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Long-term follow-up of a randomized trial of biliary drainage in perihilar cholangiocarcinoma

Open AccessPublished:October 20, 2022DOI:https://doi.org/10.1016/j.hpb.2022.10.009

      Abstract

      Background and aims

      The DRAINAGE trial was a randomized controlled trial comparing preoperative endoscopic (EBD) and percutaneous biliary drainage (PTBD) in patients with potentially resectable, perihilar cholangiocarcinoma (pCCA). The aim of this study was to compare the long-term outcomes.

      Methods

      Patients were randomized in four tertiary referral centers. Follow-up data were available for all included patients. Primary outcome was overall survival (OS). Secondary outcomes were readmissions, and re-interventions not including in-trial interventions.

      Results

      A total of 54 patients were randomized; 27 in both groups. Median follow-up for both groups was 62 months (95% CI 54–70). The median OS was 13 months (95% CI 7.9–18.1) in the EBD and 7 months (95% CI 0.0–17.2) in the PTBD group (P = 0.28). Twenty (37%, n = 8 EBD vs n = 12 PTBD, P = 0.43) of 54 patients were readmitted at least once, mostly due to drainage-related complications (n = 13, 24%). Of note, 14 out of the 54 patients died within the trial. A total of 76 drainage procedures (32 EBD and 44 PTBD) were performed in 28 patients. The median number of stent or drain placements was 2 (2–4) for the EBD group and 2 (1–3) for the PTBD group (P = 0.77).

      Discussion

      Although this follow-up study represented a small cohort, no long-term differences in survival, readmissions, and drainage procedures for EBD and PTBD were found, even when comparing the resected and unresected group. However, this study demonstrates the complexity of biliary drainage for patients with potentially resectable pCCA, even in tertiary referral centers.

      Graphical abstract

      Introduction

      Perihilar cholangiocarcinoma (pCCA) is a rare disease with a poor prognosis. Surgery with curative intent offers the only chance of long-term overall survival (OS), with 5-year OS rates of 43% after radical resection.
      • Cillo U.
      • Fondevila C.
      • Donadon M.
      • Gringeri E.
      • Mocchegiani F.
      • Schlitt H.J.
      • et al.
      Surgery for cholangiocarcinoma.
      ,
      • Ruzzenente A.
      • Bagante F.
      • Olthof P.B.
      • Aldrighetti L.
      • Alikhanov R.
      • Cescon M.
      • et al.
      Surgery for Bismuth-Corlette type 4 perihilar cholangiocarcinoma: results from a western multicenter collaborative group.
      Unfortunately, most patients present with metastatic or locally advanced disease, which leaves only a minority of 20% eligible for resection.
      • Cillo U.
      • Fondevila C.
      • Donadon M.
      • Gringeri E.
      • Mocchegiani F.
      • Schlitt H.J.
      • et al.
      Surgery for cholangiocarcinoma.
      The work-up prior to resection usually consists of biliary drainage, liver volume measurement (or calculation) and/or liver function tests and, if necessary, portal vein embolization.
      • Valle J.W.
      • Borbath I.
      • Khan S.A.
      • Huguet F.
      • Gruenberger T.
      • Arnold D.
      Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      The goal of biliary drainage is to decrease morbidity and mortality due to postoperative liver failure.
      • Wiggers J.K.
      • Groot Koerkamp B.
      • Cieslak K.P.
      • Doussot A.
      • van Klaveren D.
      • Allen P.J.
      • 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.
      • Olthof P.B.
      • Wiggers J.K.
      • Groot Koerkamp B.
      • Coelen R.J.
      • Allen P.J.
      • Besselink M.G.
      • et al.
      Postoperative liver failure risk score: identifying patients with resectable perihilar cholangiocarcinoma who can Benefit from portal vein embolization.
      • 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.
      • Nakanishi Y.
      • Tsuchikawa T.
      • Okamura K.
      • Nakamura T.
      • Tamoto E.
      • Noji T.
      • et al.
      Risk factors for a high Comprehensive Complication Index score after major hepatectomy for biliary cancer: a study of 229 patients at a single institution.
      Biliary drainage however, comes with a high risk of complications itself
      • Coelen R.J.S.
      • Roos E.
      • Wiggers J.K.
      • Besselink M.G.
      • Buis C.I.
      • Busch O.R.C.
      • et al.
      Endoscopic versus percutaneous biliary drainage in patients with resectable perihilar cholangiocarcinoma: a multicentre, randomised controlled trial.
      • Chen G.F.
      • Yu W.D.
      • Wang J.R.
      • Qi F.Z.
      • Qiu Y.D.
      The methods of preoperative biliary drainage for resectable hilar cholangiocarcinoma patients: a protocol for systematic review and meta analysis.
      • Yang G.
      • Xiong Y.
      • Sun J.
      • Tang T.
      • Li W.
      • Wang G.
      • et al.
      Effects of different preoperative biliary drainage methods for resected malignant obstruction jaundice on the incidence rate of implantation metastasis: a meta-analysis.
      and the optimal drainage method remains a matter of debate.
      • Coelen R.J.S.
      • Roos E.
      • Wiggers J.K.
      • Besselink M.G.
      • Buis C.I.
      • Busch O.R.C.
      • et al.
      Endoscopic versus percutaneous biliary drainage in patients with resectable perihilar cholangiocarcinoma: a multicentre, randomised controlled trial.
      ,
      • Al-Kawas F.
      • Aslanian H.
      • Baillie J.
      • Banovac F.
      • Buscaglia J.M.
      • Buxbaum J.
      • et al.
      Percutaneous transhepatic vs. endoscopic retrograde biliary drainage for suspected malignant hilar obstruction: study protocol for a randomized controlled trial.
      ,
      • Kawakami H.
      • Kuwatani M.
      • Onodera M.
      • Haba S.
      • Eto K.
      • Ehira N.
      • et al.
      Endoscopic nasobiliary drainage is the most suitable preoperative biliary drainage method in the management of patients with hilar cholangiocarcinoma.
      The DRAINAGE trial, which ran from 2013 to 2016 was a multicenter randomized controlled trial (RCT) comparing preoperative endoscopic (EBD) and percutaneous biliary drainage (PTBD) in patients with potentially resectable pCCA.
      • Coelen R.J.S.
      • Roos E.
      • Wiggers J.K.
      • Besselink M.G.
      • Buis C.I.
      • Busch O.R.C.
      • et al.
      Endoscopic versus percutaneous biliary drainage in patients with resectable perihilar cholangiocarcinoma: a multicentre, randomised controlled trial.
      ,
      • Wiggers J.K.
      • Coelen R.J.
      • Rauws E.A.
      • van Delden O.M.
      • van Eijck C.H.
      • de Jonge J.
      • et al.
      Preoperative endoscopic versus percutaneous transhepatic biliary drainage in potentially resectable perihilar cholangiocarcinoma (DRAINAGE trial): design and rationale of a randomized controlled trial.
      The trial included 54 patients and was terminated at 50% accrual because of higher mortality in the PTBD group (11% EBD versus 41% PTBD). Post-drainage related complications were comparable between both groups (67% EBD versus 63% PTBD). In addition, 15 (56%) patients treated with initial EBD required additional PTBD, whereas one (4%) patient required EBD after PTBD. For the initial study analysis, patients were followed until 90 days after surgery.
      The INTERCPT study, a second RCT that compared PTBD and EBD in suspected malignant biliary hilar obstruction, was prematurely terminated due to slow accrual.
      • Al-Kawas F.
      • Aslanian H.
      • Baillie J.
      • Banovac F.
      • Buscaglia J.M.
      • Buxbaum J.
      • et al.
      Percutaneous transhepatic vs. endoscopic retrograde biliary drainage for suspected malignant hilar obstruction: study protocol for a randomized controlled trial.
      ,
      • Elmunzer B.J.
      • Smith Z.L.
      • Tarnasky P.
      • Wang A.Y.
      • Yachimski P.
      • Banovac F.
      • et al.
      An unsuccessful randomized trial of percutaneous vs endoscopic drainage of suspected malignant hilar obstruction.
      Only 13 patients were included. This study also showed high morbidity and mortality rates. Post-drainage related complications were comparable between both groups (75% EBD versus 80% PTBD). In addition, eight patients died within 3 months follow-up (50% EBD versus 80% PTBD).
      No other RCTs or prospective cohort studies comparing EBD and PTBD have been published. Therefore, no long-term follow-up studies comparing EBD and PTBD in potentially resectable pCCA patients are available. Short-term complications found in both the DRAINAGE trial and INTERCPT study have a significant impact on long-term OS. Therefore, the primary objective of present study was to compare OS after EBD and PTBD for potentially resectable pCCA in the DRAINAGE trial.

