Validation study of postoperative liver failure and mortality risk scores after liver resection for perihilar cholangiocarcinoma.

Background: Surgery for perihilar cholangiocarcinoma (PHCC) remains a challenging procedure with high morbidity and mortality. The Academic Medical Center (Amsterdam UMC) and Memorial Sloan Kettering Cancer Center proposed a postoperative mortality risk score (POMRS) and post-hepatectomy liver failure score (PHLFS) to predict patient outcomes. This study aimed to validate the POMRS and PHLFS for PHCC patients at Hokkaido University. Methods: Medical records of 260 consecutive PHCC patients who had undergone major hepatectomy with extrahepatic bile duct resection without pancreaticoduodenectomy at Hokkaido University between March 2001 and November 2018 were evaluated to validate the PHLFS and POMRS. Results: The observed risks for PHLF were 13.7%, 24.5%, and 39.8% for the low-risk, intermediate-risk, and high-risk groups, respectively, in the study cohort. A receiver-operator characteristic (ROC) analysis revealed that the PHLFS had moderate predictive value, with an analysis under the curve (AUC) value of 0.62. Mortality rates based on the POMRS were 1.7%, 5%, and 5.1% for the low-risk, intermediate-risk, and high-risk groups, respectively. The ROC analysis demonstrated an AUC value of 0.58. Conclusions: This external validation study showed that for PHLFS the threshold for discrimination in an Eastern cohort was reached (AUC >0.6), but it would require optimization of the model before use in clinical practice is acceptable. The POMRS were not applicable in the eastern cohort. Further external validation is recommended.

A comparison of treatment and outcomes of perihilar cholangiocarcinoma between Eastern and Western centers.

BACKGROUND: Perihilar cholangiocarcinoma (PHC) often requires extensive surgery which is associated with substantial morbidity and mortality. This study aimed to compare an Eastern and Western PHC cohort in terms of patient characteristics, treatment strategies and outcomes including a propensity score matched analysis. METHODS: All consecutive patients who underwent combined biliary and liver resection for PHC between 2005 and 2016 at two Western and one Eastern center were included. The overall perioperative and long-term outcomes of the cohorts were compared and a propensity score matched analysis was performed to compare perioperative outcomes. RESULTS: A total of 210 Western patients were compared to 164 Eastern patients. Western patients had inferior survival compared to the East (hazard-ratio 1.72 (1-23-2.40) P < 0.001) corrected for age, ASA score, tumor stage and margin status. After propensity score matching, liver failure rate, morbidity, and mortality were similar. There was more biliary leakage (38% versus 13%, p = 0.015) in the West. CONCLUSION: There were major differences in patient characteristics, treatment strategies, perioperative outcomes and survival between Eastern and Western PHC cohorts. Future studies should focus whether these findings are due to the differences in the treatment or the disease itself.

A preoperative prognostic model to predict surgical success in patients with perihilar cholangiocarcinoma.

BACKGROUND: Patients with resectable perihilar cholangiocarcinoma (PHC) on imaging have a substantial risk of metastatic or locally advanced disease, incomplete (R1) resection, and 90-day mortality. Our aim was to develop a preoperative prognostic model to predict surgical success, defined as a complete (R0) resection without 90-day mortality, in patients with resectable PHC on imaging. STUDY DESIGN: Patients with PHC who underwent exploratory laparotomy in three tertiary referral centers were identified. Multivariable logistic regression was performed to identify preoperatively available prognostic factors. A prognostic model was developed using data from two European centers and validated in one American center. RESULTS: In total, 671 patients with PHC underwent exploratory laparotomy. In the derivation cohort, surgical success was achieved in 102 of 331 patients (30.8%). No resection was performed in 176 patients (53.2%) because of metastatic or locally advanced disease. Of the 155 patients (46.8%) who underwent a resection, 38 (24.5%) had an R1-resection. Of the remaining 117 (35.3%), 15 (12.8%) had 90-day mortality. Independent poor prognostic factors for surgical success were identified, and a preoperative prognostic model was developed with a concordance index of 0.71. External validation showed good concordance (0.70). CONCLUSION: Surgical success was achieved in only 30% of patients with PHC undergoing exploratory laparotomy and could be predicted by age, cholangitis, hepatic artery involvement, lymph node metastases, and Blumgart stage.

