Robert J.S. Coelen

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 endoscopic versus percutaneous transhepatic biliary drainage in potentially resectable perihilar cholangiocarcinoma (DRAINAGE trial): design and rationale of a randomized controlled trial

BackgroundLiver surgery in perihilar cholangiocarcinoma (PHC) is associated with high postoperative morbidity because the tumor typically causes biliary obstruction. Preoperative biliary drainage is used to create a safer environment prior to liver surgery, but biliary drainage may be harmful when severe drainage-related complications deteriorate the patients’ condition or increase the risk of postoperative morbidity. Biliary drainage can cause cholangitis/cholecystitis, pancreatitis, hemorrhage, portal vein thrombosis, bowel wall perforation, or dehydration. Two methods of preoperative biliary drainage are mostly applied: endoscopic biliary drainage, which is currently used in most regional centers before referring patients for surgical treatment, and percutaneous transhepatic biliary drainage. Both methods are associated with severe drainage-related complications, but two small retrospective series found a lower incidence in the number of preoperative complications after percutaneous drainage compared to endoscopic drainage (18-25% versus 38-60%, respectively). The present study randomizes patients with potentially resectable PHC and biliary obstruction between preoperative endoscopic or percutaneous transhepatic biliary drainage.Methods/DesignThe study is a multi-center trial with an “all-comers” design, randomizing patients between endoscopic or percutaneous transhepatic biliary drainage. All patients selected to potentially undergo a major liver resection for presumed PHC are eligible for inclusion in the study provided that the biliary system in the future liver remnant is obstructed (even if they underwent previous inadequate endoscopic drainage). Primary outcome measure is the total number of severe preoperative complications between randomization and exploratory laparotomy. The study is designed to detect superiority of percutaneous drainage: a provisional sample size of 106 patients is required to detect a relative decrease of 50% in the number of severe preoperative complications (alpha = 0.95; beta = 0.8). Interim analysis after inclusion of 53 patients (50%) will provide the definitive sample size. Secondary outcome measures encompass the success of biliary drainage, quality of life, and postoperative morbidity and mortality.DiscussionThe DRAINAGE trial is designed to identify a difference in the number of severe drainage-related complications after endoscopic and percutaneous transhepatic biliary drainage in patients selected to undergo a major liver resection for perihilar cholangiocarcinoma.Trial registrationNetherlands Trial Register [NTR4243, 11 October 2013].

Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients with IDH1-mutated or IDH2-mutated solid tumours

Introduction High-grade chondrosarcoma, high-grade glioma and intrahepatic cholangiocarcinoma are aggressive types of cancer with a dismal outcome. This is due to the lack of effective treatment options, emphasising the need for novel therapies. Mutations in the genes IDH1 and IDH2 (isocitrate dehydrogenase 1 and 2) occur in 60% of chondrosarcoma, 80% of WHO grade II–IV glioma and 20% of intrahepatic cholangiocarcinoma. IDH1/2-mutated cancer cells produce the oncometabolite D-2-hydroxyglutarate (D-2HG) and are metabolically vulnerable to treatment with the oral antidiabetic metformin and the oral antimalarial drug chloroquine. Methods and analysis We describe a dose-finding phase Ib/II clinical trial, in which patients with IDH1/2-mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma are treated with a combination of metformin and chloroquine. Dose escalation is performed according to a 3+3 dose-escalation scheme. The primary objective is to determine the maximum tolerated dose to establish the recommended dose for a phase II clinical trial. Secondary objectives of the study include (1) determination of pharmacokinetics and toxic effects of the study therapy, for which metformin and chloroquine serum levels will be determined over time; (2) investigation of tumour responses to metformin plus chloroquine in IDH1/2-mutated cancers using CT/MRI scans; and (3) whether tumour responses can be measured by non-invasive D-2HG measurements (mass spectrometry and magnetic resonance spectroscopy) of tumour tissue, serum, urine, and/or bile or next-generation sequencing of circulating tumour DNA (liquid biopsies). This study may open a novel treatment avenue for IDH1/2-mutated high-grade chondrosarcoma, glioma and intrahepatic cholangiocarcinoma by repurposing the combination of two inexpensive drugs that are already approved for other indications. Ethics and dissemination This study has been approved by the medical-ethical review committee of the Academic Medical Center, Amsterdam, The Netherlands. The report will be submitted to a peer-reviewed journal. Trial registration number This article was registered at ClinicalTrials.gov identifier (NCT02496741): Pre-results.