      Methods

      Study population

      The DRAINAGE trial was a multicenter randomized controlled trial including patients with potentially resectable pCCA requiring biliary drainage prior to a planned major hepatectomy.
      • Coelen R.J.S.
      • Roos E.
      • Wiggers J.K.
      • Besselink M.G.
      • Buis C.I.
      • Busch O.R.C.
      • et al.
      Endoscopic versus percutaneous biliary drainage in patients with resectable perihilar cholangiocarcinoma: a multicentre, randomised controlled trial.
      ,
      • Wiggers J.K.
      • Coelen R.J.
      • Rauws E.A.
      • van Delden O.M.
      • van Eijck C.H.
      • de Jonge J.
      • et al.
      Preoperative endoscopic versus percutaneous transhepatic biliary drainage in potentially resectable perihilar cholangiocarcinoma (DRAINAGE trial): design and rationale of a randomized controlled trial.

      Follow-up after trial ending

      Follow-up data until dead or last follow-up of all patients included in the DRAINAGE trial were included in this study. For patients who underwent resection, follow-up data were collected starting from the trial endpoint.
      • Coelen R.J.S.
      • Roos E.
      • Wiggers J.K.
      • Besselink M.G.
      • Buis C.I.
      • Busch O.R.C.
      • et al.
      Endoscopic versus percutaneous biliary drainage in patients with resectable perihilar cholangiocarcinoma: a multicentre, randomised controlled trial.
      Data included survival, disease recurrence or progression, presence of (seeding) metastases and adjuvant or palliative chemotherapy. In addition, the number of drainage procedures, drainage complications and readmissions after the end of DRAINAGE trial follow-up were included.

      Outcomes

      Primary outcome was OS according to initial biliary drainage type. Secondary outcomes were disease free survival (DFS) or progression free survival (PFS), the number of readmissions, days of readmission, number of re-interventions after ending of the initial trial, metal stent placements, permanent external drains, and drainage related complications. Readmissions included all in-hospital admissions (short stay or day treatment admissions for planned stent revisions and emergency department visits without admission were excluded). Unplanned stent placements were placements or revisions due to dislocation or leaking drains, recurrent biliary obstruction due to stent obstruction, dysfunction, or replacements during unplanned readmissions. Planned stent placements were defined as all scheduled stent/drain exchanges and revisions.

