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Clinical outcomes of biliary drainage of malignant biliary obstruction due to colorectal cancer metastases: A systematic review

Open AccessPublished:April 27, 2021DOI:https://doi.org/10.1016/j.ejim.2021.03.032

      Highlights

      • Effective drainage of malignant biliary obstruction in mCRC patients can be challenging.
      • Repeat ERCP or PTC are frequently required.
      • Adverse events are common, mostly consisting of cholangitis.
      • Survival significantly improved in patients who could receive subsequent systemic therapy.

      Abstract

      Background and aims

      Malignant biliary obstruction is an ominous complication of metastatic colorectal cancer (mCRC). Biliary drainage is frequently performed to relieve symptoms of jaundice or enable palliative systemic therapy, but effective drainage can be difficult to accomplish. The aim of this study is to summarize literature on clinical outcomes of biliary drainage in mCRC patients with malignant biliary obstruction.

      Methods

      We searched Medline and EMBASE for studies that included patients with malignant biliary obstruction secondary to mCRC, treated with endoscopic and/or percutaneous biliary drainage. We summarized available data on technical success, clinical success, adverse events, systemic therapy administration and survival after biliary drainage.

      Results

      After screening 3584 references and assessing 509 full-text articles, seven cohort studies were included. In these studies, rates of technical success, clinical success and adverse events varied between 63%-94%, 42%-81%, and 19%-39%, respectively. Subsequent chemotherapy was administered in 17%-56% of patients. Overall survival varied between 40 and 122 days across studies (278-365 days in patients who received subsequent chemotherapy, 42-61 days in patients who did not).

      Conclusions

      Successful biliary drainage in mCRC patients can be challenging to achieve and is frequently associated with adverse events. Overall survival after biliary drainage is limited, but is significantly longer in patients treated with subsequent systemic therapy. Expected benefits of biliary drainage should be carefully weighed against its risks.

      Keywords

      Abbreviations:

      mCRC (metastatic colorectal cancer)

      1. Introduction

      Malignant biliary obstruction is an ominous complication of metastatic colorectal cancer (mCRC) and is associated with a poor prognosis.[
      • Nichols S.D.
      • Albert S.
      • Shirley L.
      • et al.
      Outcomes in patients with obstructive jaundice from metastatic colorectal cancer and implications for management.
      ,
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ,
      • Walia T.
      • Quevedo J.F.
      • Hobday T.J.
      • et al.
      Colorectal cancer patients with liver metastases and severe hyperbilirubinemia: a consecutive series that explores the benefits and risks of chemotherapy.
      ] It has been reported to occur in 10% of patients with known mCRC.[
      • Nichols S.D.
      • Albert S.
      • Shirley L.
      • et al.
      Outcomes in patients with obstructive jaundice from metastatic colorectal cancer and implications for management.
      ] Malignant biliary obstruction can be caused by either intrahepatic metastases or extrahepatic lymph node or peritoneal metastases located at the liver hilum or along the extrahepatic bile duct. It significantly impacts clinical outcomes and is often treated in palliative settings. Median survival after the onset of jaundice is only around one month when treated with supportive care.[
      • Nichols S.D.
      • Albert S.
      • Shirley L.
      • et al.
      Outcomes in patients with obstructive jaundice from metastatic colorectal cancer and implications for management.
      ,
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ,
      • Walia T.
      • Quevedo J.F.
      • Hobday T.J.
      • et al.
      Colorectal cancer patients with liver metastases and severe hyperbilirubinemia: a consecutive series that explores the benefits and risks of chemotherapy.
      ] Improved palliative systemic therapy regimens, along with increased use of hepatic resections, showed improved overall survival in mCRC patients. Some agents however, in particular irinotecan, are contraindicated in patients with obstructive jaundice and hyperbilirubinemia.[
      • Schaaf L.J.
      • Hammond L.A.
      • Tipping S.J.
      • et al.
      Phase 1 and pharmacokinetic study of intravenous irinotecan in refractory solid tumor patients with hepatic dysfunction.
      ,
      • Kopetz S.
      • Chang G.J.
      • Overman M.J.
      • et al.
      Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy.
      ,
      • van der Pool A.E.
      • Damhuis R.A.
      • Ijzermans J.N.
      • et al.
      Trends in incidence, treatment and survival of patients with stage IV colorectal cancer: a population-based series.
      ]
      Biliary drainage aims to lower the hyperbilirubinemia, either to relieve jaundice related symptoms or to enable administration of systemic therapy.[
      • Caillol F.
      • Bories E.
      • Zemmour C.
      • et al.
      Palliative endoscopic drainage of malignant stenosis of biliary confluence: efficiency of multiple drainage approach to drain a maximum of liver segments.
      ] Different modalities are available for biliary drainage such as endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic cholangiography (PTC) and endoscopic ultrasound (EUS). Usually ERCP is the first choice, but PTC or EUS can be considered if ERCP fails or is not feasible, for example due to surgically altered anatomy or duodenal obstruction.[
      • 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.
      ] Effective biliary drainage can be difficult to achieve, especially in case of complex hilar strictures. In addition, biliary drainage carries the risk of adverse events such as cholangitis, pancreatitis or stent dysfunction. These events may negatively impact survival and the quality of the last phase of patients’ life. The potential benefit of biliary drainage should be weighed against the risks of biliary drainage. This is especially relevant for mCRC patients, since survival can be significantly improved by currently available palliative treatment regimens.[
      • Kopetz S.
      • Chang G.J.
      • Overman M.J.
      • et al.
      Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy.
      ,
      • van der Pool A.E.
      • Damhuis R.A.
      • Ijzermans J.N.
      • et al.
      Trends in incidence, treatment and survival of patients with stage IV colorectal cancer: a population-based series.
      ] However, little is known about the technical and clinical results, adverse event rate, survival benefit, and the prognostic factors associated with successful biliary drainage and clinical outcomes in mCRC patients.
      Therefore, we conducted the first systematic review to identify available literature, to quantify technical success, clinical success, adverse events, systemic therapy administration and survival after biliary drainage in mCRC patients, and to summarize determinants that influenced these outcomes.

      2. Methods

      This systematic review was conducted according to a predefined protocol, registered prospectively in the international prospective registry for systematic reviews (PROSPERO): CRD42019132671. Our study adhered to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) checklist (Appendix 1).[
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
      ]

      2.1 Search strategy and selection criteria

      We searched Medline (via PubMed) and EMBASE (via EMBASE) for studies published from January 1, 2000 until August 1, 2019, that met our predefined eligibility criteria. (Appendix 2). We applied the following eligibility criteria: 1) description of 10 or more adults, with 2) malignant biliary obstruction, secondary to 3) CRC metastases, treated with 4) biliary drainage by either ERCP, PTC, EUS or a combination of these procedures. Studies describing a subset of mCRC patients as part of a larger cohort of patients undergoing biliary drainage were included if outcomes for mCRC were provided separately. We included articles that were written in English, published in peer-reviewed journals and reported original data from clinical trials or observational studies. Abstracts or conference correspondence were excluded, because these may lack peer-reviewed evaluation.

      2.2 Study selection

      Two authors (JK and MvdL) independently screened titles and abstracts identified by our search. Subsequently, full-text articles were independently assessed for final inclusion in this study. We cross-checked reference lists of included studies and screened references that cited the included articles identified using Scopus. Consensus was reached in a meeting with senior authors (LM and FV) in case of uncertainty about eligibility.