Endoscopic versus percutaneous biliary drainage in patients with resectable perihilar cholangiocarcinoma: a multicentre, randomised controlled trial.

BACKGROUND: In patients with resectable perihilar cholangiocarcinoma, biliary drainage is recommended to treat obstructive jaundice and optimise the clinical condition before liver resection. Little evidence exists on the preferred initial method of biliary drainage. We therefore investigated the incidence of severe drainage-related complications of endoscopic biliary drainage or percutaneous transhepatic biliary drainage in patients with potentially resectable perihilar cholangiocarcinoma. METHODS: We did a multicentre, randomised controlled trial at four academic centres in the Netherlands. Patients who were aged at least 18 years with potentially resectable perihilar cholangiocarcinoma requiring major liver resection, and biliary obstruction of the future liver remnant (defined as a bilirubin concentration of >50 µmol/L [2·9 mg/dL]), were randomly assigned (1:1) to receive endoscopic biliary drainage or percutaneous transhepatic biliary drainage through the use of computer-generated allocation. Randomisation, done by the trial coordinator, was stratified for previous (attempted) biliary drainage, the extent of bile duct involvement, and enrolling centre. Patients were enrolled by clinicians of the participating centres. The primary outcome was the number of severe complications between randomisation and surgery in the intention-to-treat population. The trial was registered at the Netherlands National Trial Register, number NTR4243. FINDINGS: From Sept 26, 2013, to April 29, 2016, 261 patients were screened for participation, and 54 eligible patients were randomly assigned to endoscopic biliary drainage (n=27) or percutaneous transhepatic biliary drainage (n=27). The study was prematurely closed because of higher mortality in the percutaneous transhepatic biliary drainage group (11 [41%] of 27 patients) than in the endoscopic biliary drainage group (three [11%] of 27 patients; relative risk 3·67, 95% CI 1·15-11·69; p=0·03). Three of the 11 deaths among patients in the percutaneous transhepatic biliary drainage group occurred before surgery. The proportion of patients with severe preoperative drainage-related complications was similar between the groups (17 [63%] patients in the percutaneous transhepatic biliary drainage group vs 18 [67%] in the endoscopic biliary drainage group; relative risk 0·94, 95% CI 0·64-1·40). 16 (59%) patients in the percutaneous transhepatic biliary drainage group and ten (37%) patients in the endoscopic biliary drainage group developed preoperative cholangitis (p=0·1). 15 (56%) patients required additional percutaneous transhepatic biliary drainage after endoscopic biliary drainage, whereas only one (4%) patient required endoscopic biliary drainage after percutaneous transhepatic biliary drainage. INTERPRETATION: The study was prematurely stopped because of higher all-cause mortality in the percutaneous transhepatic biliary drainage group. Post-drainage complications were similar between groups, but the data should be interpreted with caution because of the small sample size. The results call for further prospective studies and reconsideration of indications and strategy towards biliary drainage in this complex disease. FUNDING: Dutch Cancer Foundation.

Preoperative Risk Score to Predict Occult Metastatic or Locally Advanced Disease in Patients with Resectable Perihilar Cholangiocarcinoma on Imaging.

BACKGROUND: Many patients with resectable perihilar cholangiocarcinoma (PHC) on imaging are diagnosed intraoperatively with occult metastatic or locally advanced disease, precluding a curative-intent resection. This study aimed to develop and validate a preoperative risk score. STUDY DESIGN: Patients with resectable PHC on imaging who underwent operations in 2 high-volume centers (US and Europe) between 2000 and 2015 were included. Multivariable logistic regression analysis was used to develop the risk score. Cross-validation was used to validate the score, alternating the 2 centers as "training" and "testing" datasets. RESULTS: Of 566 patients who underwent operations, 309 (55%) patients had a resection, and in 257 (45%) patients, a curative-intent resection was precluded due to distant metastasis (n = 151 [27%]) or locally advanced disease (n = 106 [19%]). Preoperative predictors included bilirubin >2 mg/dL, bile duct involvement on imaging, portal vein involvement on imaging (≥180 degrees), hepatic artery involvement on imaging (≥180 degrees), and suspicious lymph nodes on imaging. The new risk score (c-index 0.75 after cross-validation) provided significantly more accurate predictions than the Bismuth classification (c-index 0.62), Blumgart T-staging (c-index 0.67), and cTNM staging (c-index 0.68). The new risk score identified 4 risk groups for occult metastatic or locally advanced disease: low (14.7%), intermediate (29.5%), high (47.3%), and very high risk (81.3%). The preoperative score groups also predicted survival after operation, irrespective of intraoperative findings (p < 0.001). CONCLUSIONS: The validated risk score can predict occult distant metastatic or locally advanced PHC based on 5 preoperatively available factors. The score can be useful in preoperative shared decision making and selection of patients in neoadjuvant clinical trials.

