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Major complications and mortality after resection of intrahepatic cholangiocarcinoma: A systematic review and meta-analysis

Open AccessPublished:December 26, 2022DOI:https://doi.org/10.1016/j.surg.2022.11.027

      Abstract

      Background

      Evaluation of morbidity and mortality after hepatic resection often lacks stratification by extent of resection or diagnosis. Although a liver resection for different indications may have technical similarities, postoperative outcomes differ. The aim of this systematic review and meta-analysis was to determine the risk of major complications and mortality after resection of intrahepatic cholangiocarcinoma.

      Methods

      Meta-analysis was performed to assess postoperative mortality (in-hospital, 30-, and 90-day) and major complications (Clavien-Dindo grade ≥III).

      Results

      A total of 32 studies that reported on 19,503 patients were included. Pooled in-hospital, 30-day, and 90-day mortality were 5.9% (95% confidence interval 4.1–8.4); 4.6% (95% confidence interval 4.0–5.2); and 6.1% (95% confidence interval 5.0–7.3), respectively. Pooled proportion of major complications was 22.2% (95% confidence interval 17.7–27.5) for all resections. The pooled 90-day mortality was 3.1% (95% confidence interval 1.8–5.2) for a minor resection, 7.4% (95% confidence interval 5.9–9.3) for all major resections, and 11.4% (95% confidence interval 6.9–18.7) for extended resections (P = .001). Major complications were 38.8% (95% confidence interval 29.5–49) after a major hepatectomy compared to 11.3% (95% confidence interval 5.0–24.0) after a minor hepatectomy (P = .001). Asian studies had a pooled 90-day mortality of 4.4% (95% confidence interval 3.3–5.9) compared to 6.8% (95% confidence interval 5.6–8.2) for Western studies (P = .02). Cohorts with patients included before 2000 had a pooled 90-day mortality of 5.9% (95% confidence interval 4.8–7.3) compared to 6.8% (95% confidence interval 5.1–9.1) after 2000 (P = .44).

      Conclusion

      When informing patients or comparing outcomes across hospitals, postoperative mortality rates after liver resection should be reported for 90-days with consideration of the diagnosis and the extent of liver resection.

      Introduction

      Cholangiocarcinoma is a heterogenous group of malignancies in the biliary tree and accounts for 3% of all gastrointestinal cancers worldwide.
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      Intrahepatic cholangiocarcinoma (iCCA) arises from the epithelial cells of the peripheral bile ducts proximal to the second-order bile ducts.
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      Intrahepatic cholangiocarcinoma represents around 20% of all cholangiocarcinoma and its incidence in Western countries is 1 to 2 per 100,000.
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      The incidence of cholangiocarcinoma in Asian countries exceeds that in Western countries, up to >6 per 100,000.
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      Treatment and diagnosis of patients with iCCA entails many challenges. Patients with iCCA are initially asymptomatic and 20% of patients are diagnosed in the absence of symptoms.
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      When symptomatic, most patients present with unresectable disease due to locally advanced or metastatic disease.
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      Five-year overall survival (OS) rate after curative-intent resection of iCCA is about 30% and median OS about 30 months after surgery.
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      • Ribero D.
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      • et al.
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      Resection usually involves a major hepatectomy (82%) (3 segments or more) and sometimes resection of the (common) bile duct (23%) requiring an additional hepatico-jejunostomy.
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      In addition, most patients have underlying liver disease or postcholestatic liver dysfunction. Therefore, these extensive resections come with substantially higher risks than for instance resections for colorectal metastasis. The most frequent postoperative complications are liver failure, biliary leakage, and intra-abdominal abscess.
      • Ribero D.
      • Pinna A.D.
      • Guglielmi A.
      • et al.
      Surgical approach for long-term survival of patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis of 434 patients.
      ,
      • Ma K.W.
      • Cheung T.T.
      • She W.H.
      • et al.
      Major postoperative complications compromise oncological outcomes of patients with intrahepatic cholangiocarcinoma after curative resection - A 13-year cohort in a tertiary center.
      ,
      • Lang H.
      • Sotiropoulos G.C.
      • Sgourakis G.
      • et al.
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      Postoperative morbidity and mortality rates vary in the literature. Postoperative major complication risks vary from 18% to 52%,
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      • Chakedis J.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      ,
      • Hobeika C.
      • Cauchy F.
      • Poté N.
      • et al.
      Short- and long-term outcomes of liver resection for intrahepatic cholangiocarcinoma associated with the metabolic syndrome.
      whereas overall 90-day postoperative mortality ranges from 2% to 11%.
      • Hobeika C.
      • Cauchy F.
      • Poté N.
      • et al.
      Short- and long-term outcomes of liver resection for intrahepatic cholangiocarcinoma associated with the metabolic syndrome.
      ,
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      • Fabregat J.
      • et al.
      Intrahepatic cholangiocarcinoma: prognostic factors for recurrence and survival in a series of 67 patients treated surgically at a single center.
      The evaluation of morbidity and mortality after hepatic resection often lacks stratification by the extent of resection or diagnosis. Although a hepatectomy for different indications may have technical similarities, postoperative outcomes differ.
      • Shubert C.R.
      • Habermann E.B.
      • Truty M.J.
      • Thomsen K.M.
      • Kendrick M.L.
      • Nagorney D.M.
      Defining perioperative risk after hepatectomy based on diagnosis and extent of resection.
      Due to the low incidence of iCCA, postoperative morbidity and mortality rates are mainly derived from observational cohort studies or case series. Therefore, the aim of this systematic review and meta-analysis was to determine the risk of postoperative major complications and mortality after resection of iCCA. With subgroup analyses for the extent of liver resection, region, and time period.

      Methods

      This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses statement.
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.

      Literature search

      A librarian was consulted to perform a systematic search on February 19, 2021. Databases of MEDLINE, Embase, the Cochrane Library, and Web of Science were queried. A combination of keywords and Medical Subject Headings terms were used for the search: bile duct neoplasms, intrahepatic cholangiocarcinoma, hepatectomy, postoperative morbidity, postoperative mortality and variations thereof. No restriction on date, language, or publication type was applied in the search. The complete search strategy is presented in Supplementary Table S1. Two independent authors (A.K. and S.B.) screened the title and abstract of each identified publication for eligibility. Publications that seemed eligible for inclusion were retrieved for full text reading by A.K. Discrepancies at any stage were resolved by a third author (P.B.O.).

      Eligibility criteria

      All studies that reported on complications and mortality after resection of iCCA were eligible for inclusion. Non-English and non-original publications such as reviews, case reports, letters, editorials, or conference abstracts were excluded. Studies including patients who underwent a resection before 1990 were excluded. Studies that reported a combined study population (eg, intrahepatic- and extrahepatic cholangiocarcinoma) were only included if outcomes were presented separately for iCCA. If a population had mixed pathology (eg, iCCA and hepatocellular carcinoma), the study was excluded. Studies that lacked data on the outcomes of interest were excluded, as well as studies that reported on treatments other than initial complete resection of iCCA (eg, associating liver partition and portal vein ligation for staged hepatectomy and resection of recurrences). In case of overlapping cohorts, the largest or the most recent series was included. Studies with <50 patients were excluded.

      Data collection

      The extracted data included study characteristics (ie, author, year of publication, inclusion period, and number of patients), patient characteristics (ie, age, sex, and American Society of Anesthesiologists classification [ASA]), preoperative characteristics (ie, portal vein embolization), operative characteristics (ie, type of resection, vascular reconstruction, and biliary reconstruction), and postoperative details (ie, major complications and mortality). Authors from some studies were contacted for lacking data. The primary outcome was postoperative mortality, defined as in-hospital, 30-day, or 90-day mortality. The secondary outcome was major complications (Clavien-Dindo grade ≥III). Subgroup analyses were prespecified for 90-day mortality and major complications in relation to the extent of liver resection (ie, minor, major, and extended), period (ie, start of inclusion period before or after 2000), and region (ie, Asian or Western studies). A study was classified as Asian or Western if the origin of the participating centers originated for at least 80% from Asian or Western countries. A minor hepatectomy was defined as resection of <3 Couinaud segments, a major hepatectomy was defined as resection of ≥3 Couinaud segments, and an extended hepatectomy was defined as resection of ≥5 Couinaud segments.

      Quality assessment

      Risk of bias was assessed by the Joanna Briggs Institute checklist that is specifically designed for case series.
      • Moola S.M.Z.
      • Tufanaru C.
      • Aromataris E.
      • et al.
      The checklist consists of 10 predefined items that can be specified to questions particularly relevant for the interest of this systematic review, which can be answered with ‘yes,’ ‘no,’ and ‘unclear or not applicable’ (Supplementary Table S2).
      Figure thumbnail gr2
      Figure 2Risk of bias graph according to the Joanna Briggs Institute checklist.

      Statistical analysis

      The categorical values are presented as numbers and percentages. Continuous data are presented as mean with SD. Studies were pooled separately for in-hospital, 30-day, and 90-day mortality. Studies were pooled for postoperative morbidity if they reported major complications (Clavien-Dindo grade ≥III). The I2 statistic was used to quantify the heterogeneity across studies. An I2 value >50% indicated significant heterogeneity. A random-effects model was used for all analyses. Pooled analyses were visualized with forest plots. Statistical analyses were performed using R version 4.1.1 (http://www.r-project.org; R Foundation for Statistical Computing, Vienna, Austria).

      Results

      The search and screening process of the literature search is presented in Figure 1. A total of 9,821 records were identified through database searching. The duplicate records were removed. The title and abstract of 7,076 records were screened for eligibility. This led to full-text assessment of 184 studies, of which 32 were included in the meta-analysis.
      Figure thumbnail gr1
      Figure 1Preferred Reporting Items for Systematic Review and Meta-Analyses flowchart of the study selection process.