      3. Data collection

      Two authors (JK and MvdL) used a predesigned data extraction form to extract relevant data from included studies independently. Disagreements were resolved by discussion between the two authors. If no agreement could be reached, it was discussed with senior authors (LM and FV). In studies reporting various malignancies of which mCRC was a subgroup, data were extracted for the mCRC patients only. Prognostic factors, however, were extracted from studies regardless of whether these were determined in mCRC patients only or in mCRC patients as subset of a larger cohort.
      We extracted the following data: 1) Study characteristics: author, year of publication, study design, design of data-collection, study years, country where study was performed, study setting, number of study centers, number of included patients, number of patients with mCRC; 2) Patient characteristics: age, sex, previous lines of chemotherapy, WHO/Eastern Cooperative Oncology Group (ECOG) performance status; 3) Disease characteristics: previous oncologic treatment, indication for drainage, fever, ascites, peritoneal carcinomatosis, location of obstruction (as reported by authors, e.g. intra- or extrahepatic or by the Bismuth-classification [
      • Bismuth H.
      • Nakache R.
      • Diamond T.
      Management strategies in resection for hilar cholangiocarcinoma.
      ]), extent of hepatic tumor involvement; 4) Procedural characteristics: type of intervention (ERCP, PTC, or EUS), number of interventions performed, percentage of liver volume drained, unilateral or bilateral drainage; 5) Outcomes: technical success, clinical success, adverse events, systemic therapy administration after biliary drainage and overall survival.
      Prognostic factors that were significantly (p<0.05) associated with outcomes in multivariable analyses were extracted. We extracted risk ratios, odds ratios or hazard ratios, as provided.
      When relevant data were not reported or incomplete, we contacted authors to request additional data. Of the three authors contacted, one author provided additional numerical data on outcomes of the mCRC subgroup and two authors did not respond.

      3.1 Outcome measures and definitions

      The outcomes of interest for this study were technical success, defined as adequate positioning of the stent across the stricture; clinical success, as defined by authors, but at least involving bilirubin level and/or resolving cholangitis; adverse events, defined as adverse events related to biliary drainage; survival, defined as days of survival after biliary drainage, overall and with or without systemic therapy after biliary drainage.

      3.2 Risk of bias assessment

      Two authors (JK and PW) independently assessed the quality of the included studies at study level, using the QUality In Prognostic Studies (QUIPS) tool.[
      • Hayden J.A.
      • van der Windt D.A.
      • Cartwright J.L.
      • et al.
      Assessing bias in studies of prognostic factors.
      ] The risk of bias was assessed using the following components: Study participation, study attrition, prognostic factor measurement, outcome measurement, study confounding, statistical analysis and reporting. The component ‘Statistical analysis and reporting’ was assessed for outcomes (i.e. calculation and reporting prevalences) and for prognostic factors (i.e. strategy for statistical model building) separately. Consensus was sought in case of discrepancies.

      3.3 Summary measures and synthesis of results

      A quantitative data synthesis for the occurrence of outcomes and the influence of patient and disease characteristics was performed. We summarized numbers and ranges of the prevalence of the outcomes of interest and provided effect estimates of adjusted prognostic factors.

      4. Results

      After screening 3584 abstracts and assessing 509 full-text articles, seven studies were included (Fig. 1, Appendix 3).[
      • Nichols S.D.
      • Albert S.
      • Shirley L.
      • et al.
      Outcomes in patients with obstructive jaundice from metastatic colorectal cancer and implications for management.
      ,
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ,
      • Kasuga A.
      • Ishii H.
      • Ozaka M.
      • et al.
      Clinical outcome of biliary drainage for obstructive jaundice caused by colorectal and gastric cancers.
      ,
      • Niemelä J.
      • Kallio R.
      • Ohtonen P.
      • et al.
      Is palliative percutaneous drainage for malignant biliary obstruction useful?.
      ,
      • Valiozis I.
      • Zekry A.
      • Williams S.J.
      • et al.
      Palliation of hilar biliary obstruction from colorectal metastases by endoscopic stent insertion.
      ,
      • Van Laethem J.L.
      • De Broux S.
      • Eisendrath P.
      • et al.
      Clinical impact of biliary drainage and jaundice resolution in patients with obstructive metastases at the hilum.
      ,
      • Vandenabeele L.A.M.
      • Dhondt E.
      • Geboes K.P.
      • et al.
      Percutaneous stenting in malignant biliary obstruction caused by metastatic disease: clinical outcome and prediction of survival according to tumor type and further therapeutic options.
      ] All studies were cohort studies without comparison group and patients were identified retrospectively. Five studies were single-center and two were multicenter studies. Study characteristics are provided in Table 1. Inclusion criteria used by each included study are specified in Appendix 4. In total, 257 patients were included. The number of mCRC patients included ranged from 28 to 69 per study. Two studies reported mCRC patients with malignant biliary obstruction initially treated with ERCP.[
      • Valiozis I.
      • Zekry A.
      • Williams S.J.
      • et al.
      Palliation of hilar biliary obstruction from colorectal metastases by endoscopic stent insertion.
      ,
      • Van Laethem J.L.
      • De Broux S.
      • Eisendrath P.
      • et al.
      Clinical impact of biliary drainage and jaundice resolution in patients with obstructive metastases at the hilum.
      ] Three studies reported treatment with PTC, of which two studies included patients after ERCP had failed, was insufficient or anatomically not possible.[
      • Kasuga A.
      • Ishii H.
      • Ozaka M.
      • et al.
      Clinical outcome of biliary drainage for obstructive jaundice caused by colorectal and gastric cancers.
      ,
      • Niemelä J.
      • Kallio R.
      • Ohtonen P.
      • et al.
      Is palliative percutaneous drainage for malignant biliary obstruction useful?.
      ,
      • Vandenabeele L.A.M.
      • Dhondt E.
      • Geboes K.P.
      • et al.
      Percutaneous stenting in malignant biliary obstruction caused by metastatic disease: clinical outcome and prediction of survival according to tumor type and further therapeutic options.
      ] In two studies either ERCP or PTC was initially used.[
      • Nichols S.D.
      • Albert S.
      • Shirley L.
      • et al.
      Outcomes in patients with obstructive jaundice from metastatic colorectal cancer and implications for management.
      ,
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ] EUS was performed in two patients described in one study in whom initial ERCP failed.[
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ] Patient and disease characteristics are provided in Table 2. We refrained from pooling the available data because of considerable heterogeneity between studies.
      Table 1Study characteristics.
      Author, yearNumber of mCRC patients treated with biliary drainage (% of total included patients)CountryStudy designData collectionTreatment yearsNumber of centersModality initially described in study
      Valliozis, 2000 [14]33 (100)AustraliaCohort study without comparison groupRetrospective1992-19962ERCP1
      Van Laethem, 2003 [15]16 (46)BelgiumCohort study without comparison groupRetrospective1993-19981ERCP1
      Kasuga, 2012 [12]32 (35)JapanCohort study without comparison groupRetrospective2005-20111PTC1
      Vandenabeele, 2017 [16]28 (30)BelgiumCohort study without comparison groupRetrospective2007-20131PTC2
      Niemelä, 2018 [13]43 (7)FinlandCohort study without comparison groupRetrospective1999-20161PTC3
      Nichols, 2014 [1]36 (58)USACohort study without comparison groupRetrospective2004-20101ERCP or PTC1
      Sellier, 2018 [2]69 (100)FranceCohort study without comparison groupRetrospective2005-20142ERCP or PTC1
      Abbreviations: mCRC: metastatic colorectal carcinoma
      Footnotes:
      1Reasons for initial modality of choice were not specified
      2Indications for PTC were previously failed ERCP or the presence of a biliodigestive anastomosis
      3Indications for PTC were unsuccessful, insufficient or infeasible ERCP
      Table 2Patient and disease characteristics.
      Author, yearType of biliary drainage performed, n patients (%)Age in years1Male sex, n (%)Previous lines of chemotherapy, n patients (%)WHO status, n patients (%)Location of obstruction, n patients (%)Hepatic tumor load
      Valliozis, 2000 [14]ERCP: 16 (49)