Postoperative Liver Failure Risk Score: Identifying Patients with Resectable Perihilar Cholangiocarcinoma Who Can Benefit from Portal Vein Embolization.

BACKGROUND: Major liver resection for perihilar cholangiocarcinoma (PHC) is associated with a 22% to 33% postoperative liver failure incidence. The aim of this study was analyze the predictive value of future liver remnant (FLR) volume for postoperative liver failure after resection for PHC and to develop a risk score to improve patient selection for portal vein embolization. STUDY DESIGN: A consecutive series of 217 patients underwent major liver resection for PHC between 1997 and 2014 at 2 Western centers; FLR volumes were calculated with CT volumetry; other variables included jaundice at presentation, immediate preoperative bilirubin, and preoperative cholangitis. The FLR volume was categorized as <30%, 30% to 45%, or >45%. A risk score for postoperative liver failure (grade B/C according to the International Study Group of Liver Surgery criteria) was developed using multivariable logistic regression with 5 predefined variables. RESULTS: Postoperative liver failure incidence was 24% and liver failure-related mortality was 12%. Risk factors for liver failure were FLR volume <30% (odds ratio 4.2; 95% CI 1.77 to 10.3) and FLR volume 30% to 45% (odds ratio 1.4; 95% CI 10.6 to 3.4). In addition, jaundice at presentation (odds ratio 3.1; 95% CI 1.1 to 9.0), immediate preoperative bilirubin >50 µmol/L (>2.9 mg/dL) (odds ratio 4.3; 95% CI 1.7 to 10.7), and preoperative cholangitis (odds ratio 3.4; 95% CI 1.6 to 7.4) were risk factors for liver failure. These variables were included in a risk score that showed good discrimination (area under the curve 0.79; 95% CI 0.72 to 0.86) and ranking patients in 3 risk sub-groups with predicted liver failure incidence of 4%, 14%, and 44%. CONCLUSIONS: The selection of patients for portal vein embolization using only liver volume is insufficient, considering the other predictors of liver failure in PHC patients. The proposed risk score can be used for selection of patients for portal vein embolization, for adequate patient counseling, and identification of other modifiable risk factors besides liver volume.

Compliance with evidence-based multidisciplinary guidelines on perihilar cholangiocarcinoma.

BACKGROUND: Discrepancies are often noted between management of perihilar cholangiocarcinoma (PHC) in regional hospitals and the eventual treatment plan in specialized centers. OBJECTIVE: The objective of this article is to evaluate whether regional centers adhere to guideline recommendations following implementation in 2013. METHODS: Data were analyzed from all consecutive patients with suspected PHC referred to our academic center between June 2013 and December 2015. Frequency and quality of biliary drainage and imaging at referring centers were assessed as well as the impact of inadequate initial drainage. RESULTS: Biliary drainage was attempted at regional centers in 83 of 158 patients (52.5%), with a technical and therapeutic success rate of 79.5% and 50%, respectively, and a complication rate of 45.8%. The computed tomography protocol was not in accordance with guidelines in 52.8% of referrals. In 45 patients (54.2%) who underwent drainage in regional centers, additional drainage procedures were required after referral. Initial inadequate biliary drainage at a regional center was significantly associated with more procedures and a prolonged waiting time until surgery. A trend toward more drainage-related complications was observed among patients with inadequate initial drainage (54.7% vs. 39.0%, p = 0.061). CONCLUSION: Despite available guidelines, suboptimal management of PHC persists in many regional centers and affects eventual treatment strategies.

Atorvastatin does not protect against ischemia-reperfusion damage in cholestatic rat livers.

