Efficacy and safety of irreversible electroporation in unresectable perihilar cholangiocarcinoma: a systematic review and meta-analysis.

OBJECTIVES: The prognosis of patients with perihilar-cholangiocarcinoma (PHC) is poor, with the majority presenting with unresectable disease at diagnosis. Palliative chemotherapy (CHT) is the standard treatment for unresectable PHC. Irreversible electroporation (IRE) has been introduced as a novel ablation technique, working predominantly nonthermal. This review aims to analyse the efficacy and safety of IRE in treating unresectable PHC. METHODS: This systematic review and meta-analysis was performed according to a specific protocol designed a priori, and reported according to the PRISMA. PubMed/MEDLINE, Scopus, and Cochrane CENTRAL were searched up to December 2023. Primary Outcome of interest of our meta-analysis was the mean Overall Survival (OS). Secondary outcomes were progression-free survival (PFS) and adverse event rate (AE). RESULTS: The mean OS was estimated at 25.49 months (CI, 21.47-38.72, I2 81.37%), PFS 17.86 (CI, 13.00-22.72, I2 11.42%), with an AE incidence of 12% (CI, 7%-31%, I2 83.57%). High heterogeneity was found among studies, with no single study fully responsible for it, suggesting high variability among facilities/populations. CONCLUSION: IRE is effective and relatively safe for unresectable PHC. However, the lack of prospective studies and randomized trials comparing chemotherapy or locoregional treatment with IRE prevents drawing sufficiently robust conclusions. ADVANCES IN KNOWLEDGE: IRE appears a safe and effective technique for treating unresectable perihilar cholangiocarcinoma.

National guidelines for the diagnosis and treatment of hilar cholangiocarcinoma.

A consensus meeting of national experts from all major national hepatobiliary centres in the country was held on May 26, 2023, at the Pakistan Kidney and Liver Institute & Research Centre (PKLI & RC) after initial consultations with the experts. The Pakistan Society for the Study of Liver Diseases (PSSLD) and PKLI & RC jointly organised this meeting. This effort was based on a comprehensive literature review to establish national practice guidelines for hilar cholangiocarcinoma (hCCA). The consensus was that hCCA is a complex disease and requires a multidisciplinary team approach to best manage these patients. This coordinated effort can minimise delays and give patients a chance for curative treatment and effective palliation. The diagnostic and staging workup includes high-quality computed tomography, magnetic resonance imaging, and magnetic resonance cholangiopancreatography. Brush cytology or biopsy utilizing endoscopic retrograde cholangiopancreatography is a mainstay for diagnosis. However, histopathologic confirmation is not always required before resection. Endoscopic ultrasound with fine needle aspiration of regional lymph nodes and positron emission tomography scan are valuable adjuncts for staging. The only curative treatment is the surgical resection of the biliary tree based on the Bismuth-Corlette classification. Selected patients with unresectable hCCA can be considered for liver transplantation. Adjuvant chemotherapy should be offered to patients with a high risk of recurrence. The use of preoperative biliary drainage and the need for portal vein embolisation should be based on local multidisciplinary discussions. Patients with acute cholangitis can be drained with endoscopic or percutaneous biliary drainage. Palliative chemotherapy with cisplatin and gemcitabine has shown improved survival in patients with irresectable and recurrent hCCA.

Diagnosis and Treatment of Perihilar Cholangiocarcinoma: A National Survey from the Korean Pancreatobiliary Association.