      ERCP+PTC: 17 (51)
      65 (37-81)1a23 (70)NRNRBismuth I: 11 (33.3)

      Bismuth II: 11 (33.3)

      Bismuth III: 11 (33.3)
      ≤ 3: 15 (45)3

      >3:18 (55)
      Van Laethem, 2003 [15]ERCP, ERCP+PTC: 16 (46)2NR mCRCNR mCRCFirst-line: 6 (38)

      NR: 10 (63)
      NRHilarNR
      Kasuga, 2012 [12]PTC: 32 (35)NR mCRCNR mCRCNR mCRCNR mCRCNR mCRCNR mCRC
      Vandenabeele, 2017 [16]*PTC: 28 (30)60.3 (13)1b18 (64)Chemo-naïve: 2 (7)WHO 0: 0 (-)NRNR
      First-line: 8 (29)WHO 1: 13 (46)
      Second-line: 4 (14)WHO 2: 12 (43)
      Third-line: 9 (32)WHO 3: 2 (7)
      Fourth-line: 2 (7)WHO 4: 0 (-)
      ≥Fifth-line: 3 (11)WHO Unknown: 1
      Niemelä, 2018 [13]PTC: 43 (7)NR mCRCNR mCRCNRNR mCRCNR mCRCNR
      Nichols, 2014 [1]ERCP: 17 (47)

      PTC: 18 (50)

      ERCP+PTC: 1 (3)
      NR32 (52)NR mCRCNRIntrahepatic: 14 (39)

      Extrahepatic: 22 (61)(
      NR
      Sellier, 2018 [2]ERCP: 59 (86)

      PTC: 2 (3)

      ERCP+PTC: 5 (7)

      ERCP+EUS: 1 (1)

      ERCP+PTC+EUS: 2 (3)
      71 (31-93)1a48 (70)Chemo-naïve: 6 (9)

      First-line: 15 (22)

      Second-line: 13 (19)

      ≥Third-line: 35 (51)
      WHO 0: 19 (28)

      WHO 1: 22 (32)

      WHO 2: 20 (29)

      WHO 3: 7 (10)

      WHO 4: 1 (2)
      CHD: 20 (29)

      Hilar: 37 (54)

      Secondary bile ducts: 12 (17)
      <50%: 46 (69)4
      Abbreviations: NR: not reported in the study; NR mCRC: not separately provided for mCRC patients treated with biliary drainage; CHD: Common hepatic duct.
      Footnotes:
      *Additional unpublished data for the mCRC subset was provided by the author of this study
      1Age was reported in median (range)1a or mean (±standard deviation)1b
      2Exact number of patients undergoing ERCP or ERCP combined with PTC not provided for mCRC patients separately
      3Number of patients (%) with ≤3 (including porta hepatis lymph node metastases) or >3 intrahepatic metastases
      4Number of patients (%) with <50% hepatic tumor involvement.

      4.1 Technical and clinical success

      Technical success of biliary drainage in mCRC patients was reported in three studies.[
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ,
      • Valiozis I.
      • Zekry A.
      • Williams S.J.
      • et al.
      Palliation of hilar biliary obstruction from colorectal metastases by endoscopic stent insertion.
      ,
      • Vandenabeele L.A.M.
      • Dhondt E.
      • Geboes K.P.
      • et al.
      Percutaneous stenting in malignant biliary obstruction caused by metastatic disease: clinical outcome and prediction of survival according to tumor type and further therapeutic options.
      ] Rates of cumulative technical success were 63%, 94% and 100%, but multiple attempts and different drainage modalities were frequently required.[
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ,
      • Valiozis I.
      • Zekry A.
      • Williams S.J.
      • et al.
      Palliation of hilar biliary obstruction from colorectal metastases by endoscopic stent insertion.
      ,
      • Vandenabeele L.A.M.
      • Dhondt E.
      • Geboes K.P.
      • et al.
      Percutaneous stenting in malignant biliary obstruction caused by metastatic disease: clinical outcome and prediction of survival according to tumor type and further therapeutic options.
      ] In a study of 33 mCRC patients, ERCP had an initial technical success rate of 13 (39%) after the first attempt and an additional 3 (9%) after repeat ERCP. Fifteen (45%) patients eventually required a combined endoscopic-percutaneous approach. Of these 15 patients, 14 (93%) had a Bismuth type II or III stricture, indicating involvement of at least the hepatic duct bifurcation. A permanent external drain was required in two (6%) patients to achieve decompression.[
      • Valiozis I.
      • Zekry A.
      • Williams S.J.
      • et al.
      Palliation of hilar biliary obstruction from colorectal metastases by endoscopic stent insertion.
      ] In another study of 69 patients, the vast majority (86%) was treated with ERCP only, 2 (3%) patients with PTC and 8 (12%) with an additional intervention with PTC and/or EUS.[
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ] Technical success was achieved in 42 (63%) patients, in whom all biliary strictures needed to be drained before the definition of technical success was met. In 21 (31%) patients partial technical success was achieved, defined as the persistence of dilated undrained areas, and in four (6%) patients technical success was not achieved.[
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ] Treatment with PTC in 28 mCRC patients with a biliodigestive anastomosis rendering them unsuitable for ERCP, or in whom previous ERCP failed, was technically successful in all patients after one attempt.[
      • Vandenabeele L.A.M.
      • Dhondt E.
      • Geboes K.P.
      • et al.
      Percutaneous stenting in malignant biliary obstruction caused by metastatic disease: clinical outcome and prediction of survival according to tumor type and further therapeutic options.
      ] (Table 3)
      Table 3Outcomes.
      Author, yearTechnical success, n (%)Clinical success, n (%)Adverse events, n (%)Chemotherapy administration, n (%)Survival after attempted biliary drainage in days (95%CI) (n patients)
      With subsequent chemotherapyWithout subsequent chemotherapyOverall
      Valliozis, 2000 [14]31 (94)113 (45)13 (39)NR81 (-)NRNR
      Van Laethem, 2003 [15]NR mCRC13 (81)NR mCRC6 (38)122 (-) (n=16)365 (n=6)261 (n=10)3
      Kasuga, 2012 [12]NR26 (81)NRNR mCRC122 (-)NR mCRCNR mCRC
      Vandenabeele, 2017 [16]*28 (100)21 (75)10 (36)9 (32)67 (40-94) (n=28)316 (0-760) (n=9)57 (44-70) (n=19)4
      Niemelä, 2018[13]NRNRNRNR40 (22-56)NRNR
      Nichols, 2014[1]NR15 (42)7 (19)6 (17)45 (-) (n=36)293 (n=6)42 (n=30)
      Sellier, 2018[2]42 (63)544 (65)20 (29)38 (56)115 (72-208) (n=69)278 (n=38)642 (n=31)7
      Abbreviations: NR: not reported in the study; NR mCRC: not provided for metastatic colorectal carcinoma patients separately.
      Footnotes:
      * Additional unpublished data for the mCRC subset was provided by the author of this study
      1Thirteen (39%) after the first attempt, 3 (9%) after repeat ERCP, 15 (45%) required a combined ERCP+PTC procedure.
      2Chemotherapy administration after complete resolution of jaundice, all 6 patients received second-line chemotherapy.
      3Of these 10 patients, jaundice failed to resolve in 3 patients (median survival 30 days), 7 patients achieved complete resolution of jaundice (median survival 61 days)
      4Reasons to refrain from chemotherapy: insufficient decrease of bilirubin (n=12); poor condition (n=5); indication was symptom relief, not chemotherapy (n=2).
      5In addition, 21 (31%) patients reached partial technical success, defined as the persistence of dilated undrained areas
      6Thirty-two patients had clinical success, 6 patients did not.
      7Twelve patients had clinical success, 19 patients did not.
      Clinical success rates were reported in six studies and varied between 42% and 81%.[
      • Nichols S.D.
      • Albert S.
      • Shirley L.
      • et al.
      Outcomes in patients with obstructive jaundice from metastatic colorectal cancer and implications for management.
      ,
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ,
      • Kasuga A.
      • Ishii H.
      • Ozaka M.
      • et al.
      Clinical outcome of biliary drainage for obstructive jaundice caused by colorectal and gastric cancers.
      ,
      • Valiozis I.
      • Zekry A.
      • Williams S.J.
      • et al.
      Palliation of hilar biliary obstruction from colorectal metastases by endoscopic stent insertion.
      ,
      • Van Laethem J.L.
      • De Broux S.
      • Eisendrath P.
      • et al.
      Clinical impact of biliary drainage and jaundice resolution in patients with obstructive metastases at the hilum.
      ,
      • Vandenabeele L.A.M.
      • Dhondt E.
      • Geboes K.P.
      • et al.
      Percutaneous stenting in malignant biliary obstruction caused by metastatic disease: clinical outcome and prediction of survival according to tumor type and further therapeutic options.
      ] (Table 3) Different definitions were applied, though all definitions included decrease of bilirubin level to some extent (Appendix 5).[
      • Nichols S.D.
      • Albert S.
      • Shirley L.
      • et al.
      Outcomes in patients with obstructive jaundice from metastatic colorectal cancer and implications for management.
      ,
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ,
      • Kasuga A.
      • Ishii H.
      • Ozaka M.
      • et al.
      Clinical outcome of biliary drainage for obstructive jaundice caused by colorectal and gastric cancers.
      ,
      • Valiozis I.
      • Zekry A.
      • Williams S.J.
      • et al.
      Palliation of hilar biliary obstruction from colorectal metastases by endoscopic stent insertion.
      ,
      • Van Laethem J.L.
      • De Broux S.
      • Eisendrath P.
      • et al.
      Clinical impact of biliary drainage and jaundice resolution in patients with obstructive metastases at the hilum.
      ,
      • Vandenabeele L.A.M.
      • Dhondt E.
      • Geboes K.P.
      • et al.
      Percutaneous stenting in malignant biliary obstruction caused by metastatic disease: clinical outcome and prediction of survival according to tumor type and further therapeutic options.
      ] One study provided clinical success rates of initial ERCP or PTC separately and found clinical success in 9 (50%) patients after ERCP compared with 6 (35%) after PTC, but indications for the chosen treatment modality and the disease severity of these patients were not reported.[
      • Nichols S.D.
      • Albert S.
      • Shirley L.
      • et al.
      Outcomes in patients with obstructive jaundice from metastatic colorectal cancer and implications for management.
      ] With regard to the number of interventions, Nichols et al. reported a mean number of 2.1 (range 1-5) attempts to relieve jaundice.[
      • Nichols S.D.
      • Albert S.
      • Shirley L.
      • et al.
      Outcomes in patients with obstructive jaundice from metastatic colorectal cancer and implications for management.
      ] Other studies did not report the number of procedures performed as an attempt to achieve clinical success.