BACKGROUND: Extrahepatic cholestasis sensitizes the liver to ischemia/reperfusion (I/R) injury during surgery for perihilar cholangiocarcinoma. It is associated with pre-existent sterile inflammation, microvascular perfusion defects, and impaired energy status. Statins have been shown to protect against I/R injury in normal and steatotic mouse livers. Therefore, the hepatoprotective properties of atorvastatin were evaluated in a rat model of cholestatic I/R injury. METHODS: Male Wistar rats were subjected to 70% hepatic ischemia (during 30 min) at 7 days after bile duct ligation. Rats were randomized to atorvastatin treatment or vehicle-control in three test arms: (1) oral treatment with 5 mg/kg during 7 days after bile duct ligation; (2) intravenous treatment with 2.5, 5, or 7.5 mg/kg at 24 h before ischemia; and (3) intravenous treatment with 5 mg/kg at 30 min before ischemia. Hepatocellular damage was assessed by plasma alanine aminotransferase (ALT) and histological necrosis. RESULTS: I/R induced severe hepatocellular injury in the cholestatic rat livers (~10-fold increase in ALT at 6 h after I/R and ~30% necrotic areas at 24 h after I/R). Both oral and intravenous atorvastatin treatment decreased ALT levels before ischemia. Intravenous atorvastatin treatment at 5 mg/kg at 24 h before ischemia was the only regimen that reduced ALT levels at 6 h after reperfusion, but not at 24 h after reperfusion. None of the tested regimens were able to reduce histological necrosis at 24 h after reperfusion. CONCLUSION: Pre-treatment with atorvastatin did not protect cholestatic livers from hepatocellular damage after I/R. Clinical studies investigating the role of statins in the protection against hepatic I/R injury should not include cholestatic patients with perihilar cholangiocarcinoma. These patients require (pharmacological) interventions that specifically target the cholestasis-associated hepatopathology.

High mortality after ALPPS for perihilar cholangiocarcinoma: case-control analysis including the first series from the international ALPPS registry.

INTRODUCTION: Resection of perihilar cholangiocarcinoma (PHC) entails high-risk surgery with postoperative mortality reported up to 18%, even in specialized centers. The aim of this study was to compare outcomes of PHC patients who underwent associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) to patients who underwent resection without ALPPS. METHODS: All patients who underwent ALPPS for PHC were identified from the international ALPPS registry and matched controls were selected from a standard resection cohort from two centers based on future remnant liver size. Outcomes included morbidity, mortality, and overall survival. RESULTS: ALPPS for PHC was associated with 48% (14/29) 90-day mortality. 90-day mortality was 13% in 257 patients who underwent major liver resection for PHC without ALPPS. The 29 ALPPS patients were matched to 29 patients resected without ALPPS, with similar future liver remnant volume (P = 0.480). Mortality in the matched control group was 24% (P = 0.100) and median OS was 27 months, comparted to 6 months after ALPPS (P = 0.064). DISCUSSION: Outcomes of ALPPS for PHC appear inferior compared to standard extended resections in high-risk patients. Therefore, portal vein embolization should remain the preferred method to increase future remnant liver volume in patients with PHC. ALPPS is not recommended for PHC.

Development of a Risk Score to Predict Detection of Metastasized or Locally Advanced Perihilar Cholangiocarcinoma at Staging Laparoscopy.

BACKGROUND: Nearly half of patients with perihilar cholangiocarcinoma (PHC) have incurable tumors at laparotomy. Staging laparoscopy (SL) potentially detects metastases or locally advanced disease, thereby avoiding unnecessary laparotomy. However, the diagnostic yield of SL has decreased with improved imaging in recent years. OBJECTIVE: The aim of this study was to identify predictors for detecting metastasized or locally advanced PHC at SL and to develop a risk score to select patients who may benefit most from this procedure. METHODS: Data of patients with potentially resectable PHC who underwent SL between 2000 and 2015 in our center were retrospectively analyzed. Multivariable logistic regression analysis was used to identify independent predictors and to develop a preoperative risk score. RESULTS: Unresectable PHC was detected in 41 of 273 patients undergoing SL (yield 15 %). Overall sensitivity of SL was 30 %, with highest sensitivity for detecting peritoneal metastases (73 %). Preoperative imaging factors that were independently associated with unresectability at SL were tumor size ≥4.5 cm, bilateral portal vein involvement, suspected lymph node metastases, and suspected (extra)hepatic metastases on imaging without the possibility of diagnosis by percutaneous- or endoscopic ultrasound-guided biopsy. The derived preoperative risk score showed good discrimination to predict unresectability (area under the curve 0.77, 95 % confidence interval 0.68-0.86) and identified three subgroups with a predicted low-risk of 7 % (N = 203 patients), intermediate-risk of 21 % (N = 39), and high-risk of 58 % (N = 31). CONCLUSIONS: A selective approach for SL in PHC is recommended since the overall yield is low. The proposed preoperative risk score is useful in selecting patients for SL.