Background/Aims: Based on their anatomy, cholangiocarcinomas (CCAs) are classified into intrahepatic, hilar, and distal CCAs. Although the diagnosis and treatment of each type of CCA are thought to be different, real-world data studies on the current practice are limited. Therefore, this study was designed to capture the current practice of diagnosing and treating perihilar CCA in Korea. Methods: We conducted a survey using an online platform. The questionnaire consisted of 18 questions designed to evaluate the current practice of diagnosing and treating perihilar CCA in Korea. The targets of this survey were biliary endoscopists who are members of the Korean Pancreatobiliary Association. Results: In total, 119 biliary endoscopists completed the survey. Of the respondents, 89.9% thought that the use of the International Classification of Diseases, 11th Revision (ICD-11) system is necessary to classify CCA. Approximately half of the respondents would recommend surgery or chemotherapy until patients were 80 years of age. For the pathological diagnosis of CCA, endoscopic retrograde cholangiopancreatography with biopsy was the most preferred modality. Routine preoperative biliary drainage was performed by 44.5% of the respondents. For operable CCAs, 64.7% of the respondents preferred endoscopic biliary drainage using plastic stents. For palliative biliary drainage, 69.7% of the respondents used plastic stents. For palliative endoscopic biliary drainage using metal stents, 63% of the respondents preferred the stent-in-stent method. Conclusions: A new coding system using the ICD-11 is needed for classifying CCAs. Guidelines for diagnosing and treating CCA based on the clinical situation in Korea are needed.

Comparison between Suprapapillary and Transpapillary Uncovered Self-Expandable Metallic Stent Placement for Perihilar Cholangiocarcinoma.

PURPOSE: To compare the effectiveness, adverse events (AEs), stent patency, and patient survival with suprapapillary and transpapillary uncovered self-expandable metallic stent placement for perihilar cholangiocarcinoma. MATERIALS AND METHODS: A single-center retrospective study of 54 patients with inoperable perihilar cholangiocarcinoma who underwent percutaneous transhepatic biliary stent placement between January 1, 2019, and August 31, 2021, was conducted. According to stent location, the patients were classified into 2 groups: suprapapillary (S) and transpapillary (T). Demographic data, Bismuth-Corlette classification, type and location of the stent, laboratory data, postprocedural AEs, procedural success, stent occlusion, reintervention rate, and mortality were compared between the groups. RESULTS: Stent placement was suprapapillary in 13 (24.1%) patients and transpapillary in 41 (75.9%) patients. Mean age was higher in Group T (78 vs 70.5 years; P = .046). Stent occlusion rates were similar in the 2 groups (Group S, 23.8%; Group T, 19.5%), as were AE rates, the most common being cholangitis (Group S, 23.1%; Group T, 24.4%). There were no significant differences in revision rate (Group S, 7.7%; Group T, 12.2%) and 30-day mortality rate (Group S, 15.4%; Group T, 19.5%). Ninety-day mortality rate was statistically significantly higher in Group T (46.3% vs 15.4%; P = .046). Preprocedural bilirubin level was higher in Group T, as were postprocedural leukocyte and C-reactive protein (CRP) levels. CONCLUSIONS: Suprapapillary and transpapillary stent placement procedures were similar in terms of procedural success, occlusion rate, revision rate, postprocedural AEs, and 30-day mortality. Ninety-day mortality rate and postprocedural leukocyte and CRP levels were higher in Group T, although these patients were also older and had higher preprocedural bilirubin levels.

Clinical treatment of cholangiocarcinoma: an updated comprehensive review.

Cholangiocarcinoma (CCA) is a heterogeneous group of neoplasms of the bile ducts and represents the second most common hepatic cancer after hepatocellular carcinoma; it is sub-classified as intrahepatic cholangiocarcinoma (iCCA) and extrahepatic cholangiocarcinoma (eCCA), the latter comprising both perihilar cholangiocarcinoma (pCCA or Klatskin tumor), and distal cholangiocarcinoma (dCCA). The global incidence of CCA has increased worldwide in recent decades. Chronic inflammation of biliary epithelium and bile stasis represent the main risk factors shared by all CCA sub-types. When feasible, liver resection is the treatment of choice for CCA, followed by systemic chemotherapy with capecitabine. Liver transplants represent a treatment option in patients with very early iCCA, in referral centers only. CCA diagnosis is often performed at an advanced stage when CCA is unresectable. In this setting, systemic chemotherapy with gemcitabine and cisplatin represents the first treatment option, but the prognosis remains poor. In order to ameliorate patients' survival, new drugs have been studied in the last few years. Target therapies are directed against different molecules, which are altered in CCA cells. These therapies have been studied as second-line therapy, alone or in combination with chemotherapy. In the same setting, the immune checkpoints inhibitors targeting programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen-4 (CTLA-4), have been proposed, as well as cancer vaccines and adoptive cell therapy (ACT). These experimental treatments showed promising results and have been proposed as second- or third-line treatment, alone or in combination with chemotherapy or target therapies.