      Statistical analysis

      Normally distributed continuous variables were presented as mean ± standard deviation (SD) and, non-normal distributed continuous variables as median with interquartile range. Comparisons between EBD and PTBD were analyzed using chi-square tests for proportions, Mann–Whitney U test for medians and independent sample T test for means. OS, disease free survival, and progression free survival were calculated using the Kaplan–Meier method. Survival curves were compared using the log-rank test. OS was measured from date of randomization to date of death or last follow-up. PFS was calculated from the day of chemotherapy start until the day of disease progression or last radiological imaging. DFS was calculated from the day of resection until the day of recurrent disease or last radiological imaging. The reverse Kaplan–Meier based method was used to calculate median follow-up. Analysis were performed according to an intention-to-treat principle. A P-value of <0.05 was considered statistically significant. Data were analyzed using IBM SPSS statistics, version 25.0 (IBM Corp). Survival curves were displayed using GraphPad Prism 8.

      Results

      Trial treatment and patient characteristics

      A total of 54 patients were included in the DRAINAGE trial, twenty-seven patients in each arm. Out of 54 patients, 12 (22%) did not undergo an explorative laparotomy due to occult metastasis (n = 3), local tumor progression (n = 3), clinical deterioration (n = 2), benign disease (n = 1), or pre-operative mortality (n = 3). 42 patients were operated of whom 19 (45%) patients underwent exploration without resection and 23 (55%) underwent resection. This included 12 patients out of the EBD (44%) and 11 patients out of the PTBD (41%) group. During the trial, the median number of stent or drain placements was 2
      • Ruzzenente A.
      • Bagante F.
      • Olthof P.B.
      • Aldrighetti L.
      • Alikhanov R.
      • Cescon M.
      • et al.
      Surgery for Bismuth-Corlette type 4 perihilar cholangiocarcinoma: results from a western multicenter collaborative group.
      ,
      • Valle J.W.
      • Borbath I.
      • Khan S.A.
      • Huguet F.
      • Gruenberger T.
      • Arnold D.
      Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      for the EBD group and 2
      • Ruzzenente A.
      • Bagante F.
      • Olthof P.B.
      • Aldrighetti L.
      • Alikhanov R.
      • Cescon M.
      • et al.
      Surgery for Bismuth-Corlette type 4 perihilar cholangiocarcinoma: results from a western multicenter collaborative group.
      ,
      • Valle J.W.
      • Borbath I.
      • Khan S.A.
      • Huguet F.
      • Gruenberger T.
      • Arnold D.
      Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      for the PTBD group. A flow diagram of the study is displayed in Fig. 1. All baseline characteristics are displayed in Table 1.
      Figure 1
      Figure 1Flowchart of patients in the DRAINAGE trial
      Table 1Baseline characteristics
      Total (n = 54)EBD (n = 27)PTBD (n = 27)
      Age (years)69.2 (61.2–73.5)66.9 (60.8–72.9)69.8 (64.1–73.5)
      Male patients36 (67%)18 (67%)18 (67%)
      ECOG performance status
      Age at inclusion.
       019 (35%)9 (33%)10 (37%)
       120 (37%)9 (33%)11 (41%)
       212 (22%)6 (22%)6 (22%)
      Bismuth-Corlette classification
       11 (2%)1 (4%)0
       24 (7%)3 (11%)1 (4%)
       3A22 (41%)10 (37%)12 (44%)
       3B11 (20%)4 (15%)7 (26%)
       416 (30%)9 (33%)7 (26%)
      DRAINAGE trial (intention to treat)54 (100%)27 (100%)27 (100%)
      DRAINAGE trial (per protocol)54 (100%)21 (78%)33 (122%)
      Exploratory laparotomy42 (78%)22 (81%)20 (74%)
      Resection
      Resection details excluding patients with benign disease (total, n = 20).
      23 (43%)12 (44%)11 (41%)
      resection margin
       R09 (45%)4 (40%)5 (50%)
       R1/R211 (55%)6 (60%)5 (50%)
      T stage
       T211 (55%)5 (50%)6 (60%)
       T37 (35%)4 (40%)3 (30%)
       T42 (10%)1 (10%)1 (10%)
      Lymph node status
       N08 (40%)2 (20%)6 (60%)
       N112 (60%)8 (80%)4 (40%)
      Differentiation
      Well differentiated2 (10%)02 (20%)
      Poorly differentiated18 (90%)10 (100%)8 (80%)
      Benign disease
      n = 3 resected, EBD = endoscopic biliary drainage, PTBD = percutaneous biliary drainage.
      4 (7%)3 (11%)1 (4%)
      a Resection details excluding patients with benign disease (total, n = 20).
      b n = 3 resected, EBD = endoscopic biliary drainage, PTBD = percutaneous biliary drainage.
      c Age at inclusion.
      Table 2Secondary outcomes
      Total (n = 54)EBD (n = 27)PTBD (n = 27)P value
      P-values based on complete case analysis unless unknown is displayed. Statistical analysis using chi square test. EBD = endoscopic biliary drainage, PTBD = percutaneous biliary drainage.
      (EBD vs PTBD)
      Chemotherapy
       Adjuvant2 (9%)02 (7%)0.211
       Palliative8 (26%)5 (19%)3 (11%)0.406
      Recurrence11 (48%)8 (30%)3 (11%)0.087
       Local recurrence10 (43%)7 (26%)3 (11%)1.000
       Peritoneum1 (4%)1 (4%)0
      Progression after chemotherapy5 (16%)2 (7%)3 (11%)1.000
      a P-values based on complete case analysis unless unknown is displayed. Statistical analysis using chi square test. EBD = endoscopic biliary drainage, PTBD = percutaneous biliary drainage.