Combined liver and extrahepatic bile duct resection for biliary invasion of colorectal metastasis: a case-cohort analysis and systematic review.

BACKGROUND: Colorectal liver metastases (CRLMs) with biliary invasion can be treated with a combined liver and extrahepatic bile duct resection. The aim of this study was to analyze outcomes of this procedure in a case-cohort analysis and systematic review. METHODS: Consecutive patients who underwent a major liver resection for CRLM between 2003 and 2013 were selected from a single center prospective database, comparing patients with and without biliary invasion. A specific and a general search strategy were used to identify relevant articles in the systematic review. RESULTS: Ten patients (13.2%) underwent combined liver and extrahepatic bile duct resection for CLRM with biliary invasion, among 76 patients included. An R0 resection was achieved in five of ten patients (50%); one of ten patients died postoperatively. Median overall survival was 19 months among patients with biliary invasion, versus 106 months among patients without biliary invasion (P=0.12). The systematic review yielded a large variability in 5-year survival after resection of CLRM with biliary invasion, ranging between 33-80%. CONCLUSIONS: Surgical resection of CLRM with central biliary invasion is feasible, but survival in these patients tends to be lower due to a high rate of non-radical resections.

Recurrence Patterns and Disease-Free Survival after Resection of Intrahepatic Cholangiocarcinoma: Preoperative and Postoperative Prognostic Models.

BACKGROUND: Liver resection is the most effective treatment for intrahepatic cholangiocarcinoma. Recurrent disease is frequent; however, recurrence patterns are ill-defined and prognostic models are lacking. STUDY DESIGN: A primary cohort of 189 patients who underwent resection for intrahepatic cholangiocarcinoma was used for recurrence patterns analysis within and after 24 months. Based on independent factors for disease-free survival identified in Cox regression analysis, preoperative and postoperative models were developed using a recursive partitioning method. Models were externally validated using a multicenter cohort of 522 resected patients (Association Française de Chirurgie intrahepatic cholangiocarcinoma study group). RESULTS: Recurrence within 24 months most often involved the liver (82.7%), and most recurrences after 24 months were strictly extrahepatic (61.1%). In multivariable analysis of the primary cohort, independent preoperative factors for disease-free survival were tumor size and multifocality (based on imaging); tumor size, multifocality, vascular invasion, and lymph node metastases (based on pathology) were independent postoperative factors. The preoperative model allowed patient classification into low-risk and high-risk groups for recurrence. In the validation cohort (n = 522), high-risk patients had a greater likelihood of recurrence (hazard ratio = 2.17; 95% CI, 1.74-2.72; p < 0.001). The postoperative model included tumor size, vascular invasion, and positive nodal disease on pathology and classified patients in low-, intermediate-, and high-risk groups in the primary cohort. As compared with low-risk patients in the validation cohort, intermediate- and high-risk patients were more likely to experience recurrence (hazard ratio = 1.9; 95% CI, 1.41-2.47; p < 0.001 and hazard ratio = 2.99; 95% CI, 2.08-4.31; p < 0.001, respectively). CONCLUSIONS: Recurrence patterns are time dependent. Both models as developed and validated in this study classified patients in distinct recurrence risk groups, which can guide treatment recommendations.

External biliary drainage following major liver resection for perihilar cholangiocarcinoma: impact on development of liver failure and biliary leakage.