      4.2 Adverse events

      Adverse events after biliary drainage were reported in four studies and varied between 19% and 39%.[
      • Nichols S.D.
      • Albert S.
      • Shirley L.
      • et al.
      Outcomes in patients with obstructive jaundice from metastatic colorectal cancer and implications for management.
      ,
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ,
      • Valiozis I.
      • Zekry A.
      • Williams S.J.
      • et al.
      Palliation of hilar biliary obstruction from colorectal metastases by endoscopic stent insertion.
      ,
      • Vandenabeele L.A.M.
      • Dhondt E.
      • Geboes K.P.
      • et al.
      Percutaneous stenting in malignant biliary obstruction caused by metastatic disease: clinical outcome and prediction of survival according to tumor type and further therapeutic options.
      ] Three of these studies reported adverse events occurring within 30 days after the initial treatment,[
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ,
      • Valiozis I.
      • Zekry A.
      • Williams S.J.
      • et al.
      Palliation of hilar biliary obstruction from colorectal metastases by endoscopic stent insertion.
      ,
      • Vandenabeele L.A.M.
      • Dhondt E.
      • Geboes K.P.
      • et al.
      Percutaneous stenting in malignant biliary obstruction caused by metastatic disease: clinical outcome and prediction of survival according to tumor type and further therapeutic options.
      ] one study did not specify the timeframe in which adverse events occurred.[
      • Nichols S.D.
      • Albert S.
      • Shirley L.
      • et al.
      Outcomes in patients with obstructive jaundice from metastatic colorectal cancer and implications for management.
      ] Cholangitis was most commonly reported and occurred in around 20% of patients. [
      • Nichols S.D.
      • Albert S.
      • Shirley L.
      • et al.
      Outcomes in patients with obstructive jaundice from metastatic colorectal cancer and implications for management.
      ,
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ,
      • Valiozis I.
      • Zekry A.
      • Williams S.J.
      • et al.
      Palliation of hilar biliary obstruction from colorectal metastases by endoscopic stent insertion.
      ,
      • Vandenabeele L.A.M.
      • Dhondt E.
      • Geboes K.P.
      • et al.
      Percutaneous stenting in malignant biliary obstruction caused by metastatic disease: clinical outcome and prediction of survival according to tumor type and further therapeutic options.
      ] Other adverse events included pancreatitis, acute renal failure, pneumonia and duodenal ulceration due to a metal biliary stent.[
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ,
      • Valiozis I.
      • Zekry A.
      • Williams S.J.
      • et al.
      Palliation of hilar biliary obstruction from colorectal metastases by endoscopic stent insertion.
      ] Duodenal perforation and stent migration were reported as peri-procedural adverse events in two (3%) patients.[
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ] Bleeding, biliary leakage, abscess, sepsis, hypovolemic shock and pain after PTC were also reported.[
      • Vandenabeele L.A.M.
      • Dhondt E.
      • Geboes K.P.
      • et al.
      Percutaneous stenting in malignant biliary obstruction caused by metastatic disease: clinical outcome and prediction of survival according to tumor type and further therapeutic options.
      ]
      Stent dysfunction was reported in two studies.[
      • Valiozis I.
      • Zekry A.
      • Williams S.J.
      • et al.
      Palliation of hilar biliary obstruction from colorectal metastases by endoscopic stent insertion.
      ,
      • Vandenabeele L.A.M.
      • Dhondt E.
      • Geboes K.P.
      • et al.
      Percutaneous stenting in malignant biliary obstruction caused by metastatic disease: clinical outcome and prediction of survival according to tumor type and further therapeutic options.
      ] One study reported clogging requiring stent replacement in 16 (48%) patients who were initially treated with ERCP and plastic stent placements.[
      • Valiozis I.
      • Zekry A.
      • Williams S.J.
      • et al.
      Palliation of hilar biliary obstruction from colorectal metastases by endoscopic stent insertion.
      ] In the other study, involving patients treated with PTC and metallic stent placement, 3 (10.7%) patients required one (in 2 patients) or two (in one patient) additional PTCs because of stent obstruction.[
      • Vandenabeele L.A.M.
      • Dhondt E.
      • Geboes K.P.
      • et al.
      Percutaneous stenting in malignant biliary obstruction caused by metastatic disease: clinical outcome and prediction of survival according to tumor type and further therapeutic options.
      ]