      Study characteristics

      The 32 included studies reported on 19,503 patients who underwent resection of iCCA between 1990 and 2018. The main characteristics of the included studies are presented in Table I. Fourteen studies had a multicenter design,
      • Ribero D.
      • Pinna A.D.
      • Guglielmi A.
      • et al.
      Surgical approach for long-term survival of patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis of 434 patients.
      ,
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      ,
      • Conci S.
      • Viganò L.
      • Ercolani G.
      • et al.
      Outcomes of vascular resection associated with curative intent hepatectomy for intrahepatic cholangiocarcinoma.
      • Morimoto Y.
      • Tanaka Y.
      • Ito T.
      • et al.
      Long-term survival and prognostic factors in the surgical treatment for intrahepatic cholangiocarcinoma.
      • Schnitzbauer A.A.
      • Eberhard J.
      • Bartsch F.
      • et al.
      The MEGNA score and preoperative anemia are major prognostic factors after resection in the German intrahepatic cholangiocarcinoma cohort.
      • Buettner S.
      • Ten Cate D.W.G.
      • Bagante F.
      • et al.
      Survival after resection of multiple tumor foci of intrahepatic cholangiocarcinoma.
      • Spolverato G.
      • Yakoob M.Y.
      • Kim Y.
      • et al.
      Impact of complications on long-term survival after resection of intrahepatic cholangiocarcinoma.
      • Reames B.N.
      • Ejaz A.
      • Koerkamp B.G.
      • et al.
      Impact of major vascular resection on outcomes and survival in patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis.
      • Merath K.
      • Chen Q.
      • Bagante F.
      • et al.
      A multi-institutional international analysis of textbook outcomes among patients undergoing curative-intent resection of intrahepatic cholangiocarcinoma.
      • Olthof P.B.
      • Elfrink A.K.E.
      • Marra E.
      • et al.
      Volume-outcome relationship of liver surgery: a nationwide analysis.
      • Lee G.C.
      • Gamblin T.C.
      • Fong Z.V.
      • et al.
      Facility type is associated with margin status and overall survival of patients with resected intrahepatic cholangiocarcinoma.
      • Liu H.
      • Cen X.
      • Suo T.
      • et al.
      Trends and hospital variations in surgical outcomes for cholangiocarcinoma in New York state.
      • Jutric Z.
      • Johnston W.C.
      • Hoen H.M.
      • et al.
      Impact of lymph node status in patients with intrahepatic cholangiocarcinoma treated by major hepatectomy: a review of the National Cancer Database.
      • Filmann N.
      • Walter D.
      • Schadde E.
      • et al.
      Mortality after liver surgery in Germany.
      of which 4 studies queried nationwide databases.
      • Lee G.C.
      • Gamblin T.C.
      • Fong Z.V.
      • et al.
      Facility type is associated with margin status and overall survival of patients with resected intrahepatic cholangiocarcinoma.
      • Liu H.
      • Cen X.
      • Suo T.
      • et al.
      Trends and hospital variations in surgical outcomes for cholangiocarcinoma in New York state.
      • Jutric Z.
      • Johnston W.C.
      • Hoen H.M.
      • et al.
      Impact of lymph node status in patients with intrahepatic cholangiocarcinoma treated by major hepatectomy: a review of the National Cancer Database.
      • Filmann N.
      • Walter D.
      • Schadde E.
      • et al.
      Mortality after liver surgery in Germany.
      Of the 14 multicenter studies, 5 studies were multinational.
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      ,
      • Buettner S.
      • Ten Cate D.W.G.
      • Bagante F.
      • et al.
      Survival after resection of multiple tumor foci of intrahepatic cholangiocarcinoma.
      • Spolverato G.
      • Yakoob M.Y.
      • Kim Y.
      • et al.
      Impact of complications on long-term survival after resection of intrahepatic cholangiocarcinoma.
      • Reames B.N.
      • Ejaz A.
      • Koerkamp B.G.
      • et al.
      Impact of major vascular resection on outcomes and survival in patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis.
      • Merath K.
      • Chen Q.
      • Bagante F.
      • et al.
      A multi-institutional international analysis of textbook outcomes among patients undergoing curative-intent resection of intrahepatic cholangiocarcinoma.
      None of these studies presented the results separately per center or per country. Twenty-two studies originated from Western countries,
      • Ribero D.
      • Pinna A.D.
      • Guglielmi A.
      • et al.
      Surgical approach for long-term survival of patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis of 434 patients.
      ,
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      ,
      • Hobeika C.
      • Cauchy F.
      • Poté N.
      • et al.
      Short- and long-term outcomes of liver resection for intrahepatic cholangiocarcinoma associated with the metabolic syndrome.
      ,
      • Shubert C.R.
      • Habermann E.B.
      • Truty M.J.
      • Thomsen K.M.
      • Kendrick M.L.
      • Nagorney D.M.
      Defining perioperative risk after hepatectomy based on diagnosis and extent of resection.
      ,
      • Conci S.
      • Viganò L.
      • Ercolani G.
      • et al.
      Outcomes of vascular resection associated with curative intent hepatectomy for intrahepatic cholangiocarcinoma.
      ,
      • Morimoto Y.
      • Tanaka Y.
      • Ito T.
      • et al.
      Long-term survival and prognostic factors in the surgical treatment for intrahepatic cholangiocarcinoma.
      • Schnitzbauer A.A.
      • Eberhard J.
      • Bartsch F.
      • et al.
      The MEGNA score and preoperative anemia are major prognostic factors after resection in the German intrahepatic cholangiocarcinoma cohort.
      • Buettner S.
      • Ten Cate D.W.G.
      • Bagante F.
      • et al.
      Survival after resection of multiple tumor foci of intrahepatic cholangiocarcinoma.
      • Spolverato G.
      • Yakoob M.Y.
      • Kim Y.
      • et al.
      Impact of complications on long-term survival after resection of intrahepatic cholangiocarcinoma.
      • Reames B.N.
      • Ejaz A.
      • Koerkamp B.G.
      • et al.
      Impact of major vascular resection on outcomes and survival in patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis.
      • Merath K.
      • Chen Q.
      • Bagante F.
      • et al.
      A multi-institutional international analysis of textbook outcomes among patients undergoing curative-intent resection of intrahepatic cholangiocarcinoma.
      • Olthof P.B.
      • Elfrink A.K.E.
      • Marra E.
      • et al.
      Volume-outcome relationship of liver surgery: a nationwide analysis.
      • Lee G.C.
      • Gamblin T.C.
      • Fong Z.V.
      • et al.
      Facility type is associated with margin status and overall survival of patients with resected intrahepatic cholangiocarcinoma.
      • Liu H.
      • Cen X.
      • Suo T.
      • et al.
      Trends and hospital variations in surgical outcomes for cholangiocarcinoma in New York state.
      • Jutric Z.
      • Johnston W.C.
      • Hoen H.M.
      • et al.
      Impact of lymph node status in patients with intrahepatic cholangiocarcinoma treated by major hepatectomy: a review of the National Cancer Database.
      • Filmann N.
      • Walter D.
      • Schadde E.
      • et al.
      Mortality after liver surgery in Germany.
      • Bartsch F.
      • Tripke V.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Heinrich S.
      • Lang H.
      Extended resection of intrahepatic cholangiocarcinoma: a retrospective single-center cohort study.
      • Beetz O.
      • Weigle C.A.
      • Cammann S.
      • et al.
      Preoperative leukocytosis and the resection severity index are independent risk factors for survival in patients with intrahepatic cholangiocarcinoma.
      • Bektas H.
      • Yeyrek C.
      • Kleine M.
      • et al.
      Surgical treatment for intrahepatic cholangiocarcinoma in Europe: a single center experience.
      • Bergeat D.
      • Sulpice L.
      • Rayar M.
      • et al.
      Extended liver resections for intrahepatic cholangiocarcinoma: friend or foe?.
      • Guglielmi A.
      • Ruzzenente A.
      • Campagnaro T.
      • et al.
      Intrahepatic cholangiocarcinoma: prognostic factors after surgical resection.
      • Lurje G.
      • Bednarsch J.
      • Czigany Z.
      • et al.
      The prognostic role of lymphovascular invasion and lymph node metastasis in perihilar and intrahepatic cholangiocarcinoma.
      • Nickkholgh A.
      • Ghamarnejad O.
      • Khajeh E.
      • et al.
      Outcome after liver resection for primary and recurrent intrahepatic cholangiocarcinoma.
      whereas 10 studies originated from Asian countries.
      • Ma K.W.
      • Cheung T.T.
      • She W.H.
      • et al.
      Major postoperative complications compromise oncological outcomes of patients with intrahepatic cholangiocarcinoma after curative resection - A 13-year cohort in a tertiary center.
      ,
      • Morimoto Y.
      • Tanaka Y.
      • Ito T.
      • et al.
      Long-term survival and prognostic factors in the surgical treatment for intrahepatic cholangiocarcinoma.
      ,
      • Cho S.Y.
      • Park S.J.
      • Kim S.H.
      • et al.
      Survival analysis of intrahepatic cholangiocarcinoma after resection.
      • Li H.
      • Wu J.S.
      • Wang X.T.
      • et al.
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      • Luo X.
      • Yuan L.
      • Wang Y.
      • Ge R.
      • Sun Y.
      • Wei G.
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      • Miyata T.
      • Yamashita Y.I.
      • Yamao T.
      • et al.
      Prognostic impacts of postoperative complications in patients with intrahepatic cholangiocarcinoma after curative operations.
      • Si A.
      • Li J.
      • Yang Z.
      • et al.
      Impact of anatomical versus non-anatomical liver resection on short- and long-term outcomes for patients with intrahepatic cholangiocarcinoma.
      • Yoh T.
      • Hatano E.
      • Nishio T.
      • et al.
      Significant improvement in outcomes of patients with intrahepatic cholangiocarcinoma after surgery.
      • Zhu Y.
      • Song J.
      • Xu X.
      • Tan Y.
      • Yang J.
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      • An S.-L.
      • Liu L.-G.
      • Rong W.
      • et al.
      Surgical outcome and prognostic factors in intrahepatic cholangiocarcinoma: a single-center experience of 114 cases.
      Western countries included the USA,
      • Lee G.C.
      • Gamblin T.C.
      • Fong Z.V.
      • et al.
      Facility type is associated with margin status and overall survival of patients with resected intrahepatic cholangiocarcinoma.
      • Liu H.
      • Cen X.
      • Suo T.
      • et al.
      Trends and hospital variations in surgical outcomes for cholangiocarcinoma in New York state.
      • Jutric Z.
      • Johnston W.C.
      • Hoen H.M.
      • et al.
      Impact of lymph node status in patients with intrahepatic cholangiocarcinoma treated by major hepatectomy: a review of the National Cancer Database.
      Germany,
      • Schnitzbauer A.A.
      • Eberhard J.
      • Bartsch F.
      • et al.
      The MEGNA score and preoperative anemia are major prognostic factors after resection in the German intrahepatic cholangiocarcinoma cohort.
      ,
      • Filmann N.
      • Walter D.
      • Schadde E.
      • et al.
      Mortality after liver surgery in Germany.
      • Bartsch F.
      • Tripke V.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Heinrich S.
      • Lang H.
      Extended resection of intrahepatic cholangiocarcinoma: a retrospective single-center cohort study.
      • Beetz O.
      • Weigle C.A.
      • Cammann S.
      • et al.
      Preoperative leukocytosis and the resection severity index are independent risk factors for survival in patients with intrahepatic cholangiocarcinoma.
      • Bektas H.
      • Yeyrek C.
      • Kleine M.
      • et al.
      Surgical treatment for intrahepatic cholangiocarcinoma in Europe: a single center experience.
      ,
      • Lurje G.
      • Bednarsch J.
      • Czigany Z.
      • et al.
      The prognostic role of lymphovascular invasion and lymph node metastasis in perihilar and intrahepatic cholangiocarcinoma.
      ,
      • Nickkholgh A.
      • Ghamarnejad O.