      Overall survival

      Follow-up data were available for all 54 patients. 47 patients (87%) died during follow-up and median follow-up of patients alive at last follow-up was 62 months (95% CI 54–70). This was 65 months (95% 59–71) in the EBD and 56 months (95% CI 35–77) in the PTBD group. Median OS from randomization was not significantly different between study arms; 13 months (95% CI 7.9–18.1) in the EBD and 7 months (95% CI 0.00–17.2) in the PTBD group (P = 0.28) (Fig. 2). The 1-, 3- and 5-year OS rates were 52%, 26% and 14% after initial EBD and 44%, 19% and 11% after initial PTBD, respectively.
      Figure 2
      Figure 2Kaplan–Meier curve of overall survival after PTBD and EBD for overall pCCA cohort
      When the group was further divided in a resected (n = 23) and unresected (n = 31) subgroup, OS was not significantly different between drainage types. In the resected group, median OS was 15 months (95% CI 2.6–27.5) in the EBD and 17 months (95% CI 0–35.6) in the PTBD group (P = 0.75). This included seven patients with 90-day post-operative mortality (n = 2 EBD and n = 5 PTBD). In the unresected group, median OS was 11 months (95% CI 7.3–14.7) in the EBD group and 7 months (95% CI 3.1–10.9) in the PTBD group, respectively (P = 0.31).

      Recurrence and disease-free survival, progression, and progression free survival

      Two out of the 23 (9%) resected patients received adjuvant chemotherapy. During follow-up, eleven patients (48%, n = 8 EBD and n = 3 PTBD (P = 0.41)) had disease recurrence. One of these patients received adjuvant chemotherapy. Ten patients who underwent resection had local recurrence (n = 7 EBD and n = 3 PTBD) and one patient (EBD group) had peritoneal recurrence. Three of these eleven patients received palliative chemotherapy. For the patients who underwent resection, median time to recurrence was 15 months (95% CI 9.5–20.5). The median time to recurrence was not significantly different between EBD and PTBD group; 15 months (95% CI 7.6–22.4) and 17 months (95% CI 10.6–23.4), respectively (P = 0.42).
      Eight out of 31 (26%) patients who did not undergo a resection received palliative chemotherapy. Five out of eight patients (63%, n = 2 EBD, n = 3 PTBD (P = 1.0)) had progression after chemotherapy. For the overall group, median time to progression was 9 months (95% CI 0–20.0). The median time to progression was not significantly different between groups; 33 months (95% CI could not be executed) for the EBD group vs 9 months (95% CI 0–23.4) for the PTBD group (P = 0.24). All secondary outcomes are displayed in Table 2.