      4.3 Survival and chemotherapy administration

      Median overall survival after biliary drainage was reported in all seven studies and varied between 40 and 122 days. Survival across studies did not appear to be different for the different drainage modalities.[
      • Nichols S.D.
      • Albert S.
      • Shirley L.
      • et al.
      Outcomes in patients with obstructive jaundice from metastatic colorectal cancer and implications for management.
      ,
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ,
      • Kasuga A.
      • Ishii H.
      • Ozaka M.
      • et al.
      Clinical outcome of biliary drainage for obstructive jaundice caused by colorectal and gastric cancers.
      ,
      • Niemelä J.
      • Kallio R.
      • Ohtonen P.
      • et al.
      Is palliative percutaneous drainage for malignant biliary obstruction useful?.
      ,
      • Valiozis I.
      • Zekry A.
      • Williams S.J.
      • et al.
      Palliation of hilar biliary obstruction from colorectal metastases by endoscopic stent insertion.
      ,
      • Van Laethem J.L.
      • De Broux S.
      • Eisendrath P.
      • et al.
      Clinical impact of biliary drainage and jaundice resolution in patients with obstructive metastases at the hilum.
      ,
      • Vandenabeele L.A.M.
      • Dhondt E.
      • Geboes K.P.
      • et al.
      Percutaneous stenting in malignant biliary obstruction caused by metastatic disease: clinical outcome and prediction of survival according to tumor type and further therapeutic options.
      ]
      Four studies reported rates of chemotherapy administration after biliary drainage.[
      • Nichols S.D.
      • Albert S.
      • Shirley L.
      • et al.
      Outcomes in patients with obstructive jaundice from metastatic colorectal cancer and implications for management.
      ,
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ,
      • Van Laethem J.L.
      • De Broux S.
      • Eisendrath P.
      • et al.
      Clinical impact of biliary drainage and jaundice resolution in patients with obstructive metastases at the hilum.
      ,
      • Vandenabeele L.A.M.
      • Dhondt E.
      • Geboes K.P.
      • et al.
      Percutaneous stenting in malignant biliary obstruction caused by metastatic disease: clinical outcome and prediction of survival according to tumor type and further therapeutic options.
      ] These rates varied between 17% and 56%.[
      • Nichols S.D.
      • Albert S.
      • Shirley L.
      • et al.
      Outcomes in patients with obstructive jaundice from metastatic colorectal cancer and implications for management.
      ,
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ,
      • Van Laethem J.L.
      • De Broux S.
      • Eisendrath P.
      • et al.
      Clinical impact of biliary drainage and jaundice resolution in patients with obstructive metastases at the hilum.
      ,
      • Vandenabeele L.A.M.
      • Dhondt E.
      • Geboes K.P.
      • et al.
      Percutaneous stenting in malignant biliary obstruction caused by metastatic disease: clinical outcome and prediction of survival according to tumor type and further therapeutic options.
      ] Across studies, median survival varied from 278 to 365 days in patients treated with chemotherapy, compared with 42 to 61 days in patients who did not receive subsequent chemotherapy.[
      • Nichols S.D.
      • Albert S.
      • Shirley L.
      • et al.
      Outcomes in patients with obstructive jaundice from metastatic colorectal cancer and implications for management.
      ,
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ,
      • Van Laethem J.L.
      • De Broux S.
      • Eisendrath P.
      • et al.
      Clinical impact of biliary drainage and jaundice resolution in patients with obstructive metastases at the hilum.
      ,
      • Vandenabeele L.A.M.
      • Dhondt E.
      • Geboes K.P.
      • et al.
      Percutaneous stenting in malignant biliary obstruction caused by metastatic disease: clinical outcome and prediction of survival according to tumor type and further therapeutic options.
      ] In two studies that specified reasons to refrain from chemotherapy, 17of 48 (29%) patients indicated for chemotherapy did not receive it due to a poor performance status, despite successful drainage.[
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ,
      • Vandenabeele L.A.M.
      • Dhondt E.
      • Geboes K.P.
      • et al.
      Percutaneous stenting in malignant biliary obstruction caused by metastatic disease: clinical outcome and prediction of survival according to tumor type and further therapeutic options.
      ]

      4.4 Prognostic factors

      Multivariable analysis was performed in three studies.[
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ,
      • Kasuga A.
      • Ishii H.
      • Ozaka M.
      • et al.
      Clinical outcome of biliary drainage for obstructive jaundice caused by colorectal and gastric cancers.
      ,
      • Niemelä J.
      • Kallio R.
      • Ohtonen P.
      • et al.
      Is palliative percutaneous drainage for malignant biliary obstruction useful?.
      ] Predictors of unsuccessful PTC were hepatic hilar bile duct stricture and larger hepatic tumor load (presence of >5 liver metastases, largest diameter >5 cm).[
      • Kasuga A.
      • Ishii H.
      • Ozaka M.
      • et al.
      Clinical outcome of biliary drainage for obstructive jaundice caused by colorectal and gastric cancers.
      ]
      Survival was significantly improved after clinical success, previous hepatectomy, absence of fever and fewer lines of chemotherapy. A 1.6 times increased risk of death with each additional line of chemotherapy was found.[
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ] Predictors of poor survival after PTC included poor performance status (WHO>1)[12,13], ASA class ≥ 3, and post-drainage bilirubin value ≥60 umol/L (≥ 3.5mg/dL).[
      • Niemelä J.
      • Kallio R.
      • Ohtonen P.
      • et al.
      Is palliative percutaneous drainage for malignant biliary obstruction useful?.
      ] Patients treated with PTC in an earlier time period (before 2010) had poorer outcomes than those treated at a later period.[
      • Niemelä J.
      • Kallio R.
      • Ohtonen P.
      • et al.
      Is palliative percutaneous drainage for malignant biliary obstruction useful?.
      ] Larger hepatic tumor load (presence of >5 liver metastases, largest diameter >5 cm), multiple prior chemotherapy lines, ascites, undifferentiated type histology, and high serum CA19-9 levels were also identified as factors that are associated with a poor prognosis after PTC.[
      • Kasuga A.
      • Ishii H.
      • Ozaka M.
      • et al.
      Clinical outcome of biliary drainage for obstructive jaundice caused by colorectal and gastric cancers.
      ] (Table 4)
      Table 4Prognostic factors of clinical success and survival.
      AuthorPrognostic factors for clinical successHR (95%CI)Modality used
      Kasuga, 2012[12]Hilar bile duct stricture4.049 (1.173-13.977)PTC
      >5 liver metastases, largest >5cm5.893 (1.750-19.840)
      AuthorPrognostic factors for survivalHR (95% CI)Modality used
      Sellier, 2018[2]Clinical success0.29 (0.15-0.56)ERCP/PTC
      Previous hepatectomy0.41 (0.22-0.75)
      Fever before drainage* (1.39-6.36)
      Increased previous chemotherapy lines1.68 (1.36-2.06)
      Kasuga, 2012[12]>5 liver metastases, largest >5cm3.254 (1.793-5.906)PTC
      Prior chemotherapy > first line2.661 (1.554-4.556)
      Ascites2.381 (1.383-4.101)
      Histology, undifferentiated type2.402 (1.398-4.128)
      CA19-9 (iU/ml) > 5001.663 (1.043-2.653)
      ECOG performance status > 12.830 (1.538-5.209)
      Niemelä, 2018[13]ECOG performance statusPTC
      2 vs 0-12.3 (1.8-2.8)
      3-4 vs 0-13.5 (2.8-4.4)
      ASA class 4 vs 1-22.1 (1.5-2.9
      Bilirubin after drainage ≥60 umol/L1.3 (1.1-1.6)
      Intervention time period1.4 (1.1-1.7)

      1.4 (1.2-1.8)
      2005-2010 vs. 2011-2016
      1999-2004 vs. 2011-2016
      Abbreviations: ECOG PS = Eastern Cooperative Oncology Group Performance Status
      Footnotes: * Reported HR was omitted as it did not fall within the confidence interval.