NTCP Change in Rats of Hilar Cholangiocarcinoma and Therapeutic Significance.

Background: The study aims to detect the expression of Na+/taurocholate cotransporter polypeptide in hilar cholangiocarcinoma of rat model, to provide a new therapeutic target for gene therapy of hilar cholangiocarcinoma. Methods: 60 male Wistar rats (weighing 190 ± 8 g) were randomly divided into 3 groups (experimental group, control group, and sham operation group; 20 rats in each group). The 3 groups were fed with standard diet. The QBC939 cell suspension of cholangiocarcinoma was injected into the hilar bile duct in the experimental group with a micro syringe. The control group was injected with normal saline, and the sham operation group was not injected with any drugs. Comprehensive behavior score and Basso Beattie Bresnahan were used to evaluate the mental state and exercise of rats every day. At 5 weeks, one rat in the experimental group was killed, and the changes in hilar bile duct were recorded. The procedure was repeated at one and half months. After one and half months, hilar cholangiocarcinoma only occurred in the experimental group. Pathological examination confirmed the formation of tumor, and hilar bile duct tissues were taken from the 3 groups. Na+/taurocholate cotransporter polypeptide expression in hilar bile duct was detected by real-time polymerase chain reaction and immunohistochemistry. Results: After 2 weeks, the rats in experimental group ate less, and their weight was significantly reduced compared with the other 2 groups. One and half months later, hilar cholangiocarcinoma was detected in 16 rats in the experimental group. The levels of alanine aminotransferase and aspartate transaminase in the experimental group were higher than those in the other 2 groups. The ratio of Na+/taurocholate cotransporter polypeptide/GAPDH mRNA in hilar cholangiocarcinoma, control group, and sham operation group was significantly different. Under the light microscope, Na+/taurocholate cotransporter polypeptide protein reacted with anti-Na+/taurocholate cotransporter polypeptide antibody and showed granular expression. Every pathological section included 4800 cells. 3823 positive cells were in the experimental group, 1765 positive cells were in the control group, and 1823 positive cells were in the sham operation group. Conclusions: Na+/taurocholate cotransporter polypeptide expression in hilar cholangiocarcinoma of rats was significantly higher than normal hilar bile duct tissues, suggesting that drugs targeting Na+/taurocholate cotransporter polypeptide may be a new strategy for the treatment of hilar cholangiocarcinoma.

Perihilar cholangiocarcinoma: What the radiologist needs to know.

Perihilar cholangiocarcinoma (PHC) is a common and highly intractable malignancy of the main biliary tree confluence. PHC is associated with a poor prognosis because of its insidious local spread that makes it challenging to diagnose and assess. Surgical resection remains the standard curative treatment (up to 50% 5-year overall survival after negative-margin resection). More aggressive surgical approaches have recently emerged, pushing the boundaries of PHC resectability at the cost of a higher morbidity. As such, adequate preoperative preparation (i.e., biliary drainage, venous embolization) is now regarded as a critical issue to increase the number of patients amenable to extended liver resection. Thorough imaging plays a pivotal role in the preoperative setting in both PHC resectability assessment and patient preparation to surgery. Despite recent improvement in PHC imaging, its assessment remains challenging and only 50-60% of patients who are scheduled to undergo surgery are ultimately amenable to curative resection. Therefore, a knowledge of available diagnostic and interventional imaging techniques is important to improve PHC management. Herein, we review the various imaging techniques and preoperative radiological interventions such as biliary drainage, portal vein embolization and liver venous deprivation that are available in PHC management focusing on the anatomical and oncological considerations that are crucial to prepare and guide curative surgical resection.

Outcomes of Irreversible Electroporation for Perihilar Cholangiocarcinoma: A Prospective Pilot Study.