      Readmissions and stent revisions

      Twenty of 54 patients (37%, n = 8 EBD vs n = 12 PTBD, P = 0.43) were readmitted at least once after trial ending, 13 patients due to drainage-related complications (24%, n = 7 EBD and n = 6 PTBD, P = 0.25) (Table 3). Note that 14 out of these 54 patients died within the trial. The median number of readmissions was 1.
      • Cillo U.
      • Fondevila C.
      • Donadon M.
      • Gringeri E.
      • Mocchegiani F.
      • Schlitt H.J.
      • et al.
      Surgery for cholangiocarcinoma.
      ,
      • Ruzzenente A.
      • Bagante F.
      • Olthof P.B.
      • Aldrighetti L.
      • Alikhanov R.
      • Cescon M.
      • et al.
      Surgery for Bismuth-Corlette type 4 perihilar cholangiocarcinoma: results from a western multicenter collaborative group.
      There were no differences between groups; 1
      • Cillo U.
      • Fondevila C.
      • Donadon M.
      • Gringeri E.
      • Mocchegiani F.
      • Schlitt H.J.
      • et al.
      Surgery for cholangiocarcinoma.
      • Ruzzenente A.
      • Bagante F.
      • Olthof P.B.
      • Aldrighetti L.
      • Alikhanov R.
      • Cescon M.
      • et al.
      Surgery for Bismuth-Corlette type 4 perihilar cholangiocarcinoma: results from a western multicenter collaborative group.
      • Valle J.W.
      • Borbath I.
      • Khan S.A.
      • Huguet F.
      • Gruenberger T.
      • Arnold D.
      Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      for the EBD group and 1
      • Cillo U.
      • Fondevila C.
      • Donadon M.
      • Gringeri E.
      • Mocchegiani F.
      • Schlitt H.J.
      • et al.
      Surgery for cholangiocarcinoma.
      ,
      • Ruzzenente A.
      • Bagante F.
      • Olthof P.B.
      • Aldrighetti L.
      • Alikhanov R.
      • Cescon M.
      • et al.
      Surgery for Bismuth-Corlette type 4 perihilar cholangiocarcinoma: results from a western multicenter collaborative group.
      for the PTBD group (P = 0.50). The median time of hospitalization after readmission was also not significantly different; for the EBD group this was 10 (2–27) days and for the PTBD group this was 13
      • Nakanishi Y.
      • Tsuchikawa T.
      • Okamura K.
      • Nakamura T.
      • Tamoto E.
      • Noji T.
      • et al.
      Risk factors for a high Comprehensive Complication Index score after major hepatectomy for biliary cancer: a study of 229 patients at a single institution.
      • Coelen R.J.S.
      • Roos E.
      • Wiggers J.K.
      • Besselink M.G.
      • Buis C.I.
      • Busch O.R.C.
      • et al.
      Endoscopic versus percutaneous biliary drainage in patients with resectable perihilar cholangiocarcinoma: a multicentre, randomised controlled trial.
      • Chen G.F.
      • Yu W.D.
      • Wang J.R.
      • Qi F.Z.
      • Qiu Y.D.
      The methods of preoperative biliary drainage for resectable hilar cholangiocarcinoma patients: a protocol for systematic review and meta analysis.
      • Yang G.
      • Xiong Y.
      • Sun J.
      • Tang T.
      • Li W.
      • Wang G.
      • et al.
      Effects of different preoperative biliary drainage methods for resected malignant obstruction jaundice on the incidence rate of implantation metastasis: a meta-analysis.
      • Al-Kawas F.
      • Aslanian H.
      • Baillie J.
      • Banovac F.
      • Buscaglia J.M.
      • Buxbaum J.
      • et al.
      Percutaneous transhepatic vs. endoscopic retrograde biliary drainage for suspected malignant hilar obstruction: study protocol for a randomized controlled trial.
      • Kawakami H.
      • Kuwatani M.
      • Onodera M.
      • Haba S.
      • Eto K.
      • Ehira N.
      • et al.
      Endoscopic nasobiliary drainage is the most suitable preoperative biliary drainage method in the management of patients with hilar cholangiocarcinoma.
      • Wiggers J.K.
      • Coelen R.J.
      • Rauws E.A.
      • van Delden O.M.
      • van Eijck C.H.
      • de Jonge J.
      • et al.
      Preoperative endoscopic versus percutaneous transhepatic biliary drainage in potentially resectable perihilar cholangiocarcinoma (DRAINAGE trial): design and rationale of a randomized controlled trial.
      • Elmunzer B.J.
      • Smith Z.L.
      • Tarnasky P.
      • Wang A.Y.
      • Yachimski P.
      • Banovac F.
      • et al.
      An unsuccessful randomized trial of percutaneous vs endoscopic drainage of suspected malignant hilar obstruction.
      • Hajibandeh S.
      • Hajibandeh S.
      • Satyadas T.
      Endoscopic versus percutaneous preoperative biliary drainage in patients with Klatskin tumor undergoing curative surgery: a systematic review and meta-analysis of short-term and long-term outcomes.
      • Zhang X.F.
      • Beal E.W.
      • Merath K.
      • Ethun C.G.
      • Salem A.
      • Weber S.M.
      • et al.
      Oncologic effects of preoperative biliary drainage in resectable hilar cholangiocarcinoma: percutaneous biliary drainage has no adverse effects on survival.
      • Wiggers J.K.
      • Groot Koerkamp B.
      • Coelen R.J.
      • Doussot A.
      • van Dieren S.
      • Rauws E.A.
      • et al.
      Percutaneous preoperative biliary drainage for resectable perihilar cholangiocarcinoma: No association with survival and No increase in seeding metastases.
      • Groot Koerkamp B.
      • Wiggers J.K.
      • Allen P.J.
      • Besselink M.G.
      • Blumgart L.H.
      • Busch O.R.
      • et al.
      Recurrence rate and pattern of perihilar cholangiocarcinoma after curative intent resection.
      • Komaya K.
      • Ebata T.
      • Yokoyama Y.
      • Igami T.
      • Sugawara G.
      • Mizuno T.
      • et al.
      Recurrence after curative-intent resection of perihilar cholangiocarcinoma: analysis of a large cohort with a close postoperative follow-up approach.
      • O'Brien S.
      • Bhutiani N.
      • Egger M.E.
      • Brown A.N.
      • Weaver K.H.
      • Kline D.
      • et al.
      Comparing the efficacy of initial percutaneous transhepatic biliary drainage and endoscopic retrograde cholangiopancreatography with stenting for relief of biliary obstruction in unresectable cholangiocarcinoma.
      • Kogure H.
      • Kato H.
      • Kawakubo K.
      • Ishiwatari H.
      • Katanuma A.
      • Okabe Y.
      • et al.
      A prospective multicenter study of "inside stents" for biliary stricture: multicenter evolving inside stent registry (MEISteR).
      • Hameed A.
      • Pang T.
      • Chiou J.
