure rates are comparable with recently published randomized trials on drainage of malignant biliary obstructions. A randomized trial (the INTERCPT trial) comparing EBD and PTBD for initial biliary drainage in patients with cholestasis and suspicion of malignant hilar obstruction was discontinued early because of lack of accrual.
      • Elmunzer B.J.
      • Smith Z.L.
      • Tarnasky P.
      • et al.
      An unsuccessful randomized trial of percutaneous vs endoscopic drainage of suspected malignant Hilar obstruction.
      In 2 years, only 13 patients were included. Less than half of all patients achieved the primary endpoint of 50% bilirubin level decrease in 3 weeks. Ninety-day mortality of the entire cohort was 62% (8/13). Biliary drainage has been evaluated mostly in cohorts of pCCA patients eligible for resection to optimize condition before liver resection. In these cohorts, high complication rates have been reported.
      • Wiggers J.K.
      • Groot Koerkamp B.
      • Coelen R.J.
      • et al.
      Percutaneous preoperative biliary drainage for resectable perihilar cholangiocarcinoma: no association with survival and no increase in seeding metastases.
      • Iacono C.
      • Ruzzenente A.
      • Campagnaro T.
      • Bortolasi L.
      • Valdegamberi A.
      • Guglielmi A.
      Role of preoperative biliary drainage in jaundiced patients who are candidates for pancreatoduodenectomy or hepatic resection: highlights and drawbacks.
      • Al Mahjoub A.
      • Menahem B.
      • Fohlen A.
      • et al.
      Preoperative biliary drainage in patients with resectable perihilar cholangiocarcinoma: is percutaneous transhepatic biliary drainage safer and more effective than endoscopic biliary drainage? A meta-analysis.
      A Dutch randomized controlled trial (DRAINAGE trial) comparing preoperative EBD to preoperative PTBD in potentially resectable pCCA was prematurely stopped because of increased 90-day mortality in the PTBD group (41% vs 11% in the EBD group, P = .03).
      • Coelen R.J.S.
      • Roos E.
      • Wiggers J.K.
      • et al.
      Endoscopic versus percutaneous biliary drainage in patients with resectable perihilar cholangiocarcinoma: a multicentre, randomised controlled trial.
      Severe complications after biliary drainage were common and similar between the groups (PTBD 63% vs EBD 67%). The authors hypothesized that extracting bile from the enterohepatic cycle in severely ill patients with external biliary drainage may have increased mortality in the PTBD group. A review by Kato et al described studies with a variety of definitions to determine technical and clinical success of biliary drainage for unresectable malignant hilar obstruction.
      • Kato H.
      • Matsumoto K.
      • Okada H.
      Recent advances regarding endoscopic biliary drainage for unresectable malignant hilar biliary obstruction.
      Technical success was often defined as successful stent placement or stent deployment across the obstruction, sometimes confirmed by contrast flow through the stent.
      • Ishigaki K.
      • Hamada T.
      • Nakai Y.
      • et al.
      Retrospective Comparative study of side-by-side and stent-in-stent metal stent placement for Hilar malignant biliary obstruction.
      • Lee T.H.
      • Kim T.H.
      • Moon J.H.
      • et al.
      Bilateral versus unilateral placement of metal stents for inoperable high-grade malignant hilar biliary strictures: a multicenter, prospective, randomized study (with video).
      • Teng F.
      • Xian Y.T.
      • Lin J.
      • Li Y.
      • Wu A.L.
      Comparison of unilateral with bilateral metal stenting for malignant Hilar biliary obstruction.
      • Staub J.
      • Siddiqui A.
      • Murphy M.
      • et al.
      Unilateral versus bilateral hilar stents for the treatment of cholangiocarcinoma: a multicenter international study.
      Clinical success was determined by any up to 75% bilirubin decrease in a time period varying from 1 to 4 weeks.
      • Ishigaki K.
      • Hamada T.
      • Nakai Y.
      • et al.
      Retrospective Comparative study of side-by-side and stent-in-stent metal stent placement for Hilar malignant biliary obstruction.
      • Lee T.H.
      • Kim T.H.
      • Moon J.H.
      • et al.
      Bilateral versus unilateral placement of metal stents for inoperable high-grade malignant hilar biliary strictures: a multicenter, prospective, randomized study (with video).
      • Teng F.
      • Xian Y.T.
      • Lin J.
      • Li Y.
      • Wu A.L.
      Comparison of unilateral with bilateral metal stenting for malignant Hilar biliary obstruction.
      • Staub J.
      • Siddiqui A.
      • Murphy M.
      • et al.
      Unilateral versus bilateral hilar stents for the treatment of cholangiocarcinoma: a multicenter international study.
      • Park D.H.
      • Lee S.S.
      • Moon J.H.
      • Choi H.J.
      • Cha S.W.
      • Kim J.H.
      • et al.
      Newly designed stent for endoscopic bilateral stent-in-stent placement of metallic stents in patients with malignant hilar biliary strictures: multicenter prospective feasibility study (with videos).
      A direct comparison of success rates is impossible with this variation in definitions. Moreover, we included “no unplanned reintervention” in our definition of success, which added up to lower success rates.
      Inadequate decrease of bilirubin within 2 weeks was observed in 53% of patients. A previous study found that the duration of normalization of bilirubin levels was dependent on the bilirubin level before biliary stenting. Bilirubin levels ≥171 μmol/L (ie, 10 mg/dL) could take >6 weeks to return to normal levels after drainage.
      • Weston B.R.
      • Ross W.A.
      • Wolff R.A.
      • et al.
      Rate of bilirubin regression after stenting in malignant biliary obstruction for the initiation of chemotherapy: how soon should we repeat endoscopic retrograde cholangiopancreatography?.
      The median bilirubin level before biliary drainage was 248 (IQR 138–377) μmol/L (ie, 15.1 [IQR 8.1–22.1] mg/dL) for the entire cohort. Therefore, the period of 2 weeks was sufficient to assess successful drainage, but not to determine that bilirubin declined to normal levels.
      We found severe drainage-related complications (eg, cholangitis, acute cholecystitis, and acute pancreatitis) in 19 patients (12%) after EBD and in 3 (12%) after PTBD. A randomized controlled trial of patients with unresectable pCCA comparing metal and plastic stents reported postdrainage pancreatitis in 15% and cholangitis in 19%.
      • Sangchan A.
      • Kongkasame W.
      • Pugkhem A.
      • Jenwitheesuk K.
      • Mairiang P.
      Efficacy of metal and plastic stents in unresectable complex hilar cholangiocarcinoma: a randomized controlled trial.
      No patient developed cholecystitis in our study, whereas 3% of patients developed cholecystitis in another randomized controlled trial comparing metal and plastic stents.
      • Mukai T.
      • Yasuda I.
      • Nakashima M.
      • et al.
      Metallic stents are more efficacious than plastic stents in unresectable malignant hilar biliary strictures: a randomized controlled trial.
      The difference is partially explained by the differences in definitions. Moreover, pancreatitis, cholecystitis, and cholangitis may be underreported in the present study because of the retrospective study design. Furthermore, prophylactic measures such as pancreatic duct stenting and administration of nonsteroidal inflammatory drugs may have reduced the rate of pancreatitis.
      The median OS in our cohort of 6.7 months is similar to reported outcomes in previous studies on EBD in patients with unresectable malignant hilar biliary strictures.
      • Sangchan A.
      • Kongkasame W.
      • Pugkhem A.
      • Jenwitheesuk K.
      • Mairiang P.
      Efficacy of metal and plastic stents in unresectable complex hilar cholangiocarcinoma: a randomized controlled trial.
      • Mukai T.
      • Yasuda I.
      • Nakashima M.
      • et al.
      Metallic stents are more efficacious than plastic stents in unresectable malignant hilar biliary strictures: a randomized controlled trial.
      • Paik W.H.
      • Park Y.S.
      • Hwang J.H.
      • et al.
      Palliative treatment with self-expandable metallic stents in patients with advanced type III or IV hilar cholangiocarcinoma: a percutaneous versus endoscopic approach.
      The 30-day and 90-day mortality rates after initial biliary drainage in our cohort were 11% and 36%. No difference in 90-day mortality was found between initial EBD and PTBD. In the randomized trial comparing plastic and metal stents for unresectable pCCA, the 30-day mortality rate was 29%.
      • Sangchan A.
      • Kongkasame W.
      • Pugkhem A.
      • Jenwitheesuk K.
      • Mairiang P.
      Efficacy of metal and plastic stents in unresectable complex hilar cholangiocarcinoma: a randomized controlled trial.
      In the present study, most of the patients died in the absence of metastatic disease on imaging. Inadequate biliary drainage and complications of biliary drainage, leading to cholangitis and clinical deterioration, appear to be the root cause of 90-day mortality in these patients. Local disease progression with isolation of segmental bile ducts and liver failure is responsible for mortality beyond 90 days.
      Resectable pCCA is most often treated with a right or left hemihepatectomy with a bile duct resection and reconstruction, resulting in 90-day mortality rates of 12% in Western centers.
      • Franken L.C.
      • Schreuder A.M.
      • Roos E.
      • et al.
      Morbidity and mortality after major liver resection in patients with perihilar cholangiocarcinoma: a systematic review and meta-analysis.
      • Abbas S.
      • Sandroussi C.
      Systematic review and meta-analysis of the role of vascular resection in the treatment of hilar cholangiocarcinoma.
      • Lafaro K.
      • Buettner S.
      • Maqsood H.
      • et al.
      Defining post hepatectomy liver insufficiency: where do we stand?.
      Most of the patients die from liver failure, typically caused by an inadequate liver remnant and cholangiosepsis. In the present study we found that 90-day mortality after biliary drainage for patients with pCCA who did not undergo resection was even worse with 36%. This difference in mortality is most likely explained by more extensive disease and frailty in the unresectable pCCA group. Moreover, series of patients who underwent resection of pCCA rarely report outcomes of patients with resectable pCCA who did not undergo resection because of clinical deterioration during preoperative biliary drainage. Only the Dutch RCT demonstrated that many patients with resectable pCCA die after preoperative biliary drainage before surgery.
      • Coelen R.J.S.
      • Roos E.
      • Wiggers J.K.
      • et al.
      Endoscopic versus percutaneous biliary drainage in patients with resectable perihilar cholangiocarcinoma: a multicentre, randomised controlled trial.
      This study had several limitations. Due to the retrospective nature, details related to the biliary drainage procedure were sometimes missing, and complication rates may have been underreported. Mortality, however, was retrieved for all of the patients from municipal records. A few of the patients without a drainage report had to be excluded, which may have led to selection bias. Also, the reason for patients undergoing EBD or PTBD is unknown, potentially leading to selection bias. Finally, although the described cohort is large, the number of patients undergoing initial PTBD was too low to draw statistical conclusions in the comparison with EBD.
      Future studies should focus on improving the success rate of initial palliative initial biliary drainage. The need for reintervention might decrease by more liberal use of metal stents and placement of bilateral stents at initial biliary drainage as recommended by the European Society of Gastrointestinal Endoscopy guidelines.
      • Lee T.H.
      • Kim T.H.
      • Moon J.H.
      • et al.
      Bilateral versus unilateral placement of metal stents for inoperable high-grade malignant hilar biliary strictures: a multicenter, prospective, randomized study (with video).
      ,
      • Sangchan A.
      • Kongkasame W.
      • Pugkhem A.
      • Jenwitheesuk K.
      • Mairiang P.
      Efficacy of metal and plastic stents in unresectable complex hilar cholangiocarcinoma: a randomized controlled trial.
      ,
      • Lee T.H.
      • Moon J.H.
      • Choi J.H.
      • et al.
      Prospective comparison of endoscopic bilateral stent-in-stent versus stent-by-stent deployment for inoperable advanced malignant hilar biliary stricture.
      ,
      • Dumonceau J.M.
      • Tringali A.
      • Papanikolaou I.S.
      • et al.
      Endoscopic biliary stenting: indications, choice of stents, and results: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline—Updated October 2017.
      The ongoing TESLA trial (NL9624) investigates initial percutaneous placement of a metal stent that does not cross the ampulla, to avoid contamination of intrahepatic the bile ducts. Randomized trials for initial biliary drainage remain challenging as demonstrated by a multicenter study that was closed early because of lack of accrual.
      • Elmunzer B.J.
      • Smith Z.L.
      • Tarnasky P.
      • et al.
      An unsuccessful randomized trial of percutaneous vs endoscopic drainage of suspected malignant Hilar obstruction.
      In conclusion, in patients who were ineligible for resection of pCCA and underwent palliative biliary drainage, we found that the initial biliary drainage had a low success rate of 45% and a high 90-day mortality rate of 36%. Future studies for patients with pCCA should focus on improving biliary drainage.

      Funding/Support

      This research did not receive any specific funding from any agencies in the public, commercial, or not-for-profit areas.

      Conflict of interest/Disclosure

      The authors have no conflicts of interests or disclosures to report.

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