      4.5 Risk of bias

      Where provided, median age and sex ratio were comparable between studies and deemed representative for the population of mCRC patients, but representativeness of other patient and disease characteristics could not be determined since these were not always reported for mCRC patients separately. Measures of disease, such as hepatic tumor load, extent of strictures, and performance status, were only reported in two studies.[
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ,
      • Valiozis I.
      • Zekry A.
      • Williams S.J.
      • et al.
      Palliation of hilar biliary obstruction from colorectal metastases by endoscopic stent insertion.
      ] Therefore, selection bias based on disease status, possibly influencing outcomes, could not be ruled out. There was a moderate to high risk of bias by confounding in all studies, because confounders were not or only partly taken into account in analyses. In addition, we included all provided prognostic factors that were reported to be statistically significant in multivariable analysis. Some of these, however, were determined by studies that included CRC along with various other types of malignancy, potentially introducing bias. (Table 5)
      Table 5Risk of bias assessment using the QUIPS tool.
      Author, year of publicationVan Laethem, 2003[15]Valliozis, 2000[14]Kasuga, 2012[12]Vandenabeele, 2017[16]*Nichols, 2014[1]Niemelä, 2018[13]Sellier, 2018[2]
      QUIPS components
      1. Study participationL/MLL/MLL/ML/ML
      2. Study attritionLLLLLLM
      3. Prognostic factor measurementLLLLLLL
      4. Outcome measurementLLLLLLL
      5. Study confoundingHHMHHMM
      6. Statistical analysis and reporting:
      - Prognostic factorsHHMHHMM
      - Occurrence of outcomesLLLLLLL
      Abbreviations: L=Low risk of bias; M=Moderate risk of bias; H=High risk of bias.
      *Additional information about the mCRC subset was provided by the author.