Preoperative computed tomography assessment of skeletal muscle mass is valuable in predicting outcomes following hepatectomy for perihilar cholangiocarcinoma

BACKGROUND Liver surgery for perihilar cholangiocarcinoma (PHC) is associated with high rates of morbidity and mortality. OBJECTIVES This study investigated the impact of low skeletal muscle mass on short- and longterm outcomes following hepatectomy for PHC. METHODS Patients included underwent liver surgery for PHC between 1998 and 2013. Total skeletal muscle mass was measured at the level of the third lumbar vertebra using available preoperative computed tomography images. Sex-specific cut-offs for low skeletal muscle mass were determined by optimal stratification. RESULTS In 100 patients, low skeletal muscle mass was present in 42 (42.0%) subjects. The rate of postoperative complications (Clavien-Dindo Grade III and higher) was greater in patients with low skeletal muscle mass (66.7% versus 48.3%; multivariable adjusted P = 0.070). Incidences of sepsis (28.6% versus 5.2%) and liver failure (35.7% versus 15.5%) were increased in patients with low skeletal muscle mass. In addition, 90-day mortality was associated with low skeletal muscle mass in univariate analysis (28.6% versus 8.6%; P = 0.009). Median overall survival was shorter in patients with low muscle mass (22.8 months versus 47.5 months; P = 0.014). On multivariable analysis, low skeletal muscle mass remained a significant prognostic factor (hazard ratio 2.02; P = 0.020). CONCLUSIONS Low skeletal muscle mass has a negative impact on postoperative mortality and overall survival following resection of PHC and should therefore be considered in preoperative risk assessment.

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.

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 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.

Validation of the Mayo Clinic Staging System in Determining Prognoses of Patients With Perihilar Cholangiocarcinoma

BACKGROUND & AIMS: Most systems for staging perihilar cholangiocarcinoma (PHC) have been developed for the minority of patients with resectable disease. The recently developed Mayo Clinic system for staging PHC requires only clinical and radiologic variables, but has not yet been validated. We performed a retrospective study to validate the Mayo Clinic staging system. METHODS: We identified consecutive patients with suspected PHC who were evaluated and treated at 2 tertiary centers in The Netherlands, from January 2002 through December 2014. Baseline characteristics (performance status, carbohydrate antigen 19‐9 level) used in the staging system were collected from medical records and imaging parameters (tumor size, suspected vascular involvement, and metastatic disease) were reassessed by 2 experienced abdominal radiologists. Overall survival was analyzed using the Kaplan–Meier method and comparison of staging groups was performed using the log‐rank test and Cox proportional hazard regression analysis. Discriminative performance was quantified by the concordance index and compared with the radiologic TNM staging of the American Joint Committee on Cancer (7th ed). RESULTS: PHCs from 600 patients were staged according to the Mayo Clinic model (23 stage I, 80 stage II, 357 stage III, and 140 stage IV). The median overall survival time was 11.6 months. The median overall survival times for patients with stages I, II, III, and IV were 33.2 months, 19.7 months, 12.1 months, and 6.0 months, respectively; with hazard ratios of 1.0 (reference), 2.02 (95% confidence interval [CI], 1.14–3.58), 2.71 (95% CI, 1.59–4.64), and 4.00 (95% CI, 2.30–6.95), respectively (P < .001). The concordance index score was 0.59 for the entire cohort (95% CI, 0.56–0.61). The Mayo Clinic model performed slightly better than the radiologic American Joint Committee on Cancer TNM system. CONCLUSIONS: In a retrospective study of 600 patients with PHC, we validated the Mayo Clinic system for staging PHC. This 4‐tier staging system may aid clinicians in making treatment decisions, such as referral for surgery, and predicting survival times.