      • Pleass H.
      • Lam V.
      • Hollands M.
      • et al.
      Percutaneous vs. endoscopic pre-operative biliary drainage in hilar cholangiocarcinoma - a systematic review and meta-analysis.
      • Nakamura S.
      • Ishii Y.
      • Serikawa M.
      • Tsuboi T.
      • Kawamura R.
      • Tsushima K.
      • et al.
      Utility of the inside stent as a preoperative biliary drainage method for patients with malignant perihilar biliary stricture.
      days (P = 0.72).
      Table 3Secondary outcomes
      Total (n = 54)EBD (n = 27)PTBD (n = 27)P value
      P-values based on complete case analysis unless unknown is displayed. Statistical analysis using chi square test but # Mann–Whitney U test.
      (EBD vs PTBD)
      totalUnresected (n = 15)Resected (n = 12)TotalUnresected (n = 16)Resected (n = 11)
      Re-admissions20 (37%)8 (30%)4 (27%)4 (33%)12 (44%)7 (44%)5 (45%)0.425
      Number of re-admissions1.000
       114 (26%)6 (22%)3 (20%)3 (25%)9 (33%)5 (31%)4 (36%)
       2 or more6 (11%)2 (7%)1 (7%)1 (8%)3 (11%)2 (13%)1 (9%)
      Number or re-admissions (median)1 (1–2)1 (1–3)1 (1–3)1 (1–3)1 (1–2)1 (1–2)1 (1–3)0.504
      Days of hospitalization after readmission
      Median, in case of multiple readmissions, only the first readmission was taken. EBD = endoscopic biliary drainage, PTBD = percutaneous biliary drainage, SEMS = self-expandable metallic stent.
      12 (3–24)10 (2–27)3 (2 – x)10 (4–23)13 (3–23)13 (7–23)11 (2–24)0.715
      Readmission due to:0.254
       Drainage related problems13 (24%)7 (26%)4 (27%)3 (25%)6 (22%)4 (25%)2 (18%)
       Ascites2 (4%)1 (4%)01 (8%)1 (4%)01 (9%)
       Liver abscess3 (6%)0003 (11%)2 (13%)1 (9%)
       Other2 (4%)0002 7%)1 (6%)1 (9%)
      Stent placement after trial
       Patients28 (52%)13 (48%)10 (67%)3 (25%)15 (56%)13 (81%)2 (18%)0.802
       Stent/drain placements (median)2 (1–4)2 (2–4)2 (2–4)2 (1 – x)2 (1–3)2 (1–2)8 (7 – x)0.770#
       Planned (median)1 (1–2)1 (1–2)1 (1–3)1 (1–1)1 (1–2)1 (1–2)5 (5–5)0.816#
       Unplanned (median)1 (1–3)1 (1–3)1 (1–2)2 (1 – x)2 (1–3)1 (1–2)3 (2 – x)0.641#
       SEMS20 (37%)7 (26%)7 (47%)013 (48%)12 (75%)1 (9%)0.079
       Permanent external drainage5 (9%)4 (15%)2 (13%)2 (17%)1 (4%)01 (9%)
       Stent in SEMS8 (15%)3 (11%)3 (20%)05 (19%)4 (25%)1 (9%)1.000
      Number of drainage procedures0.898
       18 (15%)3 (11%)2 (13%)1 (8%)5 (19%)5 (31%)0
       212 (22%)6 (22%)5 (33%)1 (8%)6 (22%)6 (38%)0
       ≥38 (15%)4 (15%)3 (20%)1 (8%)4 (15%)2 (13%)2 (18%)
      a P-values based on complete case analysis unless unknown is displayed. Statistical analysis using chi square test but # Mann–Whitney U test.
      b Median, in case of multiple readmissions, only the first readmission was taken. EBD = endoscopic biliary drainage, PTBD = percutaneous biliary drainage, SEMS = self-expandable metallic stent.
      In the complete cohort, a total of 76 drainage procedures with stent or drain placements were performed in 28 patients after trial ending. This concerned, 23 procedures in patients who underwent resection and 53 procedures in patients wo did not undergo a resection. The median number of stent or drain placements per patient was 2.
      • Cillo U.
      • Fondevila C.
      • Donadon M.
      • Gringeri E.
      • Mocchegiani F.
      • Schlitt H.J.
      • et al.
      Surgery for cholangiocarcinoma.
      • Ruzzenente A.
      • Bagante F.
      • Olthof P.B.
      • Aldrighetti L.
      • Alikhanov R.
      • Cescon M.
      • et al.
      Surgery for Bismuth-Corlette type 4 perihilar cholangiocarcinoma: results from a western multicenter collaborative group.
      • Valle J.W.
      • Borbath I.
      • Khan S.A.
      • Huguet F.
      • Gruenberger T.
      • Arnold D.
      Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      • Wiggers J.K.
      • Groot Koerkamp B.
      • Cieslak K.P.
      • Doussot A.
      • van Klaveren D.
      • Allen P.J.
      • 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.
      A total of 32 drainage procedures were performed in 13 patients of the EBD group and 44 drainage procedures were performed in 15 patients of the PTBD group. The median number of stent or drain placements was 2
      • Ruzzenente A.
      • Bagante F.
      • Olthof P.B.
      • Aldrighetti L.
      • Alikhanov R.
      • Cescon M.
      • et al.
      Surgery for Bismuth-Corlette type 4 perihilar cholangiocarcinoma: results from a western multicenter collaborative group.
      • Valle J.W.
      • Borbath I.
      • Khan S.A.
      • Huguet F.
      • Gruenberger T.
      • Arnold D.
      Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      • Wiggers J.K.
      • Groot Koerkamp B.
      • Cieslak K.P.
      • Doussot A.
      • van Klaveren D.
      • Allen P.J.
      • 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.
      for the EBD group and 2
      • Cillo U.
      • Fondevila C.
      • Donadon M.
      • Gringeri E.
      • Mocchegiani F.
      • Schlitt H.J.
      • et al.
      Surgery for cholangiocarcinoma.
      • Ruzzenente A.
      • Bagante F.
      • Olthof P.B.
      • Aldrighetti L.
      • Alikhanov R.
      • Cescon M.
      • et al.
      Surgery for Bismuth-Corlette type 4 perihilar cholangiocarcinoma: results from a western multicenter collaborative group.
      • Valle J.W.
      • Borbath I.
      • Khan S.A.
      • Huguet F.
      • Gruenberger T.
      • Arnold D.
      Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      for the PTBD group (P = 0.77). For the resected patients, stent or drain placements all consisted of PTBD replacements due to the Roux-Y construction present after resection, making endoscopic access more challenging. In this group, no double balloon enteroscopy-assisted EBD procedures were performed. Out of all 76 drainage procedures, 48 (63%) were planned and 28 (37%) were unplanned. In the EBD group 13 of 32 (41%) procedures were unplanned. In the PTBD group, 15 of 44 (34%) procedures were unplanned.
      Self-expandable metal stents (SEMS) were placed in 20 (37%) patients (n = 7 EBD vs n = 12 PTBD, P = 0.08). Five patients (9%) received permanent external drainage. In 13 patients, SEMS placement was the first stent procedure after trial ending. In eight (15%) patients stent in stent placement after initial SEMS was necessary. Presents a follow-up figure of all 54 patients, including stent revisions, metal stent placement (adjuvant or palliative) chemotherapy and recurrent disease.