      5. Discussion

      Despite increasing treatment options and improved overall survival for mCRC patients, occurrence of malignant biliary obstruction during the course of the disease frequently entails a difficulty that is challenging to solve and has major clinical consequences. Biliary drainage is often performed, yet little is known about the clinical benefits and challenges of biliary drainage in mCRC patients. This is the first study aiming to summarize data on clinical outcomes of biliary drainage in patients with malignant biliary obstruction due to mCRC.
      Rates of clinical success of biliary drainage varied widely between the included studies, from 42% to 81%.[
      • Nichols S.D.
      • Albert S.
      • Shirley L.
      • et al.
      Outcomes in patients with obstructive jaundice from metastatic colorectal cancer and implications for management.
      ,
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ,
      • Kasuga A.
      • Ishii H.
      • Ozaka M.
      • et al.
      Clinical outcome of biliary drainage for obstructive jaundice caused by colorectal and gastric cancers.
      ,
      • Valiozis I.
      • Zekry A.
      • Williams S.J.
      • et al.
      Palliation of hilar biliary obstruction from colorectal metastases by endoscopic stent insertion.
      ,
      • Van Laethem J.L.
      • De Broux S.
      • Eisendrath P.
      • et al.
      Clinical impact of biliary drainage and jaundice resolution in patients with obstructive metastases at the hilum.
      ,
      • Vandenabeele L.A.M.
      • Dhondt E.
      • Geboes K.P.
      • et al.
      Percutaneous stenting in malignant biliary obstruction caused by metastatic disease: clinical outcome and prediction of survival according to tumor type and further therapeutic options.
      ] This might be explained by differences in patient selection and in the required extent of bilirubin level decrease after biliary drainage to meet the definition of clinical success. Low clinical success rates could be attributed to the hilar location and often complex nature of CRC metastases, which, like other hilar malignant strictures, can be difficult to reach and technically challenging to drain effectively.[
      • Kasuga A.
      • Ishii H.
      • Ozaka M.
      • et al.
      Clinical outcome of biliary drainage for obstructive jaundice caused by colorectal and gastric cancers.
      ,
      • 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.
      ,
      • Vienne A.
      • Hobeika E.
      • Gouya H.
      • et al.
      Prediction of drainage effectiveness during endoscopic stenting of malignant hilar strictures: the role of liver volume assessment.
      ] Valiozis et al reported that higher rates of initial technical success and clinical success (30% fall in bilirubin by 7 days) were found in patients with a Bismuth type I stricture than in type II or type III stricture (p<0.05).[
      • Valiozis I.
      • Zekry A.
      • Williams S.J.
      • et al.
      Palliation of hilar biliary obstruction from colorectal metastases by endoscopic stent insertion.
      ] Additionally, larger hepatic tumor load seemed associated with lower clinical success rates.[
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ,
      • Kasuga A.
      • Ishii H.
      • Ozaka M.
      • et al.
      Clinical outcome of biliary drainage for obstructive jaundice caused by colorectal and gastric cancers.
      ] Previous reports on drainage of obstructive jaundice due to various malignancies showed that the presence of liver metastases was associated with a lower rate of successful drainage[19,20] and that serum bilirubin level rarely normalizes in patients with an extensive hepatic metastatic tumor burden, as a result of mechanical biliary obstruction and parenchymal replacement.[
      • Langman E.L.
      • Suhocki P.V.
      • Hurwitz H.I.
      • et al.
      Percutaneous biliary drainage catheter insertion in patients with extensive hepatic metastatic tumor burden.
      ] It illustrates the often advanced stage and severity of the disease when obstructive jaundice becomes manifest.
      Adverse events occurred in 19% to 39% of patients and was mostly cholangitis.[
      • Nichols S.D.
      • Albert S.
      • Shirley L.
      • et al.
      Outcomes in patients with obstructive jaundice from metastatic colorectal cancer and implications for management.
      ,
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ,
      • Valiozis I.
      • Zekry A.
      • Williams S.J.
      • et al.
      Palliation of hilar biliary obstruction from colorectal metastases by endoscopic stent insertion.
      ,
      • Vandenabeele L.A.M.
      • Dhondt E.
      • Geboes K.P.
      • et al.
      Percutaneous stenting in malignant biliary obstruction caused by metastatic disease: clinical outcome and prediction of survival according to tumor type and further therapeutic options.
      ] Post-ERCP cholangitis was observed in approximately one out of five patients. This was higher than the 1% generally reported for other indications of ERCP,[
      • Anderson M.A.
      • Fisher L.
      • Jain R.
      • et al.
      Complications of ERCP.
      ,
      • Andriulli A.
      • Loperfido S.
      • Napolitano G.
      • et al.
      Incidence rates of post-ERCP complications: a systematic survey of prospective studies.
      ] but was in line with frequencies reported for drainage of hilar cholangiocarcinoma.[
      • Lee S.H.
      • Park J.K.
      • Yoon W.J.
      • et al.
      Optimal biliary drainage for inoperable Klatskin's tumor based on Bismuth type.
      ,
      • Rerknimitr R.
      • Kladcharoen N.
      • Mahachai V.
      • et al.
      Result of endoscopic biliary drainage in hilar cholangiocarcinoma.
      ] Combined percutaneous-endoscopic procedures, hilar strictures, and incomplete or failed biliary drainage are frequently seen in mCRC patients and are identified as risk factors for post-ERCP cholangitis.[
      • Freeman M.L.
      • Nelson D.B.
      • Sherman S.
      • et al.
      Complications of endoscopic biliary sphincterotomy.
      ,
      • Chen M.
      • Wang L.
      • Wang Y.
      • et al.
      Risk factor analysis of post-ERCP cholangitis: a single-center experience.
      ,
      • Motte S.
      • Deviere J.
      • Dumonceau J.M.
      • et al.
      Risk factors for septicemia following endoscopic biliary stenting.
      ] Routine antibiotic prophylaxis before ERCP is not recommended, but can be considered in patients with anticipated incomplete biliary drainage.[
      • Dumonceau J.M.
      • Kapral C.
      • Aabakken L.
      • et al.
      ERCP-related adverse events: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.
      ] In addition, Sellier et al found that partial technical success, defined by persistence of dilated undrained areas, resulted in a worse prognosis compared with complete failure.[
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ] Taken together, this stresses the importance of careful pre-drainage assessment of the location, level and extent of the obstruction of the biliary tree with computed tomography (CT) or ideally magnetic resonance cholangiopancreatography (MRCP), to define the best treatment strategy, cannulate selectively to avoid unnecessary contrast injection, and perhaps even abstain from drainage in some patients with multiple complex intrahepatic stenoses that are unlikely to be fully drained.[
      • Kasuga A.
      • Ishii H.
      • Ozaka M.
      • et al.
      Clinical outcome of biliary drainage for obstructive jaundice caused by colorectal and gastric cancers.
      ,
      • 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.
      ,
      • Vienne A.
      • Hobeika E.
      • Gouya H.
      • et al.
      Prediction of drainage effectiveness during endoscopic stenting of malignant hilar strictures: the role of liver volume assessment.
      ]
      Survival was around one month in case biliary drainage clinically failed and jaundice did not resolve.[
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ,
      • Van Laethem J.L.
      • De Broux S.
      • Eisendrath P.
      • et al.
      Clinical impact of biliary drainage and jaundice resolution in patients with obstructive metastases at the hilum.
      ] This poor prognosis could be related to the difficulty of effective drainage of extensive and complex hilar strictures, where failed drainage further worsens survival.[
      • 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.
      ,
      • Vienne A.
      • Hobeika E.
      • Gouya H.
      • et al.
      Prediction of drainage effectiveness during endoscopic stenting of malignant hilar strictures: the role of liver volume assessment.
      ,
      • Polydorou A.A.
      • Cairns S.R.
      • Dowsett J.F.
      • et al.
      Palliation of proximal malignant biliary obstruction by endoscopic endoprosthesis insertion.
      ] It could, however, also be the result of a poor performance status and the advanced and metastasized malignant disease itself.[
      • Caillol F.
      • Bories E.
      • Zemmour C.
      • et al.
      Palliative endoscopic drainage of malignant stenosis of biliary confluence: efficiency of multiple drainage approach to drain a maximum of liver segments.
      ,
      • Kasuga A.
      • Ishii H.
      • Ozaka M.
      • et al.
      Clinical outcome of biliary drainage for obstructive jaundice caused by colorectal and gastric cancers.
      ,
      • Niemelä J.
      • Kallio R.
      • Ohtonen P.
      • et al.
      Is palliative percutaneous drainage for malignant biliary obstruction useful?.
      ,
      • Vandenabeele L.A.M.
      • Dhondt E.
      • Geboes K.P.
      • et al.
      Percutaneous stenting in malignant biliary obstruction caused by metastatic disease: clinical outcome and prediction of survival according to tumor type and further therapeutic options.
      ,
      • Sargent D.J.
      • Köhne C.H.
      • Sanoff H.K.
      • et al.
      Pooled safety and efficacy analysis examining the effect of performance status on outcomes in nine first-line treatment trials using individual data from patients with metastatic colorectal cancer.
      ]
      Survival benefit of successful biliary drainage alone, without (considering initiating) subsequent systemic therapy remains controversial.[
      • Nichols S.D.
      • Albert S.
      • Shirley L.
      • et al.
      Outcomes in patients with obstructive jaundice from metastatic colorectal cancer and implications for management.
      ,
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ,
      • Walia T.
      • Quevedo J.F.
      • Hobday T.J.
      • et al.
      Colorectal cancer patients with liver metastases and severe hyperbilirubinemia: a consecutive series that explores the benefits and risks of chemotherapy.
      ,
      • Van Laethem J.L.
      • De Broux S.
      • Eisendrath P.
      • et al.
      Clinical impact of biliary drainage and jaundice resolution in patients with obstructive metastases at the hilum.
      ] In the included studies, chemotherapy after biliary drainage was administered in 17% to 56% of patients. Patients able to undergo systemic therapy showed improved survival up to approximately one year.[
      • Nichols S.D.
      • Albert S.
      • Shirley L.
      • et al.
      Outcomes in patients with obstructive jaundice from metastatic colorectal cancer and implications for management.
      ,
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ,
      • Van Laethem J.L.
      • De Broux S.
      • Eisendrath P.
      • et al.
      Clinical impact of biliary drainage and jaundice resolution in patients with obstructive metastases at the hilum.
      ,
      • Vandenabeele L.A.M.
      • Dhondt E.
      • Geboes K.P.
      • et al.
      Percutaneous stenting in malignant biliary obstruction caused by metastatic disease: clinical outcome and prediction of survival according to tumor type and further therapeutic options.
      ] Series about various other types of advanced malignancies have also reported improved survival in patients who received chemotherapy after biliary stenting.[
      • Migita K.
      • Watanabe A.
      • Yoshioka T.
      • et al.
      Clinical outcome of malignant biliary obstruction caused by metastatic gastric cancer.
      ,
      • Zhang G.Y.
      • Li W.T.
      • Peng W.J.
      • et al.
      Clinical outcomes and prediction of survival following percutaneous biliary drainage for malignant obstructive jaundice.
      ,
      • Afshar M.
      • Khanom K.
      • Ma Y.T.
      • et al.
      Biliary stenting in advanced malignancy: an analysis of predictive factors for survival.
      ,
      • Dhondt E.
      • Vanlangenhove P.
      • Geboes K.
      • et al.
      No evidence of improved efficacy of covered stents over uncovered stents in percutaneous palliation of malignant hilar biliary obstruction: results of a prospective randomized trial.
      ] However, patients eligible for systemic therapy often have a better performance status, resulting in improved survival.[
      • Kasuga A.
      • Ishii H.
      • Ozaka M.
      • et al.
      Clinical outcome of biliary drainage for obstructive jaundice caused by colorectal and gastric cancers.
      ,
      • Niemelä J.
      • Kallio R.
      • Ohtonen P.
      • et al.
      Is palliative percutaneous drainage for malignant biliary obstruction useful?.
      ,
      • Vandenabeele L.A.M.
      • Dhondt E.
      • Geboes K.P.
      • et al.
      Percutaneous stenting in malignant biliary obstruction caused by metastatic disease: clinical outcome and prediction of survival according to tumor type and further therapeutic options.
      ,
      • Sargent D.J.
      • Köhne C.H.
      • Sanoff H.K.
      • et al.
      Pooled safety and efficacy analysis examining the effect of performance status on outcomes in nine first-line treatment trials using individual data from patients with metastatic colorectal cancer.
      ] Improved survival after systemic therapy could therefore be confounded by the selection of patients for systematic therapy.
      When palliative biliary drainage is indicated to relieve symptoms of jaundice, such as pruritus, without any plans to initiate further oncologic therapy, some suggest that considerable improvement of symptoms could be provided.[
      • Van Laethem J.L.
      • De Broux S.
      • Eisendrath P.
      • et al.
      Clinical impact of biliary drainage and jaundice resolution in patients with obstructive metastases at the hilum.
      ,
      • Ballinger A.B.
      • McHugh M.
      • Catnach S.M.
      • et al.
      Symptom relief and quality of life after stenting for malignant bile duct obstruction.
      ] Others question the added value of biliary drainage to overall quality of life, because of the high rates of concomitant morbidity and short-term mortality. Especially the discomfort and risks of an external PTC-drain should not be underestimated.[
      • Walia T.
      • Quevedo J.F.
      • Hobday T.J.
      • et al.
      Colorectal cancer patients with liver metastases and severe hyperbilirubinemia: a consecutive series that explores the benefits and risks of chemotherapy.
      ,
      • Vandenabeele L.A.M.
      • Dhondt E.
      • Geboes K.P.
      • et al.
      Percutaneous stenting in malignant biliary obstruction caused by metastatic disease: clinical outcome and prediction of survival according to tumor type and further therapeutic options.
      ,
      • Heedman P.A.
      • Åstradsson E.
      • Blomquist K.
      • et al.
      Palliation of malignant biliary obstruction: adverse events are common after percutaneous transhepatic biliary drainage.
      ,
      • Robson P.C.
      • Heffernan N.
      • Gonen M.
      • et al.
      Prospective study of outcomes after percutaneous biliary drainage for malignant biliary obstruction.
      ,
      • Dy S.M.
      • Harman S.M.
      • Braun U.K.
      • et al.
      To stent or not to stent: an evidence-based approach to palliative procedures at the end of life.
      ]
      The optimal drainage modality for mCRC patients cannot be determined with the available data, due to the lack of large observational studies and randomised clinical trials. For malignant biliary obstruction in general, ERCP is recommended for extrahepatic strictures and Bismuth type I and II strictures.[
      • 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.
      ] For advanced and complex malignant hilar strictures, however, evidence is less clear. In Bismuth type III and IV strictures, PTCD seems to be superior to ERCP, showing significantly higher drainage success and lower rates of cholangitis.[
      • Moole H.
      • Dharmapuri S.
      • Duvvuri A.
      • et al.
      Endoscopic versus percutaneous biliary drainage in palliation of advanced malignant hilar obstruction: a meta-analysis and systematic review.
      ] Overall adverse events were comparable for both modalities, but higher rates of postprocedural bleeding complications were reported for PTC.[
      • Moole H.
      • Dharmapuri S.
      • Duvvuri A.
      • et al.
      Endoscopic versus percutaneous biliary drainage in palliation of advanced malignant hilar obstruction: a meta-analysis and systematic review.
      ] In these patients, the preferred modality depends on several factors, such as the locally available expertise, patients’ characteristics and preference, and the characteristics of the biliary obstruction.