BACKGROUND: Preoperative biliary drainage is considered essential in perihilar cholangiocarcinoma (PHC) requiring major hepatectomy with biliary-enteric reconstruction. However, evidence for postoperative biliary drainage as to protect the anastomosis is currently lacking. This study investigated the impact of postoperative external biliary drainage on the development of post-hepatectomy biliary leakage and liver failure (PHLF). METHODS: All patients who underwent major liver resection for suspected PHC between 2000 and 2015 were retrospectively analyzed. Biliary leakage and PHLF was defined as grade B or higher according to the International Study Group of Liver Surgery (ISGLS) criteria. RESULTS: Eighty-nine out of 125 (71%) patients had postoperative external biliary drainage. PHLF was more prevalent in the drain group (29% versus 6%; P = 0.004). There was no difference in the incidence of biliary leakage (32% versus 36%). On multivariable analysis, postoperative external biliary drainage was identified as an independent risk factor for PHLF (Odds-ratio 10.3, 95% confidence interval 2.1-50.4; P = 0.004). CONCLUSIONS: External biliary drainage following major hepatectomy for PHC was associated with an increased incidence of PHLF. It is therefore not recommended to routinely use postoperative external biliary drainage, especially as there is no evidence that this decreases the risk of biliary anastomotic leakage.

Postoperative Mortality after Liver Resection for Perihilar Cholangiocarcinoma: Development of a Risk Score and Importance of Biliary Drainage of the Future Liver Remnant.

BACKGROUND: Liver surgery for perihilar cholangiocarcinoma (PHC) is associated with postoperative mortality ranging from 5% to 18%. The aim of this study was to develop a preoperative risk score for postoperative mortality after liver resection for PHC, and to assess the effect of biliary drainage of the future liver remnant (FLR). STUDY DESIGN: A consecutive series of 287 patients submitted to major liver resection for presumed PHC between 1997 and 2014 at 2 Western centers was analyzed; 228 patients (79%) underwent preoperative drainage for jaundice. Future liver remnant volumes were calculated with CT volumetry and completeness of FLR drainage was assessed on imaging. Logistic regression was used to develop a mortality risk score. RESULTS: Postoperative mortality at 90 days was 14% and was independently predicted by age (odds ratio [OR] per 10 years = 2.1), preoperative cholangitis (OR = 4.1), FLR volume <30% (OR = 2.9), portal vein reconstruction (OR = 2.3), and incomplete FLR drainage in patients with FLR volume <50% (OR = 2.8). The risk score showed good discrimination (area under the curve = 0.75 after bootstrap validation) and ranking patients in tertiles identified 3 (ie low, intermediate, and high) risk subgroups with predicted mortalities of 2%, 11%, and 37%. No postoperative mortality was observed in 33 undrained patients with FLR volumes >50%, including 10 jaundiced patients (median bilirubin level 11 mg/dL). CONCLUSIONS: The mortality risk score for patients with resectable PHC can be used for patient counseling and identification of modifiable risk factors, which include FLR volume, FLR drainage status, and preoperative cholangitis. We found no evidence to support preoperative biliary drainage in patients with an FLR volume >50%.

Perioperative blood transfusion is not associated with overall survival or time to recurrence after resection of perihilar cholangiocarcinoma.

BACKGROUND: Perioperative blood transfusions have been associated with worse oncological outcome in several types of cancer. The objective of this study was to assess the effect of perioperative blood transfusions on time to recurrence and overall survival (OS) in patients who underwent curative-intent resection of perihilar cholangiocarcinoma (PHC). METHODS: This retrospective cohort study included consecutive patients with resected PHC between 1992 and 2013 in a specialized center. Patients with 90-day mortality after surgery were excluded. Patients who did and did not receive perioperative blood transfusions were compared using univariable Kaplan-Meier analysis and multivariable Cox regression. RESULTS: Of 145 included patients, 80 (55.2%) received perioperative blood transfusions. The median OS was 49 months for patients without and 41 months for patients with blood transfusions (P = 0.46). In risk-adjusted multivariable Cox regression analysis, blood transfusion was not associated with OS (HR 1.00, 95% CI 0.59-1.68, P = 0.99) or time to recurrence (HR 1.00, 95% CI 0.57-1.78, P = 0.99). In addition, no differences in effect were found between different types of blood products transfused. CONCLUSION: Blood transfusion was not associated with survival or time to recurrence after curative resection of PHC in this series. The alleged association is presumably related to the circumstances necessitating blood transfusions.