PURPOSE: To investigate the safety and efficacy of percutaneous or open irreversible electroporation (IRE) in a prospective cohort of patients with locally advanced, unresectable perihilar cholangiocarcinoma (PHC). MATERIALS AND METHODS: In a multicenter Phase I/II study, patients with unresectable PHC due to extensive vascular involvement or N2 lymph node metastases or local recurrence after resection for PHC were included and treated by open or percutaneous IRE combined with palliative chemotherapy (current standard of care). The primary outcome was the number of major adverse events occurring within 90 d after IRE (grade ≥3), and the upper limit was predefined at 60%. Secondary outcomes included technical success rate, hospital stay, and overall survival (OS). RESULTS: Twelve patients (mean age, 63 y ± 12) were treated with IRE. The major adverse event rate was 50% (6 of 12 patients), and no 90-d mortality was observed. All procedures were technically successful, with no intraprocedural adverse events requiring additional interventions. The median OS from diagnosis was 21 mos (95% confidence interval, 15-27 mos), with a 1-y survival rate of 75% after IRE. CONCLUSIONS: Percutaneous IRE in selected patients with locally advanced PHC seems feasible, with a major adverse event rate of 50%, which was below the predefined upper safety limit in this prospective study. Future comparative research exploring the efficacy of IRE is warranted.

Prognostic value of metabolic parameters measured by pretreatment dual-time-point 18F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with intrahepatic or perihilar cholangiocarcinoma: A STROBE study.

ABSTRACT: The purpose of this study was to determine the glucose metabolism at delay phase measured by pretreatment dual-time-point 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/ computed tomography (CT) provides prognostic information independent of well-known prognostic factors in patients with intrahepatic or perihilar cholangiocarcinoma (ICC or PCC).From July 2012 to December 2017, 55 patients (men 27, women 28, mean age 68 ±â€Š11 years) with pathologically proven ICC or PCC were enrolled in this retrospective study. The dual-time-point 18F-FDG PET/CT as part of a staging workup was performed in all patients. The patient's data includes age, sex, serum CA19-9, presence of LN or distant metastasis, early SUVmax (early maximum standardized uptake value [eSUV]), delay SUVmax (delay maximum standardized uptake value [dSUV]), retention index of SUVmax (percent change of maximum standardized uptake values [ΔSUV]), neutrophil to lymphocyte ratio (NLR) and histopathology including pCEA, p53, Ki-67 index. The analysis of the relationship between metabolic parameters and survival was done using the Kaplan-Meier curve and Cox proportional hazards regression model.Median survival for all patients was 357 days. Median early and delay SUVmax was 5.2 (range: 2.0-21.4) and 6.5 (range 2.7-24.5), respectively. The overall survival was found to be significantly related to eSUV, dSUV, ΔSUV, age, serum CA19-9 and NLR in univariate analysis. In multivariate analysis, dSUV (P = .014, 95%CI; 1.30-10.7, HR 3.74) and ΔSUVmax (P = .037, 95%CI; 1.05-6.12, HR 2.5) were independent factors of overall survival. Kaplan-Meier curve analysis clearly showed the significant difference of overall survival between 2 groups (high eSUV, low eSUV + high ΔSUV vs low eSUV and ΔSUV, P < .001) among the comparisons of the SUV parameters on FDG PET. In the receiver operating characteristic analysis using combinations of the SUV parameters, the 2 groups [eSUV + ΔSUV (P = .0001, area under the curve [AUC] 0.68) and dSUV + ΔSUV (P = .0002, AUC 0.71)] showed significantly larger AUC than the other groups applying eSUV or dSUV alone (AUC 0.61 and AUC 0.68).dSUV and ΔSUV on pretreatment dual-time-point 18F-FDG PET/CT can be useful parameters in the prediction of survival in patients with ICC or PCC.

Liver transplantation for perihilar cholangiocarcinoma: patient selection and outcomes.