      5.1 Strengths and limitations

      The strengths of this review are its prespecified protocol and extensive, systematic literature searches. It provides the first overview of clinical outcomes of biliary drainage for malignant biliary obstruction due to CRC metastases and of associated prognostic factors.
      This study has several limitations. Included studies were observational and retrospective series with small sample sizes. Selection criteria of the included studies varied. Selection of patients in the included studies was mostly restricted to those who underwent biliary drainage and patients deemed ineligible for biliary drainage with reasons to refrain from biliary drainage were not described. There was no controlled population. Inclusion of patients who were ineligible for systematic therapy prior to biliary drainage might have influenced rates of subsequent chemotherapy administration in some studies. This is supported by the fact that the study reporting the highest percentage (56%) of chemotherapy administration was a study in which patients without any possible further oncologic treatment were excluded.[
      • Sellier F.
      • Bories E.
      • Sibertin-Blanc C.
      • et al.
      Clinical outcome after biliary drainage for metastatic colorectal cancer: Survival analysis and prognostic factors.
      ] Relevant baseline characteristics, such as performance status or disease extent, were not provided consistently or not provided for the subset of mCRC patients separately, potentially hampering comparability of the included studies. Reasons to refrain from palliative chemotherapy after biliary drainage were not always specified, and patients unfit for chemotherapy could have had a shorter survival due to poor performance status, rather than failed biliary drainage or the absence of systemic therapy. Reasons for choosing the primary drainage modality or for switching to another modality are known to vary according to local practice and expertise, but were often not clearly stated or predefined in the included studies. It is therefore not possible to draw conclusions on potential differences in effectiveness between the different modalities. Some of the prognostic factors were identified in studies that included various types of malignancies and generalizability to mCRC patients might be hampered. Prognostic factors were not always adjusted for all potential confounders and were determined in small sample sizes. Considerable heterogeneity between studies precluded performing a valid meta-analysis. Inclusion of articles was restricted to reports written in English and relevant non-English studies might have been excluded. Interventions were performed in various time periods between 1992 and 2016, and improvement of procedural techniques and systemic therapies over time might have influenced outcomes. The limited number of studies and aggregated data on outcomes, however, did not allow subgroup analyses for treatment period. Volume and expertise were not assessed in included studies.

      5.2 Implications for clinical practice and future research

      This systematic review provides an overview of available literature with clinical outcomes of biliary drainage in mCRC patients with malignant biliary obstruction. The guidelines on biliary drainage for malignant strictures is applicable to mCRC patients, but it remains unclear which drainage strategy is most effective in these patients specifically.[
      • 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.
      ] For treatment decisions, patients should be evaluated in a multidisciplinary hepatobiliary team, to discuss patient and disease characteristics, radiographical findings, drainage options and probabilities of starting systemic therapy. The identified prognostic factors may guide patient selection in clinical practice.
      In future research, standardization of definitions of outcomes, in particular clinical success, should be pursued to improve comparability of studies. More homogeneous and larger studies are needed to confirm identified prognostic factors for clinical success and survival after biliary drainage. Prediction models to predict outcomes after biliary drainage might help focus treatment towards patients who benefit most from it. Prospective and comparative studies with randomized treatment allocation are warranted to determine the best drainage modality in mCRC patients. Symptom relief and quality of life, major goals of palliation, should also be assessed.

      6. Conclusion

      This systematic review identified seven small-sized observational studies demonstrating that effective drainage of malignant biliary obstruction in mCRC patients can be challenging to achieve and often requires repeat ERCP or a percutaneous approach. Large variation was found in rates of technical and clinical success. Adverse events, especially cholangitis, occurred frequently after biliary drainage. Survival after biliary drainage was limited, but significantly improved in patients who received subsequent systemic therapy. Prognostic factors, such as disease extent and performance status, may guide selection of patients who are most likely to benefit from biliary drainage.

      Funding

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

      Authors' contribution

      Conception and design: FV, LM, JK; Data extraction: MvdL, JK, PW; Interpretation of the data: JK, FV, LM, MK; Drafting of the article: JK; Critical revision of the article for important intellectual content and final approval of the article: all authors.

      CRediT authorship contribution statement

      Janine B Kastelijn: Conceptualization, Data curation, Writing - original draft. Maria ATC van der Loos: Data curation, Writing - review & editing. Paco MJ Welsing: Data curation, Methodology, Writing - review & editing. Elisabeth Dhondt: Data curation, Writing - review & editing. Miriam Koopman: Supervision, Writing - review & editing. Leon MG Moons: Conceptualization, Supervision, Writing - review & editing. Frank P. Vleggaar: Conceptualization, Supervision, Writing - review & editing.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgement

      The authors are grateful to P. Wiersma, information specialist, University Medical Center Utrecht, The Netherlands, for her help defining the literature search.

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