Recurrence Rate and Pattern of Perihilar Cholangiocarcinoma after Curative Intent Resection.

BACKGROUND: The aim of this study was to investigate the rate and pattern of recurrence after curative intent resection of perihilar cholangiocarcinoma (PHC). STUDY DESIGN: Patients were included from 2 prospectively maintained databases. Recurrences were categorized by site. Time to recurrence and recurrence-free survival (RFS) were estimated using the Kaplan-Meier method. Cox proportional hazards modeling was used to identify independent poor prognostic factors. RESULTS: Between 1991 and 2012, 306 consecutive patients met inclusion criteria. Median overall survival was 40 months. A recurrence was diagnosed in 177 patients (58%). An initial local recurrence was found in 26% of patients: liver hilum (11%), hepaticojejunostomy (8%), liver resection margin (8%), or distal bile duct remnant (2%). An initial distant recurrence was observed in 40% of patients: retroperitoneal lymph nodes (14%), intrahepatic away from the resection margin (13%), peritoneum (12%), and lungs (8%). Only 18% of patients had an isolated initial local recurrence. The estimated overall recurrence rate was 76% at 8 years. After a recurrence-free period of 5 years, 28% of patients developed a recurrence in the next 3 years. Median RFS was 26 months. Independent prognostic factors for RFS were resection margin, lymph node status, and tumor differentiation. Only node-positive PHC precluded RFS beyond 7 years. CONCLUSIONS: Perihilar cholangiocarcinoma will recur in most patients (76%) after resection, emphasizing the need for better adjuvant strategies. The high recurrence rate of up to 8 years justifies prolonged surveillance. Only patients with an isolated initial local recurrence (18%) may have benefited from a more extensive resection or liver transplantation. Node-positive PHC appears incurable.

Preoperative biliary drainage in perihilar cholangiocarcinoma: identifying patients who require percutaneous drainage after failed endoscopic drainage.

BACKGROUND AND STUDY AIMS: Preoperative biliary drainage is often initiated with endoscopic retrograde cholangiopancreatography (ERCP) in patients with potentially resectable perihilar cholangiocarcinoma (PHC), but additional percutaneous transhepatic catheter (PTC) drainage is frequently required. This study aimed to develop and validate a prediction model to identify patients with a high risk of inadequate ERCP drainage. PATIENTS AND METHODS: Patients with potentially resectable PHC and (attempted) preoperative ERCP drainage were included from two specialty center cohorts between 2001 and 2013. Indications for additional PTC drainage were failure to place an endoscopic stent, failure to relieve jaundice, cholangitis, or insufficient drainage of the future liver remnant. A prediction model was derived from the European cohort and externally validated in the USA cohort. RESULTS: Of the 288 patients, 108 (38%) required additional preoperative PTC drainage after inadequate ERCP drainage. Independent risk factors for additional PTC drainage were proximal biliary obstruction on preoperative imaging (Bismuth 3 or 4) and predrainage total bilirubin level. The prediction model identified three subgroups: patients with low risk (7%), moderate risk (40%), and high risk (62%). The high-risk group consisted of patients with a total bilirubin level above 150 µmol/L and Bismuth 3a or 4 tumors, who typically require preoperative drainage of the angulated left bile ducts. The prediction model had good discrimination (area under the curve 0.74) and adequate calibration in the external validation cohort. CONCLUSIONS: Selected patients with potentially resectable PHC have a high risk (62%) of inadequate preoperative ERCP drainage requiring additional PTC drainage. These patients might do better with initial PTC drainage instead of ERCP.

Comparison of techniques for volumetric analysis of the future liver remnant: implications for major hepatic resections.