Introduction: Peri-hilar cholangiocarcinoma is an aggressive bile duct cancer. Long-term survival is possible with margin-negative surgery. Historically, unresectable disease was approached with non-curative treatment options. In recent decades, an innovative approach of neoadjuvant chemoradiation and liver transplantation has demonstrated long-term survival for highly selected patients.Areas covered: This is a critical analysis of studies published to date on neoadjuvant chemoradiation and liver transplantation for selected patients with peri-hilar cholangiocarcinoma. A PubMed literature search was conducted for years 1970-2020 with the following search criteria: ['hilar' OR 'peri-hilar' AND 'cholangiocarcinoma'] AND ['treatment' OR 'transplantation' OR 'survival' OR 'outcome']; 'neoadjuvant chemoradiation' AND 'unresectable cholangiocarcinoma'. All peer-reviewed original research studies were selected for review.Expert opinion: Neoadjuvant chemoradiation and liver transplantation for patients with early stage unresectable peri-hilar cholangiocarcinoma can achieve long-term survival in highly selected patients who survive to transplantation without disease progression. There are observed differences in survival for patients with PSC-associated versus de novo cholangiocarcinoma and transplanted versus resected patients; however, these differences are not contextualized by established tumor and patient factors that influence recurrence and survival. Therefore, these results must be interpreted within the limitations of the study designs upon which they are based.

Adjuvant radiotherapy and chemotherapy offer a recurrence and survival benefit in patients with resected perihilar cholangiocarcinoma.

BACKGROUND AND OBJECTIVES: The objective of this study was to investigate the benefits of adjuvant treatment for patients with resected perihilar cholangiocarcinoma (PHC). METHODS: Between 2001 and 2017, 196 patients with PHC adenocarcinoma underwent curative resection. The patients were divided into four groups according to adjuvant treatment type: surgery alone (S; N = 90), surgery with chemotherapy (S+CTx; N = 67), surgery with radiotherapy (S+RTx; N = 18), and surgery with chemoradiotherapy (S+ CRTx; N = 21). RESULTS: The median follow-up duration of the surviving patients was 58 months. The 5-year rate of overall survival (OS) was 32%. In multivariate analysis, receiving S+CTx and S+CRTx were significant prognostic factors for OS. In subgroup analyses of the R1 resection patients, the S+CRTx group showed better OS than the S group (p < 0.05). In subgroup analyses of the stage III-IVA patients with a negative resection margin, the S+CTx and S+CRTx groups showed superior OS than the S group (p < 0.05). CONCLUSIONS: Our data suggest that adjuvant chemoradiotherapy might be considered for PHC patients with R1 resection. Adjuvant chemotherapy or chemoradiotherapy is suggested for stage III-IVA patients with R0 resection. The results of this study require validation through further prospective studies.

Perihilar clear cell cholangiocarcinoma: an often-diagnostic challenge.

Cholangiocarcinomas are rare and often diagnosed late. Clear cell histology is a rare variant of such cancers. We report one such case of a man in his late 60s, with a history of excess alcohol intake, who was found to have deranged liver biochemical tests incidentally during an admission for an allergic reaction. Subsequent imaging to investigate this suggested a diagnosis of perihilar cholangiocarcinoma (ultrasound, CT, MRI, cholangiogram). Biopsy confirmed this to be of clear cell type on histology and immunohistochemistry. Diagnosis and further management of this rare entity was conducted in multidisciplinary meetings with the regional hepatobiliary centre. The patient was deemed unsuitable for surgical resection, underwent chemotherapy but died 1 year later.

Analysis of treatment methods and prognostic factors in 354 cases of hilar cholangiocarcinoma: A cohort study.