      • Khajeh E.
      • et al.
      Outcome after liver resection for primary and recurrent intrahepatic cholangiocarcinoma.
      France,
      • Hobeika C.
      • Cauchy F.
      • Poté N.
      • et al.
      Short- and long-term outcomes of liver resection for intrahepatic cholangiocarcinoma associated with the metabolic syndrome.
      ,
      • Bergeat D.
      • Sulpice L.
      • Rayar M.
      • et al.
      Extended liver resections for intrahepatic cholangiocarcinoma: friend or foe?.
      Italy,
      • Ribero D.
      • Pinna A.D.
      • Guglielmi A.
      • et al.
      Surgical approach for long-term survival of patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis of 434 patients.
      ,
      • Conci S.
      • Viganò L.
      • Ercolani G.
      • et al.
      Outcomes of vascular resection associated with curative intent hepatectomy for intrahepatic cholangiocarcinoma.
      ,
      • Guglielmi A.
      • Ruzzenente A.
      • Campagnaro T.
      • et al.
      Intrahepatic cholangiocarcinoma: prognostic factors after surgical resection.
      Spain,
      • Shubert C.R.
      • Habermann E.B.
      • Truty M.J.
      • Thomsen K.M.
      • Kendrick M.L.
      • Nagorney D.M.
      Defining perioperative risk after hepatectomy based on diagnosis and extent of resection.
      and the Netherlands.
      • Olthof P.B.
      • Elfrink A.K.E.
      • Marra E.
      • et al.
      Volume-outcome relationship of liver surgery: a nationwide analysis.
      Asian countries included Japan,
      • Morimoto Y.
      • Tanaka Y.
      • Ito T.
      • et al.
      Long-term survival and prognostic factors in the surgical treatment for intrahepatic cholangiocarcinoma.
      ,
      • Miyata T.
      • Yamashita Y.I.
      • Yamao T.
      • et al.
      Prognostic impacts of postoperative complications in patients with intrahepatic cholangiocarcinoma after curative operations.
      ,
      • Yoh T.
      • Hatano E.
      • Nishio T.
      • et al.
      Significant improvement in outcomes of patients with intrahepatic cholangiocarcinoma after surgery.
      China,
      • Ma K.W.
      • Cheung T.T.
      • She W.H.
      • et al.
      Major postoperative complications compromise oncological outcomes of patients with intrahepatic cholangiocarcinoma after curative resection - A 13-year cohort in a tertiary center.
      ,
      • Li H.
      • Wu J.S.
      • Wang X.T.
      • et al.
      Major hepatectomy is a safe modality for the treatment of intrahepatic cholangiocarcinoma in selected patients complicated with cirrhosis.
      ,
      • Luo X.
      • Yuan L.
      • Wang Y.
      • Ge R.
      • Sun Y.
      • Wei G.
      Survival outcomes and prognostic factors of surgical therapy for all potentially resectable intrahepatic cholangiocarcinoma: a large single-center cohort study.
      ,
      • Si A.
      • Li J.
      • Yang Z.
      • et al.
      Impact of anatomical versus non-anatomical liver resection on short- and long-term outcomes for patients with intrahepatic cholangiocarcinoma.
      ,
      • Zhu Y.
      • Song J.
      • Xu X.
      • Tan Y.
      • Yang J.
      Safety and feasibility of laparoscopic liver resection for patients with large or multiple intrahepatic cholangiocarcinomas: a propensity score based case-matched analysis from a single institute.
      ,
      • An S.-L.
      • Liu L.-G.
      • Rong W.
      • et al.
      Surgical outcome and prognostic factors in intrahepatic cholangiocarcinoma: a single-center experience of 114 cases.
      and the Republic of Korea.
      • Cho S.Y.
      • Park S.J.
      • Kim S.H.
      • et al.
      Survival analysis of intrahepatic cholangiocarcinoma after resection.
      All studies had a retrospective design.
      Table 1Study characteristics
      AuthorCountryInclusion periodLiver resectionsMale, n (%)Median age (y)ASA 3-4 n (%)Resection type (LH/RH/ELH/ERH)Bile duct n (%)Vascular resections n (%)PVE n (%)
      Asian studies
      An
      • An S.-L.
      • Liu L.-G.
      • Rong W.
      • et al.
      Surgical outcome and prognostic factors in intrahepatic cholangiocarcinoma: a single-center experience of 114 cases.
      China2004-201311466 (58)56-14/10/1/1---
      Cho
      • Cho S.Y.
      • Park S.J.
      • Kim S.H.
      • et al.
      Survival analysis of intrahepatic cholangiocarcinoma after resection.
      Korea2001-20076341 (65)61.4-8/21/13/53 (5)--
      Li
      • Li H.
      • Wu J.S.
      • Wang X.T.
      • et al.
      Major hepatectomy is a safe modality for the treatment of intrahepatic cholangiocarcinoma in selected patients complicated with cirrhosis.
      China2001-200914491 (63)--72/16/25/9---
      Luo
      • Luo X.
      • Yuan L.
      • Wang Y.
      • Ge R.
      • Sun Y.
      • Wei G.
      Survival outcomes and prognostic factors of surgical therapy for all potentially resectable intrahepatic cholangiocarcinoma: a large single-center cohort study.
      China2007-20111281912 (68)------
      Ma
      • Ma K.W.
      • Cheung T.T.
      • She W.H.
      • et al.
      Major postoperative complications compromise oncological outcomes of patients with intrahepatic cholangiocarcinoma after curative resection - A 13-year cohort in a tertiary center.
      China1991-201310759 (55)61-11/13/9/2115 (14)V: 4 (4)-
      Miyata
      • Miyata T.
      • Yamashita Y.I.
      • Yamao T.
      • et al.
      Prognostic impacts of postoperative complications in patients with intrahepatic cholangiocarcinoma after curative operations.
      Japan2002-20166014 (23)---5 (8)--
      Morimoto
      • Morimoto Y.
      • Tanaka Y.
      • Ito T.
      • et al.
      Long-term survival and prognostic factors in the surgical treatment for intrahepatic cholangiocarcinoma.
      Japan1991-20005127 (53)--13/6/7/816 (31)V: 2 (4)-
      Si
      • Si A.
      • Li J.
      • Yang Z.
      • et al.
      Impact of anatomical versus non-anatomical liver resection on short- and long-term outcomes for patients with intrahepatic cholangiocarcinoma.
      China2006-2010702428 (61)------
      Yoh
      • Yoh T.
      • Hatano E.
      • Nishio T.
      • et al.
      Significant improvement in outcomes of patients with intrahepatic cholangiocarcinoma after surgery.
      Japan1993-201414485 (59)---49 (34)--
      Zhu
      • Zhu Y.
      • Song J.
      • Xu X.
      • Tan Y.
      • Yang J.
      Safety and feasibility of laparoscopic liver resection for patients with large or multiple intrahepatic cholangiocarcinomas: a propensity score based case-matched analysis from a single institute.
      China2012-20178351 (61)-8 (10)28/17/0/0---
      Western studies
      Bartsch
      • Bartsch F.
      • Tripke V.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Heinrich S.
      • Lang H.
      Extended resection of intrahepatic cholangiocarcinoma: a retrospective single-center cohort study.
      Germany2008-201815073 (49)64.286 (57)10/25/22/26-A: 0 (0), V: 18 (12)-
      Beetz
      • Beetz O.
      • Weigle C.A.
      • Cammann S.
      • et al.
      Preoperative leukocytosis and the resection severity index are independent risk factors for survival in patients with intrahepatic cholangiocarcinoma.
      Germany1996-2018269134 (50)62-85/41/31/6451 (19)--
      Bektas
      • Bektas H.
      • Yeyrek C.
      • Kleine M.
      • et al.
      Surgical treatment for intrahepatic cholangiocarcinoma in Europe: a single center experience.
      Germany1996-201015884 (53)61--2 (1)--
      Bergeat
      • Bergeat D.
      • Sulpice L.
      • Rayar M.
      • et al.
      Extended liver resections for intrahepatic cholangiocarcinoma: friend or foe?.
      France1997-201310782 (77)---10 (9)A: 3 (3), V: 7 (7)14 (13)
      Buettner
      • Buettner S.
      • van Vugt J.L.
      • JN I.J.
      • Groot Koerkamp B.
      Intrahepatic cholangiocarcinoma: current perspectives.
      Multinational1990-20171013540 (55)59348 (34)----
      Conci
      • Conci S.
      • Viganò L.
      • Ercolani G.
      • et al.
      Outcomes of vascular resection associated with curative intent hepatectomy for intrahepatic cholangiocarcinoma.
      Italy1995-2015270137 (51)68---V: 15 (6)-
      Filmann
      • Filmann N.
      • Walter D.
      • Schadde E.
      • et al.
      Mortality after liver surgery in Germany.
      Germany2010-20154667---984/827/-/----
      Guglielmi
      • Guglielmi A.
      • Ruzzenente A.
      • Campagnaro T.
      • et al.
      Intrahepatic cholangiocarcinoma: prognostic factors after surgical resection.
      Italy1990-20075232 (62)--17/9/2/5-V: 2 (4)-
      Hobeika
      • Hobeika C.
      • Cauchy F.
      • Poté N.
      • et al.
      Short- and long-term outcomes of liver resection for intrahepatic cholangiocarcinoma associated with the metabolic syndrome.
      France2000-201611557 (50)-19 (17)---11 (10)
      Jutric
      • Jutric Z.
      • Johnston W.C.
      • Hoen H.M.
      • et al.
      Impact of lymph node status in patients with intrahepatic cholangiocarcinoma treated by major hepatectomy: a review of the National Cancer Database.
      USA1998-2011881392 (45)--140/140/39/51---
      Lee
      • Lee G.C.
      • Gamblin T.C.
      • Fong Z.V.
      • et al.
      Facility type is associated with margin status and overall survival of patients with resected intrahepatic cholangiocarcinoma.
      USA2004-201422561046 (46)------
      Liu
      • Liu H.
      • Cen X.
      • Suo T.
      • et al.
      Trends and hospital variations in surgical outcomes for cholangiocarcinoma in New York state.
      USA2005-201220891436 (69)------
      Lurje
      • Lurje G.
      • Bednarsch J.
      • Czigany Z.
      • et al.
      The prognostic role of lymphovascular invasion and lymph node metastasis in perihilar and intrahepatic cholangiocarcinoma.
      Germany2011-20167134 (48)-42 (59)---8 (11)
      Merath
      • Merath K.
      • Chen Q.
      • Bagante F.
      • et al.
      A multi-institutional international analysis of textbook outcomes among patients undergoing curative-intent resection of intrahepatic cholangiocarcinoma.
      Multinational1993-2015687370 (54)61268 (39)----
      Nickkholgh
      • Nickkholgh A.
      • Ghamarnejad O.
      • Khajeh E.
      • et al.
      Outcome after liver resection for primary and recurrent intrahepatic cholangiocarcinoma.
      Germany2001-2015190107 (56)63-45/41/21/34--4 (2)
      Olthof
      • Olthof P.B.
      • Miyasaka M.
      • Koerkamp B.G.
      • et al.
      A comparison of treatment and outcomes of perihilar cholangiocarcinoma between Eastern and Western centers.
      Netherlands2014-20179753 (55)6726 (27)24/12/5/13--13 (13)
      Rafecas
      • Rafecas A.
      • Torras J.
      • Fabregat J.
      • et al.
      Intrahepatic cholangiocarcinoma: prognostic factors for recurrence and survival in a series of 67 patients treated surgically at a single center.
      Spain1996-20176745 (67)66-20/11/4/4--4 (6)
      Reames
      • Reames B.N.
      • Ejaz A.
      • Koerkamp B.G.
      • et al.
      Impact of major vascular resection on outcomes and survival in patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis.
      Multinational1990-20161087594 (55)-438 (40)218/179/107/140190 (18)V: 98 (9)-
      Ribero
      • Ribero D.
      • Pinna A.D.
      • Guglielmi A.
      • et al.
      Surgical approach for long-term survival of patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis of 434 patients.
      Italy1990-2008434243 (56)65--/-/19/6584 (19)V: 14 (3)-
      Schnitzbauer
      • Schnitzbauer A.A.
      • Eberhard J.
      • Bartsch F.
      • et al.
      The MEGNA score and preoperative anemia are major prognostic factors after resection in the German intrahepatic cholangiocarcinoma cohort.
      Germany2004-2013488250 (51)67-----
      Spolverato
      • Spolverato G.
      • Yakoob M.Y.
      • Kim Y.
      • et al.
      Impact of complications on long-term survival after resection of intrahepatic cholangiocarcinoma.
      Multinational1990-2013583302 (52)59.9-----
      Zhang
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      Multinational1990-20161023569 (56)59-202/161/99/128177 (17)--
      A, hepatic artery reconstruction; ASA, American Society of Anesthesiologists; ELH, extended left hemihepatectomy; ERH, extended right hemihepatectomy; LH, left hemihepatectomy; PVE, portal vein embolization; RH, right hemihepatectomy; V, portal vein reconstruction.