      Discussion

      The present long-term follow-up data of a randomized trial on preoperative biliary drainage in perihilar cholangiocarcinoma showed no difference in terms of survival, readmissions and additional drainage procedures between patients who underwent endoscopic or percutaneous biliary drainage. Poor survival was observed in the overall group and there was a high rate of unplanned post-trial readmissions mostly due to stent-related complications.
      The poor survival in the patients who underwent resection could partly be attributed to the high perioperative mortality, both after initial biliary drainage and after surgical resection. In addition, approximately half of the patients who underwent resection had recurrence within one year. The survival of patients with unresectable disease observed in this study was also poor. Only a small number of patients received palliative chemotherapy with moderate PFS as a result, reflecting the poor tumor biology of pCCA.
      Most available studies comparing preoperative EBD and PTBD in patients with pCCA only described patients who eventually underwent resection and excluded patients with unresectable disease or patients with inadequate biliary drainage or clinical deterioration after biliary drainage. Such studies are prone to selection bias. The present, unselected cohort of patients from a randomized trial represent a unique group, but also makes comparison of results with previous retrospective studies difficult.
      • Chen G.F.
      • Yu W.D.
      • Wang J.R.
      • Qi F.Z.
      • Qiu Y.D.
      The methods of preoperative biliary drainage for resectable hilar cholangiocarcinoma patients: a protocol for systematic review and meta analysis.
      ,
      • Yang G.
      • Xiong Y.
      • Sun J.
      • Tang T.
      • Li W.
      • Wang G.
      • et al.
      Effects of different preoperative biliary drainage methods for resected malignant obstruction jaundice on the incidence rate of implantation metastasis: a meta-analysis.
      ,
      • Hajibandeh S.
      • Hajibandeh S.
      • Satyadas T.
      Endoscopic versus percutaneous preoperative biliary drainage in patients with Klatskin tumor undergoing curative surgery: a systematic review and meta-analysis of short-term and long-term outcomes.
      A retrospective study comparing EBD and PTBD in 196 patients with resectable pCCA found a median disease specific survival of 44 versus 37 months and a recurrence free survival of 27 versus 24 months.
      • Zhang X.F.
      • Beal E.W.
      • Merath K.
      • Ethun C.G.
      • Salem A.
      • Weber S.M.
      • et al.
      Oncologic effects of preoperative biliary drainage in resectable hilar cholangiocarcinoma: percutaneous biliary drainage has no adverse effects on survival.
      Another propensity score matched study with 245 patients with resectable pCCA found a median OS of 38 months for both EBD and PTBD.
      • Wiggers J.K.
      • Groot Koerkamp B.
      • Coelen R.J.
      • Doussot A.
      • van Dieren S.
      • Rauws E.A.
      • et al.
      Percutaneous preoperative biliary drainage for resectable perihilar cholangiocarcinoma: No association with survival and No increase in seeding metastases.
      Three recently published systematic reviews on EBD versus PTBD in the preoperative setting included a total of 14 different, mainly retrospective cohort studies. These reviews found no statistically difference in post-operative mortality. However, an increased incidence of implantation metastasis in the PTBD group was found (OR = 0.35, 95% CI: 0.23–0.53, P < 0.001). EBD was found to be associated with fewer 5-year recurrences and better 5-year OS, which could possibly be attributed to the fact that patients with PTBD had more advanced disease.
      • Chen G.F.
      • Yu W.D.
      • Wang J.R.
      • Qi F.Z.
      • Qiu Y.D.
      The methods of preoperative biliary drainage for resectable hilar cholangiocarcinoma patients: a protocol for systematic review and meta analysis.
      ,
      • Yang G.
      • Xiong Y.
      • Sun J.
      • Tang T.
      • Li W.
      • Wang G.
      • et al.
      Effects of different preoperative biliary drainage methods for resected malignant obstruction jaundice on the incidence rate of implantation metastasis: a meta-analysis.
      ,
      • Hajibandeh S.
      • Hajibandeh S.
      • Satyadas T.
      Endoscopic versus percutaneous preoperative biliary drainage in patients with Klatskin tumor undergoing curative surgery: a systematic review and meta-analysis of short-term and long-term outcomes.
      In our study, only one patient had peritoneal recurrence, which was located at the cross-over PTBD puncture track and therefore appeared to be an implantation metastasis. In addition, the median disease-free survival of 15 months in the present study was shorter compared to results found in these reviews and two other studies investigating recurrence patterns in patients with pCCA.
      • Groot Koerkamp B.
      • Wiggers J.K.
      • Allen P.J.
      • Besselink M.G.
      • Blumgart L.H.
      • Busch O.R.
      • et al.
      Recurrence rate and pattern of perihilar cholangiocarcinoma after curative intent resection.
      ,
      • Komaya K.
      • Ebata T.
      • Yokoyama Y.
      • Igami T.
      • Sugawara G.
      • Mizuno T.
      • et al.
      Recurrence after curative-intent resection of perihilar cholangiocarcinoma: analysis of a large cohort with a close postoperative follow-up approach.