CONTEXT: Better management strategies are needed to improve the survival of patients with hilar cholangiocarcinoma (HCCA). AIMS: This study was designed to examine the effects of different treatment methods on survival and prognostic factors in HCCA. SETTINGS AND DESIGN: We retrospectively analyzed the clinical data of 354 patients with HCCA treated at our institution from 2003 to 2013. MATERIALS AND METHODS: Patients were divided into three groups according to the treatment: the radical resection group, the nonradical resection group, and the biliary drainage-only group. STATISTICAL ANALYSIS USED: The Kaplan-Meier method was used to compare survival rates between the groups, and the independent prognostic factors were assessed using the Cox proportional hazards model. RESULTS: There were 110 patients in the radical resection group, 93 patients in the nonradical resection group, and 151 patients in the biliary drainage-only group, and they showed differing survival rates: 1-year survival rates of 70.7%, 49.5%, and 31.3%; 2-year survival rates of 62.9%, 24.7%, and 9.0%; 3-year survival rates of 34.7%, 4.0%, and 0%; and median survival of 21.7 months, 13.6 months, and 8.7 months, respectively. The radical resection group had the longest overall survival (P< 0.001). Treatment method, albumin (ALB), total bilirubin (TBIL), postoperative pathological T-stage, and distant metastasis were identified as independent prognostic indicators of survival. CONCLUSIONS: Radical resection significantly increases survival in patients with HCCA, and an increase in ALB and a decrease in TBIL improve the prognosis of patients with HCCA.

Contemporary role of liver transplantation for the treatment of cholangiocarcinoma.

INTRODUCTION: Cholangiocarcinoma (CCA) is a dismal disease with limited management options. Surgical resection remains the only established treatment however, due to its inherent predilection to invade vascular structures, only a fraction of patients with CCA meet resection criteria at diagnosis. Furthermore, R0 margins, crucial to obtain optimum survival can often prove elusive. AREAS COVERED: This review discusses the evolution of liver transplant for CCA, following its introduction in the 1990 s with less than exemplary outcomes. While transplantation is not standard of care, emerging data has suggested a crucial role in prolonging survival of those with CCA. Here we analyze the current role of orthotopic liver transplantation (OLT) in cirrhotic and non-cirrhotic patients, in the setting of both intrahepatic CCA and hilar CCA in order to establish whether this is a judicious use of a precious resource. EXPERT OPINION: Liver transplant has a definite role in the treatment of CCA, as highlighted by ongoing clinical trials. A greater understanding of tumor biology coupled with results of current studies will help elucidate which patients will best benefit from OLT. While significant strides are being made to improve outcomes, this must be tempered with an understanding of the finite nature of liver grafts.

Multidisciplinary treatment for hilar and intrahepatic cholangiocarcinoma: A review of the general principles.

Cholangiocarcinoma (CCA) is a rare but devastating malignancy that presents late, and associated with a high mortality if untreated. CCA is locally aggressive and located in close proximity to vital structures i.e. the portal vein and hepatic artery. A complete extirpation of the tumor including microscopically detectable disease R0 resection offers the best possibility of long-term survival in patients with CCA. As such, the surgical approach to achieve a R0 resection is dictated by the location of the tumor and the presence of underlying liver disease. The present article focuses on the general principles of the multidisciplinary treatment of hilar and intrahepatic CCA.

Neoadjuvant chemotherapy followed by curative-intent surgery for perihilar cholangiocarcinoma based on its anatomical resectability classification and lymph node status.

BACKGROUND: The prognosis of patients with perihilar cholangiocarcinoma have been unsatisfactory. We established new anatomical resectability classification for patients with localized perihilar cholangiocarcinoma and performed neoadjuvant chemotherapy followed by curative-intent surgery based on its resectability classification and lymph node status to improve prognosis. This study aimed to clarify the long-term outcomes and validation of our strategy. METHODS: Between September 2010 and August 2018, 72 consecutive patients with perihilar cholangiocarcinoma were classified into three groups: Resectable (R = 29), Borderline resectable (BR = 23), and Locally advanced (LA = 20), based on the two factors of tumor vascular and biliary extension. R with clinically lymph node metastasis, BR, and LA patients received neoadjuvant chemotherapy using gemcitabine plus S-1. RESULTS: Forty-seven patients (65.3%) received neoadjuvant chemotherapy: R in 8, BR in 21, and 18 in LA, respectively. Fifty-nine patients (68.1%) underwent curative-intent surgery: R in 26, BR in 17, and LA in 6. Five-year disease-specific survival was 31.5% (median survival time: 33.0 months): 50.3% (not reached) in R, 30.0% (31.4 months) in BR, and 16.5% (22.5 months) in LA, which were relatively stratified. Among 49 patients with resection, disease-specific survival was 43.8% (57.0 months): 57.6% (not reached) in R, 41.0% (52.4 months) in BR, and 0% (49.4 months) in LA, which were significantly good prognosis compared to 23 patients without resection (17.2 months). Multivariate analysis identified preoperative high carcinoembryonic antigen levels (more than 8.5 ng/ml) and pT4 as independent poor prognostic factor of patients with resection. CONCLUSION: Neoadjuvant chemotherapy based on resectability classification and lymph node status was feasible, and was considered efficacious in selected patients.