      Patient characteristics

      Twenty-nine studies (representing 16,199 patients) had a pooled minor hepatectomy proportion of 25.9% (95% CI 18–35.7).
      • Ribero D.
      • Pinna A.D.
      • Guglielmi A.
      • et al.
      Surgical approach for long-term survival of patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis of 434 patients.
      ,
      • Ma K.W.
      • Cheung T.T.
      • She W.H.
      • et al.
      Major postoperative complications compromise oncological outcomes of patients with intrahepatic cholangiocarcinoma after curative resection - A 13-year cohort in a tertiary center.
      ,
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      ,
      • Hobeika C.
      • Cauchy F.
      • Poté N.
      • et al.
      Short- and long-term outcomes of liver resection for intrahepatic cholangiocarcinoma associated with the metabolic syndrome.
      ,
      • Shubert C.R.
      • Habermann E.B.
      • Truty M.J.
      • Thomsen K.M.
      • Kendrick M.L.
      • Nagorney D.M.
      Defining perioperative risk after hepatectomy based on diagnosis and extent of resection.
      ,
      • Conci S.
      • Viganò L.
      • Ercolani G.
      • et al.
      Outcomes of vascular resection associated with curative intent hepatectomy for intrahepatic cholangiocarcinoma.
      • Morimoto Y.
      • Tanaka Y.
      • Ito T.
      • et al.
      Long-term survival and prognostic factors in the surgical treatment for intrahepatic cholangiocarcinoma.
      • Schnitzbauer A.A.
      • Eberhard J.
      • Bartsch F.
      • et al.
      The MEGNA score and preoperative anemia are major prognostic factors after resection in the German intrahepatic cholangiocarcinoma cohort.
      • Buettner S.
      • Ten Cate D.W.G.
      • Bagante F.
      • et al.
      Survival after resection of multiple tumor foci of intrahepatic cholangiocarcinoma.
      • Spolverato G.
      • Yakoob M.Y.
      • Kim Y.
      • et al.
      Impact of complications on long-term survival after resection of intrahepatic cholangiocarcinoma.
      • Reames B.N.
      • Ejaz A.
      • Koerkamp B.G.
      • et al.
      Impact of major vascular resection on outcomes and survival in patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis.
      • Merath K.
      • Chen Q.
      • Bagante F.
      • et al.
      A multi-institutional international analysis of textbook outcomes among patients undergoing curative-intent resection of intrahepatic cholangiocarcinoma.
      • Olthof P.B.
      • Elfrink A.K.E.
      • Marra E.
      • et al.
      Volume-outcome relationship of liver surgery: a nationwide analysis.
      • Lee G.C.
      • Gamblin T.C.
      • Fong Z.V.
      • et al.
      Facility type is associated with margin status and overall survival of patients with resected intrahepatic cholangiocarcinoma.
      ,
      • Jutric Z.
      • Johnston W.C.
      • Hoen H.M.
      • et al.
      Impact of lymph node status in patients with intrahepatic cholangiocarcinoma treated by major hepatectomy: a review of the National Cancer Database.
      • Filmann N.
      • Walter D.
      • Schadde E.
      • et al.
      Mortality after liver surgery in Germany.
      • Bartsch F.
      • Tripke V.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Heinrich S.
      • Lang H.
      Extended resection of intrahepatic cholangiocarcinoma: a retrospective single-center cohort study.
      • Beetz O.
      • Weigle C.A.
      • Cammann S.
      • et al.
      Preoperative leukocytosis and the resection severity index are independent risk factors for survival in patients with intrahepatic cholangiocarcinoma.
      • Bektas H.
      • Yeyrek C.
      • Kleine M.
      • et al.
      Surgical treatment for intrahepatic cholangiocarcinoma in Europe: a single center experience.
      ,
      • Guglielmi A.
      • Ruzzenente A.
      • Campagnaro T.
      • et al.
      Intrahepatic cholangiocarcinoma: prognostic factors after surgical resection.
      • Lurje G.
      • Bednarsch J.
      • Czigany Z.
      • et al.
      The prognostic role of lymphovascular invasion and lymph node metastasis in perihilar and intrahepatic cholangiocarcinoma.
      • Nickkholgh A.
      • Ghamarnejad O.
      • Khajeh E.
      • et al.
      Outcome after liver resection for primary and recurrent intrahepatic cholangiocarcinoma.
      • Cho S.Y.
      • Park S.J.
      • Kim S.H.
      • et al.
      Survival analysis of intrahepatic cholangiocarcinoma after resection.
      • Li H.
      • Wu J.S.
      • Wang X.T.
      • et al.
      Major hepatectomy is a safe modality for the treatment of intrahepatic cholangiocarcinoma in selected patients complicated with cirrhosis.
      • Luo X.
      • Yuan L.
      • Wang Y.
      • Ge R.
      • Sun Y.
      • Wei G.
      Survival outcomes and prognostic factors of surgical therapy for all potentially resectable intrahepatic cholangiocarcinoma: a large single-center cohort study.
      • Miyata T.
      • Yamashita Y.I.
      • Yamao T.
      • et al.
      Prognostic impacts of postoperative complications in patients with intrahepatic cholangiocarcinoma after curative operations.
      ,
      • Yoh T.
      • Hatano E.
      • Nishio T.
      • et al.
      Significant improvement in outcomes of patients with intrahepatic cholangiocarcinoma after surgery.
      • Zhu Y.
      • Song J.
      • Xu X.
      • Tan Y.
      • Yang J.
      Safety and feasibility of laparoscopic liver resection for patients with large or multiple intrahepatic cholangiocarcinomas: a propensity score based case-matched analysis from a single institute.
      • An S.-L.
      • Liu L.-G.
      • Rong W.
      • et al.
      Surgical outcome and prognostic factors in intrahepatic cholangiocarcinoma: a single-center experience of 114 cases.
      Thirty studies (representing 16,306 patients) had a pooled major hepatectomy (including extended hepatectomies) proportion of 72.8% (95% CI 62.5–81.1).
      • Ribero D.
      • Pinna A.D.
      • Guglielmi A.
      • et al.
      Surgical approach for long-term survival of patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis of 434 patients.
      ,
      • Ma K.W.
      • Cheung T.T.
      • She W.H.
      • et al.
      Major postoperative complications compromise oncological outcomes of patients with intrahepatic cholangiocarcinoma after curative resection - A 13-year cohort in a tertiary center.
      ,
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      ,
      • Hobeika C.
      • Cauchy F.
      • Poté N.
      • et al.
      Short- and long-term outcomes of liver resection for intrahepatic cholangiocarcinoma associated with the metabolic syndrome.
      ,
      • Shubert C.R.
      • Habermann E.B.
      • Truty M.J.
      • Thomsen K.M.
      • Kendrick M.L.
      • Nagorney D.M.
      Defining perioperative risk after hepatectomy based on diagnosis and extent of resection.
      ,
      • Conci S.
      • Viganò L.
      • Ercolani G.
      • et al.
      Outcomes of vascular resection associated with curative intent hepatectomy for intrahepatic cholangiocarcinoma.
      • Morimoto Y.
      • Tanaka Y.
      • Ito T.
      • et al.
      Long-term survival and prognostic factors in the surgical treatment for intrahepatic cholangiocarcinoma.
      • Schnitzbauer A.A.
      • Eberhard J.
      • Bartsch F.
      • et al.
      The MEGNA score and preoperative anemia are major prognostic factors after resection in the German intrahepatic cholangiocarcinoma cohort.
      • Buettner S.
      • Ten Cate D.W.G.
      • Bagante F.
      • et al.
      Survival after resection of multiple tumor foci of intrahepatic cholangiocarcinoma.
      • Spolverato G.
      • Yakoob M.Y.
      • Kim Y.
      • et al.
      Impact of complications on long-term survival after resection of intrahepatic cholangiocarcinoma.
      • Reames B.N.
      • Ejaz A.
      • Koerkamp B.G.
      • et al.
      Impact of major vascular resection on outcomes and survival in patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis.
      • Merath K.
      • Chen Q.
      • Bagante F.
      • et al.
      A multi-institutional international analysis of textbook outcomes among patients undergoing curative-intent resection of intrahepatic cholangiocarcinoma.
      • Olthof P.B.
      • Elfrink A.K.E.
      • Marra E.
      • et al.
      Volume-outcome relationship of liver surgery: a nationwide analysis.
      • Lee G.C.
      • Gamblin T.C.
      • Fong Z.V.
      • et al.
      Facility type is associated with margin status and overall survival of patients with resected intrahepatic cholangiocarcinoma.
      ,
      • Jutric Z.
      • Johnston W.C.
      • Hoen H.M.
      • et al.
      Impact of lymph node status in patients with intrahepatic cholangiocarcinoma treated by major hepatectomy: a review of the National Cancer Database.
      • Filmann N.
      • Walter D.
      • Schadde E.
      • et al.
      Mortality after liver surgery in Germany.
      • Bartsch F.
      • Tripke V.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Heinrich S.
      • Lang H.
      Extended resection of intrahepatic cholangiocarcinoma: a retrospective single-center cohort study.
      • Beetz O.
      • Weigle C.A.
      • Cammann S.
      • et al.
      Preoperative leukocytosis and the resection severity index are independent risk factors for survival in patients with intrahepatic cholangiocarcinoma.
      • Bektas H.
      • Yeyrek C.
      • Kleine M.
      • et al.
      Surgical treatment for intrahepatic cholangiocarcinoma in Europe: a single center experience.
      • Bergeat D.
      • Sulpice L.
      • Rayar M.
      • et al.
      Extended liver resections for intrahepatic cholangiocarcinoma: friend or foe?.
      • Guglielmi A.
      • Ruzzenente A.
      • Campagnaro T.
      • et al.
      Intrahepatic cholangiocarcinoma: prognostic factors after surgical resection.
      • Lurje G.
      • Bednarsch J.
      • Czigany Z.
      • et al.
      The prognostic role of lymphovascular invasion and lymph node metastasis in perihilar and intrahepatic cholangiocarcinoma.
      • Nickkholgh A.
      • Ghamarnejad O.
      • Khajeh E.
      • et al.
      Outcome after liver resection for primary and recurrent intrahepatic cholangiocarcinoma.
      • Cho S.Y.
      • Park S.J.
      • Kim S.H.
      • et al.
      Survival analysis of intrahepatic cholangiocarcinoma after resection.
      • Li H.
      • Wu J.S.
      • Wang X.T.
      • et al.
      Major hepatectomy is a safe modality for the treatment of intrahepatic cholangiocarcinoma in selected patients complicated with cirrhosis.
      • Luo X.
      • Yuan L.
      • Wang Y.
      • Ge R.
      • Sun Y.
      • Wei G.
      Survival outcomes and prognostic factors of surgical therapy for all potentially resectable intrahepatic cholangiocarcinoma: a large single-center cohort study.
      • Miyata T.
      • Yamashita Y.I.
      • Yamao T.
      • et al.
      Prognostic impacts of postoperative complications in patients with intrahepatic cholangiocarcinoma after curative operations.
      ,
      • Yoh T.
      • Hatano E.
      • Nishio T.
      • et al.
      Significant improvement in outcomes of patients with intrahepatic cholangiocarcinoma after surgery.
      • Zhu Y.
      • Song J.
      • Xu X.
      • Tan Y.
      • Yang J.
      Safety and feasibility of laparoscopic liver resection for patients with large or multiple intrahepatic cholangiocarcinomas: a propensity score based case-matched analysis from a single institute.
      • An S.-L.
      • Liu L.-G.
      • Rong W.
      • et al.
      Surgical outcome and prognostic factors in intrahepatic cholangiocarcinoma: a single-center experience of 114 cases.
      As a subgroup of major hepatectomies, 22 studies (representing 13,007 patients) had a pooled extended hepatectomy proportion of 22.8% (95% CI 17.3–29.4).
      • Ribero D.
      • Pinna A.D.
      • Guglielmi A.
      • et al.
      Surgical approach for long-term survival of patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis of 434 patients.
      ,
      • Ma K.W.
      • Cheung T.T.
      • She W.H.
      • et al.
      Major postoperative complications compromise oncological outcomes of patients with intrahepatic cholangiocarcinoma after curative resection - A 13-year cohort in a tertiary center.
      ,
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      ,
      • Shubert C.R.
      • Habermann E.B.
      • Truty M.J.
      • Thomsen K.M.
      • Kendrick M.L.
      • Nagorney D.M.
      Defining perioperative risk after hepatectomy based on diagnosis and extent of resection.
      ,
      • Morimoto Y.
      • Tanaka Y.
      • Ito T.
      • et al.
      Long-term survival and prognostic factors in the surgical treatment for intrahepatic cholangiocarcinoma.
      ,
      • Reames B.N.
      • Ejaz A.
      • Koerkamp B.G.
      • et al.
      Impact of major vascular resection on outcomes and survival in patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis.
      ,
      • Olthof P.B.
      • Elfrink A.K.E.
      • Marra E.
      • et al.
      Volume-outcome relationship of liver surgery: a nationwide analysis.
      ,
      • Lee G.C.
      • Gamblin T.C.
      • Fong Z.V.
      • et al.
      Facility type is associated with margin status and overall survival of patients with resected intrahepatic cholangiocarcinoma.
      ,
      • Jutric Z.
      • Johnston W.C.
      • Hoen H.M.
      • et al.
      Impact of lymph node status in patients with intrahepatic cholangiocarcinoma treated by major hepatectomy: a review of the National Cancer Database.
      • Filmann N.
      • Walter D.
      • Schadde E.
      • et al.
      Mortality after liver surgery in Germany.
      • Bartsch F.
      • Tripke V.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Heinrich S.
      • Lang H.
      Extended resection of intrahepatic cholangiocarcinoma: a retrospective single-center cohort study.
      • Beetz O.
      • Weigle C.A.
      • Cammann S.
      • et al.
      Preoperative leukocytosis and the resection severity index are independent risk factors for survival in patients with intrahepatic cholangiocarcinoma.
      • Bektas H.
      • Yeyrek C.
      • Kleine M.
      • et al.
      Surgical treatment for intrahepatic cholangiocarcinoma in Europe: a single center experience.
      • Bergeat D.
      • Sulpice L.
      • Rayar M.
      • et al.
      Extended liver resections for intrahepatic cholangiocarcinoma: friend or foe?.
      • Guglielmi A.
      • Ruzzenente A.
      • Campagnaro T.
      • et al.
      Intrahepatic cholangiocarcinoma: prognostic factors after surgical resection.
      • Lurje G.
      • Bednarsch J.
      • Czigany Z.
      • et al.
      The prognostic role of lymphovascular invasion and lymph node metastasis in perihilar and intrahepatic cholangiocarcinoma.
      • Nickkholgh A.
      • Ghamarnejad O.
      • Khajeh E.
      • et al.
      Outcome after liver resection for primary and recurrent intrahepatic cholangiocarcinoma.
      • Cho S.Y.
      • Park S.J.
      • Kim S.H.
      • et al.
      Survival analysis of intrahepatic cholangiocarcinoma after resection.
      • Li H.
      • Wu J.S.
      • Wang X.T.
      • et al.
      Major hepatectomy is a safe modality for the treatment of intrahepatic cholangiocarcinoma in selected patients complicated with cirrhosis.
      • Luo X.
      • Yuan L.
      • Wang Y.
      • Ge R.
      • Sun Y.
      • Wei G.
      Survival outcomes and prognostic factors of surgical therapy for all potentially resectable intrahepatic cholangiocarcinoma: a large single-center cohort study.
      ,
      • Yoh T.
      • Hatano E.
      • Nishio T.
      • et al.
      Significant improvement in outcomes of patients with intrahepatic cholangiocarcinoma after surgery.
      ,
      • An S.-L.
      • Liu L.-G.
      • Rong W.
      • et al.
      Surgical outcome and prognostic factors in intrahepatic cholangiocarcinoma: a single-center experience of 114 cases.
      Six studies (representing 647 patients) had a pooled rate of preoperative portal vein embolization of 8.2% (95% CI 5.0–13.1) (Supplementary Figure S1, A).
      • Hobeika C.
      • Cauchy F.
      • Poté N.
      • et al.
      Short- and long-term outcomes of liver resection for intrahepatic cholangiocarcinoma associated with the metabolic syndrome.
      ,
      • Shubert C.R.
      • Habermann E.B.
      • Truty M.J.
      • Thomsen K.M.
      • Kendrick M.L.
      • Nagorney D.M.
      Defining perioperative risk after hepatectomy based on diagnosis and extent of resection.
      ,
      • Olthof P.B.
      • Elfrink A.K.E.
      • Marra E.
      • et al.
      Volume-outcome relationship of liver surgery: a nationwide analysis.
      ,
      • Bergeat D.
      • Sulpice L.
      • Rayar M.
      • et al.
      Extended liver resections for intrahepatic cholangiocarcinoma: friend or foe?.
      ,
      • Lurje G.
      • Bednarsch J.
      • Czigany Z.
      • et al.
      The prognostic role of lymphovascular invasion and lymph node metastasis in perihilar and intrahepatic cholangiocarcinoma.
      ,
      • Nickkholgh A.
      • Ghamarnejad O.
      • Khajeh E.
      • et al.
      Outcome after liver resection for primary and recurrent intrahepatic cholangiocarcinoma.
      The pooled rate of a vascular resection was 10.2% (95% CI 6.7–15.3) and involved mostly a portal vein reconstruction (Supplementary Figure S1, B).
      • Ma K.W.
      • Cheung T.T.
      • She W.H.
      • et al.
      Major postoperative complications compromise oncological outcomes of patients with intrahepatic cholangiocarcinoma after curative resection - A 13-year cohort in a tertiary center.
      ,
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      ,
      • Hobeika C.
      • Cauchy F.
      • Poté N.
      • et al.
      Short- and long-term outcomes of liver resection for intrahepatic cholangiocarcinoma associated with the metabolic syndrome.
      ,
      • Conci S.
      • Viganò L.
      • Ercolani G.
      • et al.
      Outcomes of vascular resection associated with curative intent hepatectomy for intrahepatic cholangiocarcinoma.
      ,
      • Reames B.N.
      • Ejaz A.
      • Koerkamp B.G.
      • et al.
      Impact of major vascular resection on outcomes and survival in patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis.
      ,
      • Olthof P.B.
      • Elfrink A.K.E.
      • Marra E.
      • et al.
      Volume-outcome relationship of liver surgery: a nationwide analysis.
      ,
      • Bartsch F.
      • Tripke V.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Heinrich S.
      • Lang H.
      Extended resection of intrahepatic cholangiocarcinoma: a retrospective single-center cohort study.
      • Beetz O.
      • Weigle C.A.
      • Cammann S.
      • et al.
      Preoperative leukocytosis and the resection severity index are independent risk factors for survival in patients with intrahepatic cholangiocarcinoma.
      • Bektas H.
      • Yeyrek C.
      • Kleine M.
      • et al.
      Surgical treatment for intrahepatic cholangiocarcinoma in Europe: a single center experience.
      • Bergeat D.
      • Sulpice L.
      • Rayar M.
      • et al.
      Extended liver resections for intrahepatic cholangiocarcinoma: friend or foe?.
      ,
      • Nickkholgh A.
      • Ghamarnejad O.
      • Khajeh E.
      • et al.
      Outcome after liver resection for primary and recurrent intrahepatic cholangiocarcinoma.
      ,
      • Yoh T.
      • Hatano E.
      • Nishio T.
      • et al.
      Significant improvement in outcomes of patients with intrahepatic cholangiocarcinoma after surgery.

      Critical appraisal and risk of bias

      The individual score of risk-of-bias per study is given in Supplementary Table S3. The overall risk of bias for each item on the Joanna Briggs Institute checklist is presented in Figure 2. Incomplete reporting of clinical information (ASA classification, extent of resection) occurred in 75% (24/32) of the studies. Incomplete reporting of the demographic information occurred in 43.8% (14/32) of the studies. No multicenter studies presented the individual results of each center. Follow-up data were unclear or incomplete in 71.9% (23/32) of the studies.

      Postoperative mortality

      Supplementary Table S4 presents the mortality rates per study. In-hospital mortality was reported by 8 studies (representing 7,639 patients) and ranged from 1.6% (1/63) to 11% (513/4,667) across studies.
      • Morimoto Y.
      • Tanaka Y.
      • Ito T.
      • et al.
      Long-term survival and prognostic factors in the surgical treatment for intrahepatic cholangiocarcinoma.
      ,
      • Schnitzbauer A.A.
      • Eberhard J.
      • Bartsch F.
      • et al.
      The MEGNA score and preoperative anemia are major prognostic factors after resection in the German intrahepatic cholangiocarcinoma cohort.
      ,
      • Liu H.
      • Cen X.
      • Suo T.
      • et al.
      Trends and hospital variations in surgical outcomes for cholangiocarcinoma in New York state.
      ,
      • Filmann N.
      • Walter D.
      • Schadde E.
      • et al.
      Mortality after liver surgery in Germany.
      ,
      • Bektas H.
      • Yeyrek C.
      • Kleine M.
      • et al.
      Surgical treatment for intrahepatic cholangiocarcinoma in Europe: a single center experience.
      ,
      • Guglielmi A.
      • Ruzzenente A.
      • Campagnaro T.
      • et al.
      Intrahepatic cholangiocarcinoma: prognostic factors after surgical resection.
      ,
      • Lurje G.
      • Bednarsch J.
      • Czigany Z.
      • et al.
      The prognostic role of lymphovascular invasion and lymph node metastasis in perihilar and intrahepatic cholangiocarcinoma.
      ,
      • Cho S.Y.
      • Park S.J.
      • Kim S.H.
      • et al.
      Survival analysis of intrahepatic cholangiocarcinoma after resection.
      The pooled in-hospital mortality was 5.9% (95% CI 4.1–8.4) (Figure 3, A). Eleven studies (representing 6,847 patients) described 30-day mortality rates ranging from 0% (0/83) to 8% (12/150) across studies.
      • Ma K.W.
      • Cheung T.T.
      • She W.H.
      • et al.
      Major postoperative complications compromise oncological outcomes of patients with intrahepatic cholangiocarcinoma after curative resection - A 13-year cohort in a tertiary center.
      ,
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      ,
      • Reames B.N.
      • Ejaz A.
      • Koerkamp B.G.
      • et al.
      Impact of major vascular resection on outcomes and survival in patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis.
      ,
      • Merath K.
      • Chen Q.
      • Bagante F.
      • et al.
      A multi-institutional international analysis of textbook outcomes among patients undergoing curative-intent resection of intrahepatic cholangiocarcinoma.
      ,
      • Lee G.C.
      • Gamblin T.C.
      • Fong Z.V.
      • et al.
      Facility type is associated with margin status and overall survival of patients with resected intrahepatic cholangiocarcinoma.
      ,
      • Jutric Z.
      • Johnston W.C.
      • Hoen H.M.
      • et al.
      Impact of lymph node status in patients with intrahepatic cholangiocarcinoma treated by major hepatectomy: a review of the National Cancer Database.
      ,
      • Bartsch F.
      • Tripke V.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Heinrich S.
      • Lang H.
      Extended resection of intrahepatic cholangiocarcinoma: a retrospective single-center cohort study.
      ,
      • Beetz O.
      • Weigle C.A.
      • Cammann S.
      • et al.
      Preoperative leukocytosis and the resection severity index are independent risk factors for survival in patients with intrahepatic cholangiocarcinoma.
      ,
      • Nickkholgh A.
      • Ghamarnejad O.
      • Khajeh E.
      • et al.
      Outcome after liver resection for primary and recurrent intrahepatic cholangiocarcinoma.
      ,
      • Zhu Y.
      • Song J.
      • Xu X.
      • Tan Y.
      • Yang J.
      Safety and feasibility of laparoscopic liver resection for patients with large or multiple intrahepatic cholangiocarcinomas: a propensity score based case-matched analysis from a single institute.
      ,
      • An S.-L.
      • Liu L.-G.
      • Rong W.
      • et al.
      Surgical outcome and prognostic factors in intrahepatic cholangiocarcinoma: a single-center experience of 114 cases.
      The pooled 30-day mortality was 4.6% (95% CI 4.0–5.2) (Figure 3, B). Sixteen studies (representing 8,607 patients) reported on 90-day mortality ranging from 1.5% (1/67) to 11.3% (13/115) across studies.
      • Ribero D.
      • Pinna A.D.
      • Guglielmi A.
      • et al.
      Surgical approach for long-term survival of patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis of 434 patients.
      ,
      • Ma K.W.
      • Cheung T.T.
      • She W.H.
      • et al.
      Major postoperative complications compromise oncological outcomes of patients with intrahepatic cholangiocarcinoma after curative resection - A 13-year cohort in a tertiary center.
      ,
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      ,
      • Hobeika C.
      • Cauchy F.
      • Poté N.
      • et al.
      Short- and long-term outcomes of liver resection for intrahepatic cholangiocarcinoma associated with the metabolic syndrome.
      ,
      • Shubert C.R.
      • Habermann E.B.
      • Truty M.J.
      • Thomsen K.M.
      • Kendrick M.L.
      • Nagorney D.M.
      Defining perioperative risk after hepatectomy based on diagnosis and extent of resection.
      ,
      • Conci S.
      • Viganò L.
      • Ercolani G.
      • et al.
      Outcomes of vascular resection associated with curative intent hepatectomy for intrahepatic cholangiocarcinoma.
      ,
      • Schnitzbauer A.A.
      • Eberhard J.
      • Bartsch F.
      • et al.
      The MEGNA score and preoperative anemia are major prognostic factors after resection in the German intrahepatic cholangiocarcinoma cohort.
      • Buettner S.
      • Ten Cate D.W.G.
      • Bagante F.
      • et al.
      Survival after resection of multiple tumor foci of intrahepatic cholangiocarcinoma.
      • Spolverato G.
      • Yakoob M.Y.
      • Kim Y.
      • et al.
      Impact of complications on long-term survival after resection of intrahepatic cholangiocarcinoma.
      • Reames B.N.
      • Ejaz A.
      • Koerkamp B.G.
      • et al.
      Impact of major vascular resection on outcomes and survival in patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis.
      ,
      • Lee G.C.
      • Gamblin T.C.
      • Fong Z.V.
      • et al.
      Facility type is associated with margin status and overall survival of patients with resected intrahepatic cholangiocarcinoma.
      ,
      • Bartsch F.
      • Tripke V.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Heinrich S.
      • Lang H.
      Extended resection of intrahepatic cholangiocarcinoma: a retrospective single-center cohort study.
      ,
      • Beetz O.
      • Weigle C.A.
      • Cammann S.
      • et al.
      Preoperative leukocytosis and the resection severity index are independent risk factors for survival in patients with intrahepatic cholangiocarcinoma.
      ,
      • Bergeat D.
      • Sulpice L.
      • Rayar M.
      • et al.
      Extended liver resections for intrahepatic cholangiocarcinoma: friend or foe?.
      ,
      • Li H.
      • Wu J.S.
      • Wang X.T.
      • et al.
      Major hepatectomy is a safe modality for the treatment of intrahepatic cholangiocarcinoma in selected patients complicated with cirrhosis.
      ,
      • Miyata T.
      • Yamashita Y.I.
      • Yamao T.
      • et al.
      Prognostic impacts of postoperative complications in patients with intrahepatic cholangiocarcinoma after curative operations.
      ,
      • Si A.
      • Li J.
      • Yang Z.
      • et al.
      Impact of anatomical versus non-anatomical liver resection on short- and long-term outcomes for patients with intrahepatic cholangiocarcinoma.
      The pooled 90-day mortality of these studies was 6.1% (95% CI 5.0–7.3; Figure 3, C). Six studies reported both on 30- and 90-day mortality.
      • Ma K.W.
      • Cheung T.T.
      • She W.H.
      • et al.
      Major postoperative complications compromise oncological outcomes of patients with intrahepatic cholangiocarcinoma after curative resection - A 13-year cohort in a tertiary center.
      ,
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      ,
      • Reames B.N.
      • Ejaz A.
      • Koerkamp B.G.
      • et al.
      Impact of major vascular resection on outcomes and survival in patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis.
      ,
      • Lee G.C.
      • Gamblin T.C.
      • Fong Z.V.
      • et al.
      Facility type is associated with margin status and overall survival of patients with resected intrahepatic cholangiocarcinoma.
      ,
      • Bartsch F.
      • Tripke V.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Heinrich S.
      • Lang H.
      Extended resection of intrahepatic cholangiocarcinoma: a retrospective single-center cohort study.
      ,
      • Beetz O.
      • Weigle C.A.
      • Cammann S.
      • et al.
      Preoperative leukocytosis and the resection severity index are independent risk factors for survival in patients with intrahepatic cholangiocarcinoma.
      The pooled difference between 30- and 90-day mortality was 2.5% (95% CI 1.6–3.8) (Supplementary Figure S2, A). Six studies (representing 16 patients) reported the proportion in which liver failure was the cause of mortality, for which the pooled proportion was 29.1% (95% CI 18.7–42) (Supplementary Figure S2, B).
      • Morimoto Y.
      • Tanaka Y.
      • Ito T.
      • et al.
      Long-term survival and prognostic factors in the surgical treatment for intrahepatic cholangiocarcinoma.
      ,
      • Bartsch F.
      • Tripke V.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Heinrich S.
      • Lang H.
      Extended resection of intrahepatic cholangiocarcinoma: a retrospective single-center cohort study.
      • Beetz O.
      • Weigle C.A.
      • Cammann S.
      • et al.
      Preoperative leukocytosis and the resection severity index are independent risk factors for survival in patients with intrahepatic cholangiocarcinoma.
      • Bektas H.
      • Yeyrek C.
      • Kleine M.
      • et al.
      Surgical treatment for intrahepatic cholangiocarcinoma in Europe: a single center experience.
      • Bergeat D.
      • Sulpice L.
      • Rayar M.
      • et al.
      Extended liver resections for intrahepatic cholangiocarcinoma: friend or foe?.
      ,
      • An S.-L.
      • Liu L.-G.
      • Rong W.
      • et al.
      Surgical outcome and prognostic factors in intrahepatic cholangiocarcinoma: a single-center experience of 114 cases.
      Figure thumbnail gr3ab
      Figure 3Forest plots of postoperative mortality and morbidity rates after resection of intrahepatic cholangiocarcinoma. (A) in-hospital mortality, (B) 30-day mortality, (C) 90-day mortality, and (D) major complications (Clavien-Dindo grade ≥III) after resection of intrahepatic cholangiocarcinoma.
      Figure thumbnail gr3cd
      Figure 3Forest plots of postoperative mortality and morbidity rates after resection of intrahepatic cholangiocarcinoma. (A) in-hospital mortality, (B) 30-day mortality, (C) 90-day mortality, and (D) major complications (Clavien-Dindo grade ≥III) after resection of intrahepatic cholangiocarcinoma.

      Major complications

      Twenty studies (representing 8,213 patients) reported on major complications after resection of iCCA, ranging from 4% (51/1,281) to 52.2 (60/115) across studies.
      • Ribero D.
      • Pinna A.D.
      • Guglielmi A.
      • et al.
      Surgical approach for long-term survival of patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis of 434 patients.
      ,
      • Ma K.W.
      • Cheung T.T.
      • She W.H.
      • et al.
      Major postoperative complications compromise oncological outcomes of patients with intrahepatic cholangiocarcinoma after curative resection - A 13-year cohort in a tertiary center.
      ,
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      ,
      • Hobeika C.
      • Cauchy F.
      • Poté N.
      • et al.
      Short- and long-term outcomes of liver resection for intrahepatic cholangiocarcinoma associated with the metabolic syndrome.
      ,
      • Conci S.
      • Viganò L.
      • Ercolani G.
      • et al.
      Outcomes of vascular resection associated with curative intent hepatectomy for intrahepatic cholangiocarcinoma.
      ,
      • Schnitzbauer A.A.
      • Eberhard J.
      • Bartsch F.
      • et al.
      The MEGNA score and preoperative anemia are major prognostic factors after resection in the German intrahepatic cholangiocarcinoma cohort.
      • Buettner S.
      • Ten Cate D.W.G.
      • Bagante F.
      • et al.
      Survival after resection of multiple tumor foci of intrahepatic cholangiocarcinoma.
      • Spolverato G.
      • Yakoob M.Y.
      • Kim Y.
      • et al.
      Impact of complications on long-term survival after resection of intrahepatic cholangiocarcinoma.
      • Reames B.N.
      • Ejaz A.
      • Koerkamp B.G.
      • et al.
      Impact of major vascular resection on outcomes and survival in patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis.
      ,
      • Olthof P.B.
      • Elfrink A.K.E.
      • Marra E.
      • et al.
      Volume-outcome relationship of liver surgery: a nationwide analysis.
      ,
      • Bartsch F.
      • Tripke V.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Heinrich S.
      • Lang H.
      Extended resection of intrahepatic cholangiocarcinoma: a retrospective single-center cohort study.
      • Beetz O.
      • Weigle C.A.
      • Cammann S.
      • et al.
      Preoperative leukocytosis and the resection severity index are independent risk factors for survival in patients with intrahepatic cholangiocarcinoma.
      • Bektas H.
      • Yeyrek C.
      • Kleine M.
      • et al.
      Surgical treatment for intrahepatic cholangiocarcinoma in Europe: a single center experience.
      • Bergeat D.
      • Sulpice L.
      • Rayar M.
      • et al.
      Extended liver resections for intrahepatic cholangiocarcinoma: friend or foe?.
      • Guglielmi A.
      • Ruzzenente A.
      • Campagnaro T.
      • et al.
      Intrahepatic cholangiocarcinoma: prognostic factors after surgical resection.
      • Lurje G.
      • Bednarsch J.
      • Czigany Z.
      • et al.
      The prognostic role of lymphovascular invasion and lymph node metastasis in perihilar and intrahepatic cholangiocarcinoma.
      ,
      • Luo X.
      • Yuan L.
      • Wang Y.
      • Ge R.
      • Sun Y.
      • Wei G.
      Survival outcomes and prognostic factors of surgical therapy for all potentially resectable intrahepatic cholangiocarcinoma: a large single-center cohort study.
      • Miyata T.
      • Yamashita Y.I.
      • Yamao T.
      • et al.
      Prognostic impacts of postoperative complications in patients with intrahepatic cholangiocarcinoma after curative operations.
      • Si A.
      • Li J.
      • Yang Z.
      • et al.
      Impact of anatomical versus non-anatomical liver resection on short- and long-term outcomes for patients with intrahepatic cholangiocarcinoma.
      • Yoh T.
      • Hatano E.
      • Nishio T.
      • et al.
      Significant improvement in outcomes of patients with intrahepatic cholangiocarcinoma after surgery.
      The pooled major complication rate after resection of iCCA (Clavien-Dindo grade ≥III) was 22.2% (95% CI 17.7–27.5; Figure 3, D).

      Major complications and mortality in relation to the extent of resection

      Ninety-day mortality rates were reported for minor resections in 2 studies (representing 452 patients),
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      ,
      • Bartsch F.
      • Tripke V.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Heinrich S.
      • Lang H.
      Extended resection of intrahepatic cholangiocarcinoma: a retrospective single-center cohort study.
      major resections in 4 studies (representing 892 patients),
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      ,
      • Bartsch F.
      • Tripke V.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Heinrich S.
      • Lang H.
      Extended resection of intrahepatic cholangiocarcinoma: a retrospective single-center cohort study.
      ,
      • Bergeat D.
      • Sulpice L.
      • Rayar M.
      • et al.
      Extended liver resections for intrahepatic cholangiocarcinoma: friend or foe?.
      ,
      • Li H.
      • Wu J.S.
      • Wang X.T.
      • et al.
      Major hepatectomy is a safe modality for the treatment of intrahepatic cholangiocarcinoma in selected patients complicated with cirrhosis.
      and extended resections in 2 studies (representing 114 patients).
      • Bartsch F.
      • Tripke V.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Heinrich S.
      • Lang H.
      Extended resection of intrahepatic cholangiocarcinoma: a retrospective single-center cohort study.
      ,
      • Bergeat D.
      • Sulpice L.
      • Rayar M.
      • et al.
      Extended liver resections for intrahepatic cholangiocarcinoma: friend or foe?.
      The subgroup analysis revealed a pooled 90-day mortality of 3.1% (95% CI 1.8–5.2) for a minor hepatectomy, 7.4% (95% CI 5.9–9.3) for all major hepatectomies, and 11.4% (95% CI 6.7–18.7) after an extended hepatectomy (P = .001) (Figure 4, A).
      Figure thumbnail gr4ab
      Figure 4Forest plots of subgroup analyses. (A) 90-day mortality after a minor, major, or an extended hepatectomy (subgroup of major); (B) major complications (Clavien-Dindo grade ≥III) after a minor and major hepatectomy; (C) 90-day mortality in Asian studies and Western studies; and (D) 90-day mortality for studies that started their inclusion period before or after the year 2000.
      Figure thumbnail gr4cd
      Figure 4Forest plots of subgroup analyses. (A) 90-day mortality after a minor, major, or an extended hepatectomy (subgroup of major); (B) major complications (Clavien-Dindo grade ≥III) after a minor and major hepatectomy; (C) 90-day mortality in Asian studies and Western studies; and (D) 90-day mortality for studies that started their inclusion period before or after the year 2000.
      Six studies (representing 932 patients) reported on major complications specifically after a major hepatectomy, which ranged from 25.6% (10/39) to 59.3% (16/27) across studies.
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      ,
      • Hobeika C.
      • Cauchy F.
      • Poté N.
      • et al.
      Short- and long-term outcomes of liver resection for intrahepatic cholangiocarcinoma associated with the metabolic syndrome.
      ,
      • Olthof P.B.
      • Elfrink A.K.E.
      • Marra E.
      • et al.
      Volume-outcome relationship of liver surgery: a nationwide analysis.
      ,
      • Bartsch F.
      • Tripke V.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Heinrich S.
      • Lang H.
      Extended resection of intrahepatic cholangiocarcinoma: a retrospective single-center cohort study.
      ,
      • Bergeat D.
      • Sulpice L.
      • Rayar M.
      • et al.
      Extended liver resections for intrahepatic cholangiocarcinoma: friend or foe?.
      ,
      • Miyata T.
      • Yamashita Y.I.
      • Yamao T.
      • et al.
      Prognostic impacts of postoperative complications in patients with intrahepatic cholangiocarcinoma after curative operations.
      Two studies (representing 452 patients) reported on major complications after a minor hepatectomy, which ranged from 7.2% (30/415) to 21.6% (8/37) across studies.
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      ,
      • Bartsch F.
      • Tripke V.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Heinrich S.
      • Lang H.
      Extended resection of intrahepatic cholangiocarcinoma: a retrospective single-center cohort study.
      The pooled major complication rate after a major hepatectomy was 38.8% (95% CI 29.5–49) compared to 11.3% (95% CI 5.0–24) after a minor hepatectomy (P = .001; Figure 4, B).

      Mortality in relation to Asian versus Western studies

      Ten studies (representing 2,749 patients) originated from Asian centers and 22 studies (representing 16,754 patients) originated from Western centers. The pooled in-hospital mortality was 2.6% (95% CI 0.9–7.8) in Asian studies and 6.5% (95% CI 4.1–8.4) in Western studies (P = .12; Supplementary Figure S3, A). The pooled 30-day mortality was 1.3% (95% CI 0.4–4.3) in Asian studies and 4.8% (95% CI 4.2–5.5) in Western studies (P = .03; Supplementary Figure S3, B). The pooled 90-day mortality was 4.4% (95% CI 3.3–5.9) in Asian studies and 6.8% (95% CI 5.6–8.2) in Western studies (P = .02; Figure 4, C).

      Mortality in relation to inclusion period

      Ninety-day mortality risks were reported by 9 studies (representing 4,690 patients) that started the inclusion period before the year 2000,
      • Ribero D.
      • Pinna A.D.
      • Guglielmi A.
      • et al.
      Surgical approach for long-term survival of patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis of 434 patients.
      ,
      • Ma K.W.
      • Cheung T.T.
      • She W.H.
      • et al.
      Major postoperative complications compromise oncological outcomes of patients with intrahepatic cholangiocarcinoma after curative resection - A 13-year cohort in a tertiary center.
      ,
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      ,
      • Buettner S.
      • Ten Cate D.W.G.
      • Bagante F.
      • et al.
      Survival after resection of multiple tumor foci of intrahepatic cholangiocarcinoma.
      • Spolverato G.
      • Yakoob M.Y.
      • Kim Y.
      • et al.
      Impact of complications on long-term survival after resection of intrahepatic cholangiocarcinoma.
      • Reames B.N.
      • Ejaz A.
      • Koerkamp B.G.
      • et al.
      Impact of major vascular resection on outcomes and survival in patients with intrahepatic cholangiocarcinoma: a multi-institutional analysis.
      ,
      • Beetz O.
      • Weigle C.A.
      • Cammann S.
      • et al.
      Preoperative leukocytosis and the resection severity index are independent risk factors for survival in patients with intrahepatic cholangiocarcinoma.
      ,
      • Bergeat D.
      • Sulpice L.
      • Rayar M.
      • et al.
      Extended liver resections for intrahepatic cholangiocarcinoma: friend or foe?.
      ,
      • Nickkholgh A.
      • Ghamarnejad O.
      • Khajeh E.
      • et al.
      Outcome after liver resection for primary and recurrent intrahepatic cholangiocarcinoma.
      and 7 studies (representing 3,917 patients) that started the inclusion period after the year 2000.
      • Hobeika C.
      • Cauchy F.
      • Poté N.
      • et al.
      Short- and long-term outcomes of liver resection for intrahepatic cholangiocarcinoma associated with the metabolic syndrome.
      ,
      • Schnitzbauer A.A.
      • Eberhard J.
      • Bartsch F.
      • et al.
      The MEGNA score and preoperative anemia are major prognostic factors after resection in the German intrahepatic cholangiocarcinoma cohort.
      ,
      • Lee G.C.
      • Gamblin T.C.
      • Fong Z.V.
      • et al.
      Facility type is associated with margin status and overall survival of patients with resected intrahepatic cholangiocarcinoma.
      ,
      • Bartsch F.
      • Tripke V.
      • Baumgart J.
      • Hoppe-Lotichius M.
      • Heinrich S.
      • Lang H.
      Extended resection of intrahepatic cholangiocarcinoma: a retrospective single-center cohort study.
      ,
      • Li H.
      • Wu J.S.
      • Wang X.T.
      • et al.
      Major hepatectomy is a safe modality for the treatment of intrahepatic cholangiocarcinoma in selected patients complicated with cirrhosis.
      ,
      • Miyata T.
      • Yamashita Y.I.
      • Yamao T.
      • et al.
      Prognostic impacts of postoperative complications in patients with intrahepatic cholangiocarcinoma after curative operations.
      ,
      • Si A.
      • Li J.
      • Yang Z.
      • et al.
      Impact of anatomical versus non-anatomical liver resection on short- and long-term outcomes for patients with intrahepatic cholangiocarcinoma.
      The pooled 90-day mortality was 6.8% (95% CI 5.1–9.1) for studies that started the inclusion period after 2000, and 5.9% (95% CI 4.8–7.3) for studies that started the inclusion period before 2000 (P = .44; Figure 4, D).

      Discussion

      This systematic review and meta-analysis on postoperative major complications and mortality after resection of iCCA included 32 studies that reported on 19,503 patients. The pooled in-hospital mortality was 5.9%, the 30-day mortality 4.6%, and the 90-day mortality 6.1%. The major complication (Clavien-Dindo grade ≥III) risk after resection of iCCA was 22.2%. Differences were found for 90-day mortality in relation to the extent of resection: the pooled 90-day mortality was 3.1% for minor resections, 7.4% for major resections, and 11.4% for extended resections (P = .001). The major complication rate was higher after a major hepatectomy when compared to a minor hepatectomy (38.8% vs 11.3%; P = .001). The pooled 90-day mortality was lower for Asian studies when compared to Western studies (4.4% vs 6.8%; P = .02). Studies with patients included before 2000 had a similar pooled 90-day mortality as after 2000 (5.9% vs 6.8%; P = .44).
      Liver resections for different indications are associated with different mortality rates, despite technical similarities.
      • Olthof P.B.
      • Elfrink A.K.E.
      • Marra E.
      • et al.
      Volume-outcome relationship of liver surgery: a nationwide analysis.
      Shubert et al suggested that outcomes after hepatectomy should be stratified by the diagnosis, by showing differences in mortality for different indications using National Surgical Quality Improvement Program data of >7,000 patients.
      • Shubert C.R.
      • Habermann E.B.
      • Truty M.J.
      • Thomsen K.M.
      • Kendrick M.L.
      • Nagorney D.M.
      Defining perioperative risk after hepatectomy based on diagnosis and extent of resection.
      The highest 30-day mortality rates were observed for cholangiocarcinoma (8.2% for intrahepatic and perihilar combined) and hepatocellular carcinoma (5.2%), which were classified as ‘high risk’ diagnoses. These were followed by lower risk diagnoses such as metastatic disease (1.3%), gallbladder cancer (1%), and benign neoplasms (0.5%). This study could not be included in the current review because mortality was not reported for intrahepatic cholangiocarcinoma alone. A large cohort of >100,000 liver resections in Germany for all indications between 2010 and 2015 also found substantial difference in mortality rates depending on the diagnosis.
      • Filmann N.
      • Walter D.
      • Schadde E.
      • et al.
      Mortality after liver surgery in Germany.
      In-hospital mortality was 5.5% for colorectal liver metastases, 7.1% for gallbladder cancer, 9.3% for hepatocellular carcinoma, and 11% for iCCA. A fair comparison of postoperative mortality after liver resection requires consideration of diagnosis.
      Mortality outcomes should not only be stratified according to diagnosis, but also by the extent of the resection. In the same German cohort, in-hospital mortality (including liver resections for all diagnoses) was 3.8% for a segmental resection, 9.1% for a major hepatectomy, and 16.2% for an extended hepatectomy. The in-hospital mortality of an extended hepatectomy for iCCA (n = 709) was 21.8%, which is higher than the 11.4% in the pooled analysis for 90-day mortality in the present study.
      • Filmann N.
      • Walter D.
      • Schadde E.
      • et al.
      Mortality after liver surgery in Germany.
      A study on >1,000 liver resections for iCCA found that 30-day mortality was 5 times higher and 90-day mortality was 2.5 times higher after a major compared to a minor liver resection.
      • Zhang X.F.
      • Bagante F.
      • Chakedis J.
      • et al.
      Perioperative and long-term outcome for intrahepatic cholangiocarcinoma: impact of major versus minor hepatectomy.
      Thirty-day mortality has been used as a benchmark to assess the quality of major surgical procedures. In the present study, the pooled difference between 30-day and 90-day mortality was 2.5%, indicating that surgery related death may be underestimated at 30 days, postoperatively. Posthepatectomy liver failure (PHLF) is a major cause of death after liver resection, and 25% of patients die from PHLF >30 days after resection.
      • Hammond J.S.
      • Guha I.N.
      • Beckingham I.J.
      • Lobo D.N.
      Prediction, prevention and management of postresection liver failure.
      Posthepatectomy liver failure requires complex treatment at the intensive care unit, which prolongs hospital stay and may result in slow physical deconditioning and death eventually. Truant et al found a median time to postoperative mortality of 31 days for patients undergoing an extended hepatectomy.
      • Truant S.
      • El Amrani M.
      • Skrzypczyk C.
      • et al.
      Factors associated with fatal liver failure after extended hepatectomy.
      Twenty-two out of 26 patients (ie, 84.6%) died from PHLF, often after >30 days.
      • Truant S.
      • El Amrani M.
      • Skrzypczyk C.
      • et al.
      Factors associated with fatal liver failure after extended hepatectomy.
      Therefore, 90-day postoperative mortality is a better outcome measure when reporting outcomes of liver resection.
      A difference was found in postoperative mortality rate between Asian studies and Western studies for the 90-day mortality risk (4.4% vs 6.8%; P = .02). A lower mortality risk in Asian studies was also found for perihilar cholangiocarcinoma.
      • Olthof P.B.
      • Miyasaka M.
      • Koerkamp B.G.
      • et al.
      A comparison of treatment and outcomes of perihilar cholangiocarcinoma between Eastern and Western centers.
      The patient characteristics differ among regions, and a higher incidence of obesity is observed in Western populations. This adds to co-morbidity scores and increases the surgical risk. It remains unclear to what extent the higher postoperative mortality in Western studies is explained by differences in baseline patient and tumor characteristics or differences in patient care.
      Intrahepatic cholangiocarcinoma patients often present with multifocal disease, for which guidelines recommend palliative chemotherapy rather than surgical resection.
      • Amin M.B.
      • Greene F.L.
      • Edge S.B.
      • et al.
      The eighth edition AJCC Cancer Staging Manual: continuing to build a bridge from a population-based to a more "personalized" approach to cancer staging.
      • Bridgewater J.
      • Galle P.R.
      • Khan S.A.
      • et al.
      Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma.
      • Weber S.M.
      • Ribero D.
      • O'Reilly E.M.
      • Kokudo N.
      • Miyazaki M.
      • Pawlik T.M.
      Intrahepatic cholangiocarcinoma: expert consensus statement.
      • Massani M.
      • Nistri C.
      • Ruffolo C.
      • et al.
      Intrahepatic chemotherapy for unresectable cholangiocarcinoma: review of literature and personal experience.
      Hepatic arterial infusion pump (HAIP) has been investigated for patients with unresectable iCCA confined to the liver. The HAIP delivers high doses of chemotherapy with floxuridine directly in the hepatic artery via a surgically implantable pump. A recent study found that patients with multifocal iCCA had a similar median OS after HAIP floxuridine chemotherapy compared to surgical resection, whereas major complication (6% vs 25%) and postoperative 30-day mortality (1% vs 6%) were lower in the HAIP group.
      • Franssen S.
      • Soares K.C.
      • Jolissaint J.S.
      • et al.
      Comparison of hepatic arterial infusion pump chemotherapy vs resection for patients with multifocal intrahepatic cholangiocarcinoma.
      These results suggest consideration of HAIP instead of surgical resection in patients with multifocal iCCA, in particular in patients with an increased surgical risk.
      Several limitations should be addressed for this systematic review and meta-analysis. First, the included studies were all retrospective studies that are prone to selection bias and information bias with underreporting of postoperative complications. A high risk of bias was detected at the level of ‘clear reporting of clinical information.’ This was mainly because most studies (24/32) lacked details on the ASA classification. However, resection type was specified in most studies (24/32), which was relevant for the subgroup analyses. Postoperative morbidity and mortality are increased in patients with a poor future liver remnant function and volume. The results of the included studies were too heterogeneous for analyzing such risk factors. Furthermore, many studies include patients over a long inclusion period because of the rarity of the disease, of which some included patients from the 1990s. Since 1990, many advancements in technique and surgical management were introduced over time. The year of surgery was not reported in any of the included studies. A subgroup analysis, however, found that mortality was similar in studies with only patients after 2000. However, a difference in postoperative mortality could not be demonstrated. Finally, some of the pooled analyses included a smaller number of studies and patients resulting in wider 95% CIs.
      In conclusion, the best estimate for the 90-day postoperative mortality after resection of iCCA is 6.1% with a major complication rate of 22.2%. Ninety-day postoperative mortality rates were lower in Asian studies compared to Western centers (4.4% vs 6.8%). When informing patients or comparing outcomes across hospitals, postoperative mortality rates after liver resection should be reported for 90-days due to the significant number of patients that may survive the first 30 days (ie, PHLF) but will succumb within the following 60 days, with consideration of the diagnosis and extent of liver resection.

      Funding/Support

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

      Conflict of interest/Disclosure

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

      Acknowledgments

      The authors wish to thank Sabrina Meertens-Gunput from the Erasmus MC Medical Library for developing and updating the search strategies.

      Supplementary Materials

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