The impact of sarcopenia on survival and complications in surgical oncology: A review of the current literature: Comment on Joglekar et al

Dear Editor, We read with great interest the paper by Joglekar and colleagues that systematically reviewed the current literature regarding the impact of sarcopenia on survival and complications in patients undergoing cancer surgery [1]. To date, sarcopenia is a burning topic of clinical relevance, since preoperative body composition deviation has been identified as a strong prognostic marker in surgical oncological populations. In the last 5 years, many studies have investigated the effect of sarcopenia on outcomes in surgical oncology. As readers may go astray as a result of the plethora of publications on this topic, a systematic review enables a clear overview of all available evidence. Therefore, we congratulate the authors with their initiative. However, we would like to address some issues regarding the methodology of their study. First of all, the definition of the investigated patient population (i.e., “surgical oncology”) remains ambiguous for the uncommitted reader. On the one hand, studies describing the impact of sarcopenia in patients undergoing bladder cancer resection and lymph node resection for melanoma were included [1], whereas studies in patients undergoing surgery for endometrial [2] or penile [3] cancer were not. Besides the fact that only one database (PubMed) has been searched, the strings for the systematic search consisted of a limited number of search terms. For example, only sarcopenia was used, instead of the combination with terms like body composition, myopenia, or skeletal muscle wasting, -depletion, -atrophy, or -loss [4]. Consequently, this has led to the exclusion of multiple relevant studies that have reported the impact of sarcopenia in patients undergoing cancer surgery and were published (on-line) before the last search date (May 4th 2015). For instance, two studies among patients with perihilar cholangiocarcinoma [5,6], one with pancreatic cancer patients [7], one with colorectal cancer patients [8], and one with primary liver tumor patients [9] undergoing resection, which are populations known for their high postoperative morbidity and mortality rates and poor prognosis, were missed. Moreover, a study that has frequently been cited in the studies that were included in the review—and thus should have been identified by crossreferencing as described in themethods section—was not included [10]. Notably, the results of two studies that described an association between skeletal muscle mass and impaired postoperative outcome after colorectal cancer surgery that were referred to in the introduction of the article [11,12], have not been included. Finally, a study among patients undergoing resection for colorectal liver metastases is briefly mentioned in the text, but not depicted in table II [13]. These concerns would probably have been prevented if the authors would have complied with the PRISMA guidelines for systematic reviews and its corresponding flow-chart, depicting study selection [14]. Since all included studies have an observational, retrospective design, no causative relationship between sarcopenia and outcome measures has been established. Therefore, findings should be placed in perspective and confirmed in prospective studies. Furthermore, the majority of studies measured skeletal muscle mass using abdominal computed tomography (CT) scans. As explained by the authors, a great diversity in methods to measure or define sarcopenia (i.e., different cutoff values used, various muscles measured) was observed in these studies. These measures and definitions may not be applicable to all populations. We feel that it is important to emphasize that one should strive for a uniform definition of CT-assessed sarcopenia with outcomerelated cut-off values adjusted for age, gender, ethnicity, and tumor type to improve future comparability of studies.

99mTc-mebrofenin hepatobiliary scintigraphy predicts liver failure following major liver resection for perihilar cholangiocarcinoma

BACKGROUND Posthepatectomy liver failure (PHLF) is a threatening complication after liver surgery, especially in perihilar cholangiocarcinoma (PHC). This study aimed to assess the value of preoperative assessment of liver function using 99mTc-mebrofenin hepatobiliary scintigraphy (HBS) to predict PHLF in comparison with liver volume in PHC patients. METHODS All patients who underwent resection of suspected PHC in a single center between 2000 and 2015 were included in the analysis. PHLF was graded according to the ISGLS criteria with grade B/C considered clinically relevant. A cut-off value for the prediction of PHLF was calculated using the receiver operating characteristic curve (ROC) analysis. RESULTS A total of 116 patients were included of which 27 (23%) suffered of PHLF. ROC values for the prediction of PHLF were 0.74 (0.63-0.86) for future liver remnant function and 0.63 (0.47-0.80) for volume. A cut-off for liver function was set at 8.5%/min, which resulted in a negative predictive value of 94% and positive predictive value of 41%. CONCLUSIONS Assessment of liver function with HBS had better predictive value for PHLF than liver volume in patients undergoing major liver resection for suspected PHC. The cut-off of 8.5%/min can help to select patients for portal vein embolization and might help to reduce postoperative liver failure.