Neoadjuvant chemoradiotherapy before resection of perihilar cholangiocarcinoma: A systematic review.

BACKGROUND: Treatment with neoadjuvant chemoradiotherapy followed by liver transplantation yields promising results in perihilar cholangiocarcinoma (PH-CCA). This study reviews the literature to assess whether there is evidence to justify modern phase II studies of neoadjuvant chemoradiotherapy prior to resection of PH-CCA. DATA SOURCES: A systematic review of the literature for reports of patients undergoing resection of PH-CCA after neoadjuvant chemoradiotherapy was performed using MEDLINE and EMBASE databases for the period between 1990 and 2019. The keywords and MeSH headings "hilar cholangiocarcinoma", "Klatskin", "chemoradiotherapy" and "chemotherapy" were used. Data were extracted on demographic profile, disease staging, chemoradiotherapy protocols, complications and outcome. Risks of bias were assessed using Cochrane methodology. RESULTS: There were seven reports on this topic, with median recruitment period of 14 (range 4-31) years. The total number of patients in these studies was 87. Interval from completion of neoadjuvant treatment to surgery varied from 3 days to 6 months. Resection was by hepatectomy with three studies reporting an R0 rate of 100%, 24% and 63%, respectively. Three studies reported histopathological evidence of prior treatment response. There were two treatment related deaths at 90 days. Median survival was 19 (95% CI: 9.9-28) months and 5-year survival 20%. CONCLUSIONS: There are potential benefits of treatment on both R0 rate and complete response in resected specimens. Scientific equipoise exists in relation to neoadjuvant chemoradiotherapy for PH-CCA.

Gemcitabine Plus Cisplatin Chemotherapy Prolongs the Survival in Advanced Hilar Cholangiocarcinoma: A Large Multicenter Study.

OBJECTIVES: Gemcitabine plus cisplatin (GC) is recommended as first-line treatment for advanced cholangiocarcinoma. We investigated the impact of GC in patients with unresectable hilar cholangiocarcinoma (HC) based on the time taken for effective biliary drainage (EBD). MATERIALS AND METHODS: We retrospectively enrolled 113 patients with unresectable HC. Thirty-nine and 74 patients received GC chemotherapy and best supportive care (BSC), respectively. EBD was defined as a reduction in total bilirubin >50% or to a value <2 mg/dL after the drainage procedure. Early EBD (eEBD) and delayed EBD (dEBD) were separated by 2 weeks. Overall survival (OS) was estimated. RESULTS: The GC group showed a significantly longer median OS than the BSC group (12.8 vs. 6.1 mo; P<0.001). Moreover, the eEBD group experienced a significantly longer OS than the dEBD group (8.2 vs. 4.3 mo; P<0.001). GC led to improved OS in the eEBD (12.8 vs. 6.8 mo; P=0.003) and dEBD (12.2 vs. 3.4 mo; P=0.009) groups. In multivariate analysis, dEBD (adjusted hazard ratio [aHR], 1.785; 95% confidence interval [CI], 1.183-2.691; P=0.006), BSC (aHR, 2.409; 95% CI, 1.579-3.675; P<0.001), and an ECOG status ≥2 (aHR, 3.721; 95% CI, 2.093-6.615; P<0.001) were associated with poor prognosis. In GC group, the older (70 y and above) patients did not have a higher risk of death than younger patients. CONCLUSIONS: GC prolongs the survival of patients with unresectable HC, even those with dEBD or elderly.