OBJECTIVE: The purpose of this work was to compare measured and estimated volumetry prior to liver resection. METHODS: Data for consecutive patients submitted to major liver resection for colorectal liver metastases at two centres during 2004-2012 were reviewed. All patients underwent volumetric analysis to define the measured total liver volume (mTLV) and measured future liver remnant ratio (mR(FLR)). The estimated total liver volume (eTLV) standardized to body surface area and estimated future liver remnant ratio (eR(FLR)) were calculated. Descriptive statistics were generated and compared. A difference between mR(FLR) and eR(FLR) of ±5% was considered clinically relevant. RESULTS: Data for a total of 116 patients were included. All patients underwent major resection and 51% underwent portal vein embolization. The mean difference between mTLV and eTLV was 157 ml (P < 0.0001), whereas the mean difference between mR(FLR) and eR(FLR) was -1.7% (P = 0.013). By linear regression, eTLV was only moderately predictive of mTLV (R(2) = 0.35). The distribution of differences between mR(FLR) and eR(FLR) demonstrated that the formula over- or underestimated mR(FLR) by ≥5% in 31.9% of patients. CONCLUSIONS: Measured and estimated volumetry yielded differences in the FLR of ≥5% in almost one-third of patients, potentially affecting clinical decision making. Estimated volumetry should be used cautiously and cannot be recommended for general use.

Percutaneous Preoperative Biliary Drainage for Resectable Perihilar Cholangiocarcinoma: No Association with Survival and No Increase in Seeding Metastases.

BACKGROUND: Endoscopic biliary drainage (EBD) and percutaneous transhepatic biliary drainage (PTBD) are both used to resolve jaundice before surgery for perihilar cholangiocarcinoma (PHC). PTBD has been associated with seeding metastases. The aim of this study was to compare overall survival (OS) and the incidence of initial seeding metastases that potentially influence survival in patients with preoperative PTBD versus EBD. METHODS: Between 1991 and 2012, a total of 278 patients underwent preoperative biliary drainage and resection of PHC at 2 institutions in the Netherlands and the United States. Of these, 33 patients were excluded for postoperative mortality. Among the 245 included patients, 88 patients who underwent preoperative PTBD (with or without previous EBD) were compared to 157 patients who underwent EBD only. Survival analysis was done with Kaplan-Meier and Cox regression with propensity score adjustment. RESULTS: Unadjusted median OS was comparable between the PTBD group (35 months) and EBD-only group (41 months; P = 0.26). After adjustment for propensity score, OS between the PTBD group and EBD-only group was similar (hazard ratio, 1.05; 95 % confidence interval, 0.74-1.49; P = 0.80). Seeding metastases in the laparotomy scar occurred as initial recurrence in 7 patients, including 3 patients (3.4 %) in the PTBD group and 4 patients (2.7 %) in the EBD-only group (P = 0.71). No patient had an initial recurrence in percutaneous catheter tracts. CONCLUSIONS: The present study found no effect of PTBD on survival compared to patients with EBD and no increase in seeding metastases that developed as initial recurrence. These data suggest that PTBD can safely be used in preoperative management of PHC.

Outcomes after Resection of Intrahepatic Cholangiocarcinoma: External Validation and Comparison of Prognostic Models.

BACKGROUND: Published prognostic models for overall survival after liver resection for intrahepatic cholangiocarcinoma require external validation before use in clinical practice. STUDY DESIGN: From January 1993 to May 2013, consecutive patients who underwent resection of intrahepatic cholangiocarcinoma were identified from a prospective database. The Wang nomogram was derived in an Asian cohort (n = 367) and included clinicopathologic variables and preoperative CEA and cancer antigen 19-9 levels. The Hyder nomogram was derived in an Eastern and Western multicenter cohort (n = 514) using clinicopathologic variables only. The AJCC Cancer Staging System (7th ed) and the preoperative Fudan risk score were also evaluated. Prognostic performance was assessed in terms of discrimination, calibration, and stratification. RESULTS: One hundred and eighty-eight patients were included, with a median follow-up of 41 months. Median overall survival was 48.7 months and estimated 3-year and 5-year overall survival rates were 59% and 45%, respectively. Overall survival prediction accuracy, according to concordance-index calculation, was 0.72 with the Wang nomogram, 0.66 with the Hyder nomogram, 0.63 with the AJCC system, and 0.55 using the Fudan score. Both nomograms provided effective patient stratification in distinct survival groups. CONCLUSIONS: Both the Wang and Hyder nomograms provided accurate patient prognosis estimation after liver resection for intrahepatic cholangiocarcinoma and can be useful for decision making about adjuvant therapy. The Wang nomogram appears to be more appropriate in patients undergoing formal portal lymphadenectomy and requires preoperative CEA and cancer antigen 19-9 levels for optimal performance.