      Taking a closer look at the differences between EBD and PTBD in unresected patients, the literature shows comparable results. A recent study described 87 patients with unresectable pCCA who underwent initial EBD and PTBD.
      • O'Brien S.
      • Bhutiani N.
      • Egger M.E.
      • Brown A.N.
      • Weaver K.H.
      • Kline D.
      • et al.
      Comparing the efficacy of initial percutaneous transhepatic biliary drainage and endoscopic retrograde cholangiopancreatography with stenting for relief of biliary obstruction in unresectable cholangiocarcinoma.
      They found a median number of 1.0 (EBD) and 3.5 (PTBD) hospital readmissions, which is comparable to the results found in our unresectable EBD cohort but not for the PTBD cohort. They also found that 70% of the patients required multiple procedures with similar results for EBD and PTBD which is comparable to our study.
      Another interesting finding of the present study is that only ten patients received chemotherapy (eight palliative and two adjuvant). Most of the patients had a poor performance status and were therefore not able to receive palliative chemotherapy. In addition, in the Netherlands, adjuvant chemotherapy was until recently only available in trial setting (ACTICCA-1 study, NCT02170090). Which could explain this small number.
      Better techniques and stent technology to ensure adequate drainage without complications are necessary, and therefore several new approaches are currently being investigated. For example, a stent can be placed through endoscopic retrograde cholangiography above the papilla with the retrieval thread in the duodenum (inside stent). A study including 106 patients with malignant strictures found 8% post-drainage related complications
      • Kogure H.
      • Kato H.
      • Kawakubo K.
      • Ishiwatari H.
      • Katanuma A.
      • Okabe Y.
      • et al.
      A prospective multicenter study of "inside stents" for biliary stricture: multicenter evolving inside stent registry (MEISteR).
      instead of the approximately 30% expected with the current stents.
      • Hameed A.
      • Pang T.
      • Chiou J.
      • Pleass H.
      • Lam V.
      • Hollands M.
      • et al.
      Percutaneous vs. endoscopic pre-operative biliary drainage in hilar cholangiocarcinoma - a systematic review and meta-analysis.
      Another study including 41 patients with malignant perihilar strictures receiving an inside stent, found 10% drainage-related complications but also an in-hospital mortality rate of 7.3%.
      • Nakamura S.
      • Ishii Y.
      • Serikawa M.
      • Tsuboi T.
      • Kawamura R.
      • Tsushima K.
      • et al.
      Utility of the inside stent as a preoperative biliary drainage method for patients with malignant perihilar biliary stricture.
      In addition, additional therapy (e.g., endobiliary radiofrequency ablation) prior to stenting could prolong stent patency and therefore outcome.
      • Sofi A.A.
      • Khan M.A.
      • Das A.
      • Sachdev M.
      • Khuder S.
      • Nawras A.
      • et al.
      Radiofrequency ablation combined with biliary stent placement versus stent placement alone for malignant biliary strictures: a systematic review and meta-analysis.
      ,
      • Yang J.
      • Wang J.
      • Zhou H.
      • Zhou Y.
      • Wang Y.
      • Jin H.
      • et al.
      Efficacy and safety of endoscopic radiofrequency ablation for unresectable extrahepatic cholangiocarcinoma: a randomized trial.
      However, this might be more applicable in the palliative setting. There are also several new percutaneous options being investigated. For example percutaneous trans hepatic stenting with plastic or (fully covered) metal stents.
      • Kim J.Y.
      • Lee S.G.
      • Kang D.
      • Lee D.K.
      • Park J.K.
      • Lee K.T.
      • et al.
      The comparison of endoscopic biliary drainage in malignant hilar obstruction by cholangiocarcinoma: Bilateral metal stents versus multiple plastic stents.
      Large prospective studies are necessary to investigate and proof its superiority to current methods.
      This study has several limitations. First, due to a relatively small cohort of only 54 patients, some analyses were subject to small number of patients or low number of events. Besides, for this study an overall survival primary endpoint was chosen although this was not the primary endpoint of the initial DRAINAGE trial. Therefore, numbers are probably underpowered. In addition, these comparisons are based on an intention to treat principle, which should in theory lead to a decrease in bias. However, 16 out of the 54 patients (30%, 15 out of the 27 patients in the EBD group (56%)) of the patients required crossover treatment during the DRAINAGE trial, which could have led to a skewed distribution.
      In conclusion, this study aimed to provide insight into the long-term outcomes of an unselected group of patients with potentially resectable pCCA. Although numbers of patients might not be sufficient, no long-term differences in terms of survival, readmissions, and drainage procedures for EBD and PTBD were found, even when comparing the resected and unresected group. For this study cohort, OS was poor and a high rate of unplanned readmissions mostly due to stent-related complications were observed. This study highlights the urgent need for improvement and standardization in the care for patients with pCCA.

      Conflict of interest

      None to declare.

      Acknowledgments

      Funding for data management was received from the Dutch Cancer Foundation (grant number UVA 2013–